Drugs Used In Hemostasis And Thrombosis

Question 1

What is hemostasis?

Answer 1

The term ‘haemostasis’ refers to the normal response of the vessel to injury by forming a clot that serves to limit haemorrhage

Question 2

What is thrombosis?

Answer 2

Thrombosis is pathological clot formation that results when haemostasis is excessively activated in the absence of bleeding

Question 3

How do drugs modify hemostasis and thrombosis?

Answer 3

Drugs can be used to modify haemostasis and thrombosis in three ways: (1) By modifying coagulation (2) By modifying platelet aggregation (3) By modifying fibrinolysis

Question 4

What is the action of anti-coagulants in thrombosis?

Answer 4

Anticoagulants prevent thrombus formation or extension of an existing thrombus in the slower moving venous side of the circulation

Question 5

What is the action of anti-platelet agents in thrombosis?

Answer 5

Anti-platelet agents inhibit adhesion, activation and aggregation of platelets and therefore prevent thrombosis. They are mostly used for prevention of arterial thrombosis

Question 6

What is the action of thrombolytic drugs?

Answer 6

Thrombolytic drugs are used to lyse thrombi in blood vessels in arterial and venous thrombosis, and are useful in conditions such as acute myocardial infarction occurring due to coronary thrombosis

Question 7

What is the action of anti-thrombolytic drugs?

Answer 7

Anti-thrombolytic drugs inhibit thrombolysis and are used in conditions where there is need to inhibit excessive thrombolysis e.g. treatment of excessive effect of thrombolytic drugs

Question 8

What is an embolus?

Answer 8

Any detached, travelling intravascular mass (solid, liquid or gas) carried by circulation which is capable of clogging capillary beds

Question 9

What are the forms of vitamin K?

Answer 9

K1 (Phytomenadione) – found in plants
K2 (Menaquinone) – synthesized by bacteria e.g. E.coli in the mammalian gut
K3 (Menadiol) – synthetic and water soluble
Vitamin K1 and K2 are fat soluble and require bile for absorption while vitamin K3 does not require bile for absorption

Question 10

What is the role of vitamin K in coagulation?

Answer 10

Vitamin K in the reduced form is required as a co-factor for the final stages of the synthesis of clotting factors II, VII, IX and X (gamma carboxylation of the glutamate residues on these proteins)
When vitamin K is deficient or inhibited, the clotting factors formed are not functional

Question 11

What are the clinical uses of vitamin K?

Answer 11

1. Bleeding resulting from vitamin K antagonists such as warfarin (phytomenadione is preferred as it has a rapid action)
2. Haemorrhagic disease of the newborn
3. Vitamin K deficiency: e.g. caused by obstructive jaundice, mal-absorption syndromes and reduced gut flora (as in neonates and use of broad spectrum antibiotics)

Use the water soluble vitamin K3 for deficiency arising from biliary obstruction and mal-absorption syndromes

Question 12

List the categories of anti-coagulants with examples

Answer 12

There are four categories of anti-coagulants:
1. Oral: Vitamin K antagonists e.g. warfarin
2. Oral: Direct thrombin inhibitors and direct Xa inhibitors
3. Parenteral: Heparin and low molecular weight heparins
4. Parenteral: Hirudin and its analogues

Question 13

What are the clinical uses of anti-coagulants?

Answer 13

Anticoagulants are used in the prevention and treatment of deep vein thrombosis in the legs and pulmonary embolism
They are of less use in preventing thrombus formation in arteries

Question 14

What are the goals of anti-coagulant therapy?

Answer 14

1. To stop expansion of established clots
2. To prevent thromboembolism complications
3. To prevent formation of new thrombi
   NB: Anticoagulants do not lyse established thrombi

Question 15

What is the MoA of warfarin?

Answer 15

The first oral anticoagulant to be used clinically and is the most widely used
Warfarin is an antagonist of vitamin K (structurally similar)
It inhibits vitamin K reductase, the enzyme that reduces vitamin K. This impairs the gamma carboxylation of clotting clotting factors II, VII, IX and X and thus the clotting factors formed are not functional

Question 16

Describe the pharmacokinetics of warfarin

Answer 16

Well absorbed from the GIT
99% protein bound to albumin
Unbound warfarin readily crosses membranes including the placenta
Metabolised in the liver
Half-life is 2 days

Question 17

Outline the time course of effects for warfarin

Answer 17

Initial response starts at 8-12 hours
It takes about 72 hours for the full anticoagulant effect to be seen (warfarin has no effect on clotting factors already present prior to the time of drug administration)
On discontinuation of treatment, coagulation remains inhibited for 2-5 days due to the long half-life

Question 18

What are the clinical uses of warfarin?

