Neurosurgery notes/Pharmacology/Anti-platelet-coagulation/Coagulation cascade

Coagulation cascade

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Anti-platelet-coagulation

Platelet plug formation (primary hemostasis)

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Thrombogenesis

  • Formation of insoluble fibrin mesh.
  • Aspirin irreversibly inhibits cyclo‑oxygenase, thereby inhibiting thromboxane A₂ (TXA₂) synthesis.
  • Clopidogrel, prasugrel, and ticagrelor inhibit ADP‑induced expression of GPIIb/IIIa by blocking the P2Y₁₂ receptor.
  • Eptifibatide and tirofiban inhibit GPIIb/IIIa directly.
  • Ristocetin activates von Willebrand factor (vWF) to bind GPIb. Failure of aggregation with ristocetin assay occurs in von Willebrand disease and Bernard–Soulier syndrome. Desmopressin promotes the release of vWF and factor VIII from endothelial cells.
  • vWF carries/protects factor VIII; mnemonic: “volksWagen Factories make gr8 cars”.
  • What is in the dense granules of platelets?
    • Serotonin
    • ATP
    • PDGF
  • What disorders can lead to platelet sequestration?
    • Hypersplenism associated with cirrhosis, Gaucher disease, sarcoidosis
  • All prostaglandins cause vasoconstriction, except?
    • PGI₂
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Intrinsic and extrinsic pathway

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Coagulation and kinin pathway

  • PT monitors extrinsic and common pathway, reflecting activity of factors I, II, V, VII and X.
  • PTT monitors intrinsic and common pathway, reflecting activity of all factors except VII and XIII.
  • Hemophilia A: deficiency of factor VIII (XR)
  • Hemophilia B: deficiency of factor IX (XR)
  • Hemophilia C: deficiency of factor XI (AR)
  • Note
    • Kallikrein activates bradykinin
    • ACE inactivates bradykinin
    • #=C1-esterase inhibitor deficiency → hereditary angioedema
    • *=require Ca²⁺, phospholipid
    • Pink=vitamin K-dependent factors
    • Green=cofactor
    • - - - -=activates but not part of coagulation cascade
    • LMWH=low-molecular-weight heparin
    • HMWK=high-molecular-weight kininogen
  • What is factor XIII and in what diseases is it deficient?
    • Factor XIII is an enzyme (protransglutaminase) that stabilizes the fibrin clot and is important for crosslinking fibrin in the clotting cascade.
    • It is deficient in leukaemia, liver disease, malaria, inflammatory bowel disease, disseminated intravascular coagulopathy, and Henoch-Schönlein purpura
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Haemostatic adjuncts and their mechanism of action

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Vitamin K-dependent coagulation

Procoagulation

  • Vitamin K deficiency leads to decreased synthesis of factors II, VII, IX, X, protein C, and protein S.
  • Warfarin inhibits vitamin K epoxide reductase. Vitamin K administration can reverse the inhibitory effect of warfarin on clotting factor synthesis (delayed). Fresh frozen plasma (FFP) or prothrombin complex concentrate (PCC) reverses the action of warfarin immediately and can be given with vitamin K in severe bleeding.
  • Neonates lack enteric bacteria that produce vitamin K. Early administration of vitamin K overcomes neonatal deficiency and coagulopathy. Suppression of gut flora by broad‑spectrum antibiotics can also contribute to deficiency.
  • Factor VII has the shortest half‑life.
  • Factor II has the longest (too long) half‑life.

Anticoagulation

  • Antithrombin inhibits thrombin (factor IIa) and factors VIIa, IXa, Xa, XIa, and XIIa.
  • Heparin enhances the activity of antithrombin. The principal targets of antithrombin are thrombin and factor Xa.
  • Factor V Leiden mutation produces a factor V that is resistant to inhibition by activated protein C.
  • Tissue plasminogen activator (tPA) is used clinically as a thrombolytic.
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