Clotting, platelet activation and their measurement Flashcards
(41 cards)
Describe process of platelet aggregation (part 1)
Damage to blood vessel –> Exposure of platelets to collagen and vWF in extracellular matrix and (later) exposure to thrombin –> Platelets adhere
and activate –> Release of mediators –> Vasoconstriction + aggregation of platelets –> Formation of soft platelet plug
Describe process of platelet aggregation (part 2)
Platelets adhere to sub endo collagen exposed after vessel damage
GP1b binds to VWF expressed on damaged endo cells
GPVI + A2b1 bind to collagen
Platelets adhere to collagen + activation to release mediators: thrombin, ADP, TXA2 –> vasoconstriction of vessels
Thrombin + ADP –> further platelet activation
ADP induces expression of GPIIa/IIIa which is expressed on platelets + causes cross-linking between platelets of a fibrinogen bridge –> irrev platetet agg –> stops blood loss
What do anti-platelet drugs do?
limit growth of, or decrease risk of, arterial thrombosis
act by inhibiting platelet aggregation
List 3 anti-platelet drugs
Aspirin - inhib cyclooxygenase which need for thromboxane prod
P2Y12 antagonists – stop platelet prod by ADP
GPIIb-IIIa (aIIbb3) antagonists (GPIs)
What is the initiation process of the clotting pathway?
activated by Tissue Factor (TF)
takes place on TF-expressing cells in tissues after blood, with its clotting factors, leaks out of the blood vessel
What is the amplification process of the clotting pathway?
initiated by thrombin
involves activation of many factors, including FV, FVIII, FIX, FX
takes place on activated platelets
Briefly describe the clotting pathway
TF + FVII –> FVIIa:TF –> FX –> FXa:FVa –> FII (prothrombin) –> FIIa (thrombin)
Thrombin –> fibrinogen –> fibrin which activates platelets to form a fibrin clot
What causes TF release?
Damage to blood vessels causes TF exposure of endo behind it
TF expressed on cells not normally exposed to blood e.g. fibroblasts + monocytes outside vessels
Describe the process of initiation (detailed)
TF + VII form complex which activates VII –> VIIa
X activated by TF:VIIa in presence of Ca + PLD –> Xa
Xa forms complex with Va which causes thrombin to be prod from pro-thrombin
Describe the process of amplification (detailed)
Thrombin prod can be amplified on platelet surface à activates platelets
Release of V from platelet a-granules to prod Va expressed on platelet surface
Thrombin cleaves VIII –> Vwf which prod exposed VIIIa on platelet surface
Describe the process of propagation (detailed)
IX in plasma can be converted to IX by XI
IX activated tenase (VIIIa:IXa) which convertes X à Xa which binds to V to drive IIa (thrombin) prod
How does heparin act on the clotting cascade?
activates antithrombin which inhib IX + X.
What’s the diff between UFH + LMWH?
Unfractionated (UF) heparin variable in effect (diff saccharide lengths); low molecular weight heparins (LMWH) more predictable, more effective on FXa than on thrombin
Fondaparinux is a synthetic polysaccharide that acts like LMWH – smaller chain tf easier to monitor in blood
How does warfarin act on the clotting cascade?
inhibits vitamin K reductase in liver, required for g-carboxylation of factor II (prothrombin), VII, IX & X – tf takes long time to have an effect
List the direct inhibitors
Direct thrombin inhibitors e.g. Dabigatran, Bivalirudin
Direct FXa inhibitors E.g. Rivaroxaban
Describe fibrin deposition
fibrinogen binds to GPIIb/IIIa receptors
Fibrinogen –> fibrin by thrombin which binds to fibrin
Fibrin polymerises to form stable fibrin clot
Thromcin activates XIIIa which causes crosslinking of fibrin polymers
What do fibrinolytics do?
Activate plasminogen
Used to remove (Lyse) arterial thrombi
AMI: upto 12hrs
Stroke: upto 3hrs
What is the risk of fibrinolytics + antidote?
High risk of haemorrhage
I.V. Infusion
Antidote: Severe haemorrhage treated with transexamic acid (inhibits activation of plasminogen)
Give 2 examples of fibrinolytics
Streptokinase
Non-enzyme protein from streptococci
Binds and activates plasminogen → plasmin
Allergenic
Alteplase (r-tPA)
Non-allergenic
Clot selective? (only activates plasminogen bound to fibrin in thrombus)
What do screening tests for haemostasis involve?
Patient history
Vital: ultimately guide the extent of the laboratory evaluation
Determine how complications can be managed.
Primary haemostasis
Coagulation tests
Blood disorders
Thrombosis
Manage anti-coagulant and anti-platelet therapy
How do you take a bleeding history (who)?
Who:
Who is the patient, sex, age, race and family history?
Abnormal bleeding in both parents, maternal grandparents, aunts, uncles,
and siblings as well as any history of consanguineous marriage (or among relatives)
How do you take a bleeding history (when)?
When:
History of blood transfusion or other blood components
Review of PMHx and PSHx history.
Information on all operations including tooth extractions are to be listed together with any abnormal bleeding during or after surgery or poor wound healing.
Drug history: wide variety of drugs affect haemostasis.
Childhood history of epistaxis, umbilical stump bleeding, bleeding after circumcision, the answers to any of which would suggest inherited bleeding disorders.
How do you take a bleeding history (where)?
sites of bleeding, skin, muscle etc.
Skin (cutaneous) and mucous membranes i.e. petechiae, purpura, bruises, epistaxis, gingival bleeding, menorrhagia and/or hematuria which would suggest a platelet and/or vascular abnormality.
Bleeding into deep tissue, joints and muscles suggest a coagulation factor defect.
How do you take a bleeding history (what)?
description of the type of bleeding.
Is bleeding spontaneous or follows trauma?
A history of easy bruising or bleeding excessively after injury suggests an inherited bleeding problem.
Information on the duration must also be sought. This would indicate whether symptoms have been lifelong (since childhood) or of recent onset.