Answer 18

Prophylaxis against venous thrombosis
Prevention of thromboembolism in patients with prosthetic valves
Prophylaxis against thrombosis in the atria in atrial fibrillation
Due to slow onset of action, warfarin is not used in emergency situations (heparin is used instead)
Warfarin is the drug of choice for long-term anticoagulation for all patients except pregnant women who should be treated with heparin

Question 19

How and why is warfarin monitored in therapy?

Answer 19

Monitored by measuring prothrombin time (expressed as INR). The therapeutic target is INR 2-3.
Warfarin has a narrow therapeutic index thus close monitoring is required

Question 20

What are the adverse effects of warfarin?

Answer 20

Adverse effects: (1) Haemorrhage (2) Cutaneous reactions: purpura, dermatitis, alopecia, pruritic lesions (3) Fetotoxic and teratogenic

Question 21

How do you treat a warfarin overdose?

Answer 21

Vitamin K

Question 22

What are the contraindications of warfarin?

Answer 22

(1) Vitamin K deficiency (2) Liver disease (3) Alcoholism (4) Pregnancy (5) Lactation

Question 23

Explain how and list the drugs that increase the anti-coagulant effect of warfarin

Answer 23

1. Drugs that displace warfarin from albumin: aspirin, salicylates, phenylbutazone, sulfonamides
2. Drugs that inhibit metabolism of warfarin: cimetidine, disulfiram, phenylbutazone, metronidazole, imipramine, ciprofloxacin
3. Drugs that reduce synthesis of clotting factors: broad spectrum antibiotics e.g. ampicillin (inhibit bacterial synthesis of vitamin K)

Question 24

Which drugs have their effect on bleeding enhanced by warfarin?

Answer 24

Other anti-thrombotic drugs

Question 25

Explain how and list the drugs that reduce the effect of warfarin

Answer 25

1. Inducers of drug metabolizing enzymes e.g. barbiturates, carbamazepine, phenytoin, rifampicin, griseofulvin 2. Drugs that promote synthesis of clotting factors: vitamin K, hormonal contraceptives 3. Drugs that decrease absorption of warfarin: cholestyramine, colestipol

Question 26

How do oral direct thrombin inhibitors and oral direct Xa inhibitors differ from warfarin?

Answer 26

In comparison with warfarin, these drugs: - Have equivalent anticoagulant efficacy - Have lower bleeding rates - Have a rapid onset of action - Have a wider therapeutic window - Do not require monitoring for dosage optimization - Have fewer drug interactions

Question 27

List the oral direct Xa inhibitors

Answer 27

Include rivaroxaban and apixaban

Question 28

What is the MoA of oral direct Xa inhibitors?

Answer 28

Inhibit factor Xa, in the final common pathway of clotting They are given as fixed doses and do not require monitoring for dosage optimization They have a rapid onset of action and shorter half-lives than warfarin The main toxicity is bleeding and there is no antidote

Question 29

What are the clinical uses of oral direct Xa inhibitors?

Answer 29

Clinical uses - Prevention of embolic stroke in patients with atrial fibrillation without valvular heart disease - Prevention of venous thromboembolism following hip or knee surgery - Treatment of venous thromboembolic disease

Question 30

Give examples of oral direct thrombin inhibitors

Answer 30

Include dabigatran

Question 31

What are the advantages of oral direct thrombin inhibitors?

Answer 31

Advantages of oral direct thrombin inhibitors include 1. Predictable pharmacokinetics and bioavailability, which allow for fixed dosing and predictable anticoagulant response, thus routine coagulation monitoring not necessary 2. Rapid onset and offset of action allowing for immediate anticoagulation

Question 32

What are the clinical uses of dabigatran?

Answer 32

Prevention of embolic stroke and systemic embolism with non-valvular atrial fibrillation Treatment of venous thromboembolism following 5–7 days of initial heparin or LMWH therapy Venous thromboembolism prophylaxis following hip or knee replacement surgery

Question 33

What are the adverse effects of dabigatran?

