Clotting Flashcards
Glycoproteins provide phospholipid surface for platelets to stick to. Describe 3 glycoproteins that facilitate this step and what they bind to [3]
What other component of the blood assists in platelet adhesion?
Gp 1a/2a + 6 bind directly to exposed collagen
GP 1b bind to vWF, indirectly to collagen
GP 2b/3a bind to Fibrinogen
VWF assists inplatelt adhesion
After a platelet plug is formed, we then form a fibrin clot. What causes this? [2]
Whats the difference between primary hemostatic plug and definitive hemostasis [2]
Activation of coagulation factors by physiological activator e.g. Tissue Factor
These activate each other in a cascade like dominos.
When the primary hemostatic plug forms, its still a weak clot - only fibrinogen adheres
Definitive hemostasis is when fibrin forms
What are the final steps in the coagulation cascade
Prothrombin cleaved to Thrombin
Its then cleaves Fibrinogen to Fibrin which forms the clot
Describe 3 natural anti-coagulants and their function
Overall function: confine clot formation
TFPI - switches off factors 7a and 10a
Proteins C + S - Switch off 5 and 8a, reducing thrombin production
Anti-thrombin - Switches of 5, 8 , 9, 10, 11, thrombin
What triggers fibrinolysis?
[3]
Endothelial cells releasing plasminogen activators (t-PA, u-PA)
What do Tissue Plasminogen Activators do?
They cleave plasminogen into plasmin allowing fibrinolysis to occur
What do we test for in a D-dimer? [1]
Fibrin Degradation Products
Anti-thrombotic drugs include antiplatelets and anticoagulants.
Anti-platelets act in 3 pathways. Give examples of each.
- Target adhering Gylcoproteins eg Abciximab
- Target surface receptors eg Clopidogrel, prasugrel, Ticagrelor
- Inhibition of COX pathway preventing AA> TXA2, prevents platelet aggregation eg aspirin
Warfarin is a common anti-coagulant what does it do? [3]
- Inhibits epoxide reductase, prevents reduction of vitamin K (Vitamin K antagonist)
- Prevents coagulation cascade
- Reduces conc of various clotting factors inc 2, 7, 9, 10 and prothrombin
Other anti-coagulants include heparins and DOACs, what are their MOAs? Give 2 examples of DOACs
Heparins inhibit thrombin
Direct Oral AntiCoagulants:
1) Rivaroxaban inhibits factor Xa
2) Dabigatran inhibits thrombin
Endothelium produces a variety of substances in a physiological state in a blood vessel. What are these substances that cause endothelium to act as a non-stick pan? [5]
Heparans TFPI - tissue factor pathway inhibitor Thrombomodulin Prostacyclin NO
Vessel damage results in platelet adhesion: 3 steps
Describe the last 2 steps
Platelets adhere, activate and aggregate
Platelet activation - platelets release ADP, thromboxane A2 and serotonin which attract more platelets causing…
Platelet aggregation - platelet plug formation
What inhibits t-PA and u-PA? [2]
What inactivates plasmin [3]
Describe TAFI
Regulators:
Inhibitors of plasminogen t-PA and u-PA: PAI-1 and PAI-2
Inhibitors of plasmin - alpha2-antiplasmin, alpha2-macroglobulin
Thrombin activatable fibrinolysis inhibitor (TAFI) which modifies fibrin to make it more resistant to t-PA
Warfarin
Indications [3]
Side effects
Indications
- VTE
- AF
- Mechanical heart valves
SE
- Hemorrhage
- Teratogenic
- Skin necrosis
- Purple toes
How does skin necrosis occur as a side effect in warfarin?
How can it be avoided?
synthesis of protein C reduced at first when started causing temporary pro-coagulant state (normally avoided by concurrent heparin administration) so thrombosis across venules leads to skin necrosis
Warfarin: interactions
Potentiators [8]
Reduce effects [3]
P450 enzyme inhibitors - potentiate effect Ciprofloxacin, erythromycin Omeprazole Amiodarone Allopurinol Ketoconazole, fluconazole Sertraline, Fluoxetine Sodium valproate Acute alcohol intoxication
P450 enzyme inducers - reduce effect Phenytoin, Carbamazepine, Phenobarbitone St John’s wort Chronic alcohol intake Smoking (affects CVP1A2)
Advise going on warfarin [2]
- monitored by INR
- long half-life means takes a number of days to achieve a stable INR
Management of high INR:
- Major bleeding [3]
- INR >8 with minor bleeding [3]
Major bleeding:
STOP warfarin and give IV VITAMIN K 5mg and PROTHROMBIN COMPLEX CONCENTRATE (FFP if not available)
INR>8 and minor bleeding:
STOP warfarin and give IV VITAMIN K 1-3mg (repeat dose after 24h if INR still too high); restart WARFARIN when INR <5
Management of INR 5-8 and no bleeding [2]
INR 5-8 and no bleeding: WITHOLD 1-2 doses of warfarin and then reduce subsequent maintenance dose
Antithrombin activators are another form of anticoagulant medications. Describe their MOA
Give 4 examples
Activates antithrombin III to form a complex [1] that inhibits thrombin, factors Xa, IXa, Xia and XIIa [1]
Eg: heparin, LMWH
Enoxaparin, dalteparin, fondaparinux
In what situation would heparin [2] and LMWH [2] be indicated
o Heparin: situations where high risk of bleeding as anticoagulation can be terminated rapidly, renal failure
o LMWH: VTE treatment and prophylaxis, ACS
Complications of Antithrombin activators [2]
Active bleeding
Bacterial endocarditis
Antithrombin activators SE [6]
Bleeding Osteoporosis (lower risk with LMWH) Heparin induced Thrombocytopenia (lower risk with LMWH) Hyperkalaemia
What do you do for overdose reversal of heparins and LMWH
Protamine sulphate fully reverses effect of heparin
Partially reverses effects of LMWH
Interactions [2]
NSAIDs, SSRIs, platelets
Increased bleeding risk
MOA of aspirin [3]
Indications
COX inhibitor preventing TXA2 formation
Promotes platelet aggregation
Indications
- Atherosclerotic disease secondary prevention
- ACS
- Suspected/actual TIA
Aspirin SE [3]
Interactions [4]
- Gastric erosions
- Bronchospasm
- Tinnitus
Interactions:
- Increased bleeding risk with SSRIs
- NSAIDs inhibit platelet action
- Aspirin reduces methotrexate excretion
- Toxicity with acetazolamide
Dypyramidole
Indications [2]
SE [4]
Indicated:
- Secondary stroke and TIA prevention
- Anticoagulant adjunct in thromboembolism prophylaxis if prosthetic heart valve
SE:
- GI upset
- Vasodilation
- Hemorrhage less common
- Worsens IHD symptoms
Reversal of dabigatran?
Idarucizumab
What are indications of NOAC? [3]
Prevention of VTE following hip/knee surgery
Mx of DVT/PE
Prevention of stroke in non-valvular AF
Comparing UH with LMWH
Standard heparin (mini-Hep)
- Activates antithrombin III
- Forms complex that inhibits thrombin, factors Xa, IXa, Xia and XIIa
- RENAL failure
- Short acting
LMWH
- Only increases the action of antithrombin III on factor Xa
- Cannot be used in renal failure
- Long acting
Low molecular weight heparins are renally excreted and hence accumulate in severe renal impairment. While the doses recommended for prophylaxis
against DVT and prevention of thrombus formation in extracorporeal circuits are well tolerated in patients with ERF, the doses recommended for treatment of DVT and PE have been associated with severe, sometimes fatal, bleeding episodes in such patients. Hence the use of unfractionated heparin
would be preferable in these instances.
Comparing monitoring in UH and LMWH
UH - APTT
LMWH - anti factor Xa monitored although not routinely monitored
Heparin induced thrombocytopenia pathophysiology [2]
Immune mediated antibodies form against complexes of platelet factor 4 and heparin
Abs bind to PF4-heparin complexes on platelet surface and activate platelets
HIT
Onset
Features
Treatment
usually does not develop until after 5-10 days of treatment
despite being associated with low platelets HIT is actually a prothrombotic condition
features include a greater than 50% reduction in platelets, thrombosis and skin allergy
treatment options include alternative anticoagulants such as lepirudin and danaparoid
