**1.5 Portal vein thrombosis**

PVT refers to a total or partial obstruction of the blood flow in the portal vein due to formation of thrombus or clot [6] that blocks the main portal vein going to the liver. It may result from previous use of an umbilical catheter during the neonatal period, a clotting disorder, or infection or injury. In 50% of cases, it may be idiopathic [7, 8]. It is an important cause of portal hypertension in the pediatric age group with high morbidity rate due to its main complication of upper gastrointestinal bleeding [6].

PVT is a risky disease with potentially fatal complications, mainly post splenectomy, especially if there are delays in diagnosis and treatment. It can be diagnosed early with advanced X-ray imaging [9].

Risk factors of PVT can be systemic or local [10]. Inherited systemic risk factors include:

• factor V Leiden mutation

*Portal Vein Thrombosis in Patients with β-Thalassemia DOI: http://dx.doi.org/10.5772/intechopen.106564*


Acquired systemic risk factors include:


Local risk factors for PVT include: focal inflammatory lesion:


#### **1.6 Clinical presentation of PVT**

PVT leads to portal hypertension and can cause growth of new blood vessels called varices around the blockage. It may connect blood flow from the intestine directly to the general circulation, bypassing the liver [7].

Portal hypertension can produce an enlarged spleen, low platelet count, and gastrointestinal bleeding, and may increase production of ammonia, leading to encephalopathy [7].

#### **1.7 Portal vein thrombosis in thalassemia**

PVT is a rare serious complication post splenectomy, especially for thalassemia. It requires a very high index of suspicion to confirm early diagnosis and administer urgent therapy to prevent fatal complications such as portal vein hypertension in a thalassemia patient or bowel infarction [11].

Studies have shown that red blood cells (RBCs) from β-thalassemia major and β-thalassemia intermedia increase adhesion to endothelial cells (ECs). Also, thalassemia patients have low levels of protein C and S compared with healthy people. Prothrombin fragment 1.2 (F1.2) is a marker of thrombin generation and increases in thalassemia intermedia patients [3].

There is no role for prothrombotic mutations on the increasing incidence of coagulopathy in thalassemia patients. Studies in Lebanon and Italy show that the presence of factor V Leiden, prothrombin, and methylene tetrahydrofolate reductase mutations is not related to the increased risk of thrombosis in thalassemia patients [12].

The presence of hepatic, cardiac, or endocrine dysfunction may contribute to hypercoagulability in thalassemia; when pathologic processes overwhelm the regulatory mechanisms of hemostasis, the result is increasing amount of thrombin formation, which leads to thrombosis [12].

#### **1.8 Incidence**

The incidence of PVT in all thalassemia patients is between 1.7% and 9.2%, which is approximately ten times greater than in the normal population. The incidence is 4.4 times more prevalent in non-transfusion-dependent thalassemia patients (NTDT) than patients with transfusion-dependent thalassemia (TDT). However, PVT can occur in patients with either α- or β-thalassemia diseases [2].

Around 4% of β-thalassemia major patients and 9.6% of thalassemia intermedia patients develop TEE. The same group have shown 6 years later that 1.1% of TM patients in seven Italian centers had thrombosis [3].

PVT incidence in thalassemia is different in many centers. Some centers have reported single case reports, whereas others have reported cases in 3.3–6.6% of patients. Some centers recommend screening those patients referred for blood transfusion due to the risk of thrombosis [12].

Studies in different countries show varying incidence rates, for example, 5.5% in Al Najaf, Iraq [9], 3.12% in Babol, Iran [12], 3.5% in Ahvas, Iran [13], 3.85% in Italy [12], and 8.4% in Greece [13].

Different results could be explained by the different methods and cohorts used in different studies. Some studies included younger patients and used only Doppler ultrasound for diagnosis of PVT, while other studies used more advanced investigations in the detection of PVT, including magnetic resonance imaging (MRI), computed tomography (CT) scan, angiography, and Doppler ultrasound, in addition to using older cohorts [9].

