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HAEMOSTASIS & COAGULATION

Breakdown of Haemostasis & Coagulation: their in depth physiology, pathology & pharmacology. Will be updated regularly. Cf: Dr Najeeb, Robbins&Cotran, Kumar&Clark, Waller&Renwick
by

Sumayyah Mian

on 7 January 2013

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Transcript of HAEMOSTASIS & COAGULATION

PGI2 NO ADP Dephosphatases Anti-Platelet Agents Produced by healthy endothelial: Inactivate platelet receptors - platelets unable to bind to endothelial lining/ ECM HEPARIN SULPHATE AT III Thrombin
Serine Proteases (IXa, Xa, XIa, XIIa THROMBO-MODULIN Thrombin Factor Va
Factor VIIIa Protein Kinase C (Tissue Plasminogen Activator) Plasminogen Plasmin F.D.P.
Fibrin Split Products Fibrin Anti-Coagulant Mechanisms/ Properties of Healthy Endothelium VASOCONSTRICTION Reflex Neurogenic Constriction
Myogenic Constriction
Endothelium-derived Endothelin Endothelin Endothelin vW vW vW vW PLATELET-ECM ADHESION PhosphoLipase A2 Activation Phospholipids Arachidonic Acid (AA) TxA2
(Thromboxin A2) Vasoconstrictor
Platelet Aggregator PLATELET ACTIVATION TxA2 PGI2 Cyclooxygenase Hameostasis Balance Scale Vasoconstrictor
Platelet Aggregator Vasodilator
Platelet Activation Inhibitor Serotonin
ADP
Ca++ Platelet activation & aggregation Mediates complex binding (of coag' factors) via terminal gamma-carboxy residues on FXa/FIXa->platelet phospholipid surfaces Delta granule Alpha granule Coagulation factors (V, VIII)
Fibrinogen
PDGF
Vasoactive Amines RELEASE REACTION (platelet granule secretion) Expression of Phospholipid Complex P-Selectin CAMs Promotes platelet recruitment & aggregation via platelet-fibrin + platelet-platelet binding Platelet-Platelet binding promoted by ADP & Thromboxane A2 PLATELET AGGREGATION GpIIb-IIIa Receptor Conformation Integrin complex found on platelets. Receptor for fibrinogen = bridges multiple platelets -> large aggregates Formed via Ca-dependant gpIIb - gpIIa binding 1' HAEMOSTATIC PLUG TxA2 ADP P-Selectin CAM P-Selectin CAM P-Selectin CAM ERYTHROCYTES LEUKOCYTES Initial 'clot' formed by platelet aggregation after adhesion & release reaction XII Coagulation factors from Liver XIIa Hageman's Factor makes contact w/ injured epithelial lining, 1' platelet plugs, ECM -> Activated XI XIa IX IXa X Xa P.L. + Ca++
VIIIa Prothrombin THROMBIN Fibrinogen FIBRIN T.S.F XIIIa Tissue Stabilising Factor P.L. + Ca++
Va Fibrin monomers deposit over 1' haemostatic plug;
Activated XIII -> Cross-linking of fibrin monomers THE CLOTTING CASCADE 2' HEAEMOSTATIC PLUG TF VII VIIa THE INTRINSIC SYSTEM THE EXTRINSIC SYSTEM Membrane Associated Thrombomodulin:
Modify thrombin so can cleave proteins C & S -> inactivate Va +VIIIa PAIs (Plasminogen Activator Inhibitors) limit fibrinolysis: inhibit t-PA binding to fibrin.
Released by thrombin & certain cytokines > Intracellular Ca++ Glycoprotein/ Integrin Receptors GP1b GP1b Activation (1) < Prostacyclin (Prostaglandin I2) synthesis by vascular endothelium =>
vasoconstriction
< inhibition to platelet aggregation
(2) Inhibit action of Heparin Sulphate =>
> coagulation cascade activity MAJOR INHIBITOR of platelet aggregation:
> cAMP in platelet -> GpIIb/IIIa surface receptor inhibition PGI3
(e.g. via Omega-3 fatty acids) = anti-aggregatory t-PA Triggered by contact of blood w/ a -vely charge surface e.g. subendothelial collagen w/ ~ >10min delay post-tissue disruption Rapidly initiated by release of TF from damaged tissue cells w/in mins of tissue disruption IIa Ca++ Ca++ (Tissue Factor) Cleaves & interferes w/ fibrin polymerisation weak anti-coagulants
> vascular permeability Free plasmin rapidly neutralised by serum a2-plasmin inhibitors Mediated by PARs (protein-activated receptors)
Limits Haemostasis
V -> Va
VIII -> VIIIa
> t-PA release PTT (Partial Thromboplastin Time): screens for function of proteins in intrinsic pathway (XII, XI, IX, VIII, X, V, II, fibrinogen) PT (Thromboplastin Time): Screens for function of proteins in the extrinsic pathway Dissolution of the Thrombus:
Activated clotting factors diluted by flow + cleared by liver&tissue macrophages & control mechanisms (t-PA, thrombomodulin, heparin sulphate etc. )
Dissolution/Disintegration by fibrinolytic activity

