6.3 Anticoagulants, Antiplatelets & Hematology Agents

Warfarin: The Vitamin K Antagonist

Warfarin inhibits vitamin K epoxide reductase complex 1 (VKORC1), blocking regeneration of reduced vitamin K and thereby the gamma-carboxylation of clotting factors II, VII, IX and X (and anticoagulant proteins C and S). Because factor II has a long half-life, full anticoagulation takes several days - which is why bridging with heparin or a low-molecular-weight heparin is used when rapid anticoagulation is needed and when warfarin is interrupted around surgery in high-risk patients.

Monitoring is by the international normalised ratio (INR): target 2.0-3.0 for atrial fibrillation and venous thromboembolism, and 2.5-3.5 for mechanical heart valves (particularly mitral). Response varies with CYP2C9 and VKORC1 genetics, and with dietary vitamin K - advise patients to keep green leafy vegetable intake consistent, not absent. Major interactions that raise the INR include antibiotics (metronidazole, co-trimoxazole, macrolides, fluoroquinolones), amiodarone, azole antifungals and acute alcohol binges; enzyme inducers (rifampicin, carbamazepine, St John's wort) lower it. NSAIDs and antiplatelets add bleeding risk pharmacodynamically. For reversal: withhold warfarin and give oral/IV vitamin K for elevated INR without serious bleeding; for major or life-threatening bleeding use four-factor prothrombin complex concentrate (PCC) plus IV vitamin K, with fresh frozen plasma only if PCC is unavailable.

Heparin, LMWH and Fondaparinux

Unfractionated heparin (UFH) binds antithrombin and accelerates its inhibition of thrombin (IIa) and factor Xa; it is monitored by the aPTT and reversed by protamine sulfate. Low-molecular-weight heparins (LMWH) such as enoxaparin act predominantly against factor Xa, have predictable pharmacokinetics allowing fixed weight-based dosing without routine monitoring (anti-Xa levels only in pregnancy, obesity or renal failure), and require dose reduction in renal impairment (creatinine clearance below 30 mL/min). All heparins can cause heparin-induced thrombocytopenia (HIT) - an immune-mediated prothrombotic state with a falling platelet count, typically 5-10 days after starting. Management: stop all heparin immediately, never give warfarin alone during acute HIT (it can cause venous limb gangrene via protein C depletion), and anticoagulate with a non-heparin agent such as argatroban or fondaparinux. Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa via antithrombin; it is renally cleared and has a very low HIT risk.

Direct Oral Anticoagulants (DOACs)

DOAC advantages: fixed dosing with no routine coagulation monitoring and far fewer food interactions than warfarin. Limitations the exam tests: all are renally cleared to some degree (dabigatran most, so avoid in severe renal impairment); they are contraindicated with mechanical heart valves (the RE-ALIGN trial showed excess thrombosis with dabigatran) and should be avoided in triple-positive antiphospholipid syndrome, where warfarin remains standard. Strong CYP3A4/P-glycoprotein inhibitors and inducers alter levels of the anti-Xa agents.

Antiplatelet Agents

• Aspirin irreversibly acetylates cyclo-oxygenase-1 (COX-1), abolishing thromboxane A2 production for the platelet's 7-10 day lifespan; low doses (75-100 mg) are antiplatelet. Avoid in children (Reye's syndrome) and caution in asthma and peptic ulcer disease.
• Clopidogrel is a prodrug activated by CYP2C19 that irreversibly blocks the platelet P2Y12 ADP receptor. Poor metabolisers gain little benefit, and omeprazole/esomeprazole blunt its activation - the classic interaction with acid-suppressing therapy.
• Ticagrelor is a reversible P2Y12 antagonist needing no metabolic activation; characteristic adverse effects are dyspnea (usually transient) and ventricular pauses; it is a CYP3A4 substrate/inhibitor.
• Prasugrel is the most potent thienopyridine but is contraindicated in patients with prior stroke or transient ischaemic attack because of intracranial bleeding risk, and is generally avoided over age 75 or under 60 kg body weight.

Anemia Therapy

Oral iron (ferrous sulfate, fumarate, gluconate) is first-line for iron-deficiency anemia: give on an empty stomach for best absorption (with food if gastrointestinal upset is intolerable), optionally with vitamin C to enhance uptake, and warn about black stools and constipation. Iron chelates tetracyclines and fluoroquinolones (separate by 2-4 hours), and its own absorption is reduced by PPIs, antacids, tea and dairy. Intravenous iron (iron sucrose, ferric carboxymaltose) is used for intolerance, malabsorption, inflammatory bowel disease or chronic kidney disease, with a small hypersensitivity risk.

Distinguish the macrocytic anemias: vitamin B12 deficiency causes macrocytosis plus neurological features (peripheral neuropathy, subacute combined degeneration of the cord), while folate deficiency does not. The critical rule: never give folic acid alone when B12 deficiency is possible - it corrects the anemia while neurological damage progresses silently. Treat with hydroxocobalamin first, or give both.

Finally, granulocyte colony-stimulating factor (G-CSF) - filgrastim, pegfilgrastim - stimulates neutrophil production and is used to prevent or treat chemotherapy-induced neutropenia; its characteristic adverse effect is bone pain, and it is typically started 24-72 hours after chemotherapy.

Practical counselling closes the anticoagulation picture. Warfarin patients should take the dose at the same time each day, report any new prescription, over-the-counter product or herbal supplement before starting it, watch for bleeding signs (black stools, haematuria, prolonged nosebleeds, unusual bruising) and carry an anticoagulant alert card. Early in warfarin therapy there is a brief prothrombotic window because anticoagulant protein C falls before factor II - one more reason heparin bridging overlaps the first days of treatment. DOAC patients should be told that adherence matters even more than with warfarin because of the short half-lives: a missed dose leaves them unprotected within a day, and dabigatran capsules must be swallowed whole since opening them sharply increases bioavailability and bleeding risk.