Blood

Anticoagulants — Classification

Parenteral: UFH · LMWH(enoxaparin, dalteparin) · fondaparinux(synthetic pentasaccharide) · direct thrombin inhibitors(bivalirudin, argatroban). Oral: warfarin(vit K antagonist) · DOACs — dabigatran(direct IIa) · rivaroxaban/apixaban/edoxaban(direct Xa).

Anticoagulants — Mechanism

UFH: binds antithrombin III→↑its inhibition of thrombin(IIa)+Xa ~1000-fold (catalytic). Long chains bridge antithrombin+thrombin simultaneously → strong anti-IIa AND anti-Xa.

LMWH: shorter chains → CAN’T bridge to thrombin → weak anti-IIa, retains anti-Xa. → predictable PK, longer t½, once/twice-daily SC, usually no monitoring needed → preferred over UFH except when rapid reversibility needed or renal failure(LMWH renally cleared, accumulates — UFH preferred there).

Fondaparinux: minimum antithrombin-binding pentasaccharide — PURE anti-Xa, ZERO anti-IIa (too short to bridge). No HIT risk (doesn’t bind PF4).

Warfarin: inhibits VKORC1(vitamin K epoxide reductase) → blocks γ-carboxylation of factors II,VII,IX,X + protein C,S. Onset DELAYED (days) = governed by half-lives of EXISTING factors, not drug PK. Factor VII(t½6h) falls FIRST but full effect needs factor II(t½60h) to fall too → INR takes days. Protein C(short t½) falls before procoagulant factors → transient HYPERCOAGULABLE window early → warfarin skin necrosis + why overlap with heparin/LMWH for rapid anticoagulation.

DOACs: dabigatran=direct IIa inhibitor; rivaroxaban/apixaban/edoxaban=direct Xa inhibitors. No antithrombin intermediary → predictable PK, fixed dose, rapid on/off, no routine monitoring. Reversal: idarucizumab(dabigatran), andexanet alfa(Xa inhibitors).

Anticoagulants — Adverse Effects

Heparin/LMWH: bleeding · HIT (immune Ab vs heparin-PF4 complex → PARADOXICAL platelet activation → PROTHROMBOTIC despite ↓platelet count; more with UFH; switch to non-heparin anticoagulant, NEVER just another heparin) · osteoporosis(UFH>LMWH, prolonged use) · hyperkalaemia(↓aldosterone synthesis).

Warfarin: bleeding + narrow TI + major interactions(CYP2C9 inhibitors/albumin displacement/↓dietary vit K potentiate; inducers/↑dietary vit K antagonize — keep leafy greens CONSISTENT not avoided) · TERATOGENIC(warfarin embryopathy: nasal hypoplasia, skeletal abnormalities — CI in pregnancy, use LMWH instead, doesn’t cross placenta) · warfarin skin necrosis(protein C mechanism above).

DOACs: bleeding(lower ICH risk than warfarin in trials; dabigatran = higher GI bleed risk) · dose adjust/CI in significant renal impairment(dabigatran most renally cleared).

Antiplatelets — Classification

COX inhibitor: aspirin(low-dose, irreversible). ADP/P2Y12 antagonists: clopidogrel, prasugrel, ticagrelor. GP IIb/IIIa inhibitors: abciximab, tirofiban, eptifibatide. PDE inhibitor: dipyridamole. PAR-1 antagonist: vorapaxar.

Antiplatelets — Mechanism

Aspirin: IRREVERSIBLY acetylates COX-1 in platelets → blocks TXA2 synthesis for platelet’s WHOLE LIFESPAN(anucleate, can’t resynthesize COX) → single low dose lasts 7-10 days. Low dose deliberately BELOW anti-inflammatory(COX-2) dose → preserves endothelial PGI2(antiplatelet, vasodilator; endothelium CAN resynthesize COX) relative to platelet TXA2.

