Haemostasis: platelets, clotting and clot breakdown
How the body plugs a cut blood vessel, keeps clots from spreading and later dissolves them, and where anticlotting drugs act.
Haemostasis stops bleeding through three linked steps: platelets form a plug, the coagulation cascade builds a fibrin mesh, and fibrinolysis later removes the clot. Natural anticoagulants keep the process local. Every antiplatelet, anticoagulant, fibrinolytic and antifibrinolytic drug acts on one of these steps, so the physiology explains both their effects and their bleeding risks.
Primary haemostasis: the platelet plug
When the endothelium is damaged, collagen and von Willebrand factor are exposed. Platelets attach through their GPIb receptor and to collagen directly, then change shape and release granule contents. ADP (acting on P2Y12) and thromboxane A2 (made by COX-1) recruit more platelets, and thrombin activates them powerfully through PAR receptors. Activation switches on GPIIb/IIIa, which binds fibrinogen and links platelets into an aggregate. Healthy endothelium normally prevents this by making prostacyclin and nitric oxide.
- Aspirin blocks COX-1 irreversibly, so thromboxane falls for the platelet's life.
- Clopidogrel, prasugrel and ticagrelor block P2Y12.
- Abciximab, eptifibatide and tirofiban block GPIIb/IIIa.
- Vorapaxar blocks the thrombin receptor PAR-1.
Secondary haemostasis: the coagulation cascade
Clotting factors are mostly liver proteins that circulate as inactive enzymes. In the body, coagulation starts on cells that carry tissue factor: tissue factor binds factor VIIa and activates factors X and IX. Factor Xa with its cofactor Va (the prothrombinase complex) makes a first burst of thrombin. That thrombin activates factors V, VIII and XI and platelets, so factor IXa with cofactor VIIIa (the tenase complex) produces much more factor Xa, and thrombin generation explodes on the platelet surface. Calcium and phospholipid are needed throughout. Thrombin cleaves fibrinogen to fibrin and activates factor XIII, which cross-links fibrin. The classic 'intrinsic' and 'extrinsic' pathways are laboratory concepts: the prothrombin time tests the tissue factor route (and is used for warfarin as the INR), the aPTT tests the contact route (used for unfractionated heparin).
- Factors II, VII, IX and X and proteins C and S need vitamin K to be carboxylated; warfarin blocks vitamin K recycling.
- Rivaroxaban, apixaban and edoxaban inhibit factor Xa directly; dabigatran, argatroban and bivalirudin inhibit thrombin.
- Haemophilia A and B are deficiencies of factors VIII and IX, the tenase complex.
Natural anticoagulants
Without brakes, a small clot could spread through the vessel tree. Three systems keep clotting local.
- Antithrombin: inactivates thrombin and factor Xa (and other factors). Heparin speeds this reaction greatly; low-molecular-weight heparins and fondaparinux favour factor Xa.
- Protein C pathway: thrombin bound to thrombomodulin on intact endothelium activates protein C; activated protein C, with protein S, destroys factors Va and VIIIa. Factor V Leiden resists this, the most common inherited thrombophilia in people of European ancestry.
- Tissue factor pathway inhibitor: shuts down the tissue factor–VIIa–Xa complex after the first burst.
- Inherited lack of antithrombin, protein C or protein S raises the risk of venous thrombosis. Because protein C falls quickly when warfarin starts, a short procoagulant phase can occur, which is why heparin overlaps at the start and why warfarin skin necrosis is linked to protein C deficiency.
Fibrinolysis
Once the vessel heals, the clot is removed. Endothelial cells release tissue plasminogen activator (t-PA), which converts plasminogen bound to fibrin into plasmin; plasmin cuts fibrin into fragments, including D-dimer, measured in the laboratory. Plasminogen activator inhibitor-1 and alpha-2-antiplasmin limit the process. Fibrinolytic drugs (alteplase, tenecteplase, reteplase) are recombinant activators used to dissolve clots in stroke, myocardial infarction and massive pulmonary embolism; tranexamic acid blocks plasminogen binding to fibrin and is used to reduce bleeding.
Why the physiology matters for drugs
Arterial clots form under high flow and are platelet rich, so antiplatelet drugs dominate in coronary and cerebrovascular disease. Venous clots form under slow flow and are fibrin rich, so anticoagulants dominate in deep vein thrombosis, pulmonary embolism and atrial fibrillation. Knowing which step a drug hits also tells which reversal works: vitamin K and prothrombin complex concentrate for warfarin, protamine for heparin, idarucizumab for dabigatran and andexanet alfa for factor Xa inhibitors.
Test yourself
Think of the answer, then tap the question to see it.
Which complex starts coagulation in the body?
Tissue factor exposed at the injury, bound to factor VIIa, which activates factors X and IX.
What do activated protein C and protein S inactivate?
Factors Va and VIIIa, the cofactors of the prothrombinase and tenase complexes; factor V Leiden resists this inactivation.
How does heparin prevent clotting?
It binds antithrombin and greatly speeds its inactivation of thrombin and factor Xa; heparin itself has little direct effect.
Why can warfarin briefly favour clotting when it is started?
Protein C has a short half-life, so it falls before factors II, IX and X; heparin is overlapped to cover that window.
Where do fibrinolytic drugs and tranexamic acid act in fibrinolysis?
Fibrinolytics such as alteplase turn plasminogen into plasmin to dissolve fibrin; tranexamic acid stops plasminogen binding to fibrin, preserving the clot.
Example drugs
- Acetylsalicylic acid
- Clopidogrel
- Ticagrelor
- Abciximab
- Heparin
- Enoxaparin
- Fondaparinux
- Warfarin
- Rivaroxaban
- Apixaban
- Dabigatran
- Bivalirudin
- Alteplase
- Tranexamic acid
- Phytomenadione (vitamin K1)
Connections
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: Factor V Leiden thrombophilia: MedlinePlus Genetics (MedlinePlus Genetics (U.S. National Library of Medicine), 2026); Hereditary antithrombin deficiency: MedlinePlus Genetics (MedlinePlus Genetics (U.S. National Library of Medicine), 2026); Protein C deficiency: MedlinePlus Genetics (MedlinePlus Genetics (U.S. National Library of Medicine), 2026).
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Representative model, for educational purposes only.