Secondary Haemostasis Flashcards
Difference in cell based model compared to traditional coag cascade
Takes into account tissue factor and platelet involvement as well as interactions of the extrinsic and intrinsic coagulation pathways
Steps of secondary haemostasis
- Initiation - TF activates extrinsic path generating low amounts of thrombin and activatic F9 on platelet surface
- Amplification - Thrombin activates F11 on platelet surface which combined with F9 activation starts the intrinsic cascade generating larger amounts of Thrombin
- Propagation - cofactor 8 amplify the extrinsic activation of Factor 10; and cofactor 5 amplifies conversion of prothrombin to thrombin. Both released from platelet alkpha granules. Formation of prothrombinase complex.
Activation of TAFI fibrinolysis inhibitor - Fibrin Formation - generated by thrombin/prothrombinase complex converting fibrinogen to fibirin which binds to plt surface GP IIb/IIIa R and crosslinks
Physiological inhibitors of secondary haemostasis
TF Pathway inhibitor - inhibits extrinsic pathway activation. enhanced by heparin
Protein C - vit K dependent protein from liver in circulation. Inhibits cofactors 8 and 5 thus reducing thrombin generation. Enhanced by thrombin and endothelial cell factors
Protein S - in circulation, enhances protein C activity
Antithrombin - also produced in liver, is in circulation. Enhanced activity by heparins released from damaged endothelial cells.
Plasmin - inactivates cofactor 13 which crosslinks Fibrin
What is Hageman factor deficiency
Factor 12 deficiency
Common in cats but does not result in clinical bleeding as intrinsic cascade is not reliant on F12 and will proceed without it - however in vitro this is what is activated to assess intrinsic path so APTT is prolonged.
Steps of Fibrinolysis and fibrinolysis inhibitors
Plasminogen from liver binds to activated platelet surface
Converted to plasmin by tPA, urokinase from damaged endothelium and F11/12
Promoted by Fibrin
Plasmin cleaves cross-linked fibrin generating fibrin degradation products
tPA and urokinase are inhibited by PAIs from platelet granules
Plasmin is inhibited by TAFI, macroglobulins and antiplasmin
Fibrinolysis is inhibited by presence of DNA/RBC in fibrin clot or polyphosphate dense fibrin
What are alpha-macroglobulins
they are non-specific protease inhibitors produced by the liver and in circulation. They can inhibit coagulation factor activity as well as plasmin mediated fibrinolysis
What does prothrombin time measure
EXTRINSIC path - FVII
and common path
Needs >30% reduction in one or more of the evaluated factors
What does activated partial thromboplastin time (APTT) measure
INTRINSIC path - activation of F12 but subsequent activation of F11 and F9. and common path.
(similar mechanism for ACT test but more sensitive for deficiency)
Prolonged with Hagemann F12 deficiency in cats.
Requires >30% reduction in any of the factors in this path
What are common causes of APTT prolongation
Haemophilia A - F8 deficiency
Haemophilia B - F9 deficiency
Haemophilia C - F11 deficiency
Hageman factor deficiency
Also prolonged from heparin tx, DIC (and liver disease but not without PT prolongation)
Prolonged by underfilling of tubes or by prolonged storage of sample
If PT normal then common path is not affected
What causes PT prolongation
Factor 7 deficiency from liver disease or vit K antagonists, inherited deficiency, warfarin tx or DIC.
May be prolonged if underfilled tubes
Not affected by thrombocytopenia
Can also be prolonged by low fibrinogen - interpret in light of APTT (if latter normal then common pathway defect is unlikely)
When are specific factor levels measured
For diagnosis of Haemophilia A/B/C which all cause prolonged APTT with normal PT
Factor deficiencies of <30% normal are associated with clinical bleeding
What are tests for fibrinolysis
Fibrin levels - can be quantitative or qualitative. Can be helpful in identification of dysfibrinogenemia. Tru deficiency causes prolongation of PT, APTT and TCT
Thrombin Clot time - direct measure of fibrinogen conversion to fibrin
FDPs - not specific for clot lysis just plasmin activity (so b/d of any fibrin in blood).
Ddimers - specific FDP that comes only from clot lysis. Increase is much greater in DIC but also seen in other inflammatory or systemic diseases. Though increase is not always present
TEG - not perfect for measurement, can improve sensitivity by adding tPA so that fibrinolysis starts before clot dries out (fibrinolysis inhibitors in blood may prevent lysis occurring in vitro)
What does PIVKA measure
Non-activated Vit K dependent clotting factors.
Increase in Vit K deficiency or antagonism
What is viscoelastic testing or TEG
Thromboelastography - Test performed on whole blood that measures time to clot formation, strength of clot and time to fibrinolysis
Provides a closer representation of invivo haemostasis cell based model.
Platelet # and function are major determinants of overall function.
