**1.5.2 Thrombolysis**

Based on this complex classification a planned approach is essential. The aim of the management of acute severe PE is the resolution of the pulmonary artery obstruction. The most common procedure is TL, but invasive radiology procedures (clot fragmentation and vacuum evacuation, or selective TL through catheter arteriography, Class IIb C) or acute surgical embolectomy (Class I C) can also remove PE.

In critical patients with severe shock and confirmed PE the indication of urgent systemic TL is absolute (Class I A). The recommended medications and appropriate dosage is available in the current PE guideline (Table 3). The authors support the accelerated TL (rt-PA or SK) protocol in haemodynamically instable patients. According to our experience the ultra-high dose streptokinase is an economically reasonable and effective alternative to rt-PA (Sárosi et al., 1997; Sárosi et al., 1995).


Table 3. Recommended thrombolytic regimens (Torbicki et al., 2008)

In the intermediate-risk group, with main arterial embolism and increased RV load, positive D-sign, elevated troponin and BNP levels but without haemodynamical impairment, TL is recommended only after considering relative contraindications and acquisition of written informed consent (Class IIb B).

Certain patient history *absolutely contraindicates TL*: haemorrhagic stroke, or stroke of unconfirmed origin, ischemic stroke in the last 6 months, central nervous system tumour, neuro, trauma, or general surgery intervention in the last 3 weeks, gastrointestinal bleeding in the last 30 days, known bleeding, or bleeding disorder.

The *relative contraindications* are: transient ischemic attack in the last 6 months, oral anticoagulation (vitamin K antagonists), pregnancy and the 1st week following labour, organ biopsy and non-compressible puncture, traumatic resuscitation, critical hypertension (RRs > 180 mmHg), advanced liver disease, infective endocarditis, active peptic ulcer (Torbicki et al., 2008). In life-threatening situations, every contraindication can be considered to be relative.

The effectiveness of TL should be controlled between 12 and 24 hours by a second look MDCT or other available diagnostic procedure (perfusion lung scan or echocardiography). If the decrease of unperfused area does not improve by 30% following the first treatment cycle, TL should be repeated after 24 hours.

During *resuscitation*, chest compressions assist the mechanical fragmentation of clot and improve the infiltration of drugs into the clot. Urokinase 2-3 MIU, rt-PA 2 × 50 mg or streptokinase 1.5 MIU (may repeat once after 15 minutes) can be used for TL. Compressions should continue for at least 90 minutes during TL. As TL is beneficial in PE and also in acute myocardial infarction, no firm diagnostic evidence is needed for the treatment (Böttiger & Spöhr, 2003). One main advantage of TL is the possibility of prompt use and that it may improve overall microcirculation (Böttiger & Martin, 2001).

Based on this complex classification a planned approach is essential. The aim of the management of acute severe PE is the resolution of the pulmonary artery obstruction. The most common procedure is TL, but invasive radiology procedures (clot fragmentation and vacuum evacuation, or selective TL through catheter arteriography, Class IIb C) or acute

In critical patients with severe shock and confirmed PE the indication of urgent systemic TL is absolute (Class I A). The recommended medications and appropriate dosage is available in the current PE guideline (Table 3). The authors support the accelerated TL (rt-PA or SK) protocol in haemodynamically instable patients. According to our experience the ultra-high dose streptokinase is an economically reasonable and effective alternative to rt-PA (Sárosi et

**Medication Continuous TL Accelerated TL** 

rt-PA 100 mg/2 hours 0.6 mg/kg/15 min

In the intermediate-risk group, with main arterial embolism and increased RV load, positive D-sign, elevated troponin and BNP levels but without haemodynamical impairment, TL is recommended only after considering relative contraindications and acquisition of written

Certain patient history *absolutely contraindicates TL*: haemorrhagic stroke, or stroke of unconfirmed origin, ischemic stroke in the last 6 months, central nervous system tumour, neuro, trauma, or general surgery intervention in the last 3 weeks, gastrointestinal bleeding

The *relative contraindications* are: transient ischemic attack in the last 6 months, oral anticoagulation (vitamin K antagonists), pregnancy and the 1st week following labour, organ biopsy and non-compressible puncture, traumatic resuscitation, critical hypertension (RRs > 180 mmHg), advanced liver disease, infective endocarditis, active peptic ulcer (Torbicki et al., 2008). In life-threatening situations, every contraindication

