Anti-Coagulants

Question 1

Factors that predispose to thrombosis:?

Answer 1

1) Atheromatous plug rupture;
2) Altered blood flow- Blood stasis (atrial fibrillation and long flights);
3) abnormal coagulability
(Pregnancy, oral contraceptives and thrombophilia);
4) Thrombi can break away forming an embolus. It can interrupt blood flow causing ischemia or infarction

Question 2

Drugs used in the tx of Venous Thrombi?

Answer 2

Anticoagulants

Question 3

Drugs used in the Tx of Arterial thrombi?

Answer 3

Antiplatelets

Question 4

Anticoagulant Drugs

Answer 4

1) Heparins (LMWH,HMWH) - 1st line
2) Hirudins (direct thombin inhibitors) - 2nd line
3) Novel oarl Anticoagulants (NOAC) -
direct thrombin inhibitros and Selective Xa inhibitors
4) Vitamine K Antagonists

Question 5

Clinical uses of Heparin (HMWH/LMWH)

Answer 5

1st line
- DVT
- PE
- MI
* safe in pregnancy

* LMWH are prefered over HMWH

Question 6

LMWH examples

* Low molecular weight heparin (LMWH)

Answer 6

enoxaparin,
dalteparin,
fondaparinux

- parin

Question 7

Contraindications of LMWH

Answer 7

1) renal failure (As they are eliminated by renal excretion)
2) ATIII deficiency (rare) –> can cause Thrombophilia

Question 8

Heparin inhibits thrombin (IIa) and factor Xa activation. How?

Answer 8

Actiavtion of ATIII (Anti-thrombin III), thus ATIII conformation changes and increases its affinity for serine proteases–> inhibits Thrombin (IIa) and factor Xa.

Question 9

What is the pathogenesis of Heparin-induced Thrombocytopneia (HIT)

Answer 9

IgG Abs form a complex w/ Heparin bound to platelet factor IV –> platelet activation -> thrombosis –> ↓↓ Platelets

• LMWH are less likely to cause HIT than HMWH

Question 10

MoA of LMWH

Answer 10

LMWH increases the action of ATIII on Xa only –> it cannot increase the action on ATIII on thrombin and it cannot bind both simultaneouslY

       **Act mainly on factor Xa ONLY**

Question 11

what is used to reverse Heparin AE?

Answer 11

Protamine sulfate

Question 12

AE of Heparin

Answer 12

1) Haemorrage (bleeding)
2) Heparin -induced Thrombocytopenia (HIT) - caused mainly by Unfractioned Heparins (HMWH)
3) Osteoperosis
4) Drug-Drug rxn- hypersensitivity
5) Hyperaldosteronism (w/ Hyperkalaemia) - Uncommon but monitore K+ levels if tx is to be continued for > 7days

Question 13

Administration of HMWH

Answer 13

IV- they cannot be absorbed from the gut

Question 14

Monitoring method for HMWH (Unfractioned Heparin)

Answer 14

Activated Partial Thromboplastin Time (aPTT)
- The dose must be adjusted to reach a value within a target range (eg 1.5-2.5 times control)

Question 15

Monitoring method for LMWH

Answer 15

anti-Factor Xa assays
NOTE:
Monitoring not required routinely,eliminated
mainly by renal excretion

Question 16

Direct thrombin inhibitors Examples

Answer 16

Hirudins
Lepidurin,
Bivalirudin,
Argatroban(IV)
LAB

Question 17

MoA Bivalirudin, Argatroban, Dabigatran?

Answer 17

Direct thrombin inhibitors (Factor IIa)

Question 18

Clinical uses of Direct thrombin inhibitors?

Answer 18

• Used as an alternative to heparins in patients with type II HIT (and for HIT treatment)
• DVT
• Afib

*HIT : herapin induced thrombocytopnia

Question 19

main AE of Direct thrombin inhibitors and selvetive Xa inhibitors?

Answer 19

bleeding

Question 20

bleeding caused by Selective Xa inhibitors can reversed by?

Answer 20

Andexanet alfa

Question 21

An oral direct thrombin inhibitor

*inhibits the converstion of fibrinogen to fibrin

Answer 21

Dabigatran

*NOAC

Question 22

MoA of Dabigatran

Answer 22

Pro-drug direct thrombin inhibitor which inhibits the conversion of fibrinogen into fibrin

Question 23

Clinical uses of Direct thrombin inhibitors and Selective Xa inhibitors

Answer 23

1) Tx and prophylaxis for DVT and PE (followed by knee or hip replacement)
2) Prophylaxis for stroke in patients w/ Afib

Question 24

Antidote for Dabigatran

Answer 24

idarucizumab
( info:antibody fragment that can reverse the anticoagulant effects of dabigatran)

Question 25

Factor Xa inhibitors?

