Oral Anticoagulants — NOACs, Antiplatelets & Fibrinolytics

Oral Anticoagulants, NOACs, Antiplatelets & Fibrinolytics

1. Haemostasis, the coagulation cascade & natural anticoagulants

• Haemostasis is the finely regulated arrest of blood loss from a damaged vessel while blood remains fluid within the intact vasculature; a delicate balance between coagulation and fibrinolysis normally prevents both thrombosis and haemorrhage (G&G 14e Ch.36, pp.709–10).
• Three sequential events: (i) platelet adhesion to subendothelial macromolecules → activation; (ii) release of mediators that recruit/activate nearby platelets → aggregation to form the primary haemostatic plug; (iii) vessel-wall injury exposes tissue factor (TF) which initiates coagulation, generating a burst of thrombin (factor IIa) that converts fibrinogen → fibrin, stabilising the plug (G&G 14e Ch.36, p.709; Katzung 16e Ch.34, pp.640–1).
• Conversion of fibrinogen to fibrin: fibrinogen is a 340-kDa dimer of three paired chains (Aα, Bβ, γ). Thrombin releases fibrinopeptide A (16-aa) and fibrinopeptide B (14-aa) from the amino-termini, creating "knobs" that fit "holes" on other monomers → a non-covalent fibrin gel (the end-point of in-vitro clotting tests). Factor XIIIa (a thrombin-activated transglutaminase) then covalently cross-links adjacent monomers to strengthen the clot (G&G 14e Ch.36, p.710).
• Vitamin K–dependent factors = II (prothrombin), VII, IX, X (plus anticoagulant proteins C, S, Z). 9–13 amino-terminal Glu residues are γ-carboxylated to Gla (γ-carboxyglutamic acid) post-translationally; Gla residues bind Ca²⁺ and anchor the factors to the anionic phospholipid membrane of activated platelets — essential for coagulant activity (G&G 14e Ch.36, p.710; KDT 8e Ch.45, p.661).
• Non-enzymatic cofactors: TF (constitutively on subendothelial smooth muscle/fibroblasts, exposed on injury; binds factor VIIa), factor V and factor VIII (procofactors). Thrombin activates V→Va and VIII→VIIIa; VIIIa is the receptor for IXa, Va is the receptor for Xa on the activated platelet surface (G&G 14e Ch.36, p.710).
• Prothrombinase complex (Xa + Va + anionic phospholipid + Ca²⁺) activates prothrombin 10⁹-fold more efficiently than factor Xa alone (G&G 14e Ch.36, p.711).
• Initiation — extrinsic (TF/VIIa) pathway: TF–VIIa, in the presence of anionic phospholipid and Ca²⁺ (extrinsic tenase), shows 30,000-fold increased activity over VIIa alone; activates X and IX. This is the main physiological initiator in vivo (G&G 14e Ch.36, p.711; Katzung 16e Ch.34, p.642).
• Intrinsic (contact) pathway: factor XII + prekallikrein + HMW kininogen on a negatively charged surface (kaolin, glass, also cell-free DNA, NETs, platelet polyphosphates) → XIIa → XIa → IXa. Intrinsic tenase (IXa + VIIIa + phospholipid + Ca²⁺) activates X more efficiently than TF–VIIa, so optimal thrombin generation depends on it (G&G 14e Ch.36, p.711).
• Clinically silent contact factors: deficiency of XII, prekallikrein or HMW kininogen does NOT cause bleeding; factor XI deficiency = mild/variable bleeding; factor VIII or IX deficiency = haemophilia A or B (spontaneous, potentially fatal bleeding) (G&G 14e Ch.36, pp.711–12; Katzung 16e Ch.34, p.642).
• In-vitro tests (KDT framing): aPTT tests intrinsic + common pathway (normal 26–32 s; intrinsic-pathway defect → prolonged aPTT, normal PT); PT tests extrinsic + common pathway (normal 12–14 s; extrinsic defect → prolonged PT, normal aPTT); common-pathway defect → both prolonged (KDT 8e Ch.45, p.659).
• Natural anticoagulant mechanisms (4): (i) endothelial NO + prostacyclin (PGI₂) + CD39 inhibit platelet activation; (ii) antithrombin (AT/AT-III) — a serpin that "suicide-substrate" inhibits thrombin, Xa (and IXa, XIa, XIIa); heparan sulfate enhances it ~1000-fold; (iii) protein C — bound to endothelial protein C receptor (EPCR), activated by thrombin–thrombomodulin, then with cofactor protein S degrades Va and VIIIa; (iv) tissue factor pathway inhibitor (TFPI) — binds Xa, then the binary complex inhibits TF-bound VIIa (G&G 14e Ch.36, p.712; Katzung 16e Ch.34, p.643).
• Arterial vs venous thrombi (therapeutic corollary): arterial = platelet-rich "white" thrombi (high shear) → antiplatelet drugs more useful; venous = fibrin-rich "red" thrombi with trapped RBCs (sluggish flow, "red tail") → anticoagulants more useful (KDT 8e Ch.45, p.676; Katzung 16e Ch.34, pp.641–2).
• Factor V Leiden (resistance to inactivation by protein C/S) is the commonest inherited thrombophilia; deficiencies of AT, protein C or protein S also raise venous-thrombosis risk; antiphospholipid antibody syndrome is a key acquired risk factor (Katzung 16e Ch.34, pp.643, 653).