13.3 Haemostasis, Coagulation Disorders & Anticoagulant Reversal

Haemostasis, Coagulation Disorders & Anticoagulant Reversal

Haemostasis is the physiological mechanism that prevents excessive blood loss following vascular disruption while maintaining blood in a fluid state within intact vessels.

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1. Physiology of Haemostasis & Coagulation Profile Interpretation

Haemostasis proceeds in two tightly coordinated physiological phases:

• Primary Haemostasis (Platelet Plug Formation): Endothelial injury exposes subendothelial collagen. Circulating von Willebrand factor (vWF) binds to exposed collagen, allowing platelet adhesion via the platelet membrane glycoprotein Ib (GpIb) receptor. Adherent platelets activate, undergo conformational shape changes, and secrete chemical mediators (thromboxane A2, ADP) that recruit and activate additional circulating platelets. Platelets aggregate via glycoprotein IIb/IIIa (GpIIb/IIIa) receptors cross-linked by fibrinogen, forming an unstable primary platelet plug. Deficiencies in primary haemostasis cause mucocutaneous bleeding (epistaxis, menorrhagia, gingival bleeding, petechiae, and purpura).
• Secondary Haemostasis (Coagulation Cascade): Tissue factor exposed at the injury site activates the extrinsic pathway, leading via Factor X activation to the common pathway. Small amounts of thrombin (Factor IIa) trigger massive feedback amplification of the intrinsic tenase complex (Factors VIIIa, IXa) on the negatively charged platelet membrane surface. Thrombin rapidly cleaves soluble fibrinogen into insoluble fibrin monomers, which are covalently cross-linked by Factor XIIIa into a stable secondary haemostatic fibrin meshwork. Deficiencies in secondary haemostasis cause deep tissue bleeding (haemarthroses, muscle haematomas, and delayed secondary postoperative haemorrhage).

Interpretation of Standard Coagulation Profiles

• Prothrombin Time (PT / INR): Measures the extrinsic (Factor VII) and common pathways (Factors X, V, II [prothrombin], I [fibrinogen]). Prolonged by warfarin, vitamin K deficiency, liver failure, and DIC.
• Activated Partial Thromboplastin Time (APTT): Measures the intrinsic (Factors XII, XI, IX, VIII) and common pathways (Factors X, V, II, I). Prolonged by unfractionated heparin, haemophilia A (VIII) and B (IX), von Willebrand disease (variable/mild), and lupus anticoagulant (paradoxical in vitro artefact; prothrombotic in vivo).
• Fibrinogen / Thrombin Time (TT): Evaluates the conversion of fibrinogen to fibrin. Depleted in severe DIC, massive haemorrhage, and severe hepatic synthesis failure; inhibited by dabigatran and direct thrombin inhibitors.

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2. Inherited Bleeding Disorders

Haemophilia A & B

• Haemophilia A: Deficiency or functional absence of Factor VIII. Inherited as an X-linked recessive trait (~85% of all haemophilia cases; predominantly affects males; females are typically asymptomatic obligate or facultative carriers).
• Haemophilia B (Christmas Disease): Deficiency or functional absence of Factor IX. Also inherited as an X-linked recessive trait (~15% of cases). Clinically indistinguishable from Haemophilia A.
• Clinical Features: Deep, painful, recurrent bleeding episodes into large synovial joints (haemarthroses, most commonly knees, elbows, and ankles), leading to chronic hypertrophic synovitis and crippling fixed joint arthropathy. Large intramuscular haematomas occur after minimal trauma. Superficial cuts and mucosal bleeding are characteristically absent.
• Coagulation Profile: Isolated, significantly prolonged APTT with a completely normal PT, normal platelet count, and normal bleeding time / vWF profile.
• Management:
  • Definitive Therapy: Prompt intravenous administration of recombinant Factor VIII (for Haemophilia A) or recombinant Factor IX (for Haemophilia B) concentrates.
  • Mild Haemophilia A: Intravenous or intranasal Desmopressin (DDAVP) stimulates the exocytosis of endogenous Factor VIII and vWF from endothelial Weibel-Palade bodies, temporarily raising circulating FVIII levels 2- to 4-fold.
  • Precautions: Strictly avoid intramuscular injections, non-steroidal anti-inflammatory drugs (NSAIDs), and aspirin. Maintain regular prophylactic factor infusions in severe disease (factor level <1%).