TEG and ROTEM are available for use in vet med but limited.
TEG there is rotation of the cup to detect torque, ROTEM it is a pin rotating. Changes in clot strength are graphed against time.
Different clot activators are used to evaluate different pathways
What factors can confound TEG results
Low Hct - hyper
High Hct - hypo
Type of activator used - different activators are not directly comparable
Different analyser or changes in analyser environment can alter results –> not directly comparable
Delay in processing results in hypocoagulability
Advantages of TEG
Global assessment reflecting patient physiology
rapid TAT
Small volume of blood required
Evaluates for hyper and hypo-coagulable conditions
Also evaluates fibrinolysis
Analyses platelet function
Disadvantages of TEG
Does not evaluate endothelial contribution to coagulation
Limited availability and poor reproducibility due to variability of results
Different activators add to variability
Affected by Hct of sample
Low sensitivity for mild defects/factor deficiency
What are the parts of TEG curve evaluated
CT - clot formation time, lag from start to 2mm deviation
K = clot kinetics. Time to deviate 20mm from baseline (from end of CT
Alpha angle - calculated from angle at end of K. reflects speed and kinetics of fibrin formation
Max amp - maximum strength of fibrin-plt clot. Strong association with fibrinogen levels
Clot lysis time - % lysed at 30 and 60 minutes
Sensitivity and Specificity of POC PT/APTT
AVJ 2018 paper compared IDEXX cartridges to lab run samples.
APTT - Sens 92%; Spec 47%
PT 96% accuracy
Moderate to good agreement with lab.
Inconsistent bias between measurements
Differentials for hypocoagulability
Platelet decrease or reduced function
Inhibition of platelets
E.canis
Vit K abnormalities - deficiencies (Vit K antagonist poisoning or treatment).
Inherited abnormalities in function
reduced GI absorption or intestinal dysbiosis
Factor deficiencies - 8=A
9=B
11 = C
7 - Min Schnauzer
AutoAb against factors
Neoplasia (consumption, association with DIC)
Liver Disease (reduced vit K dependent clotting factors, reduced antifibrinolytic factors)
Renal Disease (uraemia induced platelet dysfunction)
Haemophilia types, inheritance, affected breeds and severity
A = Factor 8
GSD and Boxer.
X linked recessive. Bleed if challenged in homozygotes, no effect in heterozygote females
B= factor 9
Lhasa apso, Labrador, GSD. British shorthair
Also de novo mutations reported.
X linked recessive.
can be mod to severe bleeding
C = factor 11
X linked recessive
Springer spaniel and Weimereiner
Mild bleeding
Virchow’s Triad
Increased procoagulant factors (plt activity, aggregation, clotting factors, decreased anticoagulant factors)
Vascular stasis
Endothelial damage
Causes of Hypercoagulability with pathogenesis
IMHA - release of ADP from cells; Hgb scavenging NO (plt inhibitor)
Protein losing diseases (loss of anti>pro coagulant factors, reduced NO production)
Cardiac disease in cats (turbulent flow in LA, damage to cardiac endothelium)
Inflammatory Disease (increased thrombin leads to platelet activation, cytokines enhance endothelial adhesion; endothelial dysfunction reduces NO and PGE2)
Neoplasia (increased plt activation, promotion of thrombocytosis, endothelial disruption, proinflammatory factors)
Endocrine disease (HAC - increased fibrinogen and thrombin-antithrombin promote plt aggregation, DM - hyperglycaemia promotes platelet aggregation, HyperTH) Changes persist after treatment
Inflammatory disease
Liver Disease (reduced protein C and S and antithrombin)
What is the proposed cause of hyperfibrinolysis (delayed postop bleeding) in greyhounds
Deficiency in antiplasmin and antithrombin have been reported in a population of GH with delayed bleeding (still within normal range but significantly reduced compared to non-bleeding controls)
suggests that enhanced fibrinolysis may be the primary mechanism behind post-operative bleeding in this breed
Supported by the fact that anti-fibrinolytic medications reduce the incidence of delayed haemorrhage in this breed
Liver disease alterations to coagulation
HYPO:
reduced clotting factors
acquired vitamin K deficiency
reduced clearance of plasminogen and tPA results in hyperfibrinolysis
HYPER
Reduced protein C and S and antithrombin
Reduced plasminogen clearance.
reduced clearance of
Differentials for hyperfibrinolysis
Acute trauma
DIC
Angiostrongylus vasorum (lungworm)
Cavitary effusions (absorption of fibrinolytic substances)
Liver failure
Goals of Tx in venous thrombosis
Improve blood flow - use antiplatelet agents as these reduce amount of vasoactive substance release (occurs when platelets are activated)
other vasodilators have generally not been as successful
Pain management
reduction in thrombus formation - LMWH, plt inhibitors
