22.4 Coagulation Cascade & Inherited Bleeding Disorders

Hemostasis, thrombosis, and transfusion medicine constitute critical domains of acute internal medicine tested extensively in the MRCP(UK) Part 1 examination. Candidates must master the physiological pathways of platelet plug formation and coagulation cascade serine proteases, distinguish inherited bleeding diatheses, manage life-threatening microangiopathies and thrombotic emergencies, and rapidly recognize and treat adverse transfusion reactions.

1. Hemostasis & Coagulation Cascade Architecture

Hemostasis is divided into two interdependent physiological phases: primary hemostasis (platelet plug formation) and secondary hemostasis (fibrin clot generation).

                             The Hemostatic Cascade
                                        |
            +---------------------------+---------------------------+
            |                                                       |
   Primary Hemostasis                                      Secondary Hemostasis
   (Platelets & vWF)                                        (Coagulation Cascade)
            |                                                       |
   1. Adhesion (vWF -> GpIb)                               +--------+--------+
   2. Activation (ADP, TxA2)                               |                 |
   3. Aggregation (GpIIb/IIIa -> Fibrinogen)          Intrinsic         Extrinsic
            |                                         (XII, XI, IX, VIII)  (Tissue Factor, VII)
   Defect: Mucocutaneous bleeding                          |                 |
   (Petechiae, epistaxis, menorrhagia)                 [ aPTT ]            [ PT ]
                                                           +--------+--------+
                                                                    |
                                                             Common Pathway
                                                             (X, V, II, I)
                                                             [ Both Prolonged ]

Primary Hemostasis

• Endothelial Injury & Platelet Adhesion: Vascular injury exposes subendothelial type I/IV collagen and von Willebrand factor (vWF). Circulating platelets adhere to exposed subendothelial vWF via the Glycoprotein Ib-IX-V (GpIb) receptor complex on the platelet surface.
• Platelet Activation & Secretion: Adherent platelets undergo shape change (discoid to pseudopodial) and degranulate:
  • Dense granules: Release adenosine diphosphate (ADP; activates P2Y12 receptors) and calcium (mandatory for clotting factor assembly).
  • Alpha granules: Release vWF, fibrinogen, factor V, and platelet factor 4 (PF4).
  • Thromboxane A2 (TxA2): Platelet membrane arachidonic acid is converted by cyclooxygenase-1 (COX-1) and thromboxane synthase into TxA2, a potent platelet activator and local vasoconstrictor.
• Platelet Aggregation: Activation induces a conformational change in the Glycoprotein IIb/IIIa (GpIIb/IIIa / integrin aIIb-b3) receptor complex, exposing high-affinity binding sites for dimeric fibrinogen (and vWF). Fibrinogen forms bridges between adjacent platelets, assembling the primary, friable hemostatic plug.
• Clinical Manifestations of Primary Hemostatic Defects: Mucocutaneous bleeding: Petechiae (pinpoint capillary haemorrhages, pathognomonic of thrombocytopenia), purpura, superficial ecchymoses, recurrent epistaxis, gingival bleeding, menorrhagia, and immediate, persistent oozing following minor cuts or dental extractions.

Secondary Hemostasis

Secondary hemostasis stabilizes the primary platelet plug through sequential enzymatic activation of circulating plasma serine proteases, culminating in thrombin generation and insoluble crosslinked fibrin mesh formation.

1. Intrinsic Pathway (Contact Activation):

   • Initiated when Factor XII (Hageman factor) contacts negatively charged subendothelial surfaces. Factor XIIa activates Factor XI -> XIa activates Factor IX. Factor IXa complexes with its activated cofactor Factor VIIIa, phospholipid, and calcium to form the "tenase complex", which activates Factor X.
   • Monitored by: Activated Partial Thromboplastin Time (aPTT) (normal range: 25–35 seconds).

2. Extrinsic Pathway (Tissue Factor Pathway):

   • Initiated when subendothelial Tissue Factor (TF / thromboplastin) is exposed to circulating blood at the injury site. TF complexes with and activates Factor VII. The TF-VIIa complex directly cleaves and activates Factor X.
   • Monitored by: Prothrombin Time (PT) (