von Willebrand Disease (vWD)

• Pathophysiology: The most common inherited bleeding disorder, affecting approximately 1% of the population. Characterised by quantitative or qualitative deficiencies in von Willebrand factor (vWF). Inherited predominantly as an autosomal dominant trait (Types 1 and 2; Type 3 is autosomal recessive and severe).
• Dual Functions of vWF:
  1. Binds platelets to subendothelial collagen at sites of vascular shear stress (primary haemostasis).
  2. Acts as the protective circulating carrier chaperone protein for Factor VIII, preventing its rapid proteolytic degradation by activated protein C.
• Clinical Presentation: Defective primary haemostasis: recurrent epistaxis, easy spontaneous bruising, heavy menstrual bleeding (menorrhagia in adolescent and adult females), prolonged oozing after dental extractions or minor cutaneous lacerations.
• Laboratory Profile: Bleeding time / platelet function analyser (PFA-100) is prolonged. APTT is normal or mildly prolonged (secondary to reduced FVIII levels). PT and platelet counts are normal (except in rare Type 2B vWD where platelet count is low).
• Management:
  • Antifibrinolytic agents (oral or IV tranexamic acid) for minor dental or mucosal bleeding.
  • Desmopressin (DDAVP): Highly effective in Type 1 vWD to release stored endothelial vWF pools.
  • Severe bleeding or Type 2/3 vWD: Plasma-derived or recombinant vWF-containing Factor VIII concentrates (e.g. Haemate P).

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3. Acquired Platelet & Consumptive Disorders

Immune Thrombocytopenia (ITP)

• Pathophysiology: Acquired autoimmune disorder characterised by circulating IgG autoantibodies directed against platelet membrane glycoproteins (GpIIb/IIIa). Antibody-coated platelets undergo premature destruction by Fc-receptor mediated phagocytosis within splenic macrophages.
• Clinical Presentation: Isolated thrombocytopenia manifesting as petechiae, spontaneous purpura, gingival bleeding, or epistaxis in an otherwise systemically well patient. Splenomegaly is notably absent; presence of lymphadenopathy or splenomegaly should prompt search for leukaemia or lymphoma.
• Laboratory Profile: Isolated severe thrombocytopenia (<50 x 10^9/L; often <20 x 10^9/L). Coagulation screen (PT, APTT, fibrinogen) and peripheral blood film red/white cell morphology are entirely normal.
• Management:
  • Mild/Asymptomatic: Platelets >30 x 10^9/L without bleeding: observation and outpatient monitoring.
  • First-Line Active Therapy: Oral prednisolone (1 mg/kg/day) tapered over several weeks, OR Intravenous Immunoglobulin (IVIG) (preferred when a rapid platelet rise is mandated for active haemorrhage or emergency surgery).
  • Second-Line: Thrombopoietin receptor agonists (Eltrombopag, Romiplostim), Rituximab, or Laparoscopic Splenectomy.

Thrombotic Thrombocytopenic Purpura (TTP)

• Pathophysiology: A life-threatening thrombotic microangiopathy caused by severe functional deficiency of the ADAMTS13 metalloprotease (<10% activity), most commonly secondary to acquired IgG autoantibodies. ADAMTS13 is responsible for cleaving ultra-large vWF multimers into smaller physiological units. In its absence, uncleaved ultra-large vWF multimers bind platelets spontaneously, generating widespread platelet-rich microvascular thrombi that shear circulating erythrocytes and cause end-organ ischaemia.
• The Classic Pentad of TTP:
  1. Microangiopathic Haemolytic Anaemia (MAHA): Jaundice, elevated LDH, undetectable haptoglobin, and prominent schistocytes ("helmet cells") on blood film.
  2. Severe Thrombocytopenia: Petechiae, purpura, bruising.
  3. Neurological Fluctuations: Transient ischaemic attacks, fluctuating confusion, headache, visual changes, seizures, or coma.
  4. Renal Dysfunction: Proteinuria, microscopic haematuria, acute kidney injury (usually milder than in HUS).
  5. Fever: Mild pyrexia.

