Principal Developer: P. Wells
Secondary Developers: G. Turpie, C. Demers, V. Oliva

Background and Rationale

The purpose of thrombolytic therapy in VTE is to restore vessel patency more rapidly and completely than the resolution that occurs with natural fibrinolysis.

In the case of pulmonary embolism (PE) rapid fibrinolysis should result in increased cardiac output, in improved oxygenation, and decreased pulmonary hypertension.

In the case of deep venous thrombosis (DVT) the aim is to restore venous anatomy as closely as possible to the pre-thrombosis state with a view to minimizing the post phlebitic syndrome.

Systemic fibrinolytic activity and clinical bleeding can occur to varying degrees with all preparations. The available drugs in Canada are Streptokinase (SK), Tissue Plasminogen Activator (rt-PA) and Urokinase (UK).

Indications

Deep Venous Thrombosis (DVT).

The long-term benefits of thrombolytic therapy for DVT are unclear. Numerous studies have confirmed a rapid resolution of thrombus and, in some cases, restoration of venous valve function. These changes are presumed to result in a lower incidence of the post phlebitic syndrome although this has never been adequately demonstrated in a well-designed clinical trial. Notwithstanding the limited data the preference is to use thrombolytic treatment for patients where post phlebitic signs and symptoms tend to be severe or incapacitating. On this basis thrombolytic agents tend to be given to young patients with extensive proximal thrombosis, especially ilio-femoral thrombosis and axillary vein thrombosis. These subjects should not have contraindications to thrombolytic therapy (see below)

Pulmonary Embolism. (PE)

In the case p of PE the majority of patients will do well on heparin therapy alone. Patients who may be considered for thrombolytic therapy are those with massive embolism, those who are haemodynamically unstable, and those who are having problems with maintaining adequate oxygenation. In other words patients who could be considered potential candidates for surgical embolectomy.

The objective benefits of thrombolytic therapy versus heparin alone, for PE, include a rapid improvement in angiographic appearances at 24 hours, and a decrease in pulmonary vascular pressure. Long term benefits include a small improvement in lung volume and gas diffusion capacity. Since the prognosis of PE with heparin alone is generally favorable no studies, to date, have demonstrated a decreased mortality with thrombolytic agents relative to therapy with heparin alone. For this reason, as in the case of DVT, thrombolytic therapy tends to be reserved for the more severe cases of PE and in subjects without major contraindications to thrombolysis.

Contra-indications

Absolute

suspected aortic dissection
acute pericarditis
active bleeding any site

Relative

previous CNS hemorrhage, neoplasm or vascular lesion.
hepatic dysfunction
diabetic proliferative retinopathy
bleeding diathesis
pregnancy
endocarditis
recent GI or GU bleeding
stroke within last 6 months
severe hypertension (SBP > 200 mmHg, DBP > 120 mmHg)
head injury within last month
major surgery, organ biopsy, trauma, prolonged CPR or puncture of a non-compressible vessel     within last 2-4 weeks.

Dose Regimens and Monitoring

Given below are commonly recommended dose regimens. Alternate regimens are also available.

Venous Thrombosis

1. Intrathrombus (generally preferred where feasible) UK 4000 U/min until flow is achieved; then 2000 U/min for 1 hour; then 1000 U/min until patency achieved, usually 12-18 hours.
   
   Or intrathrombus SK 5000-10,000 U/hr until patency achieved. In general clots that are susceptible to lysis will improve for up to 18 hours and thrombolytic treatment beyond this is not recommended.
   
2. Intravenous UK bolus of 4400 U/kg over 10 minutes followed by a continuous infusion of 4400 U/kg/hr or SK bolus of 250,000 units over 30 minutes and then continuous infusion of 100,000 units per hour for 24-72 hours. Fibrinolytic status should be demonstrable at 4-6 hours. rt-PA has been demonstrated to have efficacy but is currently not approved for this indication in Canada.
   
   Upon cessation of thrombolytic therapy heparin treatment should be instigated followed by a minimum of three months oral anticoagulation.

Venous or Dialysis Catheter Occlusion

SK 10,000 or UK 5000 units in 1-2 ml volume into each port of the catheter. Leave for 60-120 min. Aspirate the contents of the catheter to remove drug and determine patency. Flush and heparinize the catheter.

Pulmonary Embolism

Urokinase or Streptokinase intravenously using the same dosage regimen as in DVT (see Method 2 above)

Alternatively, give rt-PA by intravenous infusion at a dose of 50mg per hour for two hours.

All of the thrombolytic agents should be followed by unfractionated heparin to maintain a therapeutic APTT or low molecular weight heparin. Heparin therapy should be followed by a minimum of three months oral anticoagulation.

Monitoring

In the past it has been recommended to perform a thrombin time or APTT, or fibrinogen level to check that a thrombolytic state has been achieved. This probably related to theoretical concerns about natural streptokinase antibodies and the tradition of close laboratory monitoring when using heparin. The value of monitoring during acute lysis has never been shown to be of benefit. With the increase in local intrathrombus or intarvenous bolus therapy as opposed to prolonged intravenous infusion the theoretical case for monitoring is even weaker. On this basis no monitoring of coagulation parameters during the acute lysis phase of the treatment is required.

Management of Bleeding Complications

Bleeding often occurs at venous access sites especially around in situ catheters used to perform pulmonary angiography. Bleeding can be minimized by using non-invasive diagnostic methods, such as lung scans. If bleeding occurs the following procedures are recommended:-

1. Apply manual pressure, discontinue infusions of heparin or thrombolytic agent. Obtain PT/INR, PTT, thrombin time, fibrinogen level, group and screen. Replace volume as necessary.
2. If applicable, reverse effects of heparin with protamine.
3. If life-threatening or if fibrinogen < 1 g/L, give cryoprecipitate 10 units IV to replace fibrinogen. Maintain fibrinogen > 1g/L.
4. If life-threatening or ongoing bleeding, consider an antifibrinolytic agent.

References:

1. Mewissen MW et al. Radiology 1999;211:39-49. This article summarizes an extensive multi-center experience of catheter directed venous thrombolysis cases
2. Kakkar VV and Lawrence D. Am J Surg 1985:150:54-63. This article addresses post phlebitic complications and questions the benefit of thrombolysis
3. .Stein PD, Hull RD, Raskod G. Ann Int Med 1994;121:313-317
4. Goldhaber SZ et al. J Am Coll Cardiol 1992;20:24-30. This article compares a rapid rt-PA infusion protocol with the traditonal urokinase approach.