Haematology

Question 1

Anti-Coagulation: Heparins

What is the mechanism of heparins? What are the differences and indications for unfractionated heparins vs. low molecualr weight heparins?

Answer 1

1. Mechanism: glycosaminoglycan extracted from porcine mucosa, causing anticoagulation through binding to anti-thrombin and **potentiating **its activity.
2. Heparin: initiates anticoagulation rapidly, but has a short duration. Only used in preference to LMWH when:
   
   1. Patients requiring rapid cessation of anticoagulation (e.g. very high bleeding risk)
   2. Severe renal failure: easier to titrate APTT than relying on anti-Xa levels with LMWH
3. **LMWH: **(e.g dalteparin, enoxaparin and tinzeparin) preferred in **prevention **and treatment of VTE, PE, MI etc. due to:
   
   1. Lower risk of HIT, no requirement for monitoring at standard prophylactic dose
   2. Longer duration → OD S/C dosing
   3. Lower risk of osteoporosis long term

Question 2

Anticoagulation: Heparins (II)

How are unfractionated and LMW heparins monitored? What are the indications for treatment and prophylaxis? What is the guidance during pregnancy?

Answer 2

1. Monitoring: Unfractionated → aPTT, LMWH → anti-factor Xa (aPTT **not **reliable). Monitoring of LMWH only required if high bleeding risk (renal impairment, high or low BMI)
2. Treatment:
   
   1. DVT and PE: LMWH and warfarin started simultaneously; heparin continued for atleast 5 days, until INR is therapeutic for 2 consecutive days
3. Prophylaxis: based upon risk assessment:
   
   1. **High risk: **surgical patients for major trauma, #NOF, hip / knee arthroscopy, SCI. 5,000U/day dalteparin to cover surgery
4. Pregnancy: heparins do not cross placenta; LMWH preferred due to ↓ osteoporosis and HIT risk. Patients with continued anticoagulation requirements (e.g. prosthetic cardiac valves) are complex; usually heparin used in 1st and 3rd terms, and warfarin in 2nd.

Question 3

Anticoagulation: Heparins (III)

What are the adverse effects of heparins?

Answer 3

1. Haemorrhage: usually treated with withdrawal. If rapid reversal required, protamine sulphate is the specific antidote (but only partially reverses LMWH)
2. Heparin-induced thrombocytopenia:
   
   1. Immune mediated, developing after 5 - 10 days; may be complicated by thrombosis.
   2. Measure platelet count just before treatment; signs include ↓50% in platelet count, thrombosis or skin allergy.
   3. Stop heparin, give alternative anticoagulant (argatroban, danaparoid)
3. **Hyperkalaemia **(heparin inhibits aldosterone secretion → increased risk in DM, CKD and acidosis. Monitor [K+] if risk
4. Osteoporosis: if prolonged, lower with LMWH
5. Alopecia
6. Hypersensitivity: urticaria, angiooedema, anaphylaxis

Question 4

Fondaparinux

What is fondaparinux, what are indications for use?

Answer 4

1. Synthetic pentasaccharide, directing antithrombin to selectively inhibit factor Xa. Administered daily without laboratory monitoring.
2. 2009 RCT showed equivalence to LMWH in ACS with lower bleeding risk → NICE recommended as antithrombin of choice in ACS

Question 5

Oral Anticoagulants: Warfarin

What is the mechanism and indication for treatment with warfarin?

Answer 5

1. Mechanism:
   
   1. ​Antagonises effects of vitamin K, reducing synthesis of factors II, VII, IX and X. Measured by increased PT / INR
   2. Required 48 - 72h for activity, and have a paradoxical procoagulant effect initially as they deplete anticoagulant factors more quickly than pro-coagulants; often covered with LMWH.
   3. Eliminated by hepatic metabolism; multiple interactions
2. Indications:
   
   1. Treatment of VTE
   2. Stroke prevention in AF (CHADS2VASC)
   3. Mechanical heart valves

Question 6

Warfarin Interactions: Enzyme Inducers

Which drugs are **cytochrome p450 inducers, **thereby decreasing the activity of warfarin?

Answer 6

1. Phenytoin
2. Carbamazepine
3. Barbiturates
4. Rifampicin
5. Alcohol (chronic use)
6. Sulphonylurea / St-John’s wart

Question 7

Warfarin Interactions: Enzyme Inhibitors

Which drugs inhibit the cytochrome P450 system, and therefore potentiate the action of warfarin

Answer 7

1. ​​Omeprazole
2. Disulfuram
3. Erythromycin
4. Valproate
5. Isoniazid
6. Cimetidine, Ciprofloxacin
7. Ethanol (acutely)
8. Sulphonamides

Question 8

Warfarin Reversal

What are the guidelines for reversing warfarin in the setting of major bleeding, non-major bleeding, and raised INR with no bleeding?