#### **1.9 Pathophysiology**

PVT is the combination of abnormalities in different parts of the hemostatic system [2]. We discuss some of these abnormalities in the paragraphs that follow. **Figure 3** shows the pathophysiology of PVT.

Exposure of the external membrane of abnormal RBCs to phosphatidylserine (PS) results in reduction of normal dissemination of RBC membrane phospholipids. In addition, free iron stimulates lipid oxidation and increases the level of membranebounded hemichromes and immunoglobulin, leading to changes in the structures of spectrin and band 3 protein of RBC membrane. This results in aggregation and adhesion of abnormal RBCs to endothelial cells [2, 3].

In PVT, there is an elevated number of circulating and aggregated platelets, which are found mostly post splenectomy. The lifespan of these platelets is usually short, and they have a good response to many agonists like adenosine diphosphate (ADP), epinephrine, and collagen. PVT patients also have greater levels of plasma betathromboglobulin than the platelets in normal populations [3].

Increased activation of endothelial cells (due to the activation of granulocytes and monocytes) causes endothelial injury and excess level of endothelial adhesion. This leads to thromboembolic events [5].

Low nitric oxide (NO) (due to hemolysis secondary to reduced arginine level) results in pulmonary vasoconstriction and subsequently leads to chronic pulmonary thromboembolism [2].

*Portal Vein Thrombosis in Patients with β-Thalassemia DOI: http://dx.doi.org/10.5772/intechopen.106564*

**Figure 3.**

*Factors contributing to a hypercoagulable state and subsequent thrombotic events in thalassemia.*

Thrombocytosis and nucleated RBCs (NRBCs) can occur post splenectomy, especially when the platelet count is more than 600,000/mm3 and the NRBC count is greater than 300/mm3 [2].

In PVT, iron overload organ failure may develop, such as cardiac siderosis, which is complicated by cardiac arrhythmia and cardiomyopathy [2].

Deficiencies of proteins C and S and elevated anti-phospholipid antibodies (i.e., lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein) are seen in thrombophilia [2].

Excess RBCs with negatively charged phospholipids in combination with increased cohesiveness and aggregation of RBC results in thrombus formation [2].

Prothrombin mutation is also seen in PVT [2].

#### **1.10 Presentation**

PVT presents clinically as acute or chronic. The acute form usually appears within 60 days from hospital investigation and assessment. It may present initially as upper

gastrointestinal bleeding or bowel ischemia, which is suggested by an increase of bleeding, abdominal pain, abdominal distention, vomiting, and melena [10].

Initially, PVT may be asymptomatic, but symptoms gradually increase as thrombosis progresses. The easiest way to differentiate it is by using imaging study like Doppler ultrasound (to look for the presence or the absence in significant portal collateral) or by using CT of abdomen, angiograph, MRI technique [9].

#### **1.11 Acute portal vein thrombosis**

Acute PVT is associated with immediate thrombus formation, leading to partial or total obstruction of the portal vein. The cute form may present with an increase in body temperature, abdomen pain and distention, diarrhea, vomiting, rectal bleeding, and anorexia [9, 10].

#### **1.12 Physical examination**

Upon physical examination, the abdomen may be distended, guarding against internal abdominal inflammation, intestinal infarction, and perforation [9, 10].

Splenomegaly is present in 37% of patients. Sepsis may be associated with perforation, which can lead to peritonitis, shock, and even death. Ascites are rare but may develop if there is collateral circulation (mild ascites occur because of congestion of the intestinal venous without liver cirrhosis).

#### **1.13 Chronic portal vein thrombosis**

Chronic PVT is usually nearly asymptomatic except if it causes development of varices and ascites. Typically, those patients with advanced thrombosis do not remember a previous event or disease [9, 10]. Chronic PVT usually presents in the first and second decades of life as left upper abdominal pain (due to splenomegaly or splenic infraction) and recurrent gastrointestinal bleeding (in 20–40% of cases), which usually occurs in association with liver congestion or swell.