Organisation
Growth of fibrous tissue & collagen to cover/'bury' plug

Embolisation
Dislodged by blood flow -> travel to other sites

Re-canalisation of occlusive thrombus
Vascular-endothelial growth factors endothelise surface of thrombus. PDGF from disintegrating platelets enable proliferation + ingrowth of endothelial layer (& smooth muscle cells) into thrombus -> fibroblasts disintegrate central endothelial cell layer undergoes -> development of new vessel within the thrombus = reperfusion of vessel

Mycotic Aneurysm
Rare. Microbial seeding of thrombus -> mycotic aneurysm THE FATES OF THE THROMBUS THROMBUS COMPOSITION ARTERIAL
IN HIGH FLOW, HIGH SHEAR STRESS SETTINGS
Platelets play a large role in initiation & growth of thrombus

VENOUS
IN LOW FLOW, LOW SHEAR STRESS ENVIRONMENTS
Form initially in valve pockets of deep veins.
Consist of RBCs & fibrin w/ few platelets COMMON PATHWAY PAR-1 engagement:
Mobilises P-selectin -
Induces cytokine&chemokine production -
Augments endothelial CAM expression -
> Synthesis of PAF, NO + Prostaglandins - Prekallikrein Kallikrein HMWK
(circulating high-molecular-weight kinogen) BRADYKININ Vasodilation
> Vascular Permeability
Pain C5 C5a chemoattractant XII -> XIIa Kallikrein Glycoprotein-Ib/ vWF Deficiency -> bleeding disorders e.g. Bernard-Soulier Syndrome GpIIb-IIIa deficiencies -> Glanzmann Thrombasthenia bleeding disorder Vasoconstriction ADP RECEPTOR ANTAGONISTS
CLOPODOGREL
TICLODIPINE
PRASUGREL
Irreversibly bind to purinergic P2 receptors for ADP GPIIb/IIIa RECEPTOR ANTAGONISTS
ABXICIMAB
TIROFIBAN
EPTIFIBATIDE

PGI2
EPOPROSTINOL
Omega 3 Fatty Acids VIT K-DEPENDENT ENZYME
(GAMMA-GLUTAMYL CARBOXYLASE)
carboxylates coag' factors at glutamic acid residues F II, VII, IX, X + Proteins S, C, Z
Deficiencies limit pathway/ binding & activation of factors TFPI
(TISSUE FACTOR PATHWAY INHIBITOR) inactivates tisue factor-factor VIIa complexes PHOSPHODIESTERASE INHIBITORS
DIPYRIDAMOLE

Inhibits phosphodiesterase 5 (degrades cyclic nucleotides) -> > cAMP -> < GPIIb/IIIa Expression CYCLO-OXYGENASE INHIBITORS
ASPIRIN
(ACETYLSALICYLIC ACID)

Irreversibly inhibits COX-1 (PTGS) &
< expression of GPIIb/IIIa receptors HEPARINS

PROMOTE TFPI RELEASE FROM VASCULAR WALL Platelet factor 4, B-thromboglobulin HEPARIN

HMWH BINDS TO PF 4 -> INHIBIT PLATELET AGGREGATION HEPARIN
HMWH-AT COMPLEX
LMWH-AT COMPLEX

Directly inactivate factor Xa. LMWH 4x > effective at doing so than HMWH
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