Coagulation Disorders Flashcards
Roles of von Willebrand factor
- Mediates platelet adhesion
- Carrier protein for Factor VIII
Sites of action of antiplatelet agents
Notes on models of coagulation - coagulation cascade
**Waterfall/Cascade
**Circulation of coagulation proteins as inactive zymogens
Sequential activation to serim proteases in presence of PL, Ca
Explained role of known factors, correlated with PT, APTT, plasma based assays
Limitations -> patients with deficiencies in contact factors don’t tend to have bleeding in vivo. Also implies Factor VIIa and tissue activation should be able to bypass Factor VIII or Factor IX deficiency in the intrinsic pathway - not the case as haemophiliacs with Factor VIII or Factor IX deficiency do have clinical bleeding
Notes on cell based model of coagulation
Overlapping phases
1. Initiation -> trace amounts of thrombin at site of injury
2. Amplification -> assembly of factor complexes on activated platelets
3. Propagation -> thrombin “burst” converts fibrinogen to fibrin and FXIII crosslinks fibrin polymers
Notes on “natural anticoagulants”
- Anti-thrombin (AT-III) -> helps to inactivate factor X, factor II and IX, XI, XII
- Protein C and co-factor Protein S -> switch off activated Factor V and VIII
- Tissue factor pathway inhibitor -> switches off Tissue factor VII pathway
Notes on the fibrinolytic pathway
Thrombin key enzyme that converts fibrinogen -> fibrin
Plasmin is the key enzyme that converts fibrin into fibrin fragments. Plasmin in turn generated from plasminogen (activated by tissue plasminogen activator and urokinase plasminogen activator)
Plasmin - very short half life as inhibited by alpha 2 anti-plasmin. Other breaks on system plasminogen activator inhibitor (predominant inhibitor)
Notes on coagulation assays
Extrinsic/PT pathway -> assay triggered by thromboplastin = TF, phospholipid membrane and calcium
Intrinisc pathway/APTT -> assay triggered by contact activation = silica, ellegic acid with phospholipid membrane and calciu
Deficiency of Factor VII -> prolonged PT
Deficiency of Factor VIII, IX, XI, XII -> prolonged APTT
Deficiency of Factor V, X, II -> PT and APTT prolonged
Thrombin time -> small amount of exogenous thrombin added to plasma and time taken to convert fibrinogen to fibrin clot is measured
- Inhibited by dabigatran and heparin (indirect thrombin inhibitor and increases the potency of natural antithrombin to inhibit thrombin)
- Thrombin time also affected by low fibrinogen levels/dysfunctional fibrinogen & the presence of fibrin degradation products generated for instance in DIC (also act as inhibitors and prolong the thrombin time)
Notes on relationship of INR to factor levels
Non-linear
At a level of 30% factor levels -> generally see normal haemostasis
Mildly prolonged INRs do not need treatment
Usual FFP doses won’t alter mildly prolonged INRs
Notes on mixing studies/correction tests
Used when a prolonged APTT -> helps to determine if there is a factor deficiency or a specific or non-specific factor inhibitor such as a lupus anticoagulant
Sample coagulation assay results
Sample coagulation assays
Targets for anticoagulants in the coagulation cascade
Comparison of DOACs to Warfarin
Can use warfarin in breastfeeding
**Lab measurement of DOACs
**Clinical trials -> good safety without monitoring
No steady state (unlike UFH/warfarin)
Dose adjustment based on drug levels not indicated
Lab reagents show variable sensitivty to DOACs for routine coag assays
DOAC effects on routine coagulation assays
Notes on reversal agents for DOACs
Notes on perioperative management of patients with AF receiving a DOAC
PAUSE Study -> low rates of major bleeding and thromboembolism
VTE risk causes by hormon therapies
Notes on heparin induced thrombocytopaenia
- Iatrogenic disorder mediated by IgG antibodies that bind PF4-heparin complexes
- These antibodies cause a hypercoagulable state by activating platelets and procoagulant microparticles
- 1/3 - 1/2 patients develop venous, artieral or microvascular thrombosis
- Unfractionated heparin A/W 10 fold increased risk of HIT compared to LMWH
- See pre-test probability algorithm below
Notes on monitoring for HIT in asymptomatic patients receiving heparin
Notes on vaccine induced thrombocytopaenia and thrombosis
-Adverse effect of certain adenoviral vector COVID-19 vaccines - AstraZeneca, Johnson & Johnson
-Resembles HIT - high levels of anti-PF4 antibodies, platelet activating immune complexes, subsequent platelet aggregation and clot formation
- Differs from HIT in that occurs without exposure to heparin, pattern of platelet reactivity does not demonstrate typical herpain- dependence
Important points in bleeding history
Clues to source of bleeding (platelet vs clotting factor) based on history
Haemophilia A and B and bleeding symptoms
- A = Factor VIII deficiency
- B = Factor IX deficiency
- Severity of bleeding usually correlated with clotting factor level
- Majoirty of spontaneous bleeds occur into the joints or muscles
**Inheritance
**X linked recessive -> but 1/3rd won’t have a family history of the disorder when they present
Lyonisation -> random X inactivation
- Some women will have Factor VIII (or IX) levels in the mild haemophilia range due to extremem lyonisation
- Turner’s syndrome (XO) may have severe Haemophilia A
- Other bleeding disorders have AD or AR inheritance - males and females
**Prophylaxis
**Prophylaxis (with factor VIII/IX prevents joint bleeds)
Notes on rare bleeding disorders - correlation between factor levels and clinical bleeding severity
Notes on von Willebrand Disease
- Most common inherited bleeding disorder - 1% population
- Men and women in equal numbers but often more prominent in women. AD inheritance
- Most common symptoms in women is heavy/prolonged menstruation
- Risks of misdiagnosis and under/over diagnosis
**VWF levels increased by
**Advancing age, African race vs Caucasian, Non-O blood group, Lewis blood group, Adrenaline, Inflammation, Hormones - pregnancy, OCP
