**Surgical Management of Chronic Pulmonary Embolism**

Fabian Andres Giraldo Vallejo

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67708

#### **Abstract**

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but life‐threatening complication of acute pulmonary embolism (PE). This entity is the consequence of a per‐ sistent obstruction of the pulmonary arteries and progressive vascular remodeling. Some patients with CTEPH do not have a history of classic pulmonary embolism symptoms. The diagnostic process to detect CTEPH should include ventilation‐perfusion scintig‐ raphy, which has a high sensitive and negative predictive value (nearly 100%) and CT angiography demonstrating typical features of CTEPH (occlusion of pulmonary arteries, mosaic perfusion or intraluminal bands or webs). Patients suspected of having CTEPH must be referred to an experienced center in order to complete the diagnostic workup (right‐heart catheterization and pulmonary angiography) and determine the best treat‐ ment. Pulmonary endarterectomy (PEA) remains the treatment of choice for CTEPH and is associated with excellent long‐term results and a highly curative rate. Patients with inoperable CTEPH are given medical and interventional modalities.

**Keywords:** thromboembolism, pulmonary hypertension, pulmonary endarterectomy

#### **1. Introduction**

Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by a persistent obstruc‐ tion of the pulmonary arteries after a pulmonary embolism (PE) that has not resolved despite 3 months of medical therapy with anticoagulants and is defined as a raised mean pulmonary artery pressure (at least 25 mmHg at rest), a pulmonary capillary wedge pressure of ≤ 15 mmHg and at least one (segmental) perfusion defect detected by lung scanning, multi‐detec‐ tor computed tomographic angiography or pulmonary angiography [1, 2]. CTEPH is a form of pulmonary artery hypertension (PAH) characterized by the occlusion of the pulmonary

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

arteries by organized fibrotic thrombi leading to increased pulmonary vascular resistance (PVR). The consequential effect is dyspnea, right heart failure and even death. CTEPH is clas‐ sified as group IV according to the WHO classification of pulmonary hypertension [3]. Some patients may present symptoms and signs of CTEPH but no pulmonary hypertension; this presentation should be termed chronic thromboembolic disease, although the management of these patients does not differ to that of the classic CTEPH patients.

The most common cause of CTEPH is non‐resolving acute pulmonary embolism (PE) and can occur after one or multiple episodes. Occasionally, CTEPH may develop after in situ pulmo‐ nary artery thrombosis which could be associated with the inflammation of vessel walls [4].

CTEPH can be mistaken for PE; it is important to differentiate between these, in order to diagnose the chronic disease as early as possible. Once the diagnosis of CTEPH is made, care‐ ful patient selection in experienced centers is preferable in order to obtain the best results for these patients.

Because of its unique characteristics, CTEPH is the only form of PH that can be curable by pul‐ monary endarterectomy (PEA); although, this is a complicated surgery and not every patient may be fit to undergo such a procedure. The most benefited patients are those who present a proximal compromise [5].

CTEPH remains underdiagnosed and carries a poor prognosis. Medical and interventional treatment are options for patients that are not surgical candidates. In this chapter, the avail‐ able information on the surgical treatment of CTEPH is summarized.

#### **2. Historical note**

The first description of the CTEPH was made in 1928 by Dr Ljungdahl on two symptom‐ atic patients with chronic obstruction of the pulmonary arteries who ultimately died of right heart failure [6]. The first successful embolectomies for recurrent pulmonary embolism were reported by Allison and colleagues in 1958 and by Snyder and colleagues in 1962 [7, 8]. Then, Cabrol et al. refined the technique using a lateral thoracotomy in order to obtain access to dis‐ tal pulmonary branches [9]. In 1980, Daily et al. reported the use of cardiopulmonary bypass (CPB) and hypothermic circulatory arrest, allowing the reduction of severe back bleeding and improving the visualization of the pulmonary arteries during endarterectomy [10]. This is the current preferred technique.

#### **3. Morphology**

The process of the disease typically occurs in the proximal pulmonary arteries from trunk to sublobar levels. The distal vasculature remains patent. This presentation is the basis for the surgical approach of CTEPH. The disease may develop from a single embolic episode with non‐resolution of large thrombi or from repeated thromboembolic episodes [11]. The remaining unobstructed pulmonary arteries are exposed to high flow and eventually high pressure. Then, proximal patent pulmonary arteries enlarge, and the distal arterial vascula‐ ture develops changes of pulmonary hypertension such as intimal proliferation and medial hypertrophy. The characteristic diagnostic finding of primary pulmonary hypertension, the plexiform lesion, is also observed in CTEPH [12]. The occlusive process is usually central, incipient and unresponsive to antithrombotic or anticoagulant therapy when the thrombi become fibrotic and endothelialized. The thrombotic material has well‐organized fibrous tis‐ sues, penetrating blood vessels, elastic fibers and no endothelial cells. The arterial layers demonstrate intimal and medial hyperplasia. Infarction of the lung tissue is rarely observed [2]. These microvascular changes explain why CTEPH is a progressive disease even in the absence of recurrent thromboembolic events.

#### **4. Epidemiology**

arteries by organized fibrotic thrombi leading to increased pulmonary vascular resistance (PVR). The consequential effect is dyspnea, right heart failure and even death. CTEPH is clas‐ sified as group IV according to the WHO classification of pulmonary hypertension [3]. Some patients may present symptoms and signs of CTEPH but no pulmonary hypertension; this presentation should be termed chronic thromboembolic disease, although the management

The most common cause of CTEPH is non‐resolving acute pulmonary embolism (PE) and can occur after one or multiple episodes. Occasionally, CTEPH may develop after in situ pulmo‐ nary artery thrombosis which could be associated with the inflammation of vessel walls [4]. CTEPH can be mistaken for PE; it is important to differentiate between these, in order to diagnose the chronic disease as early as possible. Once the diagnosis of CTEPH is made, care‐ ful patient selection in experienced centers is preferable in order to obtain the best results for

Because of its unique characteristics, CTEPH is the only form of PH that can be curable by pul‐ monary endarterectomy (PEA); although, this is a complicated surgery and not every patient may be fit to undergo such a procedure. The most benefited patients are those who present a

CTEPH remains underdiagnosed and carries a poor prognosis. Medical and interventional treatment are options for patients that are not surgical candidates. In this chapter, the avail‐

The first description of the CTEPH was made in 1928 by Dr Ljungdahl on two symptom‐ atic patients with chronic obstruction of the pulmonary arteries who ultimately died of right heart failure [6]. The first successful embolectomies for recurrent pulmonary embolism were reported by Allison and colleagues in 1958 and by Snyder and colleagues in 1962 [7, 8]. Then, Cabrol et al. refined the technique using a lateral thoracotomy in order to obtain access to dis‐ tal pulmonary branches [9]. In 1980, Daily et al. reported the use of cardiopulmonary bypass (CPB) and hypothermic circulatory arrest, allowing the reduction of severe back bleeding and improving the visualization of the pulmonary arteries during endarterectomy [10]. This is the

The process of the disease typically occurs in the proximal pulmonary arteries from trunk to sublobar levels. The distal vasculature remains patent. This presentation is the basis for the surgical approach of CTEPH. The disease may develop from a single embolic episode with non‐resolution of large thrombi or from repeated thromboembolic episodes [11]. The

of these patients does not differ to that of the classic CTEPH patients.

able information on the surgical treatment of CTEPH is summarized.

these patients.

proximal compromise [5].

28 Embolic Diseases - Unusual Therapies and Challenges

**2. Historical note**

current preferred technique.

**3. Morphology**

The estimated prevalence of CTEPH after acute pulmonary embolism is 0.1–4% after 2 years [2, 13–16]. The median age at diagnosis is 63 years, and both genders are equally affected [17]. The risk of developing CTEPH is increased in patients with recurrent venous thromboembo‐ lism, echocardiographic signs of pulmonary hypertension at the initial presentation and large perfusion defects. Common risk factors for venous thromboembolism (factor V Leyden, factor II mutation) are not associated with the development of CTEPH except for the presence of antiphospholipid antibodies, which predispose patients to acute venous thromboembolism and CTEPH [1, 18–20]. Different disorders considered to be risk factors include inflamma‐ tory bowel disease, splenectomy, myeloproliferative disorders, chronic osteomyelitis and the presence of permanent central venous lines, pacemakers or ventriculoatrial shunts [20–23]. These disorders are associated with chronic inflammation, an increased risk of repeated bloodstream infection or both, which may contribute to the non‐resolution of thromboem‐ bolic material [1]. C‐reactive protein is also implicated in the development of CTEPH [24]. Infection of thrombotic material by blood‐borne pathogens could predispose to the develop‐ ment of CTEPH, specially in patients with permanent central venous lines, pacemakers or ventriculoatrial shunts [25].

#### **5. Natural history**

It is relatively infrequent to find a complete resolution of pulmonary embolism. If adequate anticoagulation therapy has been done, more than 50% of patients have residual perfusion defects 6 months after the diagnosis of pulmonary embolism [26]. However, the majority of these patients do not develop florid chronic pulmonary hypertension; in fact, patients pre‐ senting signs of pulmonary hypertension during an episode of acute pulmonary embolism are unlikely to develop CTEPH, and most of these patients recover a stable phase of right ven‐ tricular functions within 40 days [13]. Some patients, however, present persistent pulmonary hypertension and others develop pulmonary hypertension after a symptom‐free interval that can last from months to years [14]. Hemodynamic deterioration may be the result of recurrent thromboembolism or in situ pulmonary artery thrombosis. Without intervention, survival is compromised and proportional to the degree of pulmonary hypertension at the time of diagnosis [27, 28]. To remind, pulmonary hypertension is not a feature of acute pulmonary embolism since the right ventricle (RV) is incapable of generating high pressures in early stages. In that order, any patient presenting with acute pulmonary embolism and elevated pulmonary resistances may already have CTEPH. In a study, the 5‐year survival rate was 30% among patients with a mean pulmonary pressure > 40 mmHg at time of diagnosis, and it dropped dramatically to 10% among those with a mean pulmonary pressure > 50 mmHg [29]. In another study, a mean pulmonary artery pressure of 30 mmHg marked the threshold for poor prognosis [30].

#### **6. Clinical features and diagnosis**

#### **6.1. Symptoms**

In general, symptoms do not develop until months or years after the embolic event [2]. They occur as a result of right ventricular failure or pulmonary hypertension. Progressive dyspnea on exertion is the predominant symptom of CTEPH [11]. Additionally, patients might present with fatigue, substernal chest pain with exercise, pleuritic pain and hemoptysis [11, 31].

#### **6.2. Signs**

Relevant physical findings are related to right heart failure: jugular venous distention, ascites, hepatomegaly and peripheral edema. The right ventricle may be enlarged and palpable near the lower left sternal border. The pulmonic second sound is accentuated and split. A murmur of tricuspid regurgitation might be heard in severe right heart failure.

CTEPH should be considered in all patients who have an evident history of acute pulmonary embolism. Despite 25% of the patients diagnosed as having CTEPH, there are no documented acute pulmonary embolism events [32]. Thus, CTEPH should be suspected in any patient with otherwise unexplained pulmonary hypertension.

#### **6.3. Diagnostic studies**

The chest radiograph may demonstrate right ventricle enlargement and the prominence of central pulmonary arteries. The ECG frequently shows RV hypertrophy with strain, right axis deviation, ST depression, T‐wave inversion in the anterior precordial leads and occasionally right bundle branch block [31]. Transthoracic echocardiography provides the initial objective evidence for the presence of PAH. Findings in chronic thromboembolic and other forms of PAH include the enlargement of right cardiac chambers, tricuspid regurgitation as a conse‐ quence from this enlargement, the flattening or paradoxical motion of the interventricular septum and impaired left ventricular diastolic filling not caused by primary left ventricular diastolic dysfunction or valvular heart disease [33, 34]. Pulmonary function studies are neces‐ sary to exclude restrictive or obstructive pulmonary parenchymal disease as the cause of PAH.

Ventilation‐perfusion scanning is the preferred diagnostic tool because of its high sensitivity and a negative predictive value of almost 100% [35]. In that order, CTEPH is practically ruled out if the scan is normal [35]. A lung perfusion scan showing at least one segmental or larger defect is suggestive of chronic vascular obstruction [2]. Often, the scan underestimates the severity of an obstructive disease [36, 37]. Perfusion defects can also occur in other disorders such as pulmonary veno‐occlusive disease, pulmonary vasculitis, fibrosing mediastinitis or malignant disease [38–40]. CT scanning and MRI of the chest are important diagnostic tools and are being used with increasing frequency [41, 42]. If imaging suggests the presence of CTEPH, patients should be evaluated with right‐heart catheterization to measure the right ventricle and pulmonary artery pressures and to evaluate the presence of shunting at the atrial or ventricular level. Pulmonary angiography is safe in patients with chronic pulmonary hypertension [2, 43]. Typical findings include dilated proximal pulmonary arteries, varying degrees of obstruction of lobar arteries, filling defects, web or bands or thrombosed vessels suggesting the presence of organized thrombi [44]. In order to avoid repeat procedures, angi‐ ography should be done in a center that assesses the patient's suitability for surgery. A gen‐ eral screening after acute pulmonary embolism is not recommended, given the low risk of developing CTEPH after such an event [45–47]. Care must be taken, however, in patients who show symptoms after an episode of acute pulmonary embolism. Echocardiography is widely used when suspecting pulmonary hypertension. A diagnostic approach that combines an electrocardiogram with no signs of hypertrophy in the right ventricle and a normal natri‐ uretic peptide (N‐terminal‐pro‐brain‐type fragment) has a negative predictive value of 99% for CTEPH [48].

Angioscopy is an alternative tool adjunct to angiography, CT or MRI when these modalities cannot establish the diagnosis properly [49].

#### **7. Treatment**

can last from months to years [14]. Hemodynamic deterioration may be the result of recurrent thromboembolism or in situ pulmonary artery thrombosis. Without intervention, survival is compromised and proportional to the degree of pulmonary hypertension at the time of diagnosis [27, 28]. To remind, pulmonary hypertension is not a feature of acute pulmonary embolism since the right ventricle (RV) is incapable of generating high pressures in early stages. In that order, any patient presenting with acute pulmonary embolism and elevated pulmonary resistances may already have CTEPH. In a study, the 5‐year survival rate was 30% among patients with a mean pulmonary pressure > 40 mmHg at time of diagnosis, and it dropped dramatically to 10% among those with a mean pulmonary pressure > 50 mmHg [29]. In another study, a mean pulmonary artery pressure of 30 mmHg marked the threshold

In general, symptoms do not develop until months or years after the embolic event [2]. They occur as a result of right ventricular failure or pulmonary hypertension. Progressive dyspnea on exertion is the predominant symptom of CTEPH [11]. Additionally, patients might present with fatigue, substernal chest pain with exercise, pleuritic pain and hemoptysis [11, 31].

Relevant physical findings are related to right heart failure: jugular venous distention, ascites, hepatomegaly and peripheral edema. The right ventricle may be enlarged and palpable near the lower left sternal border. The pulmonic second sound is accentuated and split. A murmur

CTEPH should be considered in all patients who have an evident history of acute pulmonary embolism. Despite 25% of the patients diagnosed as having CTEPH, there are no documented acute pulmonary embolism events [32]. Thus, CTEPH should be suspected in any patient

The chest radiograph may demonstrate right ventricle enlargement and the prominence of central pulmonary arteries. The ECG frequently shows RV hypertrophy with strain, right axis deviation, ST depression, T‐wave inversion in the anterior precordial leads and occasionally right bundle branch block [31]. Transthoracic echocardiography provides the initial objective evidence for the presence of PAH. Findings in chronic thromboembolic and other forms of PAH include the enlargement of right cardiac chambers, tricuspid regurgitation as a conse‐ quence from this enlargement, the flattening or paradoxical motion of the interventricular septum and impaired left ventricular diastolic filling not caused by primary left ventricular

of tricuspid regurgitation might be heard in severe right heart failure.

with otherwise unexplained pulmonary hypertension.

for poor prognosis [30].