P2Y12 antagonists: block ADP receptor → ↓amplification of activation → ↓GP IIb/IIIa conformational activation(final common pathway, binds fibrinogen, cross-links platelets). Clopidogrel/prasugrel = PRODRUGS (clopidogrel via CYP2C19 — poor-metabolizer variants → ↓efficacy, examined pharmacogenomic point), IRREVERSIBLE binding. Ticagrelor = active drug, REVERSIBLE binding.

GP IIb/IIIa inhibitors: block final common receptor directly, downstream of ALL activation pathways — most potent antiplatelet mechanism, IV-only, high-risk PCI settings.

Dipyridamole: ↑platelet cAMP(PDE inhibition) + blocks adenosine reuptake(SAME mechanism as its coronary steal in Antianginals). Weak alone → always + aspirin, never monotherapy.

Antiplatelets — Adverse Effects

Bleeding(shared). Aspirin: GI ulceration/bleeding(↓cytoprotective gastric PGs) · Reye’s syndrome(avoid in children with viral febrile illness). Clopidogrel/ticagrelor: dyspepsia; ticagrelor SPECIFICALLY→dyspnoea(adenosine-related, drug-specific not class effect). GP IIb/IIIa: thrombocytopenia + bleeding.

Thrombolytics

Classification: streptokinase, urokinase, alteplase(rt-PA), reteplase, tenecteplase.

Mechanism: plasminogen→plasmin→degrades fibrin, DISSOLVES existing clot (different from anticoag/antiplatelet which only PREVENT new/extending clot). Streptokinase: bacterial protein, complexes with plasminogen→activates NON-selectively(clot-bound+circulating)→systemic lytic state. ANTIGENIC(allergic reactions, ↓efficacy on re-exposure, avoid reuse ~1yr). Alteplase/reteplase/tenecteplase: recombinant tPA, relatively FIBRIN-SELECTIVE(prefers clot-bound plasminogen)→less systemic fibrinogen depletion, though actual bleeding-risk difference smaller than selectivity suggests.

Adverse effects: bleeding incl. ICH(most feared) — strict time-window+contraindication use(STEMI, acute ischemic stroke). Streptokinase: hypotension+allergic/anaphylactoid reactions(bacterial origin).

Drugs for Bleeding Disorders

Vitamin K: reverses warfarin SLOWLY(needs new factor synthesis) — urgent reversal needs FFP/PCC(the factors themselves) ALONGSIDE vit K, not instead. Protamine sulfate: cationic protein, binds/neutralizes anionic heparin ionically. Reverses UFH COMPLETELY, LMWH only PARTIALLY(binds long anti-IIa chains, less effective vs anti-Xa activity). Tranexamic acid, aminocaproic acid: antifibrinolytics — block lysine-binding site on plasminogen→prevent fibrin binding→prevent plasmin activation. Menorrhagia, surgical/traumatic bleeding — pharmacological OPPOSITE of thrombolytics. Desmopressin(DDAVP): releases stored vWF+factor VIII from endothelium(V2-like receptor, distinct from renal antidiuretic V2 action). Mild haemophilia A, vWD — avoids factor replacement. Factor concentrates: recombinant VIII(haemophilia A), IX(haemophilia B), PCC(multiple vit-K-dependent factors, urgent warfarin reversal).

Haematinics

Iron(ferrous sulfate/fumarate/gluconate): iron deficiency anaemia. Absorption via DMT1(duodenum), ↑by acidic environment(vit C), ↓by achlorhydria/antacids/tetracycline chelation. SE: GI upset, constipation, black stools(harmless, pre-counsel). Acute overdose(children)=emergency, deferoxamine=antidote.

B12(cyanocobalamin/hydroxocobalamin) + folic acid: megaloblastic anaemia. KEY TRAP: folic acid ALONE in B12-deficient patient → corrects anaemia BUT does NOT prevent(may ACCELERATE) neurological damage(subacute combined degeneration) — always exclude B12 deficiency or give BOTH together.

