Haemostasis 2 Flashcards
What is the role of coagulation?
generate thrombin (IIa)
What does thrombin (IIa) do?
convert fibrinogen to fibrin
What does deficiency of any coagulation factor result in?
failure of thrombin generation and hence fibrin formation
What does prothrombin (PT) time measure?
Extrinsic pathway (tissue factor 7)
What does the activated partial thromboplastin time (APTT) measure?
Intrinsic pathway (trigger this with contact acitvation e.g. glass, silica)
What could cause normal PT but high APTT?
- Haemophilia A (8)
- Hamophilia B (9)
- Factor XI deficiency
- Factor XII deficiency
What could cause normal APTT but prolonged PT?
Factor VII deficiency
What could cause prolonged APTT and PT?
- Liver disease
- Anticoagulant drugs e.g. warfarin
- DIC (platelets and D dimer)
- Dilution following red cell transfusion
- Deficiency in common pathway so deficiency in factor 5,10,2
How do you treat failure of production/function in abnormal haemostasis?
-Replace missing factor/platelets
i) Prophylactic
ii) Therapeutic
-Stop drugs e.g. aspirin/NSAIDs
How do you treat immune destruction in abnormal haemostasis?
- Immunosuppression (e.g. prednisolone)
- Splenectomy for ITP
How do you treat increased consumption in abnormal haemostasis?
- Treat cause
- Replace as necessary
What are some options for factor replacement therapy?
- Fresh frozen plasma (FFP)
- Cryoprecipitate
- Factor concentrates
- Recombinant forms of FVIII and FIX
What is FFP?
Contains all coagulation factors
What is cyroprecipitate?
Rich in Fibrinogen, FVIII, VWF, Factor XIII
What are factor concentrates?
- Concentrates available for all factors except factor V.
* Prothrombin complex concentrates (PCCs) Factors II, VII, IX, X
What are recombinant forms of FVIII and FIX?
- ‘On Demand’ to treat bleeds
- Prophylaxis to prevent bleeds
What is the evolution of haemophilia treatment?
- plasma derived clotting factors (Widespread viral contamination)
- Recombinant clotting factors FVIII and FIX (eliminated potential for transmission of blood borne pathogens)
- Investigational therapies
What are some investigation therapies?
- Prolonged half life (FVIII/FIX): Fc fusion, PEG, albumin fusion
- Gene therapy (A and B)
- Novel agents:
-Bispecific antibody (emicizumab)
-Anti TFPI antibody
-Anti thrombin RNAi
(reduce antithrombin means a procoagulation effects)
What does emicizumab do?
-Just A
-Bi-specific anitbody
•Binds to FIXa and FX
•Mimics procoagulant function of FVIII
What does RNA silencing do?
-A and B
•Targets natural anticoagulant - antithrombin
What are some additional treatments for abnormal haemostasis?
- Desmopressin (DDAVP)
-Vasopressin analogue
-2-5 fold increase in VWF (and FVIII)
releases endogenous stores (so only useful in mild disorders) - Tranexamic acid
Antifibrinolytic - Fibrin glue/spray
- Other approaches e.g hormonal (oral contraceptive pill for menorrhagia)
When can bleeding result from increased fibrinolytic factors and anticoagulant proteins?
- Very rare except when induced by drugs
1. tPA (stroke) Increasing fibrinolysis
2. Heparin increases antithrombin
How does pulmonary embolism (PE) present?
- Tachycardia
- Hypoxia
- Shortness of breath
- Chest pain
- Haemopysis
- Sudden death
How does deep vein thrombosis (DVT) present?
- Painful leg
- Swelling
- Red
- Warm
- May embolise to lungs
- Post thrombotic syndrome
- Can cause damage to valves
What is thrombosis?
- Intravascular coagulation
- Inappropriate coagulation
- Venous (or arterial)
- Obstructs flow
- May embolise to lungs
What is Virchow’s triad?
three contributory factors to thrombosis
What are the three factors? When are each dominant?
- Blood: dominant in venous thrombosis
- Vessel wall:dominant in arterial thrombosis
- Blood flow: contributes to both arterial and venous thrombosis
What is thrombophilia?
Increased risk of venous thrombosis
How may thrombophilia present?
- Thrombosis at young age
- ‘spontaneous thrombosis’
- Multiple thromboses
- Thrombosis whilst anticoagulated
How can venous thrombosis happen?
- Decrease in anticoagulant factors
- Increase in coagulant factors
- Increase in platelets
Which anticoagulant proteins are decreased?
- Antithrombin
- Protein C
- Protein S
Which coagulant factors and platelets are increased?
- Factor VIII
- Factor II
- Factor V Ledien (increase activity due to activated protein C resistance)
- Myelloproliferative disorders e.g. essential thrombocythemia (increased platelets)
What does protein C and its cofactor protein S do?
- Activates factor 5a and 8a
- As soon as activated need to be inactivated by protein C helped by protein S
- Antithrombin inactivates thrombin factor 2a and factor 10a
How does the vessel wall contribute to venous thrombosis?
Many proteins active in coagulation are expressed on the surface of endothelial cells and their expression altered in inflammation (TM, EPCR, TF)
How does blood flow contribute to venous thrombosis?
Reduced flow (stasis) increases the risk of thrombosis e.g. surgery, long haul flight, pregnancy
How do you prevent venous thrombosis?
- Assess and prevent risks
* Prophylactic anticoagulant therapy
How do you reduce the risk of reccurence/extension?