Answer 33

The primary toxicity of dabigatran is bleeding Other adverse effects include gastrointestinal adverse reactions and gastrointestinal bleeding There is no antidote for dabigatran

Question 34

Describe the standard heparin

Answer 34

A large polymer composed of repeating units of two disaccharides with a molecular weight of 3000-40,000 daltons An acidic molecule Has many negatively charged groups and is therefore highly polar In the body, heparin is found in mast cells, plasma and endothelial cells

Question 35

What is the time course and MoA of standard heparin?

Answer 35

Heparin augments the effects of anti-thrombin III Anti-thrombin III is a naturally occurring inhibitor of clotting factors IIa, IXa, Xa and XIIa and thereby suppresses fibrin formation Heparin binds to anti-thrombin III and accelerates its rate of activity making it instantaneous Effects occur quickly (within minutes) because it acts directly to inhibit clotting factor activity

Question 36

Explain the pharmacokinetics of standard heparin?

Answer 36

Heparin is not absorbed from the GIT due to its large size and polarity Administered IV or SC (not given IM because of the potential for haematoma formation) Metabolized in the liver and the metabolites are excreted in urine Half-life is 40-90 minutes, and is dose dependent

Question 37

What are the clinical uses of standard heparin?

Answer 37

1. Anticoagulant of choice in pregnancy and in situations that require rapid onset of anticoagulant effects 2. Used in the management of pulmonary embolism, massive deep vein thrombosis, evolving stroke 3. Used in open heart surgery and renal dialysis to prevent coagulation in the extracorporeal circulation device 4. Used for prevention of post-operative veno-thrombosis 5. Used in the management of disseminated intravascular coagulation

Question 38

What are the adverse effects of standard heparin?

Answer 38

Adverse effects: (1) Haemorrhage (2) Thrombocytopaenia (3) Hypersensitivity reactions: chills, fever, urticaria (4) Osteoporosis (with long term therapy)

Question 39

How do you treat a standard heparin overdose?

Answer 39

Treatment of heparin overdose: Treated with protamine sulphate a strong basic protein that forms an inactive complex with heparin

Question 40

What are the contraindications of standard heparin?

Answer 40

Contra-indications: (1) Thrombocytopaenia (2) Surgery of the eye, brain and spinal cord (3) Lumbar puncture

Question 41

How and why is standard heparin monitored in therapy?

Answer 41

Heparin therapy is monitored by measuring activated partial thromboplastin time (APTT) [target: 1.5x the normal APTT] Monitoring is required because of the unpredictable pharmacokinetics of standard heparin

Question 42

List the low molecular weight heparins

Answer 42

Include enoxaparin and dalteparin

Question 43

Describe the action, adverse effects, pharmacokinetics and clinical use of low molecular weight heparins

Answer 43

LMW heparins act on anti-thrombin III to inhibit factors X and XI, and they have little effect on thrombin (factor II) As effective as standard heparin Associated with lower risk of haemorrhage Less likely to produce hypersensitivity reactions, thrombocytopaenia and osteoporosis Have longer half-lives compared to standard heparin and have more predictable pharmacokinetics Do not require APTT monitoring Can be used on an outpatient basis Given subcutaneously

Question 44

List the hirudin analogues

Answer 44

bivalirudin, desirudin and lepirudin

Question 45

What is the MoA of hirudin and its analogues?

Answer 45

Hirudin and its analogues (bivalirudin, desirudin and lepirudin) directly bind to and inhibit thrombin (they do not require anti-thrombin III) All are administered parenterally (IV or SC, and not IM)

Question 46

What is the clinical use of hirudin and its analogues?

Answer 46

They are used in patients with unstable angina undergoing angioplasty and percutaneous coronary interventions Lepirudin is used as an alternative to heparin in patients who develop heparin induced thrombocytopaenia

Question 47

What are platelet aggregation inhibitor?

Answer 47

These drugs decrease the formation or the action of chemical signals that promote platelet aggregation They inhibit thrombus formation in arteries

Question 48

List the examples of platelet aggregation inhibitors

Answer 48

1. Aspirin 2. Adenosine diphosphate (ADP) receptor inhibitors: clopidogrel, ticlopidine, prasugrel and ticagrelor 3. Glycoprotein IIb/IIIa receptor inhibitors: abciximab, eptifibatide and tirofiban

Question 49

What is the MoA of aspirin?

