disorders of blood coagulation Flashcards
why does blood clot
to keep the blood in
keep pathogens out
tightly regulated process that stops bleeding at the site of an injury
must remain localised
blood loss is stopped by formation of a plug composed of platelets and fibrin
describe clotting process
platelets and fibrinogen circulate ready to go
damage to vessel wall triggers clotting
aggregated platelets and fibrin mesh
endothelium in blood vessels normally maintains an anticoagulant surface
injury exposes collagen to come into contact with blood components to activate clotting
two main processes of haemostasis = primary and secondary
describe primary haemostasis
- endothelium releases small amounts of von willerband factor, circulates in blood. endothelial cells also store VWF in edible-palade bodies for release when stimulated.
- if collagen becomes exposed to blood, VWF binds to it.
- platelets express receptors for both collagen and VWF and become activated when these proteins bind to them. activated platelets express functional fibrinogen receptors, required for aggregation.
describe secondary haemostasis
- tissue factor expressed by nearly all sub-endothelial cells activates coagulation cascade to initiate minor burst of thrombin. factor FVIIa binds to TF, causing conversion of prothrombin to thrombin.
- thrombin activates receptors on platelets as well as endothelium, amplifying platelet aggregation and initiating release of stored VWF from endothelial cells.
amplification: each activated factor activates more of the next
thrombin activates 2 cofactors = factor VIIIa and factor Va = form calcium ion dependent complexes on surface of platelets with factor IXa and Xa. they accelerate production of factor Xa and thrombin.
= amplification stage of coagulation cascade.
greatly increased production of thrombin via tens and prothrombinase contributes considerably more to process. thrombin converts fibrinogen to fibrin mesh
describe fibrinolysis
plasminogen activated to plasmin by tissue plasminogen activator, t-PA.
plasmin degrades fibrin mesh to fibrin degradation production which can be cleared
describe natural anticoagulants
antithrombin is a serpin (serine protease inhibitor)
activity enhanced by binding heparin binding sites on endothelial cells
major checkpoint to inhibit coagulation
heparan binding domain is basis of anticoagulant activity of heparin which increases the activity of ATIII
describe natural anticoagulants II
protein C and S are natural anticoagulant plasma proteins
protein C is activated by thrombin bound to thrombomodulin on endothelial cells to form activated protein C
protein S = APC cofactor which helps binding to cell surfaces
APC degrades cofactors FVa and FVIIIa
describe the molecular basis of blood clotting disorders - HAEMOPHILIA
haemophilia = failure to clot leading to haemorrhage
- mutations in coagulation factor haemophilia A and B
- platelet disorder (von willerband disease)
- collagen abnormalities (fragile blood vessels and bruising)
defects in key components of clotting
coagulation proteins
platelets
endothelium
THROMBOPHILIA
= excessive clotting leading to thrombosis
- inherited: mutations in coagulation factors (DVT)
- acquired: malignancy increases clotting factors (DVT)
Disseminated intravascular coagulation (DIC)
= whole body clots
- infection
- depletion of clotting factors and platelets leads to bleeding
symptoms of haemophilia
bleeding into joints
symptoms of von willebrand disease
affects mucous membranes
mostly mild, but bleeding can vary in severity
describe excessive clotting
Factor V leiden mutation
resistance to APC
FVa is not inactivated
increases risk of DVT
antithrombin deficiency
thrombin, IXa, FXa are not inactivated
increases risk of DVT
protein C deficiency, protein S deficiency, increases risk of DVT
