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PH4.1-4 | PH4.1-4 | Drugs Affecting Blood and Coagulation — SDL Guide

Learning Objectives

• Explain the types, pharmacokinetics, pharmacodynamics, therapeutic uses, and adverse drug reactions of drugs used for different anaemias and thrombocytopenia (PH4.1).
• Classify anticoagulants and describe their mechanisms, monitoring parameters, drug interactions, and reversal agents (PH4.2).
• Describe fibrinolytic and antifibrinolytic agents, their mechanisms, indications, and contraindications (PH4.3).
• Classify antiplatelet drugs and explain their mechanisms, therapeutic uses, and adverse drug reactions (PH4.4).
• Devise a plan to monitor and manage adverse effects of anticoagulant therapy.

INSTRUCTIONS

Blood pharmacology spans four interrelated domains — correcting deficiencies that impair red cell or platelet production, managing abnormal haemostasis by anticoagulating or antiplatelet therapy, dissolving established clots with fibrinolytics, and reversing pathological fibrinolysis with antifibrinolytics. These are among the most frequently prescribed drug classes in all specialties. A prescribing error in anticoagulation — wrong dose, wrong monitoring, missed drug interaction, or failure to reverse before surgery — can cause a fatal bleed or thrombosis. This SDL consolidates the pharmacology of all four competency families.

References

• Tripathi KD. Essentials of Medical Pharmacology, 9th ed., Ch. 44 (Drugs Affecting Coagulation, Bleeding and Thrombosis), Ch. 45 (Haematopoietic Drugs) (textbook)
• Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed., Ch. 30 (Blood Coagulation and Anticoagulants), Ch. 37 (Haematopoietic Agents) (textbook)

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Version 2.0 | NMC CBUC 2024

Pathophysiology of Blood Disorders: From Haematopoiesis to Haemostasis

The pharmacological agents in this SDL target distinct pathological states within the continuum of blood cell production and haemostasis. Understanding these targets requires a brief pathophysiological orientation.

Anaemia pharmacology addresses deficiencies in the raw materials (iron, B12, folate) or growth factors (EPO) required for erythropoiesis. Iron deficiency is the commonest nutritional deficiency worldwide — depleted iron stores impair haemoglobin synthesis → microcytic hypochromic anaemia. Megaloblastic anaemia arises from impaired DNA synthesis due to B12 or folate deficiency → large, hypersegmented neutrophils, oval macrocytes, and pancytopenia. Pernicious anaemia is a specific form of B12 deficiency caused by absent intrinsic factor (autoimmune gastritis) — the critical point is that oral B12 cannot be absorbed without intrinsic factor, mandating parenteral (intramuscular) B12 replacement. EPO deficiency (renal anaemia in CKD) requires exogenous erythropoiesis-stimulating agents (ESAs).

Thrombocytopenia (PH4.1 mandated) requires pharmacological intervention when platelet counts are dangerously low (<20,000/μL for spontaneous bleeding risk). The most important treatable cause pharmacologically is immune thrombocytopenic purpura (ITP) — autoimmune antibodies against platelet surface antigens (GPIIb/IIIa, GPIb/IX) cause premature platelet destruction by the spleen. First-line: oral corticosteroids (prednisolone) suppress antibody production; IVIg temporarily blocks Fc receptors, sparing platelets; second-line: splenectomy or TPO receptor agonists (eltrombopag, romiplostim) for chronic ITP.

Thrombosis arises from pathological activation of haemostasis — platelet-rich arterial thrombi (treated with antiplatelets) and fibrin-rich venous thrombi (treated with anticoagulants). The drug families that modulate thrombosis include anticoagulants (prevent fibrin formation), antiplatelets (prevent platelet aggregation), fibrinolytics (dissolve formed clot), and antifibrinolytics (prevent premature fibrin dissolution in surgical bleeding).

Fibrinolysis is the physiological mechanism for dissolving formed clots — plasmin degrades fibrin into soluble D-dimers. Therapeutic fibrinolysis (thrombolysis) applies this mechanism in STEMI, large PE, and acute ischaemic stroke. Pathological fibrinolysis (excessive bleeding in trauma, surgery, hyperfibrinolysis in DIC) is treated with antifibrinolytics.

