Week 3 - Haematology

Question 1

Warfarin

Answer 1

MOA: inhibits vitamin K reductase; prevents recycling of vitamin K to reduced form after carboxylation of coagulation factors II, VII, IX and X; prevents thrombus formation.
Indications: treatment of venous thromboembolism; prophylaxis in AF/metallic heart valves/cardiomegaly.
Side effects: bleeding, wafarin necrosis, osteoporosis.
PK/PD: numerous drug/food interactions; reversable by vit K; Polymorphisms in key metabolising enzymes (VKORC1 and CYP2C9);
Needs therapeutic drug monitoring and monitored loading regimen;
Monitored with INR and dose adjusted according to indication.

Question 2

Low Molecular Weight Heparin

Answer 2

MOA: enhances activity of antithrombin III, which inhibits thrombin and multiple other factors of the coagulation cascade, produces an anticoagulant effect
Indications: treatment and prophylaxis of thromboembolic diseases, including induction of vit K antagonists; renal dialysis (haemodialysis), ACS treatment.
Side effects: bleeding, heparin=induced thrombocytopenia, osteoporosis.
PK/PD: subcutaneous injection, More predictable dose-response relationship than Unfractionated Heparin; -4 times longer plasma half-life than Unfractionated Heparin
Clearance is mostly via a renal pathway, thus the half-life can be prolonged in patients with renal failure, so dose adjustment may be needed; Regular coagulation monitoring is not required.
Less readily reversed with protamine, than Unfractionated Heparin.

Question 3

Unfractionated Heparin

Answer 3

MOA: Enhances activity of antithrombin III; inhibits thrombin and multiple other factors of the coagulation cascade; produces its anticoagulant effect.
Indications: treatment and prophylaxis of thromboembolic diseases (including induction of vit K antagonists); renal dialysis (haemodialysis); ACS treatment.
Side effects: bleeding, heparin-induced thrombocytopenia; osteoporosis.
PK/PD: Administered by continuous intravenous infusion or subcutaneous injection; Complex kinetics - non-linear relationship between dose/half-life and effect – needs TDM; Effect monitored using activated partial thromboplastin time (aPTT); Anticoagulant effect can be reversed with protamine; Unfractionated heparin has a shorter duration of action than LMW Heparin.
Used in preference to LMW Heparin, in selected patients, due to the shorter duration of action and reversability with protamine (for example, Peri-operatively.)

Question 4

Recombinant Tissue Plasminogen Activator (rtPA)

Answer 4

e.g. tenecteplase, alteplase.
MOA: Recombinant form of tissue plasminogen activator; Catalyses conversion of plasminogen to plasmin; Promotes fibrin clot lysis.
Indications: acute ischaemic stroke; MI; massive PE.
side effects:bleeding, allergy.
PK/PD: Bolus-infusion regimen is used for alteplase; Tenecteplase is given as a single bolus; Pharmacodynamic interactions with other blood thinners (antiplatelet/anticoagulant).

Question 5

Clopidogrel

Answer 5

MOA: Irreversibly blocks the ADP-receptor on platelet cell membranes.
Consequently inhibits formation of GPIIb/IIIa complex, required for platelet aggregation.
Decreased thrombus formation.
Indications: secondary prevention of thrombotic events.
SIde effects: bleeding, abdominal pain/diarrhoea.
PK/PD: avoid in liver failure.

Question 6

Aspirin (acetylsalicyclic acid)

Answer 6

MOA: Irreversible inactivation of cyclooxygenase (COX) enzyme. This reduces platelet thromboxane (TXA2) production and endothelial prostaglandin (PGI2) production. Reduced platelet thromboxane production reduces platelet aggregation and thrombus formation.
Reduced prostaglandin synthesis decreases nociceptive sensitisation and inflammation.
Indication(s): Secondary prevention of thrombotic events; Pain relief.
Side effects: Bleeding, Peptic ulceration, Angiooedema, Bronchospasm, Reye’s syndrome (very rare)
PK/PD: Half life becomes longer with very large doses (pharmacokinetics may be non-linear in overdose).