Disseminated Intravascular Coagulation (DIC)

• Etiology: Systemic activation of coagulation cascades secondary to overwhelming underlying pathology: Gram-negative sepsis (endotoxin), severe trauma/burns, obstetric catastrophes (placental abruption, amniotic fluid embolism), or malignancy (APML, adenocarcinoma).
• Pathology: Massive intravascular thrombin generation causes microvascular thrombosis and end-organ failure, accompanied by consumption and exhaustion of platelets, fibrinogen, and clotting factors (consumptive coagulopathy), driving uncontrolled catastrophic systemic haemorrhage.
• Diagnostic Profile: Prolonged PT and APTT, severe thrombocytopenia, profoundly depleted fibrinogen (<1.5 g/L), and markedly elevated D-dimer / FDPs.
• Management: Treat the underlying precipitant aggressively (antibiotics, delivery, surgical control). Provide supportive replacement: platelets (maintain >50 x 10^9/L), fresh frozen plasma (FFP for prolonged PT/APTT), and cryoprecipitate (to maintain fibrinogen >1.5 g/L).

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4. Anticoagulant Monitoring & Emergency Reversal Protocols

Warfarin (Vitamin K Antagonist)

Warfarin competitively inhibits Vitamin K Epoxide Reductase Complex 1 (VKORC1), blocking gamma-carboxylation of clotting factors II, VII, IX, and X, as well as natural anticoagulants Protein C and Protein S.

• Monitoring: Monitored via the International Normalised Ratio (INR). Target INR is 2.5 (2.0–3.0) for venous thromboembolism (DVT, PE) and non-valvular atrial fibrillation; target is 3.5 (3.0–4.0) for mechanical mitral prosthetic heart valves.
• Emergency Reversal Protocols (NICE / BCSH Guidelines):
  • Major Life-Threatening Bleeding (Intracranial, Massive GI, Retroperitoneal):
    1. Stop Warfarin immediately.
    2. Administer Four-Factor Prothrombin Complex Concentrate (4F-PCC) (e.g. Beriplex, Octaplex; contains concentrated factors II, VII, IX, X) at a dose of 25–50 IU/kg IV infusion. Reverses anticoagulation completely within 10–15 minutes.
    3. Co-administer Intravenous Phytomenadione (Vitamin K1) 5–10 mg slow IV (takes 4–6 hours to stimulate de novo hepatic factor synthesis, ensuring sustained reversal once PCC factors are cleared).
    4. Note: Fresh Frozen Plasma (FFP) is slow to infuse, requires ABO matching, risks fluid overload, and is only used if 4F-PCC is unavailable.
  • Minor Bleeding with INR >5.0: Stop warfarin, give slow IV vitamin K (phytomenadione) 1–3 mg, and restart warfarin when INR is below 5.0.
  • No Bleeding with INR >8.0: Stop warfarin, administer oral Vitamin K 1–5 mg, review INR in 24 hours.
  • No Bleeding with INR 5.0–8.0: Withhold 1–2 doses of warfarin, reduce maintenance dose, monitor INR.

Direct Oral Anticoagulants (DOACs)

• Direct Thrombin Inhibitor: Dabigatran (Pradaxa):
  • Directly inhibits free and clot-bound thrombin (Factor IIa).
  • Specific Reversal Agent: Idarucizumab (Praxbind), a humanized monoclonal antibody fragment that binds dabigatran with 350-fold higher affinity than thrombin. Administered as 5 g IV (2 x 2.5 g vials infused consecutively); achieves immediate complete reversal.
• Direct Factor Xa Inhibitors: Apixaban, Rivaroxaban, Edoxaban:
  • Directly inhibit free and bound Factor Xa.
  • Specific Reversal Agent: Andexanet alfa (Ondexxya), a recombinant modified decoy Factor Xa protein that sequesters Xa inhibitors. Where Andexanet alfa is unavailable or non-formulary, administer 4-factor PCC (25–50 IU/kg IV).

Heparin Reversal

• Unfractionated Heparin (UFH): Monitored by APTT ratio (target 1.5–2.5). Reversed completely by Protamine Sulfate (1 mg protamine neutralizes 100 units of UFH; maximum single dose 50 mg slow IV to prevent anaphylactoid hypotension and bradycardia).
• Low Molecular Weight Heparin (LMWH: Enoxaparin, Dalteparin): Protamine sulfate provides only partial reversal (~60%) due to poor binding to shorter polysaccharide chains.