Therapeutic Goals: Correcting Anaemia, Preventing Thrombosis, and Managing Bleeding

This SDL addresses four distinct therapeutic objectives, each with a clearly defined pharmacological strategy.

Goal 1 — Correct nutritional anaemia and thrombocytopenia: Replenish iron, B12, or folate to the physiological requirement for haematopoiesis. In renal anaemia, replace EPO. In ITP, immunosuppress or stimulate platelet production via TPO pathway.

Goal 2 — Prevent and treat thrombosis: Anticoagulant therapy prevents fibrin formation in venous thromboembolism (DVT, PE), AF-associated stroke, and ACS. Antiplatelet therapy prevents platelet-driven arterial thrombosis (ACS, ischaemic stroke). The goal is to shift the haemostatic balance toward bleeding prevention without causing spontaneous haemorrhage — the therapeutic window is narrow and varies by clinical context.

Goal 3 — Dissolve established thrombus: Fibrinolytic therapy is indicated in specific life-threatening thrombotic emergencies — STEMI with failed/unavailable PCI, massive PE with haemodynamic compromise, acute ischaemic stroke (within 4.5h of onset, no haemorrhage). Goal: restore flow by lysing the occlusive thrombus rapidly.

Goal 4 — Prevent excessive bleeding: Antifibrinolytic drugs (tranexamic acid, aminocaproic acid) are used in surgical bleeding, trauma (CRASH-2 trial: TXA within 3 hours of injury reduces mortality in traumatic haemorrhage), heavy menstrual bleeding, and haemophilia-associated bleeds. The corollary goal is reversal of anticoagulants when bleeding occurs or before emergency surgery.

Classification of Blood-Acting Drugs

The four competency families in this SDL are best understood as distinct pharmacological categories, each matching a different haematological indication.

Family 1 — Haematinics and anti-thrombocytopenia drugs (PH4.1):
- Haematinics (nutritional): oral iron salts (ferrous sulphate, ferrous fumarate); IV iron (ferric carboxymaltose, iron sucrose); vitamin B12 (cyanocobalamin, hydroxocobalamin); folic acid.
- Growth factors: erythropoiesis-stimulating agents (epoetin alfa/beta, darbepoetin — long-acting); G-CSF (filgrastim), GM-CSF (sargramostim) — neutrophil stimulants.
- Thrombocytopenia agents: corticosteroids (prednisolone — ITP first-line); IVIg (ITP acute); thrombopoietin receptor agonists (TPO-RAs): eltrombopag (oral), romiplostim (SC injection).

Family 2 — Anticoagulants (PH4.2):
- Parenteral: UFH (IV/SC), LMWH — enoxaparin (SC), fondaparinux (SC, anti-Xa), bivalirudin (IV, direct thrombin inhibitor).
- Oral: warfarin (vitamin K antagonist); DOACs: dabigatran (direct thrombin inhibitor), rivaroxaban/apixaban/edoxaban (direct factor Xa inhibitors).

Family 3 — Fibrinolytics and antifibrinolytics (PH4.3):
- Fibrinolytics: streptokinase (non-fibrin-specific), alteplase (fibrin-specific), tenecteplase (single IV bolus).
- Antifibrinolytics: tranexamic acid (TXA) and aminocaproic acid (ε-ACA) — lysine analogues; aprotinin (serine protease inhibitor, cardiopulmonary bypass).

Family 4 — Antiplatelet drugs (PH4.4):
- COX-1 inhibitor: aspirin.
- P2Y12 inhibitors: clopidogrel (prodrug), ticagrelor (non-prodrug, reversible), prasugrel (prodrug).
- GPIIb/IIIa inhibitors: abciximab, eptifibatide, tirofiban — IV only, for PCI.
- Other: dipyridamole (PDE inhibitor + adenosine reuptake block → ↑cAMP → platelet inhibition; combined with aspirin in modified-release form for secondary stroke prevention).