Answer 49

MOA: Inhibits the synthesis of thromboxane A2 (TXA2) in platelets by irreversible inhibition of cyclo-oxygenase, a key enzyme in TXA2 synthesis pathway. TXA2 is one of the factors required in platelet aggregation. Because platelets lack nuclei, they cannot synthesize new enzyme. Thus the lack of TXA2 persists for the lifetime of the platelet (7-10 days). Given orally

Question 50

Explain the dose usage of aspirin

Answer 50

When used to inhibit platelet aggregation, aspirin is used at much lower doses than those required for anti-inflammatory action At higher doses (> 325mg/day), aspirin will have reduced anti-thrombotic action by decreasing endothelial synthesis of prostacyclin Low doses impair prostaglandin synthesis in platelets more than in endothelial cells and thus the anti-thrombotic effect is preserved

Question 51

How is aspirin used as a platelet aggregation inhibitor?

Answer 51

Uses of aspirin as a platelet aggregation inhibitor 1. Prophylactic treatment of transient cerebral ischaemia 2. Primary and secondary prophylaxis of myocardial infarction 3. In the management of acute myocardial infarction 4. In the management of unstable angina

Question 52

What are the adverse effects of aspirin?

Answer 52

Adverse effects Increased incidence of haemorrhagic stroke Gastro-intestinal bleeding (hence contraindicated in peptic ulcer disease)

Question 53

List the ADP receptor inhibitors

Answer 53

Include ticlopidine, clopidogrel, prasugrel and ticagrelor

Question 54

What is the MoA of ADP receptor inhibitors?

Answer 54

MOA: These drugs reduce platelet aggregation by irreversibly inhibiting the platelet ADP receptor (P2Y12 receptor) (except ticagrelor is a reversible inhibitor) thus blocking ADP binding to platelets ADP is one of the main platelet-activating factors and is required for binding of platelets to fibrinogen and to each other

Question 55

What are the adverse effects of ADP receptor inhibitors?

Answer 55

Adverse effects: Haemorrhage, dyspepsia, nausea

Question 56

What are the clinical uses of ADP receptor inhibitors?

Answer 56

Clinical uses 1. Management of unstable angina 2. Primary and secondary prophylaxis of myocardial infarction 3. Prophylaxis of transient cerebral ischaemia and ischaemic stroke 4. Prevention of atherosclerotic events in peripheral arterial disease ADP receptor inhibitors can be used as alternatives to aspirin or in combination with aspirin Clopidogrel is the most widely used ADP receptor inhibitor Ticlopidine causes leukopenia and thrombocytopaenia; it is therefore no longer used Prasugrel and ticagrelor are approved for patients with acute coronary syndromes (in combination with aspirin)

Question 57

What is the contraindication of ADP receptor inhibitors?

Answer 57

Prasugrel is contraindicated in patients with history of cerebrovascular accident because of increased bleeding risk

Question 58

List the platelet glycoprotein IIb/IIIa receptor inhibitors

Answer 58

Include abciximab (monoclonal antibody), eptifibatide (peptide) and tirofiban (non-peptide). They are all given intravenously

Question 59

What is the MoA of platelet glycoprotein IIb/IIIa receptor inhibitors?

Answer 59

MOA: The glycoprotein IIb/IIIa receptor complex on platelets acts as a receptor for fibrinogen. Activation of the glycoprotein IIb/IIIa receptor complex is the final common pathway for platelet aggregation. Inhibition of the receptor prevents platelet aggregation by blocking the binding of fibrinogen to platelets

Question 60

What are the clinical uses of platelet glycoprotein IIb/IIIa receptor inhibitors?

Answer 60

Management of acute coronary syndromes (unstable angina and myocardial infarction) To prevent thrombosis in patients undergoing percutaneous coronary intervention

Question 61

What are the adverse effect of platelet glycoprotein IIb/IIIa receptor inhibitors?

Answer 61

Bleeding Abciximab also causes hypersensitivity reactions

Question 62

List the thrombolytic (fibrinolytic) drugs

Answer 62

Include streptokinase, alteplase, reteplase, tenecteplase and urokinase Promote lysis of thrombi (clots) All are given intravenously

Question 63

What is the MoA of thrombolytic drugs?