Answer 8

1. Major Bleeding:
   
   1. Stop warfarin
   2. PCC 30mg / kg,
   3. Vit K IV 5mg
2. Non-Major Bleeding
   
   1. ​If INR > 5, Stop warfarin, give 1-3mg Vit K
   2. If INR < 5, modify warfarin dose, and consider 1mg Vit K
3. No-bleeding, over anti-coagulated
   
   1. ​INR > 12: omit warfarin, 5mg Vit K
   2. INR 8 - 12: omit warfarin, 2mg Vit K
   3. INR 5 - 8: omit warfarin, restart at a lower dose when INR < 5

Question 9

New Oral Anti-Coagulants

What are the NOACs, and what are their mechanisms of action. How do they compare to warfarin?

Answer 9

1. Examples:
   
   1. Dabigatran: direct thrombin inhibitor
   2. Rivaroxaban, Apixaban: Factor Xa inhibitors
2. Comparison to warfarin:
   
   1. Faster onset, shorter half-life
   2. No requirement for monitoring
   3. No effective method of reversing haemorrhage
   4. Require compliance; clot risk if one tablet missed

Question 10

Anti-Platelets: Aspirin

What are the indications and adverse effects of aspirin?

Answer 10

1. Indications:
   
   1. Acute treatment of MI and stroke
   2. Primary prevention: individuals with high vascular risk; 10 year CV risk > 20%, patients over 50 with diabetes
2. Adverse Effects:
   
   1. Bleeding, particularly GI and intracranial. Dose related.
   2. Exacerbation of asthma
   3. Avoid until controlled HTN to ↓ risk of intracranial haemorrhage

Question 11

Anti-Platelets: Clopidogrel

What is the mechanism, indications and adverse effects of clopidogrel?

Answer 11

1. Mechanism: thienopyridine, inhibits platelet aggregation by selectively binding ADP2Y12 receptors (adenylate cyclase coupled)
2. Indications:
   
   1. Combination with aspirin in short term for ACS and after stent placement.
   2. 1st Line for ischaemic stroke and TIA
3. Adverse effects:
   
   1. Bleeding (↑ risk - combined with aspirin)
   2. Dyspepsia, abdo pain, diarrhoea
   3. Efficacy may be reduced by clopidogrel (note: think this has been disproven)

Question 12

Treatment of Anaemia: Iron

For iron (ferrous sulphage, ferrous gluconate) used in treatment of Fe-deficient anaemia, what is the:

1. Dose
2. Adverse effects
3. Duration of Treatment

Answer 12

1. Dose:
   
   1. Usual elemental Fe-requirement 1-2mg/day; ferrous sulphate 200 provides 65mg - usually given TDS.
2. Adverse effects
   
   1. GI: nausea, diarrhoea, constipation (very common, cause compliance difficulties)
   2. Black stool
3. Duration:
   
   1. Hb increases by ~0.5 - 0.8g/dL/week if cause corrected.
   2. Treat until Hb normal, then 3 months further to build iron stores

Question 13

Treatment of Anaemia: Iron (II)

What is the indication for intravenous iron treatment? What are the adverse effects and dose?

Answer 13

1. Indication:
   
   1. CKD or anaemia of malignancy, use in conjunction with erythropoiesis stimulating agents (ESA). ESAs cause functional iron deficiency (stores adequate, but Fe unavailable to developing RBCs) - only overcome by I.V not P.O iron.
   2. Poor absorption
2. Adverse effects: allergy / anaphylaxis rare. Myalgia reported by some
3. Dose: calculate on weight and target Hb. Dose given in oen infusion, or in divided doses over a few weeks

Question 14

**Anaemia: Vitamin B12 and Folate **

When is B12 given and in what form? What are the indications for folate treatment?

Answer 14

1. B12:
   
   1. Deficiency (e.g. pernicious anaemia etc). Given prophylactically after gastrectomy / ileal resection
   2. Given as Hydroxycobalamin: given 3monthly; retained by body well. Initiated with regular I.M injections to replenish depleted stores.
2. **Folate: **(deficiency → macrocytic anaemia)
   
   1. ​Pregnancy - increased requirements. Given during pre-conception and 1st trimestered to reduce NTDs.
   2. Prevention of anaemia in long term methotrexate treatment
3. Folinic acid → produced from folate metabolism. Given as folinic acid in resuce therapy for high dose MTX, and patients with ALL.

Question 15

Vitamin K

What is the mechanism, indication and administration of Vitamin K

Answer 15

1. **Mechanism: **fat soluable vitamin, acting as co-factor in the synthesis of factors II, VII, IX and X
2. Indication:
   
   1. ​Prevention of haemorrhagic disease of the newborn (phytomenadione)
   2. Reversal of clotting disorders arising from Vit K deficiency (cirrhosis, warfarin, nutritional deficiency)
3. Administration: can be given IV, IM, or orally. Given to reverse coumarins (warfarin). Usually given slowly due to risk of anaphylaxis