#### **1.14 Physical examination**

Splenomegaly is present in 10% of patients, but most cases present with multiple other signs. Ascites develop in 20% of cases and encephalopathy is unusual and transient. Cholangitis, obstructive jaundice, and sometimes gallstones or extra hepatic biliary obstruction occurs in 80% of cases. In addition, hypersplenism complicated by pancytopenia is common in chronic PVT.

### **2. Diagnosis of PVT**

#### **2.1 Laboratory tests**

The liver function test is usually normal unless it is associated with cirrhosis or extrahepatic portal vein obstruction [9].

Level of prothrombin and other factors may be low (PT is prolonged), and D-dimer and alkaline phosphatase are usually high [9].

Total serum protein is usually low, especially if albumin is decreased with prolonged PVT [9].

Liver biopsy shows atrophy and regenerative nodular hyperplasia, which is due to apoptosis and compensatory arterial vasodilation in the chronic form of PVT [14].

#### **2.2 Other lab tests**

There is derangement of proteins in the hemostatic systems of β-thalassemia patients, including increased aggregation of platelets and coagulation factors (von Willebrand factor and factor VIII) as well as low levels of proteins C and anti-thrombin [9].

Annual monitoring of thrombin-generation markers by thrombin and antithrombin factor and D-dimer tests is recommended post-splenectomy thalassemia patients [9].

## **2.3 Ultrasound**

Ultrasound displays hypo echoic, hyper echoic, or isochoric within the portal vein causing obstruction either completely or partially. It is the most cost-effective imaging modality, but its specificity and sensitivity vary (80–100%) depending on the patient and the experience of the administering radiologist. Its accuracy ranges from 88 to 98% [9].

Contrast-enhanced ultrasound is superior to ultrasound in detecting the patency of the portal vein [9, 15] and it is more reliable in patients with very low portal vein velocity [9].

Endoscopic ultrasound has specificity of 93% and sensitivity of 81% and is capable of diagnosing small and non-occluded thrombi. It is also more efficient than ultrasound or CT in detecting portal invasion by tumors [9, 10].

#### **2.4 Computed tomography and magnetic resonance imaging**

CT and MRI are more accurate for the detection of thrombus extension with presence or absence of collaterally vessels (that bypass the obstruction) especially after splenectomy. PVT appears as isodense to adjacent soft tissue [9]. Following administration of intravenous (IV) iodinated contrast, PVT shows a bland thrombus, which is seen as a low-density, non-enhancing defect within the portal vein. MRI is better than Doppler ultrasound in diagnosing a partial thrombosis and obstruction of the main portal venous trunk. In addition, it detects more sufficient portosplenic collaterals and portal vessels [9, 10]. However, currently used therapeutic methods have an essential in prolong life expectancy of thalassemia patients [9].

#### **2.5 Treatments**

The main goal of management is the same in both acute and chronic PVT. Treatment depends on causal factors and is used to prevent expansion of the thrombus and achieve portal vein patency. However, in chronic thrombosis, the treatment of complications associated with portal hypertension must be considered [10].

Recently, anticoagulant therapy has become the preferred treatment to obtain portal vein recanalization or patency. Other modalities of treatment should be used if there is partial or absent PVT resolution [10].

Before administering anticoagulant treatment, conditions such as new or old thrombosis and presence of thrombophilic condition or hepatic disease must be considered [10, 16].

RBC transfusion is indicated for management of β-thalassemia patients, especially NTDT patients (who are at risk of thromboembolism or have thromboembolic events because of transfusion native patients who are more risky to develop this complication [2]. Hemoglobin should be maintained at a level greater than 9 g/dL. The aim is to correct hypercoagulopathy and protect against thrombosis [3].