**6.1. Symptoms**

**6.2. Signs**

**6.3. Diagnostic studies**

**6. Clinical features and diagnosis**

30 Embolic Diseases - Unusual Therapies and Challenges

Patients diagnosed with CTEPH should have life‐long anticoagulation, even those who underwent successful PEA. The target international normalized ratio is 2.0 to 3.0. The use of filters in the inferior vena cava remains controversial [50]. Currently, the use of these filters is indicated when therapeutic anticoagulation is not feasible or when recurrent venous throm‐ boembolism occurred despite sufficient anticoagulation [51]. Prospective studies on this mat‐ ter are warranted.

#### **7.1. Surgical selection**

The most important criterion that determines whether a patient with CTEPH might be a can‐ didate for PEA is the presence of surgically accessible lesions. PEA should be considered in symptomatic patients who have hemodynamic or ventilatory impairment at rest or with exercise [52]. The decision to proceed with PEA in patients with CTEPH is difficult based on their preoperative pulmonary hemodynamic profile and the anticipated improvement in these hemodynamics postoperatively [27]. The basis for this concern is that the elevated vascular resistance not only arises from central (surgically accessible) vessels but also from secondary, small vessels with arteriopathy [27]. A preoperative approach should differentiate these two components and anticipate the postoperative hemodynamic outcome. This impor‐ tant issue remains relatively subjective. There is a high correlation between the postoperative level of pulmonary vascular resistance (PVR) and mortality. In a study by Jamieson and col‐ leagues including 500 consecutive operated patients with an overall mortality of 4.4%, 77% of deaths were related to residual high pulmonary artery pressures. Patients with a postop‐ erative PVR > 500 dynes‐sec‐cm−5 had a mortality rate of 30.6% compared to 0.9% in patients with a postoperative PVR < 500 dynes‐sec‐cm−5 [53]. The majority of patients who undergo a PEA have a PVR > 300 dynes‐sec‐cm−5. Experienced centers report a range of preoperative PVR between 700 and 1100 dynes‐sec‐cm−5 [53–58]. Symptomatic patients at the lower end of these values include those with involvement limited to one pulmonary artery, those accus‐ tomed to a vigorous activity and those who live at high altitudes [52]. Operations should also be considered for patients with nearly normal pulmonary hemodynamics at rest but marked pulmonary hypertension induced by exercise. The only absolute contraindication to opera‐ tion is the presence of severe underlying obstructive or restrictive lung diseases [52]. The most important risk factor for surgery is the presence of high pulmonary resistances without visible abnormalities by angiography [53]. Older patients and severe RV failure are associated with increased risk but do not preclude surgery.

#### **7.2. The technique of operation**

This is the description of the current accepted and most widely used technique for PEA. Electroencephalographic recording is essential to ensure the absence of cerebral activ‐ ity before circulatory arrest is induced. The patient's head is involved in a cooling jacket. Standard preparations for the establishment of cardiopulmonary bypass (CPB) are made. A median sternotomy is performed. Cannulas are inserted into the ascending aorta and both venae cavae, which are encircled with tapes. Immediately after CPB starts, cooling is initi‐ ated (including the head jacket and the cooling blanket). This could take 45 minutes to 1 hour [59]. A venting catheter is placed in the left atrium through the upper right pulmonary vein. If the patient's condition allows it, autologous whole blood is withdrawn for later use. The deficit can be replaced with a crystalloid solution. The aorta is clamped and cold blood car‐ dioplegia is given. Additional myocardial protection could be done by subsequent infusions of cold cardioplegic solution, every 15 to 20 minutes. During the cooling period, mobilization of the right pulmonary artery from the ascending aorta is made as well as the mobilization of the superior vena cava. Also, methylprednisolone (7 mg/kg) and thiopental (10–15 mg/kg) are administered to favor the neuroprotective effect of hypothermia. Mannitol (0.3–0.4 mg/ kg) and furosemide (100 mg) are infused to preserve the renal function. Once the core tem‐ perature has reached 12–14°C and the electroencephalogram becomes isoelectric, circulatory arrest is established [60]. Both encircling tapes of superior and inferior vena cava are secured to ensure complete drainage and to avoid air embolization into the venous cannulae during circulatory arrest. An incision is made in the right pulmonary artery between the aorta and the superior vena cava (**Figure 1**), extending the incision toward the right lower lobe artery, a few millimeters farther from the takeoff of the middle lobe artery (**Figure 2**). Using a sharp dissector can help establish an endarterectomy plane (**Figure 3**). The intima and a portion of the media are removed. Establishment of the correct plane is essential—too deep will result in artery perforation, too shallow will result in an inadequate endarterectomy [61]. When the adequate plane is achieved, the layer will dismount easily. The core of the thrombus is dissected in a circumferential manner (**Figure 4**) and removed from each subsegmental branch and from the pulmonary artery (**Figure 5**). Gentle traction with forceps is applied to the core as well as opposite force to the pulmonary wall that will facilitate the removal of the specimen (**Figure 6**). The remaining core is removed from the proximal portion of the right pulmonary artery (**Figure 7**). The arteriotomy is closed with a continuous 5–0 or 6–0 poly‐ propylene suture (**Figure 8**). If needed, a pericardial patch can be used that is sutured into place with a continuous 6–0 polypropylene suture. The period of circulatory arrest ranges from 20 to 25 minutes. Cold blood is reperfused for 8–10 minutes between these intervals. As for the left side, the incision begins in the pulmonary trunk and extends onto the left pulmonary artery to the level of the pericardial reflection (**Figure 9**). Endarterectomy of the left side mirrors that of the right pulmonary artery. The core is removed from the upper lobe artery and each subsegmental branch. The artery is closed in a continuous fashion or with

exercise [52]. The decision to proceed with PEA in patients with CTEPH is difficult based on their preoperative pulmonary hemodynamic profile and the anticipated improvement in these hemodynamics postoperatively [27]. The basis for this concern is that the elevated vascular resistance not only arises from central (surgically accessible) vessels but also from secondary, small vessels with arteriopathy [27]. A preoperative approach should differentiate these two components and anticipate the postoperative hemodynamic outcome. This impor‐ tant issue remains relatively subjective. There is a high correlation between the postoperative level of pulmonary vascular resistance (PVR) and mortality. In a study by Jamieson and col‐ leagues including 500 consecutive operated patients with an overall mortality of 4.4%, 77% of deaths were related to residual high pulmonary artery pressures. Patients with a postop‐ erative PVR > 500 dynes‐sec‐cm−5 had a mortality rate of 30.6% compared to 0.9% in patients with a postoperative PVR < 500 dynes‐sec‐cm−5 [53]. The majority of patients who undergo a PEA have a PVR > 300 dynes‐sec‐cm−5. Experienced centers report a range of preoperative PVR between 700 and 1100 dynes‐sec‐cm−5 [53–58]. Symptomatic patients at the lower end of these values include those with involvement limited to one pulmonary artery, those accus‐ tomed to a vigorous activity and those who live at high altitudes [52]. Operations should also be considered for patients with nearly normal pulmonary hemodynamics at rest but marked pulmonary hypertension induced by exercise. The only absolute contraindication to opera‐ tion is the presence of severe underlying obstructive or restrictive lung diseases [52]. The most important risk factor for surgery is the presence of high pulmonary resistances without visible abnormalities by angiography [53]. Older patients and severe RV failure are associated with

This is the description of the current accepted and most widely used technique for PEA. Electroencephalographic recording is essential to ensure the absence of cerebral activ‐ ity before circulatory arrest is induced. The patient's head is involved in a cooling jacket. Standard preparations for the establishment of cardiopulmonary bypass (CPB) are made. A median sternotomy is performed. Cannulas are inserted into the ascending aorta and both venae cavae, which are encircled with tapes. Immediately after CPB starts, cooling is initi‐ ated (including the head jacket and the cooling blanket). This could take 45 minutes to 1 hour [59]. A venting catheter is placed in the left atrium through the upper right pulmonary vein. If the patient's condition allows it, autologous whole blood is withdrawn for later use. The deficit can be replaced with a crystalloid solution. The aorta is clamped and cold blood car‐ dioplegia is given. Additional myocardial protection could be done by subsequent infusions of cold cardioplegic solution, every 15 to 20 minutes. During the cooling period, mobilization of the right pulmonary artery from the ascending aorta is made as well as the mobilization of the superior vena cava. Also, methylprednisolone (7 mg/kg) and thiopental (10–15 mg/kg) are administered to favor the neuroprotective effect of hypothermia. Mannitol (0.3–0.4 mg/ kg) and furosemide (100 mg) are infused to preserve the renal function. Once the core tem‐ perature has reached 12–14°C and the electroencephalogram becomes isoelectric, circulatory arrest is established [60]. Both encircling tapes of superior and inferior vena cava are secured to ensure complete drainage and to avoid air embolization into the venous cannulae during

increased risk but do not preclude surgery.

32 Embolic Diseases - Unusual Therapies and Challenges

**7.2. The technique of operation**

**Figure 1.** An approach to pulmonary artery. View from left side. Superior vena cava is completely mobilized and retracted laterally, and aorta is retracted medially. The incision on pulmonary artery is done between these two vessels.

**Figure 2.** Exposure of distal right pulmonary artery between aorta and superior vena cava. Dashed line indicates line of incision.

**Figure 3.** Endarterectomy plane is facilitated with a sharp dissector.

**Figure 4.** Circumferential isolation of the core of the thrombus and extraction from upper lobe and distal pulmonary artery.

**Figure 5.** Extraction of the core of the thrombus.

**Figure 2.** Exposure of distal right pulmonary artery between aorta and superior vena cava. Dashed line indicates line

**Figure 3.** Endarterectomy plane is facilitated with a sharp dissector.

of incision.

34 Embolic Diseases - Unusual Therapies and Challenges

**Figure 6.** Separation of core from proximal pulmonary artery.

**Figure 7.** Complete extraction of core specimen.

**Figure 8.** Arteriotomy is closed with a continuous 5–0 or 6–0 polypropylene suture.

**Figure 6.** Separation of core from proximal pulmonary artery.

36 Embolic Diseases - Unusual Therapies and Challenges

**Figure 7.** Complete extraction of core specimen.

**Figure 9.** Incision in left pulmonary artery (dashed line) begins in the pulmonary trunk and extends onto the left pulmonary artery.

an autologous pericardial patch. CPB begins and rewarming of the patient is established. If any other defects are present, such as patent foramen ovale or atrial septal defect, these are corrected to prevent the right‐to‐left shunting. If additional procedures are required, they are made during rewarming [62]. Right ventricle remodeling occurs within a few days, so, any tricuspid regurgitation rarely needs repair or replacement [61, 62]. Deariation maneuvers from cardiac chambers are performed, CPB is discontinued and the procedure is completed in the usual fashion.

#### **7.3. Postoperative care**

An FiO2, high enough to maintain SaO<sup>2</sup> > 95%, during mechanical ventilation, is preferred. PaCO<sup>2</sup> should be ≤ 35 mmHg. An important postoperative problem is reperfusion of the pul‐ monary edema and occurs in approximately 10% of patients [61]. Lung injury can develop within the first 2 days of exhibiting hypoxemia and radiographic infiltrates in areas where endarterectomy has been done [63]. Treatment for this condition includes maintaining a SaO<sup>2</sup> >90% and positive end‐expiratory pressures of 5–10 cm. Prostaglandin E1 at 0.01–1 mg/ min and inhaled nitric oxide (20–40 parts per million) may be useful. Diuretics use is often required to reduce the incidence of pulmonary edema [64]. Since the reperfusion injury is neutrophil mediated, treatment with agents that block the selectin‐mediated adhesion of leu‐ cocytes to the endothelium (Cylexyn) could be useful [63]. Extracorporeal support has been used in selected patients with serious reperfusion injury [52]. Permanent anticoagulation with warfarin is started on the second postoperative day [60].

#### **7.4. Results**

Experienced centers have a mortality that ranges from 4.4 to 21% [53, 64–68]. Risk fac‐ tors commonly associated with mortality in the early postoperative period are RV failure related to residual pulmonary hypertension, reperfusion lung injury and CPB duration [10, 52, 53]. Survival rates are almost the same when comparing patients who underwent pul‐ monary endarterectomy alone with other patients with additional procedures (5.8 vs. 6.7%, respectively) [62]. In the largest study with patients undergoing pulmonary endarterec‐ tomy, the 6‐year survival rate was 75% (**Figure 10**) [69]. The most common causes of late death were recurrent pulmonary embolism and persistent pulmonary hypertension [69]. Hemodynamic outcomes after pulmonary endarterectomy for most patients are favorable [56, 64–67, 70–74]. The only long‐term study on hemodynamics after PEA observed persis‐ tent pulmonary hypertension in 24% of patients who had pulmonary vascular resistance of more than 500 dynes‐sec‐cm−5 after 4 years [75]. Dramatic reduction and, sometimes, normalization of the pulmonary artery pressure and pulmonary vascular resistance can be achieved. The mean reduction in pulmonary vascular resistance is approximately 65% [52]. Most patients are in New York Heart Association Functional Classification, class III or IV, before surgery; after the procedure, they can improve to class II or I and are able to resume normal activities [11, 69, 70]. Recurrent thromboembolism requiring a second endarterec‐ tomy has occurred in several patients in whom anticoagulation was discontinued or given improperly [76].

**Figure 10.** Survival after pulmonary thromboendarterectomy in 532 patients. Adapted from Archibald et al.

#### **8. Conclusions**

an autologous pericardial patch. CPB begins and rewarming of the patient is established. If any other defects are present, such as patent foramen ovale or atrial septal defect, these are corrected to prevent the right‐to‐left shunting. If additional procedures are required, they are made during rewarming [62]. Right ventricle remodeling occurs within a few days, so, any tricuspid regurgitation rarely needs repair or replacement [61, 62]. Deariation maneuvers from cardiac chambers are performed, CPB is discontinued and the procedure is completed

 should be ≤ 35 mmHg. An important postoperative problem is reperfusion of the pul‐ monary edema and occurs in approximately 10% of patients [61]. Lung injury can develop within the first 2 days of exhibiting hypoxemia and radiographic infiltrates in areas where endarterectomy has been done [63]. Treatment for this condition includes maintaining a

 >90% and positive end‐expiratory pressures of 5–10 cm. Prostaglandin E1 at 0.01–1 mg/ min and inhaled nitric oxide (20–40 parts per million) may be useful. Diuretics use is often required to reduce the incidence of pulmonary edema [64]. Since the reperfusion injury is neutrophil mediated, treatment with agents that block the selectin‐mediated adhesion of leu‐ cocytes to the endothelium (Cylexyn) could be useful [63]. Extracorporeal support has been used in selected patients with serious reperfusion injury [52]. Permanent anticoagulation with

Experienced centers have a mortality that ranges from 4.4 to 21% [53, 64–68]. Risk fac‐ tors commonly associated with mortality in the early postoperative period are RV failure related to residual pulmonary hypertension, reperfusion lung injury and CPB duration [10, 52, 53]. Survival rates are almost the same when comparing patients who underwent pul‐ monary endarterectomy alone with other patients with additional procedures (5.8 vs. 6.7%, respectively) [62]. In the largest study with patients undergoing pulmonary endarterec‐ tomy, the 6‐year survival rate was 75% (**Figure 10**) [69]. The most common causes of late death were recurrent pulmonary embolism and persistent pulmonary hypertension [69]. Hemodynamic outcomes after pulmonary endarterectomy for most patients are favorable [56, 64–67, 70–74]. The only long‐term study on hemodynamics after PEA observed persis‐ tent pulmonary hypertension in 24% of patients who had pulmonary vascular resistance of more than 500 dynes‐sec‐cm−5 after 4 years [75]. Dramatic reduction and, sometimes, normalization of the pulmonary artery pressure and pulmonary vascular resistance can be achieved. The mean reduction in pulmonary vascular resistance is approximately 65% [52]. Most patients are in New York Heart Association Functional Classification, class III or IV, before surgery; after the procedure, they can improve to class II or I and are able to resume normal activities [11, 69, 70]. Recurrent thromboembolism requiring a second endarterec‐ tomy has occurred in several patients in whom anticoagulation was discontinued or given

> 95%, during mechanical ventilation, is preferred.

in the usual fashion.

**7.3. Postoperative care**

PaCO<sup>2</sup>

SaO<sup>2</sup>

**7.4. Results**

improperly [76].

