L11: Haemostasis 6 – Thrombosis 2

Building on the mechanisms of thrombosis, this lecture examines specific clinical scenarios, anticoagulant therapies, and the paradox of heparin-induced thrombocytopenia.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and a major cause of cardioembolic stroke. Disorganised atrial electrical activity abolishes coordinated mechanical contraction; blood pools in the left atrial appendage, a trabeculated cul-de-sac poorly cleared by forward flow. Stasis promotes thrombus formation, and when thrombus fragments embolise to the cerebral circulation, ischaemic stroke results. AF accounts for approximately 20–25% of all ischaemic strokes. Anticoagulation with warfarin or direct oral anticoagulants (DOACs: apixaban, rivaroxaban, dabigatran) reduces stroke risk by approximately two-thirds.

Arterial thrombosis from plaque rupture causes myocardial infarction and stroke. After MI, mural thrombus may form on the akinetic endocardium overlying infarcted myocardium; embolisation can cause systemic thromboembolism.

Anticoagulant drugs. Unfractionated heparin (UFH) binds antithrombin and dramatically increases its inhibition of thrombin and FXa. UFH has a short half-life (50–60 minutes) and is monitored by APTT (target approximately 2–2.5× upper limit of normal). Low molecular weight heparins (LMWH; e.g., enoxaparin) are derived from UFH by depolymerisation. They preferentially inhibit FXa over thrombin (because anti-Xa activity requires only the pentasaccharide sequence, whereas anti-IIa requires a longer chain). LMWHs have more predictable pharmacokinetics, a longer half-life (~4 hours), and do not routinely require APTT monitoring. They carry a lower risk of heparin-induced thrombocytopenia (HIT). Fondaparinux is a synthetic pentasaccharide that selectively inhibits FXa via antithrombin.

Thrombolysis (fibrinolysis therapy) uses plasminogen activators to dissolve established thrombi. Alteplase (recombinant tPA) converts plasminogen to plasmin, which degrades fibrin. It is indicated for STEMI within 12 hours when primary percutaneous coronary intervention (PPCI) is unavailable, and for acute ischaemic stroke within 4.5 hours of symptom onset (provided haemorrhagic stroke is excluded). Major risk is haemorrhage, including intracranial haemorrhage.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated complication of heparin therapy. Heparin binds platelet factor 4 (PF4), a positively charged protein released from platelet alpha granules, forming a heparin-PF4 complex. In some patients, IgG antibodies form against this complex. Antibody-bound heparin-PF4-IgG complexes then bind the platelet Fc receptor (FcγRIIa), activating platelets and generating thrombin — paradoxically causing thrombosis despite thrombocytopenia. HIT typically presents 5–10 days after UFH exposure with a platelet count fall >50% from baseline. Despite low platelet count, the risk is thrombosis (venous more than arterial), not bleeding. Management: stop all heparin immediately, use an alternative anticoagulant (argatroban, danaparoid, or fondaparinux), and avoid LMWH (cross-reacts in most HIT cases). Warfarin is contraindicated in acute HIT because it depletes Protein C (a short-lived vitamin K-dependent protein), initially worsening the hypercoagulable state.