Thrombosis and Clotting Cascade Overview

Thrombosis

• Thrombosis is the process of fibrin blood clot formation.
• An embolus is a small clot fragment that dislodges and travels within the vascular system.
• Abnormal thrombotic events can include venous thromboembolism (VTE), deep venous thrombosis (DVT), pulmonary embolism (PE), stroke, and others.
• Platelet activation, impaired protein C activation, and thrombin generation are factors in thrombosis.

Clotting Cascade

• Endothelial damage initiates the clotting cascade.
• The cascade involves a complex series of interactions among clotting factors.
• The intrinsic, extrinsic, and common pathways are part of the cascade.
• The cascade culminates in the formation of a stable fibrin clot.

Fibrin Blood Clot Formation

• Activated platelets form a sticky plug at the site of a damaged blood vessel.
• Clotting factors interact to convert fibrinogen into fibrin, forming an insoluble clot.
• Fibrin strands adhere to the platelet plug, creating a stable clot.

Anticotting Drugs

• Anticoagulants prevent the formation of clots.
• Thrombolytics dissolve existing clots.
• Antiplatelets inhibit platelet activation.
• Heparins, direct thrombin inhibitors, direct factor Xa inhibitors, Warfarin, t-PA derivatives, Streptokinase, Aspirin, Glycoprotein IIb/IIIa inhibitors, ADP inhibitors (clopidogrel), and PDE/adenosine uptake inhibitors are examples of anti-clotting medications.

Characterization of Thrombi

• Thrombi are classified by location and composition.
• Arterial thrombi form in areas of rapid blood flow, often due to atherosclerotic plaque rupture.
• Venous thrombi are primarily composed of fibrin and erythrocytes, found in slower-flowing venous circulation.

Risk Factors for Thromboembolism

• Blood flow abnormalities (e.g., atrial fibrillation, immobilization) can increase risk.
• Clotting component abnormalities (e.g., antiphospholipid antibodies, factor V Leiden) increase risk.
• Blood vessel abnormalities (e.g., atherosclerosis, chemical irritation, heart valve disease) increase risk.

Patient Assessment

• DVT typically presents with unilateral leg swelling, warmth, and tenderness.
• Many DVT cases are asymptomatic.
• PE often involves nonspecific symptoms like dyspnea, pleuritic chest pain, and apprehension.
• DVT frequently precedes PE.

Patient Assessment - Prevention

• Pregnant patients should receive unfractionated heparin or low molecular weight heparin (LMWH).
• Warfarin should not be used during pregnancy.
• Preventing thromboembolism is crucial in patients with atrial fibrillation, after cardioversion, or cardiac valve replacement, and in patients undergoing surgery.

Drug Therapy

• UFH, LMWH, factor Xa inhibitors, direct thrombin inhibitors, and warfarin are used to treat or prevent arterial and venous thrombi.
• Drugs altering platelet function (e.g., aspirin, clopidogrel) prevent arterial clots.
• Fibrinolytic agents dissolve thromboemboli.
• Bridge therapy is often needed to reverse the effects of warfarin before invasive procedures.
• The list of specific drugs used to treat thromboembolism includes; UFH, LMWH, Fondaparinux, Direct Thrombin Inhibitors, and Oral Factor Xa Inhibitors.

UFH

• UFH is a rapid-acting anticoagulant targeting factor IIa (thrombin) and factor Xa.
• UFH can be administered intravenously or subcutaneously.
• Intramuscular administration is not recommended to prevent hematoma formation.
• It possesses anticoagulant properties, impacting platelet function and vascular permeability.
• Weight-based dosing is used for IV administration.
• aPTT monitoring is used to adjust UFH doses.

LMWH

• LMWHs (e.g., dalteparin, enoxaparin, tinzaparin) are anti-Xa agents.
• LMWH has longer half-lives and more predictable responses than UFH, facilitating home treatment.
• aPTT monitoring is not typically required for LMWH.

Fondaparinux

• Fondaparinux is a selective factor Xa inhibitor administered subcutaneously once daily.
• Fondaparinux has a prolonged elimination half-life.
• Routine monitoring is not required with Fondaparinux.

UFH, LMWH, and Fondaparinux comparison

• UFH, LMWH, and Fondaparinux differ in molecular weight, anti-Xa/IIa activity, platelet factor 4 inactivation capabilities, and primary elimination route.

Direct Thrombin Inhibitors

• Direct thrombin inhibitors (e.g., lepirudin, bivalirudin, argatroban) directly target thrombin.
• They are used in patients with heparin-induced thrombocytopenia (HIT).

Direct Oral Factor Xa Inhibitors

• Direct oral factor Xa inhibitors (e.g., rivaroxaban, apixaban) directly bind and inhibit factor Xa.
• They require no routine monitoring of therapy.

Warfarin

• Warfarin inhibits vitamin K-dependent clotting factors (II, VII, IX, X).

• Warfarin's effects are delayed, taking 5-7 days to reach steady-state anticoagulation.

• Heparin therapy may be continued to provide immediate effect.

• Monitoring warfarin efficacy using the INR (international normalized ratio) is critical.

• Side effects (bleeding, skin necrosis, purple toe syndrome) and drug interactions (with vitamin K, other medications, and disease states) are important considerations in warfarin therapy.