haemostasis and thrombosis Flashcards
haemostasis
functions to limit blood loss (haemorrhage) following vascular injury, yet without compromising the fluidity of the blood
thrombosis
inappropriate occlusion of a blood vessel (venous or arterial) by an intravascular blood clot or platelet clump
blood platelets
Platelets are cell fragments (no nucleus) produced from megakaryocytes in bone marrow
Circulate in blood stream in a resting non-activated state
vasoconstriction
Vessel injury results in immediate transient vasoconstriction to reduce blood loss
Due to (i) Loss of vasodilatory signals from endothelial cells
(ii) Direct exposure of SMCs to vasoactive substances
platelet adhesion
initiated by surface integrin receptors (glycoprotein GPIb) adhering to von Willibrand factor (vWF) on the exposed sub-endothelial collagen
This tethers platelets to promote contact sites for subsequent activation
platelet plug
Platelet activation: initiated by binding of GPVI receptors directly to collagen
Platelets change shape, put out pseudopodia, and make thromboxane A2 (TXA2) via cyclooxygenase (COX)
Promotes vasoconstriction and platelet aggregation alongside 5-HT and ADP released from granules
Activated platelets expose another cell-surface integrin GPIIb/IIIa
Plasma fibrinogen sticks to GPIIb/IIIa forming cross-links with adjacent platelets causing them to aggregate
This rapidly creates a soft and fragile platelet plug = primary haemostasis
coagulation cascade
A series of reactions catalysed by plasma proteins called coagulation factors
When activated by proteolytic cleavage, these become active proteases, which trigger the conversion of other factors in a cascade
Ca2+ is required for activation of multiple factors including prothrombin
End-product is generation of the enzyme thrombin, which converts soluble fibrinogen to gel-like fibrin
coagulation cascade- fibrin
Fibrin polymerizes and is cross-linked by Factor XIIIa (activated by thrombin) to form a tough network of fibres
Fibrin strands enmesh the platelet aggregate to consolidate the haemostatic plug = secondary haemostasis
extrinsic pathway and intrinsic pathway
This initial (extrinsic pathway) makes relatively little thrombin, but triggers an amplification stage which activates additional factors and more platelets
The intrinsic pathway is activated by negatively charged subendothelial surfaces mediated by Kallikreins.
intravascular platelet activation
Platelets remain in a resting state until needed
Endothelial cells provide antithrombotic boundary layer
Continual release of prostacyclin (PGI2) and nitric oxide to inhibit platelet aggregation and promote vasodilation
NO also inhibits adhesion of platelets to the vascular wall
Membrane-bound E-NTPDase1 limits the prothrombotic signals of ADP by converting to adenosine
plasma also contains natural anticoagulants
endothelial regulation of coagulation
Healthy vessels prevent blood coagulation in multiple ways
Heparin-like molecules (Hep) expressed on endothelial surface bind circulating antithrombin III
This greatly increases the activity of ATIII to inhibit multiple coagulation factors, including thrombin
ECs express tissue factor pathway inhibitor (TFPI)
Thrombomodulin (TM) binds thrombin activating protein C
fibrinolytic system
A physiological system for removing blood clots and maintaining blood vessel patency
ECs continually produce the serine protease tissue plasminogen activator (t-PA)
t-PA cleaves liver-derived plasminogen (PLG) to form plasmin
Plasmin is a protease that degrades cross-linked fibrin into soluble fibrin degradation products
t-PA release is modified by occlusion and many vasoactive substances
arterial thrombosis
Platelet aggregate (white), usually at site of ruptured atherosclerotic plaque, then encapsulated by clot (red)
Common sites: - coronary artery myocardial infarction
- cerebral artery thrombotic stroke
Therapy: immediate - dissolve existing clots with fibrinolytics
Long term - anti-platelet drugs (antithrombotics)
venous thrombosis
Intravascular blood clot (red) forms in deep veins: i.e. deep vein thrombosis
Poor flow allows platelets to settle and clotting factors to accumulate
Fragment may bud off (embolus) and block blood vessel, often pulmonary artery causing a pulmonary embolism
genetic blood clotting disorders
Haemophilia A – deficiency of factor VIII
Haemophilia B – deficiency of factor IX: “Christmas disease”
Genes encoding factors VIII and IX are located on X chromosome