Haematopoietic Growth Factors

Erythropoietin(epoetin alfa, darbepoetin): recombinant EPO → ↑erythroid proliferation/differentiation. Anaemia of CKD(classic — replaces endogenous EPO failing kidneys don’t make) + anaemia of chronic disease/chemo. SE: HTN, ↑thromboembolic risk if Hb target OVERSHOT → dosed to target range, NOT full normalization.

G-CSF(filgrastim), GM-CSF: ↑neutrophil precursor proliferation → ↓duration of chemo-induced neutropenia/febrile neutropenia risk. SE: bone pain(marrow expansion), mild/self-limiting.

Plasma Expanders

Crystalloids(NS, Ringer’s lactate) vs colloids(albumin, HES, dextrans). Dextrans ALSO have mild antiplatelet/anticoagulant effect(↓platelet function+factor VIII/vWF) — incidental examinable property beyond volume expansion.

Clinical Relevance

Organizing distinction: PREVENT vs DISSOLVE vs STOP. Anticoagulants+antiplatelets = prevent clot forming/extending(different mechanisms — cascade vs aggregation — hence combined use in arterial thrombosis). Thrombolytics = actively DISSOLVE existing clot(narrow-window, high-risk). Antifibrinolytics/procoagulants = pharmacological OPPOSITE, stop bleeding by preserving/restoring clot. Mixing these up (antifibrinolytic for thrombosis, thrombolytic for active bleeding) = the conceptual error this topic exists to prevent.

Anticoagulants

Classification

1. Parenteral
   • Unfractionated heparin (UFH)
   • Low molecular weight heparins (LMWH): enoxaparin, dalteparin
   • Fondaparinux (synthetic pentasaccharide)
   • Direct thrombin inhibitors: bivalirudin, argatroban
2. Oral
   • Vitamin K antagonist: warfarin
   • Direct oral anticoagulants (DOACs): dabigatran (direct thrombin inhibitor), rivaroxaban/apixaban/edoxaban (direct factor Xa inhibitors)

Mechanism of Action

Heparin (UFH): binds antithrombin III and accelerates its inhibitory action on thrombin (factor IIa) and factor Xa by roughly 1000-fold — a catalytic, not stoichiometric, mechanism. UFH’s long, heterogeneous polysaccharide chains bind both antithrombin and thrombin simultaneously (a ternary complex), giving it strong anti-IIa activity in addition to anti-Xa activity.

LMWH: shorter chains — long enough to bind antithrombin and potentiate anti-Xa activity, but too short to bridge antithrombin to thrombin simultaneously, so anti-IIa activity is much weaker relative to anti-Xa. This altered chain-length dependency is the direct mechanistic reason LMWH has more predictable pharmacokinetics (less protein/cell binding), a longer half-life allowing once/twice-daily subcutaneous dosing, and generally no need for routine coagulation monitoring — advantages that have made LMWH the preferred agent over UFH for most indications, with UFH now reserved chiefly for situations needing rapid reversibility or in renal failure (LMWH is renally cleared and accumulates).

Fondaparinux: a synthetic pentasaccharide, the minimum antithrombin-binding sequence within heparin — pure anti-Xa activity, no anti-IIa activity at all (too short to bridge thrombin), and no risk of heparin-induced thrombocytopenia (see below) since it doesn’t bind platelet factor 4 the way heparin does.

Warfarin: inhibits vitamin K epoxide reductase (VKORC1), which normally recycles oxidized vitamin K back to its active reduced form — without reduced vitamin K, the γ-carboxylation of glutamate residues on clotting factors II, VII, IX, X (and the natural anticoagulants protein C and protein S) cannot occur, and these factors are synthesized but functionally inactive. Onset is delayed (days), governed by the half-lives of the existing functional factors already in circulation, not by the drug’s own pharmacokinetics — factor VII (shortest half-life, ~6 hours) falls first, but full antithrombotic effect requires factor II (prothrombin, half-life ~60 hours) to also fall, which is why a therapeutic INR takes several days to establish. Protein C’s short half-life falling before the procoagulant factors creates a transient hypercoagulable window early in warfarin therapy — the mechanistic basis for warfarin skin necrosis and for overlapping warfarin with a fast-acting parenteral anticoagulant (heparin/LMWH) when rapid anticoagulation is needed.