Answer 63

MOA: Convert plasminogen to plasmin. Plasmin digests the fibrin meshwork of clots

Question 64

What are the adverse effects of thrombolytic drugs?

Answer 64

Major adverse effect of thrombolytic drugs is haemorrhage

Question 65

What is streptokinase?

Answer 65

A protein derived from beta-haemolytic streptococci Acts on both circulating plasminogen and fibrin-bound plasminogen

Question 66

What are the ADR of streptokinase?

Answer 66

Causes allergic reactions (anaphylaxis, urticaria, fever, bronchospasm). Thus avoid re-use between 5 days and 12 months

Question 67

Describe the action of alteplase

Answer 67

Alteplase is recombinant tissue type plasminogen activator (tPA), which is selective for plasminogen bound to fibrin in thrombi. Hence the incidence of bleeding is less than with streptokinase. Alteplase is not antigenic and therefore can be re-used within 1 year

Question 68

What is urokinase? State its action, indication and clinical use

Answer 68

Prepared from cultured kidney cells using recombinant technology Activates both circulating and fibrin-bound plasminogen Used in the treatment of pulmonary embolism Less antigenic than streptokinase and so it is indicated in patients sensitive to streptokinase

Question 69

List the clinical uses of thrombolytic drugs

Answer 69

1. Lysis of coronary artery thrombi associated with acute myocardial infarction 2. Deep vein thrombosis 3. Pulmonary embolism 4. Acute ischaemic stroke (thrombotic stroke)

Question 70

What are the contraindications of thrombolytic drugs?

Answer 70

Recent haemorrhage, trauma or surgery, coagulation defects, bleeding diathesis, severe uncontrolled hypertension, recent stroke, recent symptoms of peptic ulcer disease, severe liver disease, oesophageal varices, acute pancreatitis, heavy vaginal bleeding and coma

Question 71

List the antifibrinolytic agents

Answer 71

1. Aminocaproic acid 2. Tranexamic acid

Question 72

What is the action of aminocaproic acid?

Answer 72

Aminocaproic acid, which is chemically similar to the amino acid lysine, is a synthetic inhibitor of fibrinolysis It competitively inhibits plasminogen activator Given orally or IV

Question 73

What are the adverse effects of amino caproic acid?

Answer 73

Adverse effects: Intravascular thrombosis, hypotension, myopathy, abdominal discomfort, diarrhea, and nasal stuffiness

Question 74

What are the contraindications of aminocaproic acid?

Answer 74

Contraindications: Disseminated intravascular coagulation

Question 75

What are the clinical indications of aminocaproic acid?

Answer 75

Clinical indications 1. Haemophilia 2. Bleeding from fibrinolytic therapy 3. Prophylaxis for re-bleeding from intracranial aneurysms 4. Post-surgical gastrointestinal bleeding 5. Post-prostatectomy bleeding 6. Bladder hemorrhage secondary to radiation- and drug-induced cystitis

Question 76

What is the action of tranexamic acid?

Answer 76

Tranexamic acid is an analog of aminocaproic acid and also acts by inhibiting plasminogen activator Given intravenously

Question 77

What are the adverse effects of tranexamic acid?

Answer 77

Adverse effects: Nausea, diarrhoea, orthostatic hypotension and intravascular thrombosis

Question 78

What are the clinical indications of tranexamic acid?

Answer 78

Indications: (1) To prevent hyper-plasminaemic bleeding states that result from damage to tissues rich in plasminogen activator e.g. after prostatic surgery, tonsillectomy (2) In haemophiliacs after dental extraction (3) To reduce bleeding after ocular trauma (4) Overdosage with thrombolytic agents (5) Thrombocytopaenia (6) Upper GIT haemorrhage

Question 79

List the hemostatic agents

Answer 79

Desmopressin

Question 80

What is the action and routes of administration of desmopressin?

Answer 80

Desmopressin is a longer acting analogue of vasopressin Stimulates the release of factor VIII and von Willebrand factor Routes of administration: Intranasal, oral, sublingual and IV

Question 81

What are the clinical indications of desmopressin?

Answer 81

Indications: (1) Haemophilia A (2) von Willebrand’s disease (mild disease)