haemostasis prof. k. sivapalan. june 2013haemostasis2 thrombocytes 2 – 4 μm in diameter. half...
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Haemostasis
Prof. K. Sivapalan
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June 2013 Haemostasis 2
Thrombocytes• 2 – 4 μm in diameter.• Half life – 4 days.• 300,000 / μL.• Break off from
megakaryocytes. • Colony stimulating
factors and thrombopoietin- liver and kidney.
• 60 – 70 % in circulating blood - balance in spleen.
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June 2013 Haemostasis 3
Properties of Platelets
• A ring of microtubules in periphery.• Extensively invaginated membrane.• Membrane contains receptors for:
– Collagen, von Willebrand factor and fibrin.• Dense granules in cytoplasm:
– Serotonin, ADP, other nuclear tides.• α – granules in cytoplasm :
– Clotting factors and platelet-derived growth factor [PDGF – stimulates wound healing and mitogen for vascular smooth muscle.]
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June 2013 Haemostasis 4
Platelet activation.
• Binds to exposed collagen and von Willebrand factor (when damage to blood vessel). This is platelet adhesion.
• This activates platelets [ADP]• Platelets change shape, put out
psudopodia and release granules and causes platelet aggregation.
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June 2013 Haemostasis 5
Changes in the platelet.• Platelet activation results in change in shape, putting out
psseudopodia, release of granules and aehesion to other platelets.
• Platelet Activating Factor secreted by neutrophils and monocytes stimulates G protein which activates phospholipase C to form diacylglycerol. This also causes release of granules.
• Increased cytoplasmic calcium and diacylglycerol activate Phospholipase A2. This causes release of arachidonic acid from membrane phospholipids which is converted into Thromboxan A2
• Thromboxan and other substances released cause vasoconstriction, platelet aggregation, clot formation
• Aspirin prevents the above reaction and alters the balance between thromboxan and prostacycline and prevents clotting in low doses.
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June 2013 Haemostasis 6
Effects of platelet aggregation.
• Repair of the blood vessels.
• Block damaged capillaries.
• Vasoconstriction.• Clotting.• [Test for platelet
function: bleeding time.]
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June 2013 Haemostasis 7
Thrombocytopenia.
• Results in capillary bleeding [purpura].
• Caused by-– Marrow disorders.– Alcohol, cytotoxic drugs,
viral infections.– Hereditary.– Immunologically mediated
destruction.– Increased consumption of
platelets.
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June 2013 Haemostasis 8
Thrombocytosis.
Causes:• Spleanectomy.• Postoperatively, delivery.• Haemorrhage or haemolysis.• Extreme exercise.Risk:• Thrombotic diseases- deep vein
thrombosis.
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June 2013 Haemostasis 9
Hemostasis.
• Vascular spasm: local myogenic, serotonin – lasts for about 20 – 30 minutes.
• Platelet plug.• Clotting of blood.• Organization by fibrous tissue.
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June 2013 Haemostasis 10
Coagulation of blood – clotting.
• Fibrinogen → Fibrin.• Polymerization of
fibrin with branching.• Loose mesh of
interlacing strands.• Formation of covalent
bonds → dense, tight aggrigate.
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June 2013 Haemostasis 11
Important reactions.
Fibrinogen Fibrin.
Thrombin
Prothrombin
Factor x (activated)
Intrinsic system. 2 – 5 minutes.
Extrinsic system. 15 – 30 Seconds.
Platelet Factor, Ca++,
Activated Factor V.
Stabilization.
Factor XIII
Activated XIII
Clot retraction. [platelets] 30 – 60 min.
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June 2013 Haemostasis 12
Coagulation cascade.
Contact with wettable, negatively charged surface – Intrinsic system.
Prekallikerin Kallikerin.
HMW Kilinogen
XII XIIa.
XI XIIa
IX IXa
Tissue factor – Extrinsic system.
[Tissue Thromboplastin- TPL+TFI]
VIIa VII
Ca++
TPL+TFI
X Xa
Activated VIII,
Platelet factor (PL),
Ca++
Ca++, PL, TPL
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June 2013 Haemostasis 13
Role of liver in clotting.
• Synthesizes:– Fibrinogen.– Prothrombin.– Other clotting factors.
• Needs:– Vitamin K.
• Removes activated clotting factors.
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June 2013 Haemostasis 14
Propagation of clot formation.
• Clot formation can be initiated at any vessel by damage to endothelium by platelet plug.
• Activated clotting factors on the surface of the clot can cause further clotting.
• Platelet plug can form on the surface of the clot which can initiate further clotting
• Rapid flow wash off the factors which are diluted and removed in liver.
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June 2013 Haemostasis 15
Clotting and Anti clotting mechanisms.
• Clotting and anti clotting mechanisms are balanced under normal circumstances.
• It is essential to maintain blood in liquid form but prevent loss if the vessels are damaged.
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June 2013 Haemostasis 16
Anti clotting mechanisms.
• Anti thrombin III [circulating protease] inactivates activated factors IX,X,XI and XII. Heparin facilitates it.
• Prostacycline of Endothelium antagonizes thromboxane A2 of platelets. (aggregation)
• Endothelium has thrombomodulin. It’s reaction with thrombin leads to fibrinolysis, inactivation of factor V and VIII.
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June 2013 Haemostasis 17
Fibrinolytic system.Thrombomodulin in endothelium.
Binds to Thrombin
Prtotein C. Activated protein C.[APC]
Inhibitor of tissue plasminogen activator inhibited.
PlasminogenPlasmin.
Lyses of fibrin.
VIIIa Inactive VIIIa
Va Inactive Va
Tissue plasminogen activator
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June 2013 Haemostasis 18
Abnormalities of clotting.
Defective clotting:• Abnormalities of platelet function.• Congenital deficiency of clotting factors-
– Hemophelia A – factor VIII [ X linked].– Hemophelia B – factor IX.
• Von Willebrand factor deficiency.• Vitamin K deficiency and Liver diseases.Enhanced clotting: Increased platelets. Absent Protein C.Intravascular Clotting is thrombosis and if carried in blood it
is embolism. Both can obstruct blood vessels and cause ischemia to organs.
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June 2013 Haemostasis 19
Anticoagulants.
• Heparin promotes antithrombin III which inactivates factors IX, X, XI and XII.
Warfarin inhibits Vitamin K.Streptokinase activates plasminogen and
disolves fibrin. [snake, bacteria]Aspirin reduces thromboxan A2 formation.