DOACs: dabigatran is a direct thrombin (factor IIa) inhibitor; rivaroxaban, apixaban, edoxaban are direct factor Xa inhibitors — both classes act directly on their target coagulation factor without requiring antithrombin as an intermediary, giving predictable pharmacokinetics, fixed dosing, rapid onset/offset, and no requirement for routine coagulation monitoring, at the cost of (historically) fewer reversal options than warfarin — though specific reversal agents now exist (idarucizumab for dabigatran, andexanet alfa for factor Xa inhibitors).

Adverse Effects

Heparin/LMWH: bleeding (dose-related, the class-defining risk of any anticoagulant) · heparin-induced thrombocytopenia (HIT) — an immune-mediated reaction where antibodies form against the heparin-platelet factor 4 complex, paradoxically causing platelet activation and a prothrombotic, not merely bleeding, state despite the falling platelet count; more common with UFH than LMWH, and requires switching to a non-heparin anticoagulant (a direct thrombin inhibitor or fondaparinux), never simply to a different heparin product · osteoporosis with prolonged use (UFH more than LMWH) · hyperkalaemia (heparin suppresses aldosterone synthesis).

Warfarin: bleeding, the dominant risk, compounded by a narrow therapeutic index and extensive drug/food interactions (potentiated by CYP2C9 inhibitors, displacement from albumin binding, and reduced dietary vitamin K intake; antagonized by enzyme inducers and increased dietary vitamin K — leafy greens are the classic patient-counselling point, not to be avoided but to be kept consistent) · teratogenic (warfarin embryopathy — nasal hypoplasia, skeletal abnormalities; contraindicated in pregnancy, where LMWH is used instead since it doesn’t cross the placenta) · warfarin skin necrosis (above, protein C mechanism).

DOACs: bleeding, generally with a lower intracranial haemorrhage risk than warfarin in trials, though dabigatran carries a comparatively higher GI bleeding risk; contraindicated or requiring dose adjustment in significant renal impairment (all DOACs have some renal clearance, dabigatran the most).

Antiplatelet Drugs

Classification

1. COX inhibitor: aspirin (low-dose, irreversible)
2. ADP (P2Y12) receptor antagonists: clopidogrel, prasugrel, ticagrelor
3. Glycoprotein IIb/IIIa inhibitors: abciximab, tirofiban, eptifibatide
4. Phosphodiesterase inhibitor: dipyridamole
5. PAR-1 (thrombin receptor) antagonist: vorapaxar

Mechanism of Action

Aspirin: irreversibly acetylates cyclooxygenase-1 in platelets, blocking thromboxane A2 (TXA2, a potent platelet-aggregating and vasoconstricting eicosanoid) synthesis for the platelet’s entire lifespan (platelets, being anucleate, cannot synthesize new COX-1) — this is why low-dose aspirin’s antiplatelet effect lasts the full 7–10 day platelet lifespan from a single dose, and why the low antiplatelet dose is deliberately kept below the dose needed for COX-2-mediated anti-inflammatory effects, preserving vascular endothelial prostacyclin (PGI2, an antiplatelet, vasodilator eicosanoid made via endothelial COX, which — unlike platelets — can resynthesize COX) relative to platelet TXA2.