An FiO2, high enough to maintain SaO<sup>2</sup>

38 Embolic Diseases - Unusual Therapies and Challenges

warfarin is started on the second postoperative day [60].

CTEPH is a life‐threatening complication of pulmonary embolism. There are notable dif‐ ferences in the treatment from that of other forms of pulmonary hypertension. A complete diagnostic assessment should be done in those patients with unexplained pulmonary hyper‐ tension. These studies should include a ventilation‐perfusion scintigraphy, right‐heart cath‐ eterization and pulmonary angiography. It is recommended though that the final diagnostic and therapeutic approach should be performed in experienced centers.

PEA is the preferred treatment and remains the only potentially curative approach. For patients in whom surgery is not an option, riociguat is the only approved drug that improves hemodynamics and exercise capacity. Balloon pulmonary angioplasty is yet to be proven effective in the treatment of these patients. An increased understanding of the prevalence of this condition and opportunities of surgical cure should benefit a larger volume of patients.

#### **Author details**

Fabian Andres Giraldo Vallejo

Address all correspondence to: fabiangiraldomd@gmail.com

Heart Institute of Bucaramanga, Bucaramanga, Colombia

#### **References**


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44 Embolic Diseases - Unusual Therapies and Challenges


#### **Chapter 4**

## **Pulmonary Embolism**

Fayaz Ahmed and Ahmed Elsayed Mahmoud

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/68040

#### **Abstract**

Pulmonary embolism is sudden occlusion of pulmonary arteries, usually by a clot arising in the lower limb veins. The majority of pulmonary emboli are silent, and it is only when the embolus burden is substantial that the patient becomes symptomatic. Mortality after an acute, major thromboembolic episode is significantly high. Pulmonary embolism which causes hemodynamic instability is usually associated with occlusion of more than 50% of the pulmonary vasculature. Associated severe pulmonary hypertension may cause cardiac arrest. The precipitation of RV failure is also affected by the degree of preexisting right ventricular hypertrophy or dilatation, tricuspid valve regurgitation, and the presence of coronary artery disease. Aggressive therapy is needed in this subgroup of patients. Unfortunately, surgical embolectomy is seldom even entertained as an option in the management of these patients. A critical assessment of the data reveals that there is in fact a definite place for surgical therapy in the management of massive pulmonary embolism.

**Keywords:** pulmonary embolism, pulmonary hypertension, surgical embolectomy

#### **1. Introduction**

Pulmonary embolism is sudden occlusion of pulmonary arteries, usually by a clot arising in the lower limb veins. It is not a disease by itself but rather a complication of this venous thrombosis.

Pulmonary embolism is commonly mislabeled, more likely an unrecognized phenomenon particularly in hospitalized individuals.

The majority of pulmonary emboli are silent, and it is only when the embolus burden is substantial that the patient becomes symptomatic. Mortality after an acute, major thromboembolic episode reaches about 15–20% of patients within 48 hours [1].

Aggressive therapy is needed in this subgroup of patients. Unfortunately, surgical embolectomy is seldom even entertained as an option in the management of these patients, published mortality rates for acute pulmonary embolectomy have ranged from 20 to 60%, making it difficult to argue that the surgical results were any better than the natural history. A critical assessment of the data reveals that there is in fact a definite place for surgical therapy in the management of massive pulmonary embolism [2].

#### **2. Practice essentials**

Pulmonary embolism usually presents with dyspnea, tachypnea, dull chest pain, and cardiovascular changes such as tachycardia, mild-to-moderate hypotension, and distended neck veins. Most pulmonary embolism patients are hemodynamically stable and have adequate cardiac output.

Pulmonary embolism which causes hemodynamic instability is termed massive pulmonary embolism. It is usually associated with occlusion of more than 50% of the pulmonary vasculature [3]. Pulmonary angiograms demonstrate a unique degree of blockage of the pulmonary vasculature.

The severity of symptoms may not be related to the embolus burden, particularly in patients with preexisting cardiac or pulmonary disease. Cardiac arrest may occur. The precipitation of RV failure is also affected by the degree of right ventricular hypertrophy or dilatation, tricuspid valve regurgitation, and the presence of coronary artery disease. Pulmonary hypertension is also influenced by many factors. Humoral factors such as serotonin, adenosine diphosphate (ADP), platelet-derived growth factor (PDGF), and thromboxane are released from platelets attached to the thrombi. Anoxia and tissue ischemia downstream from emboli inhibit endothelium-derived relaxing factor (EDRF) production and enhance release of superoxide anions by activated neutrophils [4].

#### **2.1. Anatomy**

The anatomy of the pulmonary vasculature should be familiar to all cardiothoracic surgeons. What may be less well appreciated, however, is the remarkable access available to the lobar vessels via median sternotomy. All lobar and segmental vessels can be accessed via incisions in the pulmonary arteries from within the pericardial space as one would during pulmonary thrombo-endarterectomy [5].

#### **2.2. Pathophysiology**

Pathophysiology of pulmonary hypertension in acute pulmonary embolism entails the release of serotonin from platelets, histamine from tissues, and circulating thrombin. Hypoxia due to ventilation/perfusion mismatch and increased dead space will also worsen pulmonary vasoconstriction and set a vicious cycle. Persistent systemic hypotension or refractory hypoxemia is an indication for aggressive interventional, surgical, or thrombolytic management. Operative risk is markedly elevated once the patient is in cardiogenic shock [6].

Right ventricular dysfunction is a harbinger of hemodynamic decompensation, an event that may unfold quite precipitously, abruptly closing the window of opportunity on a patient that has been otherwise holding on for several hours. Thrombolytics have taken center stage in the aggressive treatment of the unstable patient [7]. This is in part due to their wide availability and the familiarity many physicians have with their use in the context of treating acute coronary syndromes. However, study reports found no improvement in mortality rate when thrombolytics were used in unselected patients as compared with heparin but an almost twofold increased risk of hemorrhage. Catheter embolectomy is another option. Endovascular techniques include clot fragmentation, clot aspiration, and rheolytic therapy. The mortality rate associated with these interventions, however, has been 25–30% [8]. Surgical intervention performed before hemodynamic collapse has an operative risk no higher than that of thrombolytic therapy in most cases. Surgery is clearly the option of choice when there is a clot in transit, in the right atrium, or trapped in a patent foramen ovale [7, 9].

#### **3. Diagnosis**

Aggressive therapy is needed in this subgroup of patients. Unfortunately, surgical embolectomy is seldom even entertained as an option in the management of these patients, published mortality rates for acute pulmonary embolectomy have ranged from 20 to 60%, making it difficult to argue that the surgical results were any better than the natural history. A critical assessment of the data reveals that there is in fact a definite place for surgical therapy in the

Pulmonary embolism usually presents with dyspnea, tachypnea, dull chest pain, and cardiovascular changes such as tachycardia, mild-to-moderate hypotension, and distended neck veins. Most pulmonary embolism patients are hemodynamically stable and have adequate

Pulmonary embolism which causes hemodynamic instability is termed massive pulmonary embolism. It is usually associated with occlusion of more than 50% of the pulmonary vasculature [3]. Pulmonary angiograms demonstrate a unique degree of blockage of the pulmonary

The severity of symptoms may not be related to the embolus burden, particularly in patients with preexisting cardiac or pulmonary disease. Cardiac arrest may occur. The precipitation of RV failure is also affected by the degree of right ventricular hypertrophy or dilatation, tricuspid valve regurgitation, and the presence of coronary artery disease. Pulmonary hypertension is also influenced by many factors. Humoral factors such as serotonin, adenosine diphosphate (ADP), platelet-derived growth factor (PDGF), and thromboxane are released from platelets attached to the thrombi. Anoxia and tissue ischemia downstream from emboli inhibit endothelium-derived relaxing factor (EDRF) production and enhance release of superoxide anions

The anatomy of the pulmonary vasculature should be familiar to all cardiothoracic surgeons. What may be less well appreciated, however, is the remarkable access available to the lobar vessels via median sternotomy. All lobar and segmental vessels can be accessed via incisions in the pulmonary arteries from within the pericardial space as one would during pulmonary

Pathophysiology of pulmonary hypertension in acute pulmonary embolism entails the release of serotonin from platelets, histamine from tissues, and circulating thrombin. Hypoxia due to ventilation/perfusion mismatch and increased dead space will also worsen pulmonary vasoconstriction and set a vicious cycle. Persistent systemic hypotension or refractory hypoxemia is an indication for aggressive interventional, surgical, or thrombolytic management.

Operative risk is markedly elevated once the patient is in cardiogenic shock [6].

management of massive pulmonary embolism [2].

48 Embolic Diseases - Unusual Therapies and Challenges

**2. Practice essentials**

by activated neutrophils [4].

thrombo-endarterectomy [5].

**2.2. Pathophysiology**

cardiac output.

vasculature.

**2.1. Anatomy**

Diagnosis is suspected with a history consistent with massive pulmonary embolism. Symptoms and signs vary with the extent of blockage, the magnitude of humoral response, and the cardiac and pulmonary reserve of the patient. Routine laboratory tests are usually normal. Serum D-dimer is almost always elevated in the presence of acute pulmonary embolus and is frequently used in emergency rooms as a screening test. The most common electrocardiographic abnormalities of acute pulmonary embolism are tachycardia and nonspecific ST- and T-wave changes [5]. The major value of the electrocardiogram is excluding a myocardial infarction. A minority of patients with massive embolism may show evidence of corpulmonale, right axis deviation, or right bundle branch block. Chest X-ray may show oligemia (Westermark's sign) or linear atelectasis (Fleischner lines), both of which are nonspecific findings. Ventilation-perfusion (V/Q) scans may be used for their negative predictive value and may be unreliable because of pneumonia, atelectasis, previous pulmonary emboli, and other conditions may cause a ventilation and perfusion mismatch. In general, negative V/Q scan may rule out significant pulmonary embolism. Pulmonary angiogram provides the most definitive diagnosis for acute pulmonary embolism. Contrast-enhanced high-resolution computerized tomographic (CT) scanning is most commonly diagnostic (**Figure 1**).

Advantages of MDCTPA in the diagnosis of acute PE are as follows:


**Figure 1.** Massive PE as appears in contrast enhanced CT chest.


The most important recent diagnostic development from a surgical standpoint is transesophageal echocardiography. This modality may not visualize distal embolic material in the pulmonary vasculature but is more important to identify thrombus in transit, including paradoxical embolus in transit, and to permit evaluation of right ventricular function (**Figure 2**) [10].

#### **4. Treatment**

Oxygen should be administered to alleviate hypoxic pulmonary vasoconstriction, and it is likely that a severely affected patient will require intubation and ventilator support. Pharmacological agents, including vasopressors, may be instituted to stabilize the patient.

Pulmonary artery catheters, although obviously helpful in management, may occasionally emboli more thrombi because of the risk of dislodging further thromboembolic material [11].

#### **4.1. Thrombolysis**

Natural history of the clot in survivors of acute embolic events is fragmentation and progressive lysis. Thrombolytic agents dissolve thrombi by activating plasminogen to plasmin.

**Figure 2.** Echocardiogram demonstrating thrombus in transit across PFO.

Plasmin, when in proximity to a thrombus, degrades fibrin to soluble peptides. Circulating plasmin also degrades soluble fibrinogen and, to variable degrees, factors II, V, and VIII. In addition, increased concentrations of fibrin and fibrinogen degradation products contribute to coagulopathy by both inhibiting the conversion of fibrinogen to fibrin and interfering with fibrin polymerization. The thrombolytic agents currently reported for the treatment of acute pulmonary embolism include streptokinase, urokinase, recombinant tissue plasminogen activator (rt-PA, alteplase), anisoylated plasminogen streptokinase activator complex (APSAC, anistreplase), and reteplase [12]. There are newer agents arriving, like tenecteplase, lanoteplase, staphylokinase, and saruplase and are undergoing clinical testing.

Trials suggest a trend toward better results with thrombolytic therapy because of a more rapid diminution in right ventricular afterload and dysfunction. Compared with heparin therapy alone, thrombolytic agents carry a higher risk of bleeding problems, with up to 20% of patients experiencing a significant bleeding complication [13]. In general, thrombolytic therapy is contraindicated in patients with fresh surgical wounds, anemia, recent stroke, peptic ulcer, or bleeding dyscrasias.

#### **4.2. Anticoagulation**

• venous imaging with CTV

**4. Treatment**

**4.1. Thrombolysis**

ic pulmonary angiography)].

50 Embolic Diseases - Unusual Therapies and Challenges

**Figure 1.** Massive PE as appears in contrast enhanced CT chest.

• Ability to provide ancillary findings, which may affect management and prognosis [CTV (computed tomographic venography) and MDCTPA (multidetector computed tomograph-

The most important recent diagnostic development from a surgical standpoint is transesophageal echocardiography. This modality may not visualize distal embolic material in the pulmonary vasculature but is more important to identify thrombus in transit, including paradoxical embolus in transit, and to permit evaluation of right ventricular function (**Figure 2**) [10].

Oxygen should be administered to alleviate hypoxic pulmonary vasoconstriction, and it is likely that a severely affected patient will require intubation and ventilator support. Pharmacological

Pulmonary artery catheters, although obviously helpful in management, may occasionally emboli more thrombi because of the risk of dislodging further thromboembolic material [11].

Natural history of the clot in survivors of acute embolic events is fragmentation and progressive lysis. Thrombolytic agents dissolve thrombi by activating plasminogen to plasmin.

agents, including vasopressors, may be instituted to stabilize the patient.

Patients should be heparinized to prevent further propagation of thrombus at its origin and also in the pulmonary arterial tree. Intravenous (IV) heparin is started with an initial bolus dose of 70 U/kg followed by 18–20 U/kg/h. Heparin prevents propagation and formation of new thrombus. It rarely dissolves existing clot. Intrinsic fibrinolytic system will lyse fresh thrombi over a period of days to weeks. Evidence suggests early treatment of stable patients with acute pulmonary embolism with subcutaneous low-molecular-weight heparin (tinzaparin) given once daily has been shown to be as effective and safe as IV heparin with respect to recurrent thromboembolism, major bleeding, and death [14].

#### **4.3. Surgical embolectomy**

Emergency pulmonary embolectomy was first described by Trendelenburg in 1908, using pulmonary artery and aortic occlusion, through a transthoracic approach. There were no surviving patients [14]. Later on, the first successful open embolectomy was performed and described by Sharp using cardiopulmonary bypass [15].

If a patient has been taken directly to the operating room without a definitive diagnosis, transesophageal or epicardial echocardiography and color Doppler mapping can confirm or refute the diagnosis in the operating room.

#### *4.3.1. Indication for surgery*

Emergency pulmonary thromboembolectomy is indicated for suitable patients with lifethreatening circulatory insufficiency, where the diagnosis of acute pulmonary embolism has been established. Indications for acute surgical intervention include the following: hemodynamic instability, definitive diagnosis of pulmonary embolism in the main or lobar pulmonary arteries with compromise of gas exchange, unstable patients in whom thrombolytic or anticoagulation therapy is absolutely contraindicated, thrombus in transit or thrombus trapped within the right atrium, patent foramen ovale, or right ventricle.

Surgical embolectomy, as initial therapy for massive PE compared to thrombolytic therapy, has less early mortality rates and significantly less bleeding complications.

Patients who undergo surgical embolectomy after the failure of lysis clearly demonstrate a critically high-mortality rate.

CT-derived RV/LV ratio could be a useful parameter to identify candidates who might benefit from direct surgical therapy instead of thrombolysis [16].

#### *4.3.2. Operative procedure*

Intraoperative transesophageal echocardiography is now a routine in modern practice and greatly facilitates intraoperative decision-making particularly with regard to exploration of the right atrium and evaluation for clot in transit [10]. The groin vessels should be prepped into the field in case postoperative extracorporeal membrane oxygenation is necessary. Poor venous return from the inferior vena cava line only can be a result of clot in transit impacted in the cannula orifice (**Figure 3**). For this reason, the superior vena cava cannula is placed first so that partial bypass may be initiated if clot is dislodged from the inferior vena cava. Routine massage of the lower extremities and abdomen and open aspiration of the inferior vena cava return with cardiotomy suckers is better to extract additional material in transit. Tapes are passed around the superior vena cava and inferior vena cava, if patent foramen ovale or paradoxic embolus in transit has been identified by transesophageal echo. A brief episode of cardioplegic arrest should be instituted to examine the left atrium (**Figure 4**).