• lower procoagulant factors
e.g warfarin, DOACs
• increase anticoagulant activity
e.g: heparin
How can anticoagulants be used therapeutically for venous thrombosis?
- Initial treatment to minimise clot extension/embolisation (< 3 months)
- Long term treatment to reduce risk of recurrence
How can anticoagulants be used therapeutically for atrial fibrillation?
- 800 per 100 000 population potentially eligible in 1 year
- To reduce risk of embolic stroke
How else can anticoagulants be used therapeutically?
Mechanical prosthetic heart valve
How can anticoagulants be used in a preventative way
(Thromboprophylaxis)
•E.g. following surgery, during hospital admission, during pregnancy
What is heparin?
- Naturally occurring glycosaminoglycan
- Produced by mast cells of most species
- Porcine products used in UK
What are the chains like in heparin?
•Varying numbers of saccharides in chains – differing lengths
- Long chains - Unfractionated (UFH) – intravenous administration, short half life
- Low molecular weight (LMWH) – subcutaneous administration
How does unfractionated heparin work?
•Enhancement of Antithrombin
- Inactivation of thrombin (Hep binds AT + Thrombin)
- Inactivation of FXa (Hep binds AT only)
- (Inactivation of FIXa, FXIa, FXIIa)
How does LMW heparin work?
- Contain pentasaccharide sequence for binding AT
* Predictable dose response in most cases so does not require monitoring (cf UFH)
How does LMW heparin affect APTT?
- Not useful for monitoring so if need to measure use Anti-Xa
- No monitoring required as predictable effect
How does unfractioned heparin affect APTT?
Prolongation, used to monitor effect
How does Warfarin work?
- Blocks recycling of VitK
- So VitK dependent clotting factors 2,7,9,10 and anticoagulant factors proteins C and S
- VitK cannot be reduced back down to hydroquinone state and reused for gaba carboxylation
Why is it bad that warfarin competes with Vit K?
– complicated metabolism
•Many dietary, physiological and drug interactions
•Narrow therapeutic index and requires monitoring
What is the effect of warfarin?
- Reduces production of functional coagulation factors
* Induces an anticoagulated state slowly
Is warfarin reversible? How is it reversed slowly?
- Reversible
- Reversed slowly by Vit K administration – takes several hours to work
How is warfarin reversed rapidly?
infusion of coagulation factors:
- PCC (Prothrombin Complex Concentrate- contains Factors II, VII, IX and X)
- FFP (Fresh Frozen Plasma)
What are warfarin side effects?
-Bleeding •Minor 5% pa •Major 0.9 – 3.0% pa •Fatal 0.25% pa -Skin Necrosis -Purple toe syndrome -Embryopathy – Chondrodysplasia punctata
What is skin necorsis?
- Severe protein C deficiency
- 2-3 days After starting warfarin
- thrombosis predominately in adipose tissues
- Can start on heparin instead - need overlap
What is purple toe syndrome?
- Disrupted atheromatous plaques bleed
- Cholesterol embolI lodge in extremities
What is chondrodysplasia?
- Early fusion of epiphyses
- Warfarin teratogenic in 1st trimester
How do you monitor warfarin?
- ISI = International Sensitivity Index
- Indicates sensitivity of particular thromboplastin for warfarin
- Unanticoagulated normal INR = 1.0
- Target INR usually 2-3
Why can there be resistance to warfarin?
- Lack of patient compliance
•Measure warfarin levels
•Proteins Induced by Vitamin K Absence (PIVKA) - Diet, Increased Vit K intake
- Increased metabolism Cyt P450 (CYP2C9)
- Reduced binding (VKORC1)
Which DOAC’s work as a direct inhibitor of factor Xa?
- Rivaroxaban
- Apixaban
- Edoxaban
Which DOAC’s work as a direct inhibitor of factor IIa?
Dabigatran
What is the difference between DOACs and warfarin with onset/offset?
- Warfarin: slow
- DOACs: rapid
What is the difference between DOACs and warfarin with dosing?
- Warfarin: variable
- DOACs: fixed
What is the difference between DOACs and warfarin with food effect?
- Warfarin: yes
- DOACs: No
What is the difference between DOACs and warfarin with interactions?
- Warfarin: many
- DOACs: few
What is the difference between DOACs and warfarin with monitoring required?
- Warfarin: yes
- DOACs: no
What is the difference between DOACs and warfarin with renal dependence?
- Warfarin: no
- DOACs: some
What is the difference between DOACs and warfarin with reversibility?
- Warfarin: vitamin K / PCCs
- DOACs: specific antidotes available for dabigatran and in development for FXa inhibitors
Which anticoagulant do you use for intial treatment to minimise clot extension/embolism (<3 months) for a therapeutic effect in venous thrombosis?
-DOAC or LMWH for first few days followed by DOAC or warfarin
Which anticoagulant do you use for long term treatment to reduce risk of reccurence for a therapeutic effect in venous thrombosis?
-DOAC or warfarin
What anticoagulant do you give for a therapeutic effect in atrial fibrillation to reduce risk of embolic stroke?
-DOAC or warfarin
Which anticoagulant do you give in a therapeutic effect for those with mechanical prosthetic hear valve?
- Warfarin (DOACs not effective and should be avoided)
Which anticoagulant do you give for a preventative effect following surgery?
- lower doses used
- LMWH or DOAC
Which anticoagulant do you give for a preventative effect during hospital admission?
- lower doses used
- (DOACs not effective for use as medical thromboprophylaxis
Which anticoagulant do you give for a preventative effect during pregnancy?
- lower doses used
- LMWH (DOACs not safe in pregnancy)