P2Y12 antagonists: block the ADP receptor (P2Y12) on platelets, preventing ADP-mediated amplification of platelet activation and the resulting conformational activation of glycoprotein IIb/IIIa (the final common pathway receptor that binds fibrinogen and cross-links platelets). Clopidogrel and prasugrel are prodrugs requiring hepatic bioactivation (clopidogrel via CYP2C19, with well-documented poor-metaboliser genetic variability causing reduced efficacy in some patients — a genuinely examined pharmacogenomic point); ticagrelor is an active drug with a reversible binding mode, unlike the irreversible binding of clopidogrel/prasugrel.

GP IIb/IIIa inhibitors: block the final common receptor for platelet aggregation directly, downstream of whatever pathway activated the platelet — the most potent antiplatelet mechanism available, reserved for high-risk percutaneous coronary intervention settings given IV-only administration and bleeding risk.

Dipyridamole: inhibits phosphodiesterase (raising platelet cAMP, which itself inhibits activation) and blocks adenosine reuptake — the same adenosine-reuptake-blocking mechanism responsible for dipyridamole’s coronary steal phenomenon described under Antianginal Drugs; as an antiplatelet, it is used only in combination with aspirin, never as monotherapy, given weak effect alone.

Adverse Effects

Bleeding (the shared class risk) · aspirin: GI ulceration/bleeding (COX-1 inhibition removes cytoprotective gastric prostaglandins), Reye’s syndrome (avoided in children with viral febrile illness) · clopidogrel/ticagrelor: dyspepsia, and ticagrelor specifically causes dyspnoea (a distinct, drug-specific adverse effect via adenosine-related mechanisms, not a class effect of P2Y12 blockade) · GP IIb/IIIa inhibitors: thrombocytopenia in addition to bleeding.

Thrombolytics (Fibrinolytics)

Classification

Streptokinase, urokinase, alteplase (recombinant tissue plasminogen activator, rt-PA), reteplase, tenecteplase.

Mechanism of Action

Convert plasminogen to plasmin, which degrades fibrin and dissolves an already-formed clot — a fundamentally different action from anticoagulants/antiplatelets, which prevent new clot formation/extension but do not dissolve existing clot. Streptokinase is a bacterial protein (from Streptococcus) that forms a complex with plasminogen to activate it indirectly and non-selectively (activates both clot-bound and circulating plasminogen, producing a systemic lytic state) — being bacterial, it is antigenic (allergic reactions, and reduced efficacy on re-exposure due to antibody formation, generally restricting re-use within roughly a year). Alteplase/reteplase/tenecteplase are recombinant tissue-type plasminogen activators with relative fibrin selectivity (preferentially activate plasminogen already bound to fibrin within a clot), producing less systemic fibrinogen depletion than streptokinase, though the actual clinical bleeding risk difference is smaller than the mechanistic selectivity might suggest.

Adverse Effects

Bleeding (including intracranial haemorrhage, the most feared complication) — used only within defined time windows of an acute thrombotic event (STEMI, acute ischaemic stroke) with strict contraindication checklists (recent surgery, active bleeding, uncontrolled hypertension, prior intracranial haemorrhage) given the narrow benefit-risk margin. Streptokinase specifically: hypotension and allergic/anaphylactoid reactions given its bacterial/antigenic origin.

Drugs for Bleeding Disorders

• Vitamin K (phytonadione): reverses warfarin’s effect by restoring substrate for γ-carboxylation, but slowly (requires new factor synthesis) — for urgent warfarin reversal, fresh frozen plasma or prothrombin complex concentrate (containing the factors themselves) is used alongside vitamin K, not instead of it.
• Protamine sulfate: a strongly cationic protein that binds and neutralizes strongly anionic heparin by ionic interaction — reverses UFH essentially completely, LMWH only partially (protamine binds LMWH’s anti-IIa-active longer chains but less effectively neutralizes its anti-Xa activity).
• Tranexamic acid, aminocaproic acid: antifibrinolytics — competitively block the lysine-binding site on plasminogen, preventing its binding to fibrin and thus preventing activation to plasmin; used for menorrhagia, surgical/traumatic bleeding, and as adjunct therapy where excessive fibrinolysis contributes to bleeding (the pharmacological opposite of the thrombolytics above).
• Desmopressin (DDAVP): releases stored von Willebrand factor and factor VIII from endothelial cells (via renal V2-like receptor action on endothelium, distinct from its antidiuretic V2-receptor action in the kidney) — used in mild haemophilia A and von Willebrand disease to raise factor VIII/vWF levels without needing factor replacement.
• Factor concentrates: recombinant factor VIII (haemophilia A), factor IX (haemophilia B), and prothrombin complex concentrate (multiple vitamin K-dependent factors, for urgent warfarin reversal or specific factor deficiencies).

