Haemostasis is the interaction of
- platelets
- coagulation factors
- coagulation inhibitors
- fribrinolytic processes
- blood vessels/endothelium/cellular membranes (mononuclear cells)
What is primary haemostasis?
occurs immediately (seconds, minutes)
- vasoconstriction - limits blood flow to the injury
- platelet adhesion and aggregation - initial framework formation for fibrin
What is secondary haemostasis?
occurs minutes after injury
- activation of coagulation factors - proteins in the blood
- formation of fibirin mesh - covers the platelet plug
What is fibrinolysis?
occurs within minutes to hours of injury
- activation of fibrinolyisis
- lysis of clot - smoothes surface in the vessel to restore laminar flow
What is Virchow’s Triad?
- explains the 3 contributing factors to abnormal clotting:
- abnormalities in the vessel wall*
- abnormalities in blood flow
- abnormalities in blood composition
*we have no way of assessing vessel wall integrity; test number and function of platelets, integrity of clotting proteins instead
How do we test functionality of the clotting system?
- cannot assess blood vessel walls
- test number and function of platelets
- test integrity of the clotting proteins
The coagulation system is part of which blood component?
plasma
What is the trigger that initiates the clotting system/coagulation cascade?
exposure of tissue factor to the blood, released when vessel walls are damaged
What is the key protein in controlling the coagulation system?
Thrombin - initiates the -ve or +ve feedback loops that turn it off and on, respectively
tf a very important anti-thrombotic agent
What are the 3 phases of coagulation?
- initiation
- amplification
- propagation
What happens in the initiation phase of coagulation?
- hole in vessel wall triggers coagulation
- tissue factor is exposed to blood
What happens in the amplification phase of coagulation?
- activation of FXa triggers prothrombin–>thrombin
- thrombin postiviely feedbacks on platelets
- causes platelet activation
- increases amount of thrombin (thrombin burst)
- thrombin postiviely feedbacks on platelets
What happens in the propagation phase of coagulation?
- thrombin burst facilitaties the formation of fibrin
- fibrin forms the mesh, generating the stable clot that plugs the hole in the blood vessel wall
Thrombin
- essential for fibrinogen –> fibrin
- critical gor clot formation and reinforcement of the platelet plug
- if insufficient? bleeding
- if excessive? thrombosis
- thrombin is the regulator of haemostasis
- activates factor 13: cross-linking of fibrin
- binding to thrombomodulin: inhibits system
- activates platelets
How is thrombin inactivated?
- binding to thrombomodulin-activated protein c (APC) system
- downregulates ability to cleave fibrinogen–>fibrin
- involves protein C and protein S*
**factors that inhibit clotting are given letters; factors that promote clotting are given Roman numerals**
- irreversible inhibition by binding antithrombin (+ x1000 by Heparin)
- binding to heparin co-factor II, dermatan sulphate, alpha-2 macroglobulin
What is the haemostatic test fof platelets?
- number
- function
- appearance
What are the haemostatic tests of the coagulation (and fibrinolytic) system?
- to assess risk of bleeding or clotting, and to monitor anticoagulant drugs
- global tests:
- APTT (Activated Partial THromboplastin Time)
- INR (International Normalized Ratio)
- specific test:
- Factor 8 deficiency (haemophilia A - Queen V)
- genetic tests:
- gene abnormality
- mutation does not always mean the protein is non-functional
- tf abnormality depends on phenotype
- gene abnormality
What is the ACT haemostatic test?
- activated clotting time
- usually done in OR on cardiopulmonary bypass
What is the APTT haemostatic test?
- activated partial thromboplastin time
- usually in conjunction with a PT/INR
- pt plasma is arrested with citrate
- heated, Ca, phospholipid, and TF reagent (pro-thombitic) added
- measure time to clot
What is the PT/INR ratio?
- (patient prothrombin time/mean normal prothrombin time)^ISI
- ISI = international sensitivity index, reflects sensitivity of reagent to reduction in Vit K dependent factors - therefore it only tells you about factor 7 OR if they are on warfarin which inhibits production of vitamin K
- used to equate different international testing methods in deteriming prothrombin time
- normal INR is ~1, on Warfarin ~1-3
What are the haemostatic assays?
- factor assays e.g. Factor 8 for haemophilia
- VWF - von Willebrand factor, a blood glycoprotein related to bleeding disorder VW disease
- collagen binding assays - functional assessment of vWF protein
- measure fibrinogen (if abnormal, can’t clot)
What is a functional clot based assay?
- blood in test tube, look for clot formation
- measure time to clot in seconds
- not truly physiologic because not in vivo (no endothelial surface), cells heated
What is a chromogenic assay (haemostatic test)?
- plasma in test tube
- chromogenic substance in tube produces light when clipped
- measure light formation
- may be more reproducible but not physiologically relevant
What is an immunological assay (haemostatic test)?
- quantify hoe much protein we have
- doesn’t tell us about its functionality
- type I defect is low amount and low function
- type II defect is normal levels but low function