**Figure 3.** The pulmonary arteriotomy sites.

once daily has been shown to be as effective and safe as IV heparin with respect to recurrent

Emergency pulmonary embolectomy was first described by Trendelenburg in 1908, using pulmonary artery and aortic occlusion, through a transthoracic approach. There were no surviving patients [14]. Later on, the first successful open embolectomy was performed and

If a patient has been taken directly to the operating room without a definitive diagnosis, transesophageal or epicardial echocardiography and color Doppler mapping can confirm or refute

Emergency pulmonary thromboembolectomy is indicated for suitable patients with lifethreatening circulatory insufficiency, where the diagnosis of acute pulmonary embolism has been established. Indications for acute surgical intervention include the following: hemodynamic instability, definitive diagnosis of pulmonary embolism in the main or lobar pulmonary arteries with compromise of gas exchange, unstable patients in whom thrombolytic or anticoagulation therapy is absolutely contraindicated, thrombus in transit or thrombus

Surgical embolectomy, as initial therapy for massive PE compared to thrombolytic therapy,

Patients who undergo surgical embolectomy after the failure of lysis clearly demonstrate a

CT-derived RV/LV ratio could be a useful parameter to identify candidates who might benefit

Intraoperative transesophageal echocardiography is now a routine in modern practice and greatly facilitates intraoperative decision-making particularly with regard to exploration of the right atrium and evaluation for clot in transit [10]. The groin vessels should be prepped into the field in case postoperative extracorporeal membrane oxygenation is necessary. Poor venous return from the inferior vena cava line only can be a result of clot in transit impacted in the cannula orifice (**Figure 3**). For this reason, the superior vena cava cannula is placed first so that partial bypass may be initiated if clot is dislodged from the inferior vena cava. Routine massage of the lower extremities and abdomen and open aspiration of the inferior vena cava return with cardiotomy suckers is better to extract additional material in transit. Tapes are passed around the superior vena cava and inferior vena cava, if patent foramen ovale or paradoxic embolus in transit has been identified by transesophageal echo. A brief episode of car-

trapped within the right atrium, patent foramen ovale, or right ventricle.

has less early mortality rates and significantly less bleeding complications.

dioplegic arrest should be instituted to examine the left atrium (**Figure 4**).

from direct surgical therapy instead of thrombolysis [16].

thromboembolism, major bleeding, and death [14].

52 Embolic Diseases - Unusual Therapies and Challenges

described by Sharp using cardiopulmonary bypass [15].

**4.3. Surgical embolectomy**

the diagnosis in the operating room.

*4.3.1. Indication for surgery*

critically high-mortality rate.

*4.3.2. Operative procedure*

If embolus in transit is identified in the right atrium, this can be extracted via a standard right atrial incision without cardioplegic arrest (**Figure 4**). This approach provides optimal protection of the right ventricle during the procedure. If right atrial exploration is not required,

**Figure 4.** Approaches to explore thrombus in transit.

a bullet-tip sucker can be dropped into the right atrium via a stab wound with a purse-string suture. This will reduce the amount of blood passing through the right ventricle and into the pulmonary artery [11, 17].

The pulmonary vessels are extraordinarily fragile and rapidly taper in diameter, making rupture of the vessels a very real possibility. Thrombus in the left pulmonary artery is accessed via an incision beginning in the main pulmonary artery. Adequate access permitting direct visualization of the segmental vessels requires extension of the incision onto the left pulmonary artery itself. This may require division of the pericardial reflection over the ventral surface of the pulmonary artery (**Figure 5**).

A linear incision first in the posterior pericardium overlying the vessel and then in the vessel itself provides ready access to all of the lobar and segmental vessels. An incision such as this permits direct inspection of the right upper lobe branch, right middle lobe branch, and the segmental vessels to the right lower lobe. A flexible suction catheter passed in the pulmonary arteries with massage of the lungs, helps to dislodge smaller thrombi in the distal branches (**Figure 6**). The arteriotomies are primarily closed with running 4-0 Prolene. A final step in the procedure is insertion of an inferior vena cava filter via a purse-string suture on the right atrial appendage.

**Figure 5.** Incision to explore distal pulmonary arteries.

**Figure 6.** Lung massage to mobilise peripheral thrombi.

#### *4.3.3. Benefits of surgery*

a bullet-tip sucker can be dropped into the right atrium via a stab wound with a purse-string suture. This will reduce the amount of blood passing through the right ventricle and into the

The pulmonary vessels are extraordinarily fragile and rapidly taper in diameter, making rupture of the vessels a very real possibility. Thrombus in the left pulmonary artery is accessed via an incision beginning in the main pulmonary artery. Adequate access permitting direct visualization of the segmental vessels requires extension of the incision onto the left pulmonary artery itself. This may require division of the pericardial reflection over the ventral

A linear incision first in the posterior pericardium overlying the vessel and then in the vessel itself provides ready access to all of the lobar and segmental vessels. An incision such as this permits direct inspection of the right upper lobe branch, right middle lobe branch, and the segmental vessels to the right lower lobe. A flexible suction catheter passed in the pulmonary arteries with massage of the lungs, helps to dislodge smaller thrombi in the distal branches (**Figure 6**). The arteriotomies are primarily closed with running 4-0 Prolene. A final step in the procedure is insertion of an inferior vena cava filter via a purse-string suture on the right atrial appendage.

pulmonary artery [11, 17].

54 Embolic Diseases - Unusual Therapies and Challenges

surface of the pulmonary artery (**Figure 5**).

**Figure 5.** Incision to explore distal pulmonary arteries.

Pulmonary embolectomies demonstrate excellent early and late survival rates for patients with stable PE and unstable PE. These findings confirm pulmonary embolectomy as a beneficial therapeutic option for central PE, especially during the postoperative period when thrombolytic therapy is often contraindicated. Procoagulant risk factors such as endothelial injury, malignancy, and decreased mobility are common among postoperative patient populations across surgical specialties, but surgical options for the treatment of PE remain underappreciated and underutilized. With increasing surgical experience and improved outcomes, the role for pulmonary embolectomy in the acute setting may be expanding [18, 19]. All PE patients with imminent risk of hemodynamic decompensation due to severe RV impairment and central clot burden should be evaluated for surgical treatment [20]. Surgical embolectomy although normally confined to the most critical PE patients can be done with good longterm survival comparable to active medical treatment with thrombolysis despite the mortality risk inflicted by the surgical procedure. High-risk PE patients treated with surgical embolectomy had a significantly lower amount of residual emboli and pulmonary diffusion impairment than patients treated with thrombolysis. The clinical consequences of residual emboli were identified significant shorter 6-MWT, a higher mean pulmonary arterial pressure, and more dyspnea when compared to PE patients without residual emboli [21]. Residual clot burden is an independent risk factor for increased mortality at long-term follow-up [22]. Residual emboli after acute PE were found to be an independent predictor for chronic thromboembolic pulmonary hypertension, a severe late complication of acute PE [21, 22]. Pulmonary diffusion impairment after acute PE occurs more frequently in high-risk patients treated with thrombolysis compared to surgical embolectomy and was correlated with residual emboli. The surgical superiority on pulmonary morbidity is due to rapid removal of the total emboli resulting in fast restoration of normal pulmonary circulation, while thrombolysis either is unable to resolve the emboli due to its size or fractionates it into smaller parts which are carried to the peripheral pulmonary vasculature.

Current American Heart Association, European Society of Cardiology, and American College of Chest Physicians guidelines reserve surgical pulmonary embolectomy for central PE with hemodynamic instability and a contraindication for thrombolytic therapy, or when thrombolysis has failed [23, 24]. These treatment algorithms are based on limited data from small surgical series, and these practice patterns may be more reflective of scarce surgical expertise. Increasing evidence suggests that pulmonary embolectomy might be considered first-line therapy for select patients [25, 26]. This has resulted in the extension of eligibility for pulmonary embolectomy to include those who are hemodynamically stable but with demonstrative evidence of impending right ventricular failure [27].

#### **5. ECMO in pulmonary embolism**

Extracorporeal membrane oxygenation use (ECMO) for selected patients with massive PE is associated with good outcomes. Patients presenting in cardiac arrest have worse outcomes. Survival rates and neurological recovery are better when the cause of cardiac arrest is pulmonary embolism compared to other causes of cardiac arrest [11].

As an emergency procedure, standard femoro-femoral, venoarterial ECMO is instituted to ensure rapid and effective CPR in arrest or pre arrest patients, this can be achieved by use of smaller percutaneous cannulas limited to basic one arterial and one venous cannula (**Figure 7**) [5].

The tip of the venous catheter is advanced into the right atrium to obtain a flow rate of 2.5–4.0 l/ min using an emergency pump-oxygenator circuit primed with crystalloid.

Mortality rates for emergency pulmonary thromboembolectomy vary widely between 11 and 92% in retrospective studies with varying operative techniques, preoperative hemodynamic state of the patient populations, and treatment plans. In general, greater surgical mortality was encountered if a patient had a preoperative cardiac arrest or required ECMO support [9, 28].

Prevention of recurrence should always be stressed upon in patients with successful outcomes, by addressing factors such as obesity, tobacco abuse, use of oral contraceptives, or postmenopausal hormone replacement. Consideration should be given to a search for occult malignancy. Consultation with a hematologist and systematic search for a prothrombotic state is routine. If no treatable cause is identifiable or patients have evidence of a hypercoagulable state, warfarin therapy is indicated for life.

**Figure 7.** Arteriovenous ECMO circuit.

#### **Author details**

Pulmonary diffusion impairment after acute PE occurs more frequently in high-risk patients treated with thrombolysis compared to surgical embolectomy and was correlated with residual emboli. The surgical superiority on pulmonary morbidity is due to rapid removal of the total emboli resulting in fast restoration of normal pulmonary circulation, while thrombolysis either is unable to resolve the emboli due to its size or fractionates it into smaller parts which

Current American Heart Association, European Society of Cardiology, and American College of Chest Physicians guidelines reserve surgical pulmonary embolectomy for central PE with hemodynamic instability and a contraindication for thrombolytic therapy, or when thrombolysis has failed [23, 24]. These treatment algorithms are based on limited data from small surgical series, and these practice patterns may be more reflective of scarce surgical expertise. Increasing evidence suggests that pulmonary embolectomy might be considered first-line therapy for select patients [25, 26]. This has resulted in the extension of eligibility for pulmonary embolectomy to include those who are hemodynamically stable but with demonstrative

Extracorporeal membrane oxygenation use (ECMO) for selected patients with massive PE is associated with good outcomes. Patients presenting in cardiac arrest have worse outcomes. Survival rates and neurological recovery are better when the cause of cardiac arrest is pulmo-

As an emergency procedure, standard femoro-femoral, venoarterial ECMO is instituted to ensure rapid and effective CPR in arrest or pre arrest patients, this can be achieved by use of smaller percutaneous cannulas limited to basic one arterial and one venous cannula

The tip of the venous catheter is advanced into the right atrium to obtain a flow rate of 2.5–4.0 l/

Mortality rates for emergency pulmonary thromboembolectomy vary widely between 11 and 92% in retrospective studies with varying operative techniques, preoperative hemodynamic state of the patient populations, and treatment plans. In general, greater surgical mortality was encountered if a patient had a preoperative cardiac arrest or required ECMO

Prevention of recurrence should always be stressed upon in patients with successful outcomes, by addressing factors such as obesity, tobacco abuse, use of oral contraceptives, or postmenopausal hormone replacement. Consideration should be given to a search for occult malignancy. Consultation with a hematologist and systematic search for a prothrombotic state is routine. If no treatable cause is identifiable or patients have evidence of a hypercoagu-

are carried to the peripheral pulmonary vasculature.

56 Embolic Diseases - Unusual Therapies and Challenges

evidence of impending right ventricular failure [27].

nary embolism compared to other causes of cardiac arrest [11].

min using an emergency pump-oxygenator circuit primed with crystalloid.

**5. ECMO in pulmonary embolism**

lable state, warfarin therapy is indicated for life.

(**Figure 7**) [5].

support [9, 28].

Fayaz Ahmed\* and Ahmed Elsayed Mahmoud

\*Address all correspondence to: drfayaz@gmail.com

King Fahd Hospital of the University, AlKhobar, Saudi Arabia

#### **References**


[19] Goldhaber SZ. Surgical pulmonary embolectomy: The resurrection of an almost discarded operation. Texas Heart Institute Journal. 2013;**40**:5–8

[6] Spagnoloa S, Barbatoa L, Grassob M A, Tesler UF. Retrograde pulmonary perfusion as an adjunct to standard pulmonary embolectomy for acute pulmonary embolism. Multimedia Manual of Cardiothoracic Surgery. 2014; pii: mmu019. doi:10.1093/mmcts/

[7] Cho Y H, Sung K, Kim WS, SeopJeong AD, Lee YT, Park PW, Kim DK. Management of acute massive pulmonary embolism: Is surgical embolectomy inferior to thrombolysis?

[8] Greenfield LJ, Proctor MC, Williams DM, et al. Long-term experience with transvenous catheter pulmonary embolectomy. Journal of Vascular Surgery. 1993;**18**:450–458

[9] Lehnert P, Møller CH, Mortensen J, Kjaergaard J, Olsen PS, Carlsen J. Surgical embolectomy compared to thrombolysis in acute pulmonary embolism: Morbidity and mortal-

[10] Yalamanchili K, Fleisher AG, Lehrman SG, Axelrod HI, Lafaro RJ, Sarabu MR, Zias EA, Moggio RA. Open pulmonary embolectomy for treatment of major pulmonary embo-

[11] Goldhaber SZ, Elliott CG. Acute pulmonary embolism: Part II: Risk stratification, treat-

[12] Riedel M. Therapy for pulmonary thromboembolism. Part 1: Acute massive pulmonary

[13] Heiberg J, Lars B. Ilkjær: Pulmonary endarterectomy after pulmonary infectious embolisms. Interactive CardioVascular and Thoracic Surgery. 2013;**16**:556–557. doi:10.1093/

[14] Dalen JE, Banas Jr JS, Brooks HL, et al. Resolution rate of pulmonary embolism in man.

[15] Sharp EH. Pulmonary embolectomy: Successful removal of a massive pulmonary embolus with the support of cardiopulmonary bypass—a case report. Annals of Surgery.

[16] Aymarda T, Kadnera A, Widmera A, Bascianib R, Tevaearaia H, Webera A, Schmidlia J, Carrela T. Massive pulmonary embolism: Surgical embolectomy versus thrombolytic therapy—should surgical indications be revisited? European Journal of Cardiothoracic Surgery. 2013;**43**:90–94. doi:10.1093/ejcts/ezs123 Advance Access publication 30 March

[17] Jakob H, Vahl C, Lange R, et al. Modified surgical concept for fulminant pulmonary embo-

[18] Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism: The task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology

ity. European Journal of Cardiothoracic Surgery 2016; doi:10.1093/ejcts/ezw297.