Haematinics

• Iron: ferrous sulfate/fumarate/gluconate (oral) — treats iron deficiency anaemia, the commonest nutritional anaemia; oral absorption occurs via DMT1 in the duodenum, enhanced by an acidic environment (vitamin C co-administration classically recommended) and impaired by achlorhydria/antacids/tetracycline chelation. Adverse effects: GI upset, constipation, black stools (harmless but worth pre-counselling to avoid mistaking it for melaena); acute iron overdose in children is a genuine poisoning emergency (deferoxamine is the chelating antidote).
• Vitamin B12 (cyanocobalamin/hydroxocobalamin) and folic acid: treat megaloblastic anaemia. The critical, frequently-tested distinction: giving folic acid alone in a B12-deficient patient corrects the anaemia (haematological response) but does NOT prevent, and may accelerate, the neurological damage of B12 deficiency (subacute combined degeneration) — B12 deficiency must always be excluded, or both given together, before treating megaloblastic anaemia with folate alone.

Haematopoietic Growth Factors

• Erythropoietin (epoetin alfa, darbepoetin): recombinant erythropoietin, stimulates erythroid progenitor proliferation/differentiation — used in anaemia of chronic kidney disease (the classic indication, replacing endogenous EPO that failing kidneys no longer adequately produce) and anaemia of chronic disease/chemotherapy. Adverse effects: hypertension, and an increased thromboembolic risk if the haemoglobin target is overshot — a specific, examined reason these agents are dosed to a target range, not to normalize haemoglobin fully.
• G-CSF (filgrastim), GM-CSF: stimulate neutrophil precursor proliferation — used to shorten the duration of chemotherapy-induced neutropenia and reduce febrile neutropenia risk. Adverse effect: bone pain (from marrow expansion), generally mild and self-limiting.

Plasma Expanders

Crystalloids (normal saline, Ringer’s lactate) and colloids (albumin, hydroxyethyl starch, dextrans) used for acute volume replacement — dextrans additionally carry a mild antiplatelet/anticoagulant effect (interfering with platelet function and factor VIII/vWF) worth knowing as an incidental, examinable property beyond their volume-expanding role.

Clinical Relevance

The organizing distinction across this topic is prevent versus dissolve versus stop: anticoagulants and antiplatelets prevent a clot from forming or extending (different mechanisms — coagulation cascade versus platelet aggregation — hence their frequent combined use in arterial thrombotic disease), thrombolytics actively dissolve a clot that has already formed (a narrow-window, high-risk intervention), and antifibrinolytics/procoagulant agents do the pharmacological opposite, stopping bleeding by preserving or restoring clot rather than preventing or dissolving it. Confusing which category a clinical scenario calls for — giving an antifibrinolytic when the problem is thrombosis, or a thrombolytic when the problem is ongoing hemorrhage — is the conceptual error this whole topic exists to prevent.

• Coagulation cascade with sites of action of heparin/LMWH/fondaparinux/warfarin/DOACs marked at their specific factors.
• Platelet activation pathway showing where aspirin, P2Y12 antagonists, and GP IIb/IIIa inhibitors each act, converging on the final fibrinogen-binding step.
• Warfarin’s delayed onset explained via the differing half-lives of factors II/VII/IX/X and protein C, and the resulting early hypercoagulable window.

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