Clotting

Question 1

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?

Answer 1

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

Question 2

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]

Answer 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

Question 3

What are the final steps in the coagulation cascade

Answer 3

Prothrombin cleaved to Thrombin

Its then cleaves Fibrinogen to Fibrin which forms the clot

Question 4

Describe 3 natural anti-coagulants and their function

Answer 4

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

Question 5

What triggers fibrinolysis?

[3]

Answer 5

Endothelial cells releasing plasminogen activators (t-PA, u-PA)

Question 6

What do Tissue Plasminogen Activators do?

Answer 6

They cleave plasminogen into plasmin allowing fibrinolysis to occur

Question 7

What do we test for in a D-dimer? [1]

Answer 7

Fibrin Degradation Products

Question 8

Anti-thrombotic drugs include antiplatelets and anticoagulants.
Anti-platelets act in 3 pathways. Give examples of each.

Answer 8

• Target adhering Gylcoproteins eg Abciximab
• Target surface receptors eg Clopidogrel, prasugrel, Ticagrelor
• Inhibition of COX pathway preventing AA> TXA2, prevents platelet aggregation eg aspirin

Question 9

Warfarin is a common anti-coagulant what does it do? [3]

Answer 9

• 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

Question 10

Other anti-coagulants include heparins and DOACs, what are their MOAs? Give 2 examples of DOACs

Answer 10

Heparins inhibit thrombin

Direct Oral AntiCoagulants:

1) Rivaroxaban inhibits factor Xa
2) Dabigatran inhibits thrombin

Question 11

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]

Answer 11

Heparans
TFPI - tissue factor pathway inhibitor
Thrombomodulin
Prostacyclin
NO

Question 12

Vessel damage results in platelet adhesion: 3 steps

Describe the last 2 steps

Answer 12

Platelets adhere, activate and aggregate
Platelet activation - platelets release ADP, thromboxane A2 and serotonin which attract more platelets causing…
Platelet aggregation - platelet plug formation

Question 13

What inhibits t-PA and u-PA? [2]
What inactivates plasmin [3]
Describe TAFI

Answer 13

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

Question 14

Warfarin
Indications [3]
Side effects

Answer 14

Indications

• VTE
• AF
• Mechanical heart valves

SE

• Hemorrhage
• Teratogenic
• Skin necrosis
• Purple toes

Question 15

How does skin necrosis occur as a side effect in warfarin?

How can it be avoided?

Answer 15

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

Question 16

Warfarin: interactions
Potentiators [8]
Reduce effects [3]

Answer 16

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)

Question 17

Advise going on warfarin [2]

Answer 17

• monitored by INR

- long half-life means takes a number of days to achieve a stable INR

Question 18

Management of high INR:

• Major bleeding [3]
• INR >8 with minor bleeding [3]

Answer 18

 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

Question 19

Management of INR 5-8 and no bleeding [2]

Answer 19

 INR 5-8 and no bleeding: WITHOLD 1-2 doses of warfarin and then reduce subsequent maintenance dose

Question 20

Antithrombin activators are another form of anticoagulant medications. Describe their MOA
Give 4 examples

Answer 20

Activates antithrombin III to form a complex [1] that inhibits thrombin, factors Xa, IXa, Xia and XIIa [1]

Eg: heparin, LMWH
Enoxaparin, dalteparin, fondaparinux

Question 21

In what situation would heparin [2] and LMWH [2] be indicated

Answer 21

o Heparin: situations where high risk of bleeding as anticoagulation can be terminated rapidly, renal failure
o LMWH: VTE treatment and prophylaxis, ACS

Question 22

Complications of Antithrombin activators [2]

Answer 22

Active bleeding

Bacterial endocarditis

Question 23

Antithrombin activators SE [6]

Answer 23

Bleeding
Osteoporosis (lower risk with LMWH)
Heparin induced
Thrombocytopenia (lower risk with LMWH)
Hyperkalaemia

Question 24

What do you do for overdose reversal of heparins and LMWH

Answer 24

Protamine sulphate fully reverses effect of heparin

Partially reverses effects of LMWH

Question 25

Interactions [2]

Answer 25

NSAIDs, SSRIs, platelets | Increased bleeding risk

Question 26

MOA of aspirin [3] | Indications

Answer 26

COX inhibitor preventing TXA2 formation Promotes platelet aggregation Indications - Atherosclerotic disease secondary prevention - ACS - Suspected/actual TIA

Question 27

Aspirin SE [3] | Interactions [4]

Answer 27

- Gastric erosions - Bronchospasm - Tinnitus Interactions: - Increased bleeding risk with SSRIs - NSAIDs inhibit platelet action - Aspirin reduces methotrexate excretion - Toxicity with acetazolamide

Question 28

Dypyramidole Indications [2] SE [4]

Answer 28

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

Question 29

Reversal of dabigatran?

Answer 29

Idarucizumab

Question 30

What are indications of NOAC? [3]

Answer 30

Prevention of VTE following hip/knee surgery Mx of DVT/PE Prevention of stroke in non-valvular AF

Question 31

Comparing UH with LMWH

Answer 31

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.

Question 32

Comparing monitoring in UH and LMWH

Answer 32

UH - APTT LMWH - anti factor Xa monitored although not routinely monitored

Question 33

Heparin induced thrombocytopenia pathophysiology [2]

Answer 33

Immune mediated antibodies form against complexes of platelet factor 4 and heparin Abs bind to PF4-heparin complexes on platelet surface and activate platelets

Question 34

HIT Onset Features Treatment

Answer 34

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