The effectiveness of TL should be controlled between 12 and 24 hours by a second look MDCT or other available diagnostic procedure (perfusion lung scan or echocardiography). If the decrease of unperfused area does not improve by 30% following the first treatment

During *resuscitation*, chest compressions assist the mechanical fragmentation of clot and improve the infiltration of drugs into the clot. Urokinase 2-3 MIU, rt-PA 2 × 50 mg or streptokinase 1.5 MIU (may repeat once after 15 minutes) can be used for TL. Compressions should continue for at least 90 minutes during TL. As TL is beneficial in PE and also in acute myocardial infarction, no firm diagnostic evidence is needed for the treatment (Böttiger & Spöhr, 2003). One main advantage of TL is the possibility of prompt use and that it may

100,000 IU/h for 12-24 hours 1.5 IU/2 hours

4,400 IU/kg/h for 12-24 hours 3 IU/2 hours

(max: 50 mg)

**1.5.2 Thrombolysis** 

al., 1997; Sárosi et al., 1995).

informed consent (Class IIb B).

can be considered to be relative.

cycle, TL should be repeated after 24 hours.

surgical embolectomy (Class I C) can also remove PE.

streptokinase (SK) 250,000 IU/30 min, following

urokinase (UK) 4,400 IU/kg/10 min, following

in the last 30 days, known bleeding, or bleeding disorder.

improve overall microcirculation (Böttiger & Martin, 2001).

Table 3. Recommended thrombolytic regimens (Torbicki et al., 2008)

Based on our previous clinical investigations, in case of bleeding complications the repetitive measurement of clot formation factors (namely fibrinogen and plasminogen) may indicate the need of specific factor replacement or fresh frozen plasma infusion during or following TL. Major bleeding complications can be reduced below 5%, if factor replacement takes place in patients with fibrinogen levels below 1.5 g/l accompanied by minor bleeding disorder or fibrinogen levels < 0.6 g/l (Mühl et al., 2007).

Patients may not benefit from the TL of a more than 5-7 days old clot. Also, a second unsuccessful TL may indicate the presence of an older, connective tissue rich clot. Invasive radiology clot fragmentation and removal with or without selective TL should be used in these scenarios.

*Anticoagulation therapy during TL:* In the rt-PA group unfractionated heparin is recommended during TL (500-1000 IU/h, based on actual partial thromboplastin time (aPTT) levels on admission) (Segal, Streiff, et al., 2007).

*Anticoagulation therapy after TL:* Anticoagulant therapy starts after strepto- or urokinase TL with intravenous unfractionated heparin to maintain aPTT (check every 4 hours!) between 50-70 seconds for the first 48 hours and continues with a therapeutic dose of LMWH, if no further TL cycle is necessary. Using the "Heparin adjustment nomogram", the dose of Naheparin is adjusted to reach a target aPTT (Torbicki et al., 2008).

Anticoagulant therapy should be provided with intravenous unfractionated heparin to maintain the aPTT between 60-70 seconds for 48 hours. If TL was effective it should be continued with a therapeutic dose of LMWH. Following TL, long term anticoagulation (acenocoumarol or warfarin) can start on day 3 or 4 (Torbicki et al., 2008; Kearon et al., 2008).

In case of unfractioned heparin use, the incidence of HIT is 1-3% (about 1% with LMWH), therefore regular platelet count check is recommended (Greinacher, 2009; Morris et al., 2007). In case of confirmed HIT, one should switch from heparin/LMWH therapy to: hirudin, lepirudin, danaparoid or fondaparinux.

One of the most common complication of TL is minor bleeding (arterial/venous port bleeding, haematuria, suffusions, e.t.c.), major bleeding occurs in 13% of cases. The incidence of intracranial haemorrhage is 1.8% (Spöhr et al., 2005), (Konstantinides et al., 2002; Goldhaber et al., 1993).

#### **1.5.3 Catheter extraction and surgical embolectomy**

Indications of percutaneous catheter embolectomy and fragmentation are unsuccessful systemic TL, contraindicatons of systemic lysis, PE with haemodynamic shock (resuscitation, mechanical ventilation), clot in the right heart, and also an alternative for the surgical embolectomy if no experienced team is available (Kucher et al., 2005; Uflacker, 2001).

Surgical embolectomy has a high mortality rate in the high-risk PE group. Indications are narrow, only patients with absolute systemic TL contraindications and in the absence of consent for TL may benefit from surgical intervention (Meneveau et al., 2006). Previous unsuccessful TL is not a contraindication for surgical embolectomy (Aklog et al., 2002).