International Journal of Cardiology. 2016;**203**:579–583

lism. Annals of Thoracic Surgery. 2004;**77**:819–823

ment, and prevention. Circulation 2003;**108**:2834

icvts/ivs523 Advance Access publication 17 December 2012

lism. European J ournal of Cardiothoracic Surgery. 1995;**9**:557

(ESC). European Heart Journal. 2014;**29**:2276–315

New England Journal of Medicine. 1969;**280**:1194–1199

embolism. Cor Vasa. 1996;**38**:93–102

1962;**156**:1–4

2012.

mmu019

58 Embolic Diseases - Unusual Therapies and Challenges


### **Thromboembolism in Renal Diseases**

Milena Nikolova‐Vlahova, Marta Petrova Baleva and

Petar Krasimirov Nikolov

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68486

#### **Abstract**

Patients with renal diseases are prone to both thrombosis and bleeding, as they have profound changes in all three classic components of coagulation, defined approximately 150 years ago by Virchow: blood flow, vessel wall (endothelial injury), and coagulation properties of the blood (e.g., coagulation and fibrinolytic systems and platelets). The pro‐ thrombotic state in chronic kidney disease (CKD), glomerular diseases (including sys‐ temic lupus and vasculitis), and some less frequent conditions (idiopathic retroperitoneal fibrosis, antiphospholipid syndrome, hemolytic‐uremic syndrome, etc.) is associated with vascular endothelial damage, increase in certain coagulation and antifibrinolytic factors, decrease in anticoagulation proteins, dyslipidemia, hypoalbuminemia, changes in platelet membranes, hemo‐ and peritoneal dialysis and heparin treatment, increased microRNAs and circulating microparticles, antiphospholipid antibodies, nephrotic syn‐ drome, anemia with high platelet count, and so on. Nevertheless, the same patients have substantially increased risk of bleeding due to platelet dysfunction and intake of certain medications (antiaggregants, heparin and low‐molecular weight heparins, and anemia). The aim of this review is to present the main thrombo‐embolic risk factors in a wide vari‐ ety of patients with renal diseases, including chronic glomerulonephritis (primary and secondary), chronic renal disease, and idiopathic retroperitoneal fibrosis. We have evalu‐ ated the risk factors for arterial and venous thromboses in a wide variety of renal patients with both glomerular and non‐glomerular diseases, including the presence of nephrotic syndrome, inborn and acquired coagulation defects (i.e., factor V Leiden, MTHFR gene mutation, 20210 prothrombin gene mutation, and antiphospholipid antibodies), cortico‐ steroid treatment, and dyslipidemia. We are describing the results of these investigations and suggesting prophylactic anticoagulant strategies in such patients. Multiple risk fac‐ tors influence the coagulation system in renal disease leading to both hypercoagulation and hemorrhagic diathesis. Therefore, renal patients should be thoroughly investigated for coagulation abnormalities, especially if pathogenic (i.e., corticosteroid and immu‐ nosuppressive) and anticoagulation treatment is to be initiated. Moreover, the doses of anticoagulant/antiaggregant and hemostatic medications should be considered carefully, having in mind the underlying diseases and risk factors, renal function, and concomitant treatment.

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Keywords:** thromboembolism, glomerulonephritis, retroperitoneal fibrosis, coagulation, anticoagulation

#### **1. Introduction**

Patients with renal diseases are prone to both thrombosis and bleeding, as they have pro‐ found changes in all three classic components of coagulation, defined approximately 150 years ago by Virchow: blood flow, vessel wall (endothelial injury), and coagulation properties of the blood (e.g., coagulation and fibrinolytic systems, platelets). In this aspect, chronic kid‐ ney disease (CKD) is a unique state with the simultaneous presentation of both thrombophilia and hemorrhagic diathesis.

The *prothrombotic state* in CKD, glomerular diseases (including systemic lupus and vasculitis), and some less frequent conditions (idiopathic retroperitoneal fibrosis (RPF), antiphospholipid syndrome (APS), hemolytic‐uremic syndrome, etc.) is associated with [1–10]:


Nevertheless, the same patients have *substantially increased risk of bleeding* due to [6–8]:


#### **2. Overview of coagulation abnormalities in renal diseases**

Renal diseases have high prevalence among the population worldwide. On the other hand, thrombo‐embolic complications, including large vascular thromboses (stroke and myocar‐ dial infarction and peripheral arterial disease), deep vein thrombosis (DVT) and pulmonary embolism (PE), venous access thromboses, placental thromboses, thromboses of retinal vein and/or arteries, and so on, are also very prevalent in adults, especially in the groups > 65 years of age. Due to the specific metabolic, vascular, plasma, and platelet changes and at the background of inborn hemostasis and bleeding disorders, renal diseases can be associ‐ ated with both hypercoagulation (thrombophilia) and bleeding (hemorrhagic diathesis) [3–7]. Moreover, CKD itself, irrespective of its underlying cause, is a major risk factor for thrombo‐ embolic complications [4–8, 10].

#### **2.1. Hypercoagulation**

**Keywords:** thromboembolism, glomerulonephritis, retroperitoneal fibrosis, coagulation,

Patients with renal diseases are prone to both thrombosis and bleeding, as they have pro‐ found changes in all three classic components of coagulation, defined approximately 150 years ago by Virchow: blood flow, vessel wall (endothelial injury), and coagulation properties of the blood (e.g., coagulation and fibrinolytic systems, platelets). In this aspect, chronic kid‐ ney disease (CKD) is a unique state with the simultaneous presentation of both thrombophilia

The *prothrombotic state* in CKD, glomerular diseases (including systemic lupus and vasculitis), and some less frequent conditions (idiopathic retroperitoneal fibrosis (RPF), antiphospholipid

syndrome (APS), hemolytic‐uremic syndrome, etc.) is associated with [1–10]:

Nevertheless, the same patients have *substantially increased risk of bleeding* due to [6–8]:

• intake of certain medications (antiaggregants, heparin and low‐molecular weight heparins

• accompanying disease and conditions (i.e., anemia, myeloma, amyloidosis, etc.), and

• increase in certain coagulation and antifibrinolytic factors,

• hemo‐ and peritoneal dialysis (PD) and heparin treatment, • increased microRNAs and circulating microparticles (MPs),

anticoagulation

62 Embolic Diseases - Unusual Therapies and Challenges

and hemorrhagic diathesis.

• vascular endothelial damage,

• dyslipidemia,

• decrease in anticoagulation proteins,

• changes in platelet membranes,

• antiphospholipid antibodies,

• platelet dysfunction,

• dialysis treatment.

(LMWHs), and anemia), • vascular wall abnormalities,

• nephrotic syndrome and hypoalbuminemia,

• anemia with high platelet count, and so on.

• impaired platelet‐vessel wall interactions,

**1. Introduction**

The underlying mechanism of *thrombophilia* in renal disease, including CKD and chronic renal failure (CRF), is associated with platelet abnormalities, coagulation cascade changes, anemia, endothelial dysfunction and damage, circulating microparticles and miRNAs, atherosclero‐ sis, inborn (protein S and C and anti‐thrombin III deficiency, 20210 prothrombin gene muta‐ tion, methylene tetrahydrofolate reductase (MTHFR) gene mutation, factor V Leiden, etc.) and acquired thrombophilia (antiphospholipid syndrome and nephrotic syndrome), intake of certain medications and illicit drugs (including corticosteroids, cocaine, heparin, etc.), and dialysis [6–8, 10]. All these changes could be summarized as: increased platelet activa‐ tion/aggregation, activated coagulation and decreased endogenous anticoagulation, and decreased fibrinolysis.

#### *2.1.1. Platelet abnormalities/dysfunction*

In catabolic patients, especially on peritoneal dialysis, it has been shown that decreased plasma levels of nitric oxide (NO) and l‐arginine are associated with increased platelet aggre‐ gation. Moreover, the increase of phosphatidylserine on platelet surface in CKD/CRF leads to activation of caspase‐3 and binding of factor V with subsequent thrombin formation. Besides, CKD/CRF patients have increased PAC‐1 fibrinogen receptor and circulating P‐selectin that lead to formation of platelet‐leukocyte aggregates and formation of free oxygen radicals lead‐ ing to increased tendency toward thrombosis.

In dialysis, especially in peritoneal dialysis (PD), hypoalbuminemia is thought to lead to platelet activation.

It should be mentioned that in CKD/CRF, there are other functional platelet abnormalities asso‐ ciated with increased bleeding tendency, including decreased GPIb on platelet surface, sup‐ pressed function of GPIIb/IIIa, inhibited platelet aggregation changes in platelet alpha‐granules, changes in calcium levels, abnormalities in prostaglandin and arachidonic acid metabolism, increased circulating fibrinogen fragments, uremic toxins that inhibit both thrombopoiesis in the bone marrow and platelet aggregation, amyloid deposition in the vessel walls and bone marrow inhibits platelet‐vessel wall interactions and thrombopoiesis, and so on.

Paradoxically, in patients with CRF, the described platelet adhesion defects are accompanied by hypercoagulation due to endothelial damage and increased coagulation factor levels and activity plus decreased fibrinolytic activity.

#### *2.1.2. Coagulation cascade abnormalities*

CKD/CRF is a well‐known pro‐inflammatory state with increased acute‐phase proteins (including C‐reactive protein [CRP] and coagulation factors, i.e., fibrinogen) and interleukin 6 (IL‐6), increased plasma tissue factor (TF) levels, increased nuclear factor kappa‐B (NF‐kB) and PAR‐1 receptor, decreased levels and activity of anti‐thrombin III. On the other hand, in CKD and CRF, marked activation of rennin‐angiotensin‐aldosterone system (RAAS) is described with increase in plasma fibrinogen levels and plasminogen activator inhibitor 1 (PAI‐1). The latter mechanism is associated with both prothrombotic state and progression of CKD itself and closes a vicious circle of CKD—hypertension and prothrombotic state—CKD progression and thrombosis, leading to further worsening of CKD and thromboses.

In (auto)immune renal diseases, hypercoagulability state is due to increased acute‐phase pro‐ teins and coagulation cascade factors plasma levels and vascular wall/endothelial abnormali‐ ties with or without concomitant platelet count and/or activation changes.

#### *2.1.3. Anemia*

Anemia in CKD is due to erythropoietin deficiency, iron deficiency due to malabsorption of iron + chronic gastrointestinal tract (GIT) bleeding + intake of medications + folic acid and B12 deficiency + chronic inflammation and hypercatabolic state. Anemia is associated with both thrombophilia (especially in cases with chronic bleeding and compensatory increase in platelet count) and bleed‐ ing tendency (due to affection of platelet‐vessel wall interaction, decreased release of adenosine diphosphate (ADP) and decreased scavenging of NO, inactivation of prostaglandin I2 [PGI2]). The correction of anemia with erythropoiesis‐stimulating agents is also a double‐edged sword; it can lead to the correction of bleeding tendency but it could also increase blood viscosity and arte‐ rial pressure and lead to increased incidence of stroke and myocardial infarction.

#### *2.1.4. Endothelial dysfunction and damage*

Endothelial dysfunction and damage in CKD/CRF is associated with changes in tissue plas‐ minogen activator (tPA), PAI‐1 and von Willebrand factor (vWF) secretion and in NO synthesis and secretion. These alterations, as it has been mentioned above, can lead to both hyper‐ and hypocoagulation due to impaired platelet‐vessel wall interaction and changes in vascular tone and inflammatory response (including oxygen radical generation and scavenging).

Another suspected culprit for the development of hypercoagulation in CKD/CRF is hyper‐ homocysteinemia leading to endothelial damage, changes in fibrin formation tPA secretion, increase in PAI1, and metalloproteinase‐9 activity.

In renal transplantation (RT) patients, the calcineurin inhibitor and/or azathioprine‐induced endothelial damage + corticosteroid treatment could lead to hypercoagulation and venous thromboembolism (VTE).

In illicit drug users, the intake of heroin, cocaine, and amphetamines has been associated with both renal damage (marked vasoconstriction, rhabdomyolysis, and glomerulosclerosis) and thrombosis (thrombotic microangiopathy due to endothelial damage) [11]. Moreover, in her‐ oin‐dependent subjects, drug‐induced antiphospholipid antibodies with thrombo‐embolic complications have been described [11, 12].

#### *2.1.5. Microparticles*

the bone marrow and platelet aggregation, amyloid deposition in the vessel walls and bone

Paradoxically, in patients with CRF, the described platelet adhesion defects are accompanied by hypercoagulation due to endothelial damage and increased coagulation factor levels and

CKD/CRF is a well‐known pro‐inflammatory state with increased acute‐phase proteins (including C‐reactive protein [CRP] and coagulation factors, i.e., fibrinogen) and interleukin 6 (IL‐6), increased plasma tissue factor (TF) levels, increased nuclear factor kappa‐B (NF‐kB) and PAR‐1 receptor, decreased levels and activity of anti‐thrombin III. On the other hand, in CKD and CRF, marked activation of rennin‐angiotensin‐aldosterone system (RAAS) is described with increase in plasma fibrinogen levels and plasminogen activator inhibitor 1 (PAI‐1). The latter mechanism is associated with both prothrombotic state and progression of CKD itself and closes a vicious circle of CKD—hypertension and prothrombotic state—CKD

progression and thrombosis, leading to further worsening of CKD and thromboses.

ties with or without concomitant platelet count and/or activation changes.

rial pressure and lead to increased incidence of stroke and myocardial infarction.

In (auto)immune renal diseases, hypercoagulability state is due to increased acute‐phase pro‐ teins and coagulation cascade factors plasma levels and vascular wall/endothelial abnormali‐

Anemia in CKD is due to erythropoietin deficiency, iron deficiency due to malabsorption of iron + chronic gastrointestinal tract (GIT) bleeding + intake of medications + folic acid and B12 deficiency + chronic inflammation and hypercatabolic state. Anemia is associated with both thrombophilia (especially in cases with chronic bleeding and compensatory increase in platelet count) and bleed‐ ing tendency (due to affection of platelet‐vessel wall interaction, decreased release of adenosine diphosphate (ADP) and decreased scavenging of NO, inactivation of prostaglandin I2 [PGI2]). The correction of anemia with erythropoiesis‐stimulating agents is also a double‐edged sword; it can lead to the correction of bleeding tendency but it could also increase blood viscosity and arte‐

Endothelial dysfunction and damage in CKD/CRF is associated with changes in tissue plas‐ minogen activator (tPA), PAI‐1 and von Willebrand factor (vWF) secretion and in NO synthesis and secretion. These alterations, as it has been mentioned above, can lead to both hyper‐ and hypocoagulation due to impaired platelet‐vessel wall interaction and changes in vascular tone and inflammatory response (including oxygen radical generation and scavenging).

Another suspected culprit for the development of hypercoagulation in CKD/CRF is hyper‐ homocysteinemia leading to endothelial damage, changes in fibrin formation tPA secretion,

marrow inhibits platelet‐vessel wall interactions and thrombopoiesis, and so on.

activity plus decreased fibrinolytic activity.

*2.1.2. Coagulation cascade abnormalities*

64 Embolic Diseases - Unusual Therapies and Challenges

*2.1.4. Endothelial dysfunction and damage*

increase in PAI1, and metalloproteinase‐9 activity.

*2.1.3. Anemia*

Microparticles (MPs) are cell‐membrane residues containing phospholipids (phosphatidyl‐ serine) and proteins (tissue factor, residues of cell receptors, etc.). MPs are formed during different processes, such as cell development, differentiation and aging, inflammation, and cell death. MPs are known to have pro‐coagulant effects due to phosphatidylserine and TF. Sometimes MPs are associated with small and presumed non‐coding single‐stranded RNA molecules, called microRNAs (miRNAs). These miRNAs are known to participate in post‐tran‐ scriptional gene modulation. It has been discovered that they can modulate platelet function via the P2Y12 receptor and/or the VAMP8 or via influencing the platelet mRNA regulation.

#### *2.1.6. Atherosclerosis and vascular injury*

Atherosclerosis is a well‐known and independent risk factor for the development of large vas‐ cular incidents (including stroke and myocardial infarction). All CKD/CRF patients, especially in the presence of nephrotic syndrome, chronic inflammation, and corticosteroid treatment, have accelerated atherosclerosis development. Moreover, the co‐morbidities in atherosclerosis and CKD/CRF patients (diabetes, hypertension, obesity, and dyslipidemia) also predispose to both arterial and venous thromboses, probably via following mechanisms: endothelial/ves‐ sel wall injury and platelet dysfunction. Microalbuminuria, a marker of endothelial injury, is associated with the risk for the development of both arterial and venous thromboses.

#### *2.1.7. Hypercoagulation in glomerulonephritis*

In patients with glomerular diseases, hypercoagulation is associated with four major factors: nephrotic syndrome, vasculitis and vascular wall inflammation, and medications (corticoste‐ roids and cyclosporine A).

The nephrotic syndrome leads to hypercoagulation due to imbalance between pro‐and anti‐ coagulation factors: decreased protein C and S and anti‐thrombin III, decreased fibrinolysis, and increased coagulation factor plasma levels. The development of DVT and/or PE is one of the major complications of the nephrotic syndrome. The latter substantially increases the risk for venous thromboembolism.

