Thrombophilia

Overview & Normal Haemostasis

Haemostasis is the process of stopping blood loss through three integrated mechanisms: primary haemostasis (platelet adhesion and aggregation), secondary haemostasis (coagulation cascade and thrombin generation), and fibrinolysis (controlled clot removal).

Primary Haemostasis: Platelet Plug Formation

When a blood vessel is damaged, von Willebrand factor (vWF) is released from endothelial Weibel-Palade bodies and exposed collagen from the vessel wall. Platelets adhere to vWF via their GPIb receptor. This triggers platelet activation: shape change (spherical to dendritic), granule secretion (ADP from dense granules, thrombospondin and fibrinogen from alpha granules), and upregulation of GPIIb/IIIa receptors. Fibrinogen bridges adjacent platelets through their GPIIb/IIIa receptors, causing platelet aggregation and formation of a mechanical plug. This primary haemostatic plug forms within seconds and provides temporary sealing of the defect.

Secondary Haemostasis: The Coagulation Cascade

The coagulation cascade is a series of proteolytic reactions that amplify thrombin generation, the enzyme that converts fibrinogen to fibrin clot.

Extrinsic Pathway (Tissue Factor Pathway)

Tissue factor (TF) is a membrane-bound cofactor present on damaged endothelial cells and activated monocytes. When exposed by vessel injury, TF binds Factor VII (a serine protease zymogen). The TF-Factor VIIa complex (in the presence of calcium ions and phospholipid) activates Factor X to Factor Xa. The extrinsic pathway is the initial trigger of coagulation, providing rapid but weak activation.

Intrinsic Pathway (Contact Activation)

Contact of blood with negatively charged surfaces (exposed collagen, phosphatidylserine from activated platelets) triggers Factor XII (Hageman factor) autoactivation to Factor XIIa. Factor XIIa activates Factor XI to Factor XIa. Factor XIa then activates Factor IX to Factor IXa. Factor IXa complexes with its cofactor Factor VIIIa on the phospholipid surface (along with calcium ions) to form the “tenase complex.” This tenase complex is highly efficient at activating Factor X to Factor Xa, amplifying the coagulation response.

Common Pathway (Amplification)

Both the extrinsic and intrinsic pathways converge at Factor X activation. Factor Xa complexes with its cofactor Factor Va on the phospholipid surface to form the “prothrombinase complex.” This complex converts Factor II (prothrombin) to Factor IIa (thrombin), the most important enzyme in coagulation. Thrombin then performs three critical functions: (1) Converts fibrinogen to fibrin monomers. (2) Activates Factor XIII (fibrin-stabilising factor) to Factor XIIa, which cross-links fibrin polymers into a mechanically strong, stable clot. (3) Provides powerful positive feedback by activating Factors V, VIII, XI, and platelets, amplifying thrombin generation further.

Natural Anticoagulants: Physiological Brakes

Fibrinolysis: Controlled Clot Removal

Tissue plasminogen activator (tPA) is released by damaged endothelium and binds to fibrin within the developing clot. Fibrin binding greatly increases tPA’s catalytic efficiency. tPA converts plasminogen (also incorporated into the clot) into plasmin, the fibrin-degrading protease. Plasmin cleaves cross-linked fibrin into fibrin degradation products (FDPs) and D-dimers, which are cleared by the liver. Plasminogen activator inhibitor-1 (PAI-1) is the primary regulator of fibrinolysis — elevated PAI-1 (seen with inflammation, smoking, or metabolic syndrome) impairs fibrinolysis and may contribute to thrombosis.

Thrombophilia: Definition and Significance

Thrombophilia is an inherited or acquired disorder that predisposes to thrombosis — the formation of blood clots at the wrong place and wrong time. Inherited thrombophilias result from gene mutations affecting coagulation factors or natural anticoagulants. Acquired thrombophilias arise from secondary causes (autoimmune, malignancy, etc.). Most thrombophilias are silent; only a minority of carriers develop clinical thrombosis. Typically, a second trigger (surgery, immobility, malignancy, infection, oral contraceptives, pregnancy) is needed to precipitate a thrombotic event.

Venous vs. Arterial Thrombosis Patterns

Venous thrombosis: Associated with stasis and hypercoagulability. Most inherited thrombophilias significantly increase venous thromboembolism (VTE) risk. DVT and PE are classic presentations. Formed primarily from fibrin and platelets (“white clot”). Risk escalates with thrombophilia severity and additional risk factors.

Arterial thrombosis: Usually results from atherosclerotic plaque rupture or high-velocity flow turbulence. Most inherited thrombophilias do NOT significantly increase arterial event risk. Exceptions: ATIII deficiency, homozygous Protein C/S deficiency, and antiphospholipid syndrome increase both venous and arterial events. Arterial thrombosis in young patients without atherosclerosis warrants investigation for APS, hyperhomocysteinaemia, and thrombophilia.

Virchow’s Triad

The classic framework for understanding thrombotic risk: (1) Stasis or abnormal blood flow (immobility, atrial fibrillation, dilated cardiomyopathy). (2) Endothelial injury (trauma, atherosclerosis, surgery). (3) Hypercoagulability (thrombophilia, malignancy, pregnancy, inflammation). Most thrombotic events involve at least two of these components.

Summary Table: Main Inherited Thrombophilias