### **1.5.4 Intravenous (caval) filter**

Statistically there is no firm evidence of improved 12 days mortality of the caval filter use. Transient caval filters may be used up to 14 days. Late complications include migration and device thrombosis. Indications are not general; the main indication is suspected

Pathophysiology, Diagnosis and Treatment of Pulmonary

factor supplement can reduce bleeding complications.

(April 2007), pp. 651-8, ISSN 0094-6176

pp. 1416-9, ISSN 1524-4539

1695-707, ISSN 0012-3692

streptokinase induces the release of MMP-9.

stroke.

Palei et al., 2005).

**3. Summary** 

**4. References** 

Embolism Focusing on Thrombolysis - New approaches 131

Although there is a lack of firm evidence, the possible explanation for increased MMP-9 levels during treatment with alteplase is the promotion of MMP-9 release by neutrophils (Cuadrado et al., 2008). According to our knowledge, no previous study has reported that

A slower increase of pro-MMP-9 was found in alteplase treated patients, but the precise explanation for this difference between fibrinolytic agents is not yet elucidated. There is significant interindividual variability in neutrophil degranulation (Cuadrado et al., 2008),

No definitive conclusion can be drawn yet, but it is widely acknowledged that intracerebral hemorrhage is the most feared bleeding complication of TL (Arcasoy & Kreit, 1999). The use of alteplase enhanced MMP-9 levels, which has already been widely associated with hemorrhagic transformation after cardioembolic stroke (Rosell et al., 2008; Montaner et al., 2001). This observation offers an explanation for the hemorrhagic transformation during

It is possible that the MMP inhibitors may decrease the risk of intracerebral hemorrhage or other bleeding complication of TL for acute PE (Murata et al., 2008; Sumii & Lo, 2002; Machado et al., 2009) and may have beneficial hemodynamic effects (Fortuna et al., 2007;

Following risk stratification, prompt and specific diagnostics are life-saving in acute PE. Recommended diagnostic tools are biomarkers, MDCT and electrocardiography. Systemic TL is the first choice for high-risk PE patients, in case of contraindications surgical embolectomy or catheter clot fragmentation/removal should be considered. The fast resolution of haemodynamic shock indicates accelerated protocol systemic TL (rt-PA, SK or UK), as continuous TL dissolve clot slower and have a higher risk of bleeding disorder. The regular control of fibrinogen and plasminogen during and after TL, and clot formation

There is emerging evidence of the hypothesized role of the TIMP/MMP system in the development of bleeding complication. In future, pharmacological approach to MMP inhibition in human medicine may decrease the incidence of bleeding complications of TL.

Ageno, W., Squizzato, A., Garcia, D. & Imberti, D. (2006). Epidemiology and risk factors of

Agnelli, G., Becattini, C. & Kirschstein, T. (2002). Thrombolysis vs heparin in the treatment

Arcasoy, S.M. & Kreit, J.W. (1999). Thrombolytic therapy of pulmonary embolism: a

*medicine*, Vol.162, No.22, (December 2002), pp. 2537-41, ISSN 0003-9926 Aklog, L., Williams, C.S., Byrne, J.G. & Goldhaber, S.Z. (2002). Acute pulmonary

venous thromboembolism. *Seminars in thrombosis and hemostasis*, Vol.32, No.7,

of pulmonary embolism: a clinical outcome-based meta-analysis. *Archives of internal* 

embolectomy: a contemporary approach. *Circulation*, Vol.105, No.12, (March 2002),

comprehensive review of current evidence. *Chest*, Vol.115, No.6, (June 1999), pp.

therefore a multi-central study may draw firm evidence on this question.

reoccurrence of PE and contraindication of long-term anticoagulation (Hann & Streiff, 2005). Also, venous filters for PE prophylaxis may be beneficial in trauma patients, but further studies are required to draw firm clinical evidence (Rajasekhar et al., 2011).

#### **1.5.5 Follow-up after PE therapy**

Following PE therapy, a switch from heparin/LMWH to oral anticoagulation is recommended. Oral anticoagulation should be continued for 6 months. Following, an extended diagnostic procedure should take place to elucidate possible genetic factors or acquired thrombophylia behind the development of PE. In case of irreversible complications or positive thrombotic predisposition, continuous oral anticoagulation is needed (Kearon et al., 2008).