Vasculitis/vascular wall inflammation in systemic and renal vasculitis, including antineutro‐ phil cytoplasmic antibody (ANCA)‐positive cases, leads to hypercoagulation due to structural changes in the vessel wall, endothelial damage, and dysfunction and activation of coagulation cascade. Moreover, high platelet count is observed in acute and chronic inflammation.

Rarely, in patients with systemic vasculitis, parenchymal organ bleeding has been described, asso‐ ciated with microvascular damage and development of small cracks filled with blood (peliosis).

The intake of corticosteroids is associated with increased platelet count and aggregability, increase in coagulation factors plasma levels, and in acute‐phase proteins. On the other hand, corticosteroid treatment is associated with the development of GIT hemorrhages due to the inhibition of prostaglandin synthesis. Cyclosporine A treatment can lead to endothelial cell damage with the subsequent development of hypercoagulation and thrombotic microangi‐ opathy. Cocaine, amphetamines, and heroin also affect endothelial cells and can lead to the development of thrombotic microangiopathy.

#### *2.1.8. Antiphospholipid antibodies (APLs)*

These autoantibodies are directed against negatively charged plasma or membrane phospho‐ lipids and/or phospholipid binding proteins and/or phospholipid‐protein complexes. They are the major laboratory criterion for the classification of the antiphospholipid syndrome. APLs affect not only the coagulation system but also endothelial function and platelets. They are known to cause both arterial and venous thromboses, low platelet count, reproductive failure, and accelerated atherosclerosis.

Their determination in renal diseases is crucial because the results can affect both the diagno‐ sis (particularly in chronic glomerulonephritis patients in whom systemic lupus erythematosus (SLE) is suspected) and the treatment, especially at the background of other thrombophilic fac‐ tors, such as nephrotic syndrome, corticosteroid treatment, vasculitis, dyslipidemia, and diabetes.

The suspected pathogenic mechanism of the pro‐coagulant action of APL and the develop‐ ment of vascular injury are [13–18]:


changes in the vessel wall, endothelial damage, and dysfunction and activation of coagulation

Rarely, in patients with systemic vasculitis, parenchymal organ bleeding has been described, asso‐ ciated with microvascular damage and development of small cracks filled with blood (peliosis). The intake of corticosteroids is associated with increased platelet count and aggregability, increase in coagulation factors plasma levels, and in acute‐phase proteins. On the other hand, corticosteroid treatment is associated with the development of GIT hemorrhages due to the inhibition of prostaglandin synthesis. Cyclosporine A treatment can lead to endothelial cell damage with the subsequent development of hypercoagulation and thrombotic microangi‐ opathy. Cocaine, amphetamines, and heroin also affect endothelial cells and can lead to the

These autoantibodies are directed against negatively charged plasma or membrane phospho‐ lipids and/or phospholipid binding proteins and/or phospholipid‐protein complexes. They are the major laboratory criterion for the classification of the antiphospholipid syndrome. APLs affect not only the coagulation system but also endothelial function and platelets. They are known to cause both arterial and venous thromboses, low platelet count, reproductive

Their determination in renal diseases is crucial because the results can affect both the diagno‐ sis (particularly in chronic glomerulonephritis patients in whom systemic lupus erythematosus (SLE) is suspected) and the treatment, especially at the background of other thrombophilic fac‐ tors, such as nephrotic syndrome, corticosteroid treatment, vasculitis, dyslipidemia, and diabetes. The suspected pathogenic mechanism of the pro‐coagulant action of APL and the develop‐

• increased expression of adhesion molecules on endothelial cells and leukocyte adhesion to

• inhibition of the anticoagulant activity of beta‐2‐glycoprotein‐I (b2GPI),

cascade. Moreover, high platelet count is observed in acute and chronic inflammation.

development of thrombotic microangiopathy.

*2.1.8. Antiphospholipid antibodies (APLs)*

66 Embolic Diseases - Unusual Therapies and Challenges

failure, and accelerated atherosclerosis.

ment of vascular injury are [13–18]:

• activation of the tissue factor, • inhibition of anti‐thrombin III,

• inhibition of fibrinolysis, • endothelial cell activation,

the vascular endothelium,

• neutrophil leukocyte activation and degranulation,

• increased platelet activation and aggregation,

• inhibition of the activated protein C,

• damage of the membrane annexin V,

On the other hand, APLs have several anticoagulant effects, associated with inhibition of fac‐ tor IX and X activation and of the conversion of prothrombin to thrombin [14]. The factors that modulate the pro‐ and anticoagulant effects of ALA probably are the phospholipids that bind APL and the antigenic specificity of the latter.

The development of thrombosis in APL‐positive patients has been explained by the so‐called *second‐hit theory*: the presence of APL (first hit) itself is not sufficient for the generation of thrombus but when a second abnormality develops (i.e., endothelial damage, platelet dys‐ function, etc.), thrombus may be formed [14]. Moreover, APL could represent the second hit—at the background of inborn or acquired thrombophilia: factor V Leiden or prothrombin gene mutation, MTHFR, protein C/S or anti‐thrombin deficiency, nephritic syndrome, chronic renal failure, chronic endothelial damage or dysfunction in chronic inflammation, corticoste‐ roid treatment, and so on. In APS patients, we showed increased platelet activation markers' expression [16]. Some of the APS patients have other underlying inborn coagulation defi‐ ciency [18]: protein S/C or anti‐thrombin III deficiency, factor V Leiden, 20210 prothrombin gene mutation. This fact supports the described second‐hit theory.

#### *2.1.9. Heparin‐induced thrombocytopenia type II (HIT II)*

HIT II is associated with the heparin‐induced synthesis of platelet‐activating antibodies against the complex heparin‐platelet factor 4. It is observed in 0.5–5% of all heparin‐treated patients. In such patients, platelet levels are low but thrombo‐embolic complications (usually venous thromboses) appear due to platelet activation.

#### **2.2. Bleeding tendency (hemorrhagic diathesis)**

The underlying mechanisms of *hemorrhagic diathesis* in renal diseases, CKD and CRF, are asso‐ ciated with platelet dysfunction, uremic toxins, dialysis membranes, impaired platelet‐vessel wall interaction, anemia, and intake of certain medications (including aspirin and non‐steroid anti‐inflammatory drugs [NSAIDs], anticoagulants, antiaggregants, and antibiotics) [6–8].

#### *2.2.1. Platelet dysfunction*

The main cause of hemorrhagic diathesis in chronic renal diseases, CKD and CRF, are platelet abnormalities, including low platelet count in CKD/CRF due to bone marrow suppression and/or immune thrombocytopenia, changes in alpha‐granules with increased adenosine tri‐ phosphate (ATP)/ADP ratio, and reduced serotonin content, dysregulation of arachidonate and prostaglandin synthesis and degradation (mainly decreased thromboxane A2), increased plasma levels of fibrinogen fragments.

The changes in alpha‐granules are associated with decreased platelet factor 4, fibronectin B, platelet‐derived growth factor, vWF, fibrinogen, serotonin, factors V and XIII, transforming growth factor B, and so on.

#### *2.2.2. Uremic toxins*

In CKD and CRF, several uremic toxins affect platelet degranulation and adhesion: phenol and phenolic acid, guanidinosuccinic acid, middle molecules (molecular weight of 500–3000 Da). Moreover, uremic toxins inhibit thrombopoiesis in the bone marrow. Low calcium levels in CKD/CRF can also contribute to hypocoagulation. Hemodialysis (HD) and peritoneal dialysis have dual and controversial effect on bleeding and coagulation. Both methods are associated with hypercatabolism, pro‐inflammatory state, malabsorption, anemia, and low calcium that could cause both bleeding and hypercoagulation. Moreover, the administration of heparin could cause both bleeding and thromboses (HIT II).

Parathyroid hormone (PTH) has been shown to inhibit platelet aggregation (at least *in vitro*). In hemodialysis, the dialysis membrane can lead to platelet activation and aggre‐ gation, but the removal of uremic toxins can (at least partially) correct coagulation abnormalities.

And, finally, circulating fibrinogen fragments that are elevated in CKD/CRF can competi‐ tively bind to GPIIb/IIIa platelet receptors and decrease platelet adhesion and aggregation.

#### *2.2.3. Dialysis membranes*

Dialysis membranes lead to persistent platelet activation (including increased number and percentage of P‐selectin/CD63‐positive circulating platelets), formation of platelet‐leuko‐ cyte (with the generation of free oxygen radicals), and platelet‐erythrocyte aggregates [9]. The process of platelet activation is dependent on the type of dialyzer membranes used (more pronounced in cellulose diacetate and polysulfone membranes and less severe in EVAL membranes). The persistent chronic inflammation and hypercatabolism in CRF/CKD also contribute to hypercoagulation. Yet, some patients on dialysis develop thrombocytope‐ nia with bleeding diathesis.

The dialysis (HD and continuous ambulatory peritoneal dialysis [CAPD]) is known to correct, at least partially, the coagulation abnormalities in CKD/CRF.

#### *2.2.4. Platelet‐vessel wall interaction*

Platelet‐vessel wall interactions are associated with the binding of platelets to vWF and fibrin‐ ogen on endothelial surface and the activation of platelet receptors (GPIb and GPIIa/IIIb). In the hypercatabolic environment of CKD/CRF, significant decrease of platelet GPIb has been reported, along with decreased platelet binding to fibrinogen and vWF (plus decreased vWF levels), decreased activation of GPIIa/IIIb [6]. The impaired platelet adhesion is thought to be caused by dialyzable uremic toxins, as dialysis corrects the described abnormalities. Moreover, the administration of vWF‐containing cryoprecipitates and of desmopressin (known to stimulate endothelial release of vWF) has been shown to ameliorate platelet‐vessel wall inter‐ actions. And finally, the changes in vascular tone in response to vasoactive substances (nitric oxide and prostacyclin) associated with the accumulation of uremic toxins also contribute to the impairment of platelet‐endothelial interactions.

#### *2.2.5. Anemia*

The changes in alpha‐granules are associated with decreased platelet factor 4, fibronectin B, platelet‐derived growth factor, vWF, fibrinogen, serotonin, factors V and XIII, transforming

In CKD and CRF, several uremic toxins affect platelet degranulation and adhesion: phenol and phenolic acid, guanidinosuccinic acid, middle molecules (molecular weight of 500–3000 Da). Moreover, uremic toxins inhibit thrombopoiesis in the bone marrow. Low calcium levels in CKD/CRF can also contribute to hypocoagulation. Hemodialysis (HD) and peritoneal dialysis have dual and controversial effect on bleeding and coagulation. Both methods are associated with hypercatabolism, pro‐inflammatory state, malabsorption, anemia, and low calcium that could cause both bleeding and hypercoagulation. Moreover, the administration of heparin

Parathyroid hormone (PTH) has been shown to inhibit platelet aggregation (at least *in vitro*). In hemodialysis, the dialysis membrane can lead to platelet activation and aggre‐ gation, but the removal of uremic toxins can (at least partially) correct coagulation

And, finally, circulating fibrinogen fragments that are elevated in CKD/CRF can competi‐ tively bind to GPIIb/IIIa platelet receptors and decrease platelet adhesion and aggregation.

Dialysis membranes lead to persistent platelet activation (including increased number and percentage of P‐selectin/CD63‐positive circulating platelets), formation of platelet‐leuko‐ cyte (with the generation of free oxygen radicals), and platelet‐erythrocyte aggregates [9]. The process of platelet activation is dependent on the type of dialyzer membranes used (more pronounced in cellulose diacetate and polysulfone membranes and less severe in EVAL membranes). The persistent chronic inflammation and hypercatabolism in CRF/CKD also contribute to hypercoagulation. Yet, some patients on dialysis develop thrombocytope‐

The dialysis (HD and continuous ambulatory peritoneal dialysis [CAPD]) is known to correct,

Platelet‐vessel wall interactions are associated with the binding of platelets to vWF and fibrin‐ ogen on endothelial surface and the activation of platelet receptors (GPIb and GPIIa/IIIb). In the hypercatabolic environment of CKD/CRF, significant decrease of platelet GPIb has been reported, along with decreased platelet binding to fibrinogen and vWF (plus decreased vWF levels), decreased activation of GPIIa/IIIb [6]. The impaired platelet adhesion is thought to be caused by dialyzable uremic toxins, as dialysis corrects the described abnormalities. Moreover, the administration of vWF‐containing cryoprecipitates and of desmopressin (known

at least partially, the coagulation abnormalities in CKD/CRF.

growth factor B, and so on.

68 Embolic Diseases - Unusual Therapies and Challenges

could cause both bleeding and thromboses (HIT II).

*2.2.2. Uremic toxins*

abnormalities.

*2.2.3. Dialysis membranes*

nia with bleeding diathesis.

*2.2.4. Platelet‐vessel wall interaction*

Anemia is known to directly influence bleeding because red blood cells lead to platelet aggregation and stimulate ADP release and PGI2 inactivation. Moreover, in patients with CKD/CRF, the infusion of red blood cells and/or the correction of erythrocyte levels with erythropoiesis‐stimulating agents and iron lead to reduction of bleeding time. On the other hand, one should not forget that the correction of anemia increases the risk for major vascu‐ lar incidents (myocardial infarction and stroke).

#### *2.2.6. Drugs and medications*

In patients with renal diseases, many drugs may cause severe bleeding episodes, even life‐ threatening, due to changes in the drug clearance and drug accumulation anticoagulants: direct thrombin inhibitors, aspirin and non‐steroid anti‐inflammatory drugs [NSAIDs], interaction with platelet membranes (beta‐lactam antibiotics, inhibition of cyclooxygenase (aspirin and NSAIDs).

In patients with opioid dependence, Savona et al. [19] describe heroin‐induced autoimmune thrombocytopenia. Moreover, in heroin and cocaine/amphetamine dependency, the develop‐ ment of endothelial drug injury may lead to thrombotic microangiopathy with both throm‐ boses and bleeding [11].

The underlying mechanisms for the development of hypercoagulation and bleeding tendency in CKD are summarized in **Table 1**.

The main clinical presentations of thromboses in renal diseases are summarized in **Table 2**.



**Table 1.** Factors leading to coagulation abnormalities in renal diseases.

#### **Hypercoagulation**


#### **Bleeding**


**Table 2.** Clinical presentation of coagulation abnormalities in renal diseases.

#### **3. Coagulation abnormalities and their clinical presentation in different renal diseases**

#### **3.1. Glomerulonephritis, systemic lupus, and vasculitis**

**Hypercoagulation Bleeding** Decreased tissue plasminogen activator (tPA) Increased tPA Increased plasminogen activator inhibitor 1 (PAI1) Decreased PAI1 Uremic toxins Uremic toxins

Nephrotic syndrome Amyloidosis, myeloma

Corticosteroid treatment, cyclosporine A, cocaine Corticosteroid treatment

Hemodialysis and peritoneal dialysis Hemodialysis and peritoneal dialysis

‐ Venous thromboembolism (deep venous thrombosis [DVT] and/or pulmonary embolism [PE]). ‐ Major vascular incidents (myocardial infarction and/or stroke, peripheral arterial disease).

‐ Skin and linings: ecchymoses, epistaxis, gingival bleeding, gastrointestinal bleeding, subungual hematoma, geni‐

tal bleeding, hematuria, hemoptysis, and skin hemorrhages (petechiae, purpura, and suffusions).

Anemia Anemia

**Table 1.** Factors leading to coagulation abnormalities in renal diseases.

‐ Hemodialysis vascular access and/or central venous access thrombosis.

‐ Intracranial hemorrhage (epidural, subdural, subarachnoid, and intracranial).

**Table 2.** Clinical presentation of coagulation abnormalities in renal diseases.

Atherosclerosis: dyslipidemia, diabetes, arterial hypertension,

Medications

Vasculitis

‐ Beta‐lactam antibiotics ‐ Aspirin and NSAIDs ‐ Anticoagulants ‐ Antiaggregants

Increased rennin‐angiotensin‐aldosterone (RAAS) activity

70 Embolic Diseases - Unusual Therapies and Challenges

Antiphospholipid antibodies ‐ Pro‐thrombotic gene mutations

peripheral vascular disease

**Hypercoagulation**

**Bleeding**

‐ 20210 prothrombin gene mutation ‐ Protein C, S, and anti‐thrombin deficiency

Heparin‐induced thrombocytopenia type II

‐ Peripheral vascular access thrombosis. ‐ Thrombotic microangiopathy.