Question 7

Direct Thrombin Inhibitors

Answer 7

e.g. dabigatran.
MOA: Direct thrombin inhibitor; prevents conversion of fibrinogen to fibrin. This prevents thrombus formation.
Indication(s): Prophylaxis of venous thromboembolism (especially post-operative). Thromboprophylaxis in non-valvular AF.
Side effects: Bleeding, Dyspepsia
PK/PD:Rapid onset of action. No food/few drug interactions (not metabolised via CYP 450). No need for therapeutic monitoring. Currently no available antidote.

Question 8

Factor Xa Antagonists

Answer 8

e.g. rivaroxaban, apixaban.
MOA: inhibits conversion of prothrombin to thrombin, reducing concentrations of thrombin in the blood, inhibits formation of fibrin clots.
Indication(s): Prophylaxis of venous thromboembolism (especially post-operative). Thromboprophylaxis in non-valvular A. Treatment of venous thromboembolism
Side effects: Bleeding, Nausea.
PK/PD:Predictable drug interactions (metabolised via CYP 450, inc CYP3A4). No need for therapeutic monitoring. Currently no available antidote.

Question 9

Disseminated Intravascular Coagulation (DIC)

Answer 9

Acquired, consumptive process:
- activation of coagulation cascade (microthrombi).
- exhaustion of coagulation cascade (bleeding).
Causes: sepsis, malignancy, massive haemorrhage, severe trauma, pregnancy complications.
Systemic activation of coagulation\;
- intravascular deposition of fibrin - thrombosis of small and midsize vessels and organ failure.
- depletion of platelets and coagulation factors, bleeding.
Treatment: treat underlying cause. FFP +/- platelets if bleeding, heparin, AT concentrate, protein C concentrate, activated protein C.

Question 10

Haemophilia A

Answer 10

Classic haemophilia.
Factor VIII deficient.
X-linked inheritance.
Prolonged APTT.
Treatment: education, desmopressin, replacement therapy (FFP, plasma derived factor concentrate, recombinant produced factor concentrate, gene therapy.

Question 11

Von Willebrand Disease

Answer 11

Most common bleeding disordr.
mostly autosomal dominant with variable penetrance.
mucosal type bleeding pattern.
reduced VWF +/- reduced platelet aggregation +/- reduced FVIII.

Question 12

Severe inherited platelet disorders

Answer 12

Rare.
Autosomal recessive.
Mucosal type bleeding pattern.
Glansmanns thrombasthenia​:
- Absent/defective GP IIb/IIIa [alpha IIb beta 3]​.
- Normal platelet count​.
Bernard Soulier Syndrome​:
- Absent/defective GP Ib/V/IX.
- macrothrombocytopenia​.
Treatment of Bleeding: pressure, tranexamin acid/desmopressin (DDAVP), platelet transfusion (HLA matched), rFVIIa).

Question 13

Thrombophilia - inherited

Answer 13

deficiencies of natural anticoagulants: antithrombin, protein C, protein S.
specific genetic mutations:
- factor V Leiden (resistance to APC).
- prothrombin gene mutation (increased prothrombin).

Question 14

Lupus Anticoagulant

Answer 14

Phospholipid dependent antibody​.
Interferes with phospholipid dependent tests i.e. APTT​.
APTT prolonged​.
If persistent, may be associated with prothrombotic state​.
Persisting Lupus anticoagulant + thrombosis [or recurrent fetal loss] = Antiphospholipid Syndrome​.

Question 15

Thrombophilia - acquired

Antiphospholipid syndrome

Answer 15

presence of antiphospholipid antibodies:
- lupus anticoagulant.
- anti cardiolipin antibodies.
- beta 2 glycoprotein 1 antibodies.
Mechanism: disrupt annexin V shield, expose excess phospholipid.
Clinically: venous/arterial thrombosis, recurrent miscarriage.