Platelet And Coagulation Physiology

Primary Hemostasis: The Platelet Plug

Primary hemostasis is the rapid formation of a platelet plug at a site of vascular injury. Platelets adhere to exposed subendothelial collagen via von Willebrand factor (vWF) binding the platelet GPIb receptor. They then activate, release granule contents (ADP, thromboxane A2), and aggregate to one another through GPIIb/IIIa receptors bridged by fibrinogen.

Know the receptor-defect diseases:

A tested discriminator: ristocetin aggregation is abnormal in vWD and Bernard-Soulier but normal in Glanzmann (because Glanzmann is an aggregation, not adhesion, defect).

Platelets are not just structural - they contribute biochemically. Activated platelets release dense granules (ADP, serotonin, calcium) and alpha granules (fibrinogen, vWF, platelet-derived growth factor) and synthesize thromboxane A2 from arachidonic acid via cyclooxygenase. Aspirin irreversibly acetylates cyclooxygenase, abolishing thromboxane A2 for the platelet's lifespan (about 7-10 days), which is why aspirin's antiplatelet effect outlasts the drug in the blood.

The pattern of bleeding helps localize the defect on the exam: platelet/vascular (primary hemostasis) defects cause mucocutaneous bleeding - petechiae, epistaxis, gum bleeding, menorrhagia - whereas coagulation factor (secondary hemostasis) defects cause deep bleeding - hemarthroses, muscle hematomas, delayed bleeding after trauma.

Secondary Hemostasis: The Coagulation Cascade

Secondary hemostasis converts the platelet plug into a stable fibrin clot. The cascade has three arms:

• Intrinsic pathway: factors XII, XI, IX, VIII - monitored by the activated partial thromboplastin time (aPTT).
• Extrinsic pathway: factor VII + tissue factor - monitored by the prothrombin time (PT).
• Common pathway: factors X, V, II (prothrombin), I (fibrinogen) - prolongs both PT and aPTT.

Thrombin (factor IIa) converts fibrinogen to fibrin; factor XIII cross-links fibrin into a stable clot. A mnemonic for which test catches which factor: "PeT the extrinsic dog (VII = PT); the intrinsic table (aPTT) has 8, 9, 11, 12."

A powerful exam shortcut is to reason backward from PT/aPTT patterns to the deficient factor: prolonged PT only isolates factor VII (extrinsic); prolonged aPTT only isolates an intrinsic factor (VIII, IX, XI, or XII); both prolonged points to a common-pathway factor (X, V, II, or fibrinogen) or a global problem such as liver disease, DIC, or vitamin K deficiency. Note that factor XII deficiency prolongs the aPTT but does not cause bleeding - it is a classic distractor because the long aPTT looks alarming yet is clinically silent.

Hemophilia A (factor VIII) and hemophilia B (factor IX, "Christmas disease") both prolong only the aPTT and are X-linked recessive, so they predominantly affect males. Factor XIII deficiency is unique: PT and aPTT are normal because the clot forms, but it is unstable and dissolves, so the screening test is clot solubility in 5M urea.

Vitamin K-Dependent Factors

Factors II, VII, IX, X and the natural anticoagulants protein C and protein S require vitamin K for gamma-carboxylation. Warfarin inhibits vitamin K epoxide reductase, so these factors fall. Because factor VII has the shortest half-life (~6 hours), the PT prolongs first on warfarin, which is why PT/INR monitors warfarin therapy.

Natural Anticoagulants

Clotting is restrained by:

• Antithrombin (III): inhibits thrombin and factor Xa; potentiated by heparin.
• Protein C / Protein S: inactivate factors Va and VIIIa.
• Tissue factor pathway inhibitor (TFPI): blocks the VIIa-tissue factor complex.

Factor V Leiden is a mutation making factor Va resistant to protein C cleavage - the most common inherited thrombophilia. Other inherited thrombophilias the exam may list include the prothrombin G20210A mutation, and deficiencies of antithrombin, protein C, or protein S. The balance between procoagulant and anticoagulant forces is dynamic: a deficiency on the anticoagulant side (for example protein C deficiency) tips toward thrombosis, while a deficiency on the procoagulant side (for example factor VIII) tips toward bleeding. This is why the same cascade diagram explains both hemophilia and hypercoagulable states.

The fibrinolytic system completes the loop: plasminogen is converted to plasmin by tissue plasminogen activator (tPA), and plasmin digests fibrin into fibrin degradation products and D-dimer, the marker of clot breakdown used clinically and tested in the next section.

Worked Example

A child has easy bruising, a prolonged aPTT, a normal PT, and a markedly low factor VIII. Because the intrinsic pathway (aPTT) is affected while the extrinsic (PT) is normal, and factor VIII is the deficient factor, this is hemophilia A, an X-linked factor VIII deficiency.

Contrast this with von Willebrand disease, the most common inherited bleeding disorder, where low vWF impairs platelet adhesion and also lowers factor VIII (vWF is its carrier), giving mucocutaneous bleeding, a long bleeding time/PFA closure time, and sometimes a mildly prolonged aPTT - a useful overlap the exam exploits to test whether you understand that vWF and factor VIII travel together in plasma.

Common Traps

• Mixing up which test monitors which drug: PT/INR for warfarin, aPTT for unfractionated heparin.
• Forgetting that factor VII (extrinsic) is not in the intrinsic pathway, so its deficiency prolongs only the PT.
• Assuming vWD is a platelet-count problem - the platelet count is usually normal; the defect is adhesion.