‐ Parenchymal organ bleeding (including peliosis).

‐ Vascular access bleeding.

‐ Factor V Leiden ‐ MTHFR

Christiansen et al. [2] examined the risk of VTE in 128,096 Danish patients hospitalized for VTE for the period 1980–2010 (78,623 with DVT and 54,473 with PE) and compared them with 642,426 age‐ and gender‐matched control and found that kidney disease is associated with higher OR for VTE (range between 1.41 for hypertensive nephropathy and 2.89 for nephritic syndrome), with the association being stronger during the first 3 months after the diagnosis of CKD but remaining elevated for the following 5 years. Therefore, the authors concluded that patients with chronic nephropathies are at increased risk for VTE, especially in cases of nephritic syndrome and glomerulonephritis.

In 182 patients with idiopathic glomerulonephritis (125 male and 57 female, mean age 35.6 ± 13.4 years), hospitalized for the period 2000–2005, we observed thrombotic com‐ plications in 27: stroke in 6, myocardial infarction in 12, DVT in 15, PE in 7 (the sum is more than 27 because several patients had more than 1 thrombotic complications) [15 and unpublished data]. The main risk factors for the development of thrombotic incidents were nephrotic syndrome (OR 3.220), corticosteroid treatment (OR 2.617), and renal fail‐ ure (OR 1.51). **Figure 1** shows the typical S1Q3T3 electrocardiography (ECG) changes in a male patient with membranous glomerulonephritis and pulmonary embolism.

**Figure 1.** ECG of a patient with idiopathic membranous glomerulonephritis with nephrotic syndrome and pulmonary embolism (PE). Typical S1Q3T3 changes.

In 106 patients with SLE (63 with biopsy‐proven lupus nephritis [LN]), 7 male and 56 female, mean age 37.4 ± 10.4 years; 43 without clinical/laboratory data for renal involvement, 7 male and 36 female, mean age 44.1 ± 17.8 years) for the period 2000–2005, we observed thrombotic complications in 34 patients (32.1%) (7/43 without LN and 27/63 with LN) [15]. Following thrombotic incidents were observed:


The sum of incidents is more than 34 because several patients had more than 1 thrombotic complication.

The development of thrombotic complications correlated with the presence of positive IgG and IgM anticardiolipin antibody (ACL) and IgG b2GPI (but not IgM b2GPI) and their lev‐ els, the presence of APS, the serum cryoglobulin levels and showed weak correlation with the presence of vasculitis (thrombosis+/vasculitis+ 11/106 patients vs. thrombosis−/vasculitis+ 6/106 patients, *r* = 0.306, *p* = 0.01).

For the total population of SLE patients (with and without LN), the development of thrombotic complications correlated with systemic lupus erythematosus disease activity index (SLEDAI) (mean SLEDAI in thrombotic patients 16.2 ± 8.7 vs. 7.6 ± 3.9 for non‐thrombotic patients, *r* = 0.566, *p* = 0.0001) and systemic lupus collaborating clinics (SLICC) indices (mean SLICC 2.9 ± 2, vs. 0.7 ± 1.1, respec‐ tively, *r* = 0.593, *p* = 0.0001), with the presence of renal involvement (27/63 with LN vs. 7/43 without LN, *χ*<sup>2</sup> = 8.286, *r* = 0.380, *p* = 0.004).

For the total SLE population (with and without LN), following markers for increased thrombotic risk were identified: arthritis/arthralgiae, serositis, central nervous system involvement, renal involvement, nephritic urinary sediment, nephrotic syndrome, positive IgG and IgM ACL and IgG (but not IgM) b2GPI antibodies, APS, corticosteroid treatment, and vasculitis (**Table 3**).



**Table 3.** Markers of thrombotic risk in 106 patients with SLE [15].

In the investigated LN patients, the development of thrombotic complications correlated with the presence of vasculitis, the duration and the number of SLE criteria, the central nervous system involvement, oral ulcerations, arthritis/arthralgiae, LN histological activity index, the amount of proteinuria, serum cryoglobulin levels, the levels and positivity of IgG and IgM ACL, the mean IgG b2GPI levels, SLEDAI and SLICC, APS, and inversely correlated with serum IgG levels (lower in more severe nephrotic syndrome).

In LN patients, the following markers of increased thrombotic risk were identified: oral ulcerations and vasculitis, positive ANCA, central nervous system involvement, nephrotic syndrome, positive IgG and IgM ACL and IgG b2GPI, hypocomplementemia C3, APS, and corticosteroid treatment (**Table 4**).

The results of our studies in APS patients with and without SLE [16] showed correlation between CD63 expression and activated partial thromboplastin time (aPTT), CD61 expression and IgG and IgM ACL, and b2GPI, CD42a, and b2GPI.


**Table 4.** Markers of increased thrombotic risk in 63 LN patients [15].

**Marker OR (95% CI)** *p* Arthritis/arthralgiae 5.167 (1.433–18.627) 0.007 Serositis 2.537 (1.062–6.059) 0.034 Central nervous system involvement 9 (3.321–24.388) 0.0001

Positive IgG ACL 16.8 (6.083–46.398) 0.0001

3.857 (1.49–9.984) 0.004

In 106 patients with SLE (63 with biopsy‐proven lupus nephritis [LN]), 7 male and 56 female, mean age 37.4 ± 10.4 years; 43 without clinical/laboratory data for renal involvement, 7 male and 36 female, mean age 44.1 ± 17.8 years) for the period 2000–2005, we observed thrombotic complications in 34 patients (32.1%) (7/43 without LN and 27/63 with LN) [15]. Following

• Venous thromboses: DVT in 13, PE in 6, vena axillaris/subclavia thrombosis in 1, vena cava

The sum of incidents is more than 34 because several patients had more than 1 thrombotic

The development of thrombotic complications correlated with the presence of positive IgG and IgM anticardiolipin antibody (ACL) and IgG b2GPI (but not IgM b2GPI) and their lev‐ els, the presence of APS, the serum cryoglobulin levels and showed weak correlation with the presence of vasculitis (thrombosis+/vasculitis+ 11/106 patients vs. thrombosis−/vasculitis+

For the total population of SLE patients (with and without LN), the development of thrombotic complications correlated with systemic lupus erythematosus disease activity index (SLEDAI) (mean SLEDAI in thrombotic patients 16.2 ± 8.7 vs. 7.6 ± 3.9 for non‐thrombotic patients, *r* = 0.566, *p* = 0.0001) and systemic lupus collaborating clinics (SLICC) indices (mean SLICC 2.9 ± 2, vs. 0.7 ± 1.1, respec‐ tively, *r* = 0.593, *p* = 0.0001), with the presence of renal involvement (27/63 with LN vs. 7/43 without

For the total SLE population (with and without LN), following markers for increased thrombotic risk were identified: arthritis/arthralgiae, serositis, central nervous system involvement, renal involvement, nephritic urinary sediment, nephrotic syndrome, positive IgG and IgM ACL and IgG (but not IgM) b2GPI antibodies, APS, corticosteroid treatment,

• Arterial thromboses: coronary incidents in 3, stroke/transient ischemic attack in 8.

Renal involvement (LN, nephritic urinary sediment, proteinuria, nephrotic syndrome)

and vasculitis (**Table 3**).

thrombotic incidents were observed:

72 Embolic Diseases - Unusual Therapies and Challenges

• Thrombotic microangiopathy in 1.

6/106 patients, *r* = 0.306, *p* = 0.01).

= 8.286, *r* = 0.380, *p* = 0.004).

• Disseminated intravascular coagulation in 3.

inferior thrombosis in 1. • Reproductive failure in 8.

complication.

LN, *χ*<sup>2</sup>

The results of our investigations on the platelet activation markers in female patients with complicated pregnancy [18], including edema‐proteinuria‐hypertension (EPH) gestosis, revealed that these patients have increased anticardiolipin and beta‐2‐glycoprotein I antibod‐ ies, and the levels of ACL correlate with CD63 expression (marker of platelet degranulation). Some of the APL‐positive patients also had inborn coagulation defects (i.e., factor V Leiden 20210 prothrombin gene mutation and MTHFR gene mutation).

#### **3.2. Retroperitoneal fibrosis**

Idiopathic retroperitoneal fibrosis (RPF) is a rare autoimmune fibrosing disease associated with the development of fibrous tissue and/or chronic inflammatory infiltrates (**Figure 2**) in the retroperitoneal space that envelops the aorta, iliac vessels, and ureters (**Figure 3**) [20]. In approximately 15% of the patients, extra‐abdominal fibrosis is observed. In some RPF patients with vascular involvement, thrombotic incidents have been described [20]. For the period 1998–2017, we followed 33 patients with idiopathic retroperitoneal fibrosis (25 male and 8 female). Overall 17 patients had thrombotic incidents: iliac/femoral vein thrombosis in 8, vena cava inferior thrombosis in 4, portal vein thrombosis in 2, infiltration (with or without thrombosis) of the inferior mesenteric artery and its branches (**Figure 4**) in 3, aortic aneurism with thrombosis (**Figure 5**) in 2, DVT with or without PE in 5 (the sum of events is more

**Figure 2.** Biopsy specimen of retroperitoneal infiltrates in a patient with idiopathic retroperitoneal fibrosis (RPF) inflammatory infiltrate with abundance of lymphocytes and fibrous tissue.

**Figure 3.** CT image of a patient with idiopathic RPF. Bilateral hydronephrosis and retroperitoneal infiltrates that envelop the aorta, iliac vessels, and ureters.

**Figure 4.** Abdominal ultrasound in a patient with idiopathic RPF (arrow) with involvement of the abdominal aorta and inferior mesenteric artery (A and B), no Doppler data for stenosis of the inferior mesenteric artery (C). *Courtesy of Dr. R. Krasteva‐Lolova.*

than 17 because several patients had more than 1 thrombotic complication). In one patient, the DVT episodes with varico‐ and hyrdocele (**Figure 6**) were the first manifestation of RPF. The underlying mechanism of thrombosis in RPF is associated with vascular wall changes, endothelial dysfunction in chronic inflammation, corticosteroid/azathioprine treatment, and immune phenomena (including APL).

**Figure 2.** Biopsy specimen of retroperitoneal infiltrates in a patient with idiopathic retroperitoneal fibrosis (RPF)—

The results of our investigations on the platelet activation markers in female patients with complicated pregnancy [18], including edema‐proteinuria‐hypertension (EPH) gestosis, revealed that these patients have increased anticardiolipin and beta‐2‐glycoprotein I antibod‐ ies, and the levels of ACL correlate with CD63 expression (marker of platelet degranulation). Some of the APL‐positive patients also had inborn coagulation defects (i.e., factor V Leiden

Idiopathic retroperitoneal fibrosis (RPF) is a rare autoimmune fibrosing disease associated with the development of fibrous tissue and/or chronic inflammatory infiltrates (**Figure 2**) in the retroperitoneal space that envelops the aorta, iliac vessels, and ureters (**Figure 3**) [20]. In approximately 15% of the patients, extra‐abdominal fibrosis is observed. In some RPF patients with vascular involvement, thrombotic incidents have been described [20]. For the period 1998–2017, we followed 33 patients with idiopathic retroperitoneal fibrosis (25 male and 8 female). Overall 17 patients had thrombotic incidents: iliac/femoral vein thrombosis in 8, vena cava inferior thrombosis in 4, portal vein thrombosis in 2, infiltration (with or without thrombosis) of the inferior mesenteric artery and its branches (**Figure 4**) in 3, aortic aneurism with thrombosis (**Figure 5**) in 2, DVT with or without PE in 5 (the sum of events is more

20210 prothrombin gene mutation and MTHFR gene mutation).

**3.2. Retroperitoneal fibrosis**

74 Embolic Diseases - Unusual Therapies and Challenges

inflammatory infiltrate with abundance of lymphocytes and fibrous tissue.

**Figure 5.** Abdominal Doppler ultrasound of a patient with idiopathic RPF with aortic aneurism.

#### **3.3. Drug abuse**

The intake of illicit drugs (including heroin, cocaine, and amphetamines) has been reported to be associated with thrombotic incidents. The possible underlying mechanisms of thrombosis are overdose with rhabdomyolysis with or without acute renal failure and vascular damage; drug‐ induced endothelial cell injury with thrombotic microangiopathy; platelet and coagulation

**Figure 6.** Ultrasound examination of the testicles (right testicle) of a male patient with idiopathic RPF manifesting with femoro‐popliteal thrombosis and hydrocele.

abnormalities due to chronic inflammation, drug‐ and infection‐induced APL [11, 12, 15, 19]. In a group of 15 heroin abusers (12 male and 3 female, mean age 23.9 ± 4.2 years), we observed renal involvement in 6 [15]. One of the patients with biopsy‐proven renal involvement (chronic tubulo‐interstitial nephritis) and negative hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) developed ilio‐femoral vein thrombosis and acute renal failure at the background of positive IgG ACL. After the cessation of heroin abuse, ACL levels subsided back to the normal values that suggests heroin‐induced autoantibodies. The results of our investigations suggest that in patients with illicit drug abuse, the clinician should be aware of the possible renal and thrombotic complications.

#### **3.4. Chronic kidney disease and chronic renal failure**

Chronic renal disease and chronic renal failure are associated with significantly elevated risk for the development of venous thromboembolism due to platelet and coagulation abnormali‐ ties, impaired fibrinolysis, and endothelial damage and dysfunction. CKD is classified in five stages according to the degree of glomerular filtration rate (GFR) decrease (**Table 5**). The preva‐ lence of CKD/CRF in adults >20 years of age in the NHANES III study [21] is approximately 11%. This fact shows the social significance of CKD. Having in mind the increased thrombotic risk in mild to moderate CKD patients (1.3–2‐fold increase compared to the general population) and end‐stage renal disease (2.3‐fold compared to the general population), the clinician should be aware of VTE as a possible complication of CKD/CRF and of the need of proper anticoagula‐ tion strategy [3, 10].

#### **3.5. Hemodialysis and peritoneal dialysis**

**3.3. Drug abuse**

76 Embolic Diseases - Unusual Therapies and Challenges

femoro‐popliteal thrombosis and hydrocele.

The intake of illicit drugs (including heroin, cocaine, and amphetamines) has been reported to be associated with thrombotic incidents. The possible underlying mechanisms of thrombosis are overdose with rhabdomyolysis with or without acute renal failure and vascular damage; drug‐ induced endothelial cell injury with thrombotic microangiopathy; platelet and coagulation

**Figure 6.** Ultrasound examination of the testicles (right testicle) of a male patient with idiopathic RPF manifesting with

**Figure 5.** Abdominal Doppler ultrasound of a patient with idiopathic RPF with aortic aneurism.

As it was mentioned above, dialysis treatment is associated with both thrombosis and increased risk for bleeding episodes [1, 4–7]. The coagulation abnormalities (including the changes in the coagulation pathway, anticoagulation, and fibrinolysis/antifibrinolysis) in hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) are summarized in **Table 6**. These changes are accompanied by platelet abnormalities and altered platelet‐vascular wall interactions [7]. The


**Table 5.** Definition of chronic kidney disease and prevalence in the USA according to the NHANES III [21].


**Table 6.** Coagulation abnormalities in hemodialysis and in peritoneal dialysis.

*in vitro* and *in vivo* studies reveal somewhat contradictive results—patients on dialysis can have both increased and decreased platelet aggregation and the initiation of dialysis partially corrects the pre‐existing abnormalities in platelet function, characteristic for CKD/CRF [7, 9]. The degree of anemia and hypoalbuminemia seem to correlate with prolonged bleeding time, and the chronic inflammation seems to increase the thrombotic risk [7]. Heparin treatment in HD can induce both bleeding and thromboses (HIT II). The alterations in NO synthesis also lead to decreased platelet aggregation [7].

A major problem in these patients represents the vascular access thrombosis, especially in diabetics and in patients with systemic connective tissue disease (with or without the APS). Anticoagulation strategies in dialysis treatment are discussed further in the text.

#### **3.6. Renal transplantation**

VTE is a frequent complication of renal transplantation (RT). According to the literature, 6–7% of RT patients develop VTE [5, 22], including DVT, PE, graft thrombosis, renal vein thrombo‐ sis, and thrombotic microangiopathy [8]. The underlying mechanisms, as discussed earlier, include impaired platelet function and platelet‐vessel wall interactions, hypercoagulation at the background of chronic inflammation, corticosteroid treatment and CKD, the effect of cal‐ cineurin inhibitors and azathioprine on endothelial function, OKT3, and so on [8].

Luna et al. [5] retrospectively analyzed 577 cadaveric RTs performed for the period 1992–2009, excluding the cases with known hypercoagulability before RT. The incidence of VTE was 6%. The authors evaluated the type of thrombosis according to recipient variables, differences in dialysis within 24 h before transplantation (0 no dialysis, 13.8% dialysis out of hospital, and 4.2% dialysis in hospital; *p* = 0.029) and iliac vascular pathology (10% yes vs. 5% no; *p* < 0.04). The authors suggest that donor‐related factors are age >60 years (11% vs. 5%; *p* = 0.01), stroke versus trauma as a cause of death (9.3% vs. 4.7%; *p* = 0.049), and graft atheroma (16.7% yes vs. 5.1% no; *p* = 0.042). The authors also investigated the treatment‐associated risk factors tacroli‐ mus versus cyclosporine (7.4% vs. 2.3%; *p* = 0.001) and sequential therapy (10.7% yes vs. 3.3% no; *p* = 0.001), basiliximab (adjusted for donor and recipient age, and graft atheroma). The multivariate analysis revealed that the predictive factors for VTE after RT (increasing the risk for VTE (16‐fold)) are stroke donor death (OR 3.88), recipient iliac vascular pathology (OR 2.81), and graft atheroma (OR 3.63).

Poli et al. [22] studied 484 RT and found 7% prevalence of first episode of VTE. The authors investigated the importance of the cessation of oral anticoagulation and found that compared to VTE patients without renal disease the recurrence of VTE in RT patients is very high (50% or 14/28 compared to <10% or 8/84). In RT patients, the authors also find higher levels of homocysteine, circulating fibrinogen fragments 1 + 2 and d‐dimer that are characteristic for CKD/CRF patients in general. The authors recommend prolonged oral anticoagulation in RT patients to prevent the risk of VTE recurrence, despite the elevated bleeding risk.

#### **4. Anticoagulation strategies**

*in vitro* and *in vivo* studies reveal somewhat contradictive results—patients on dialysis can have both increased and decreased platelet aggregation and the initiation of dialysis partially corrects the pre‐existing abnormalities in platelet function, characteristic for CKD/CRF [7, 9]. The degree of anemia and hypoalbuminemia seem to correlate with prolonged bleeding time, and the chronic inflammation seems to increase the thrombotic risk [7]. Heparin treatment in HD can induce both bleeding and thromboses (HIT II). The alterations in NO synthesis also

↑ ↑

**Marker Hemodialysis Peritoneal dialysis (CAPD)**

Fibrinogen, factor VII, vWF, tissue factor ↑ ↑ Factor II, VIII, IX, X, XII ↓ ↑ Prothrombin fragments 1 + 2 ↑ ↑

Protein S ↓ ↑ Protein C, anti‐thrombin III ↓ ‐

Tissue plasminogen activator ↑ ↓ Plasminogen activator inhibitor 1 ↓ ↑ Thrombin activable fibrinolysis inhibitor ‐ ↑

**Table 6.** Coagulation abnormalities in hemodialysis and in peritoneal dialysis.

A major problem in these patients represents the vascular access thrombosis, especially in diabetics and in patients with systemic connective tissue disease (with or without the APS).

VTE is a frequent complication of renal transplantation (RT). According to the literature, 6–7% of RT patients develop VTE [5, 22], including DVT, PE, graft thrombosis, renal vein thrombo‐ sis, and thrombotic microangiopathy [8]. The underlying mechanisms, as discussed earlier, include impaired platelet function and platelet‐vessel wall interactions, hypercoagulation at the background of chronic inflammation, corticosteroid treatment and CKD, the effect of cal‐

Luna et al. [5] retrospectively analyzed 577 cadaveric RTs performed for the period 1992–2009, excluding the cases with known hypercoagulability before RT. The incidence of VTE was 6%. The authors evaluated the type of thrombosis according to recipient variables, differences in dialysis within 24 h before transplantation (0 no dialysis, 13.8% dialysis out of hospital, and

Anticoagulation strategies in dialysis treatment are discussed further in the text.

cineurin inhibitors and azathioprine on endothelial function, OKT3, and so on [8].

lead to decreased platelet aggregation [7].

**3.6. Renal transplantation**

Coagulation pathway

Anticoagulation

inhibitor

Fibrinolysis

Thrombomodulin, tissue factor pathway

78 Embolic Diseases - Unusual Therapies and Challenges

Due to the high risk of VTE all patients with chronic renal diseases, including glomerulone‐ phritis, systemic connective tissue diseases, and vasculitis with renal involvement, retroperi‐ toneal fibrosis, hemodialysis, should be considered possible candidates for anticoagulation, especially in the presence of coagulation abnormalities (anticoagulation factor deficiency, vas‐ culitis, nephrotic syndrome, and CKD/CRF) and/or predisposing factors (atrial fibrillation, various veins, cardiac and renal failure, etc.). Nevertheless, patients with renal diseases repre‐ sent significant therapeutic challenge if anticoagulation is needed, because they are prone to both thromboses and hemorrhages and because the gastrointestinal absorption and the renal clearance of certain anticoagulants are altered in CKD/CRF [3].

#### **4.1. Unfractioned heparin and low‐molecular weight heparins (LMWHs)**

Unfractionated heparin (UFH) is a 3–30 kDA sulphated polysaccharide that binds positively charged surfaces. Its anticoagulant response is mediated by binding to factor IIa and factor Xa. UFH anticoagulant effect is monitored using activated partial thromboplastin time (aPTT). UFH has reticulo‐endothelial and, to a lesser extent, renal clearance. Therefore, its clearance in CKD/CRF is unpredictable. UFH doses should be reduced in moderate to severe CRF (cre‐ atinine clearance below 30 ml/min) with close monitoring of aPTT (1.5–2x prolongation) in order to prevent over‐anticoagulation and severe bleeding episodes [6]. In VTE episodes at the background of CRF, Hughes et al. [3] recommend loading dose of 60 U/kg/h with main‐ tenance dose of 12 U/kg/h. Significant side effects of UFH include bleeding, heparin‐induced thrombocytopenia, osteopenia, and alopecia, especially in prolonged administration.

LWMHs are synthetic UFH derivatives with shorter heparin chains and stronger affinity to factor Xa with lower affinity to factor IIa. Their pharmacokinetic profile is more predictable than that of UFH. Moreover, self‐administration of the medication is possible. LMWHs have lower affinity and binding to endothelial cells and platelets and no routine monitoring of coagulation parameters is required. The only suitable monitoring parameter is anti‐Xa levels that is not routinely used in clinical practice. The most frequent side effects in prolonged administration are HIT, osteopenia, and alopecia, and their incidence is much lower com‐ pared to that on UFH.

The LMWHs dose should also be reduced in CRF [3]:


To avoid sub‐ or supradosing, monitoring of anti‐Xa levels is advisable in CRF patients with GFR <50 ml/min.

#### **4.2. Warfarin and indirect anticoagulants**

Indirect anticoagulants are vitamin K antagonists that inhibit the synthesis of vitamin K‐ dependent coagulation factors. The routine laboratory marker for the monitoring of their effect is prothrombin time (PT)/international normalized ration (INR). In CRF patients with GFR 30–59 ml/min, the maintenance dose required for stabile PT prolongation is 10% lower than that in non‐CRF population and in GFR <30 ml/min, the dose is 20% lower [3]. Moreover, CKD/CRF patients tend to have labile PT/INR and the anticoagulant effect is quite unpredict‐ able. In a review on mechanisms of vascular calcifications, El‐Abbadi et al. [23] emphasize that indirect anticoagulants can increase vascular calcifications due to vitamin K inhibi‐ tion‐dependent increase of serum phosphate levels. Another major complication is the war‐ farin‐related nephropathy—unexplained increase in serum creatinine with ≥0.3 mg% after the initiation of warfarin treatment probably due to intraglomerular bleeding and tubular obstruction by erythrocyte casts. This complication is associated with marked increase in mortality in CRF patients.

#### **4.3. Newer oral anticoagulants**

These medications are synthetic anti‐Xa agents (apixaban and rivaroxaban) or anti‐IIa agents (dabigatran and direct thrombin inhibitors). Rivaroxaban and apixaban have approximately 30% renal clearance and their effect in CRF patients is more predictable, whereas dabiga‐ tran has mainly renal clearance (85%) and in CRF patients tends to accumulate, and its effect in this population is unpredictable. Therefore, rivaroxaban and apixaban are approved for CRF patients with CFR<30 ml/min (with dose reduction of approximately 50%, the dose of rivaroxaban in CFR 15–49 ml/min is 15 mg/day, and <15 ml/min is contraindicated; the dose of apixaban in GFR 15–29 ml/min is 2.5 mg twice a day) and dabigatran is not approved in patient with GFR<30 ml/min [3]. It should be noted that both rivaroxaban and apixaban (anti‐Xa agents) have high protein binding and are metabolized via CYP3A4. Therefore, they should be used with caution in patients with nephrotic syndrome or hypoproteinemia/hypo‐ albuminemia of other origin and in combination with CYP3A4 inhibitors or inductors.

#### **4.4. Antiaggregants**

LWMHs are synthetic UFH derivatives with shorter heparin chains and stronger affinity to factor Xa with lower affinity to factor IIa. Their pharmacokinetic profile is more predictable than that of UFH. Moreover, self‐administration of the medication is possible. LMWHs have lower affinity and binding to endothelial cells and platelets and no routine monitoring of coagulation parameters is required. The only suitable monitoring parameter is anti‐Xa levels that is not routinely used in clinical practice. The most frequent side effects in prolonged administration are HIT, osteopenia, and alopecia, and their incidence is much lower com‐

To avoid sub‐ or supradosing, monitoring of anti‐Xa levels is advisable in CRF patients with

Indirect anticoagulants are vitamin K antagonists that inhibit the synthesis of vitamin K‐ dependent coagulation factors. The routine laboratory marker for the monitoring of their effect is prothrombin time (PT)/international normalized ration (INR). In CRF patients with GFR 30–59 ml/min, the maintenance dose required for stabile PT prolongation is 10% lower than that in non‐CRF population and in GFR <30 ml/min, the dose is 20% lower [3]. Moreover, CKD/CRF patients tend to have labile PT/INR and the anticoagulant effect is quite unpredict‐ able. In a review on mechanisms of vascular calcifications, El‐Abbadi et al. [23] emphasize that indirect anticoagulants can increase vascular calcifications due to vitamin K inhibi‐ tion‐dependent increase of serum phosphate levels. Another major complication is the war‐ farin‐related nephropathy—unexplained increase in serum creatinine with ≥0.3 mg% after the initiation of warfarin treatment probably due to intraglomerular bleeding and tubular obstruction by erythrocyte casts. This complication is associated with marked increase in

These medications are synthetic anti‐Xa agents (apixaban and rivaroxaban) or anti‐IIa agents (dabigatran and direct thrombin inhibitors). Rivaroxaban and apixaban have approximately 30% renal clearance and their effect in CRF patients is more predictable, whereas dabiga‐ tran has mainly renal clearance (85%) and in CRF patients tends to accumulate, and its effect in this population is unpredictable. Therefore, rivaroxaban and apixaban are approved for CRF patients with CFR<30 ml/min (with dose reduction of approximately 50%, the dose of rivaroxaban in CFR 15–49 ml/min is 15 mg/day, and <15 ml/min is contraindicated; the dose of apixaban in GFR 15–29 ml/min is 2.5 mg twice a day) and dabigatran is not approved

pared to that on UFH.

80 Embolic Diseases - Unusual Therapies and Challenges

GFR <50 ml/min.

mortality in CRF patients.

**4.3. Newer oral anticoagulants**

The LMWHs dose should also be reduced in CRF [3]:

**4.2. Warfarin and indirect anticoagulants**

• In glomerular filtration rate (GFR) >40 ml/min, full dose once daily. • In GFR 30–39 ml/min, 80–90% of the recommended dose once daily. • In GFR <30 ml/min, 60% of the recommended daily dose twice a day. Aspirin, NSAIDs, and clopidogrel should be used with caution in patients with renal dis‐ eases because their anti‐platelet effects are unpredictable in GFR <30 ml/min, because CRF patients have significant platelet function abnormalities and frequently are thrombocytopenic and anemic and because their clearance is significantly altered in severe renal impairment. Moreover, NSAIDs and aspirin tend to cause severe, even life‐threatening gastrointestinal bleeding episodes, especially at the background of uremic gastro‐enteropathy, low platelet count, or corticosteroid treatment.

#### **5. Conclusion**

Patients with renal diseases are prone to both thrombosis and bleeding. The prothrombotic state in chronic nephropathies is associated with [6–8] vascular endothelial damage, changes in certain coagulation and antifibrinolytic factors, decrease in anticoagulation proteins, dyslip‐ idemia, hypoalbuminemia, changes in platelet membranes, hemo‐ and peritoneal dialysis and heparin treatment, increased microRNAs and circulating microparticles, antiphospholipid antibodies, nephrotic syndrome, anemia with high platelet count, and so on. Nevertheless, the same patients have substantially increased risk of bleeding due to platelet dysfunction, and intake of certain medications (antiaggregants, heparin and low‐molecular weight hepa‐ rins, and anemia) [6–8].

In this review, we have presented the main thrombo‐embolic risk factors in a wide variety of patients with renal diseases, including chronic glomerulonephritis (primary and secondary), CKD/CRF, idiopathic retroperitoneal fibrosis, and dialysis treatment. We have presented our data on thrombotic incidents in patients with glomerular and non‐glomerular diseases and the role of certain prothrombotic factors, such as nephrotic syndrome, inborn and acquired coagulation defects (i.e., factor V Leiden, MTHFR gene mutation, 20210 prothrombin gene mutation, and antiphospholipid antibodies), corticosteroid treatment, and so on. Therapeutic and prophylactic anticoagulation in these patients is influenced by many factors, including the underlying renal disease, renal, hepatic, and cardiac function, co‐morbidities and accom‐ panying treatment. Moreover, the doses of anticoagulant/antiaggregant and hemostatic med‐ ications should be considered carefully. The best and the safest anticoagulant medications in patients with chronic renal diseases (including glomerulonephritis, vasculitis, and CKD/CRF) at this point seem to be LMWHs followed by UFH in dose regimens in accordance with renal function because of their favorable safety profile, flexible dosing regimen, self‐administration, short and predictable action, and the possibility to correct the dose according to GFR.

#### **Abbreviations**



#### **Author details**

**Abbreviations**

82 Embolic Diseases - Unusual Therapies and Challenges

ACL Anticardiolipin antibody

ADP Adenosine diphosphate

APL Antiphospholipid antibody

APS Antiphospholipid syndrome

b2GPI Beta‐2‐glycoprotein I antibody

ATP Adenosine triphosphate

CKD Chronic kidney disease

CT Computed tomography

DVT Deep vein thrombosis

ECG Electrocardiography

GIT Gastrointestinal tract

GP Glycoprotein

HBV Hepatitis B virus

HCV Hepatitis C virus

HD Hemodialysis

IL‐6 Interleukin 6

GFR Glomerular filtration rate

EPH Edema‐proteinuria‐hypertension

HIT II Heparin‐induced thrombocytopenia type II

HIV Human immunodeficiency virus

INR International normalized ration

LMWH Low‐molecular weight heparin

CRF Chronic renal failure

CRP C‐reactive protein

ANCA Antineutrophil cytoplasmic antibody

aPTT Activated partial thromboplastin time

CAPD Continuous ambulatory peritoneal dialysis

Milena Nikolova‐Vlahova\*, Marta Petrova Baleva and Petar Krasimirov Nikolov \*Address all correspondence to: milena\_i\_dani@abv.bg Medical University, Sofia, Bulgaria

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