Answer 25

Rivaroxaban
Apixaban
Edoxaban

*NOAC

Question 26

MoA of Rivaroxaban
Apixiban, Edoxaban

Answer 26

Factor Xa selectivity rather than for thrombin.

Question 27

AE of factor Xa inhibitors?

Answer 27

bleeding, anaemia
Rivaroxaban–> commonly causes nausea

Question 28

Characteristics of Vitamin K

Answer 28

1) fat soluble vitamin
2) Essential for the formation of clotting factors II, VII, IX and X (Glycoproteins with several γ-carboxyglutamic acid (Gla) residues)
3) Other vitamin K-dependent Gla proteins, include
proteins C and S (anticoagulants) and osteocalcin in bone

Question 29

Natural vitamin K1?

Answer 29

phytomenadione
(orally or Subcutaneously)

Question 30

synthetic Vitamin K?

Answer 30

menadiol sodium phosphate
(takes longer to act than phytomenadione)

Question 31

Clinical uses of phytomenadione (Natural Vitamin K) and menadiol sodium phosphate (synthetic)

Answer 31

Treatment and/or prevention of bleeding
* From excessive oral anticoagulation (e.g. by warfarin)
* In babies to prevent haemorrhagic disease of the newborn
* Coeliac disease
* Lack of bile (e.g. with obstructive jaundice)
* Liver disease

Question 32

Vitamine K Antagnosits Examples

Answer 32

Warfarin (oral)
Phenidione (Alternatice to warfarin in patients with idiosyncratic-distict AE)

Question 33

Clinical uses of Warfarin

Answer 33

standard anticoagulant for treatment and prevention of thromboembolic disease

Question 34

MoA of Warfarin

Answer 34

Inhibition of of vitamin K epoxide reductase —> Inhibits γ-carboxylation of factors II, VII, IX ,X, protein C,S)

Question 35

AE of warfarin

Answer 35

1) Haemorrhage - bleeding
2) skin/soft tissue necrosis –> due to microthrombi as a resutl of initial Hypercoagulable state ( by the inhibition of protein C biosynthesis)
3) Teratogenic

Question 36

A patient receiving long-term warfarin needs which weekly labs to determine if they are within therapeutic range ( to reverse/prevent AE)?

Answer 36

Prothrombine time/ International normalized ratio (INR)
(due to effect of warfarin on the extrinsic pathway of coagulation)

ADJUSTED INR 2-4

Question 37

What treatment can reverse Warfarin AE?

Answer 37

Fresh-frozen plasma (FPP) or Prothrombin complex concentrate (PCC) for rapid reversal; Vitamine K for slower reversal

Question 38

Factors that potentiate (increase) warfarin?

Answer 38

° Liver disease (coagulation factors are synthesised in the liver by hepatocytes)
° Drugs that inhibit platelet function
° Drugs that displace warfarin from albumin (NSAIDS, sulfonamides, phenytoin)
° Drugs that decrease the availability of vitamin K.(broad spectrum Abx that depress intestinal flora that synthetises vit K.)

Question 39

Factors that lessen the effect of Warfarin

Answer 39

1) Physiological state/disease
- Increased coagulation factor synthesis (eg. pregnancy)
- reduced degradation of coagulation factors in hypothyroidism.
2) Drugs:
- vit K; (synthesis of coagulation factors)
- CYP450 inducers (Rifampicin, carbamazepine, barbiturates);
- drugs that reduce absorption–> drugs that bind warfarin in the gut (Cholestyramine)

Coagulation factors: II, VII,IX,X also proteins C and S

Question 40

Contraindications of Warfarin

Answer 40

PREGNANCY - teratogenic (cosses the placenta)

Question 41

Which is teratogenic, Heparin or warfarin?

Answer 41

Warfarin
- heparin is safe in pregnancy

Question 42

Polymorphism in what gene affects the metabolism of warfarin?

Answer 42

Vitmain K epoxide reductase gene (VKORC1)

Question 43

Which hepatic enzyme is responsible for the metabolism of warfarin and is implicated in warfarin drug-drug interactions?

Answer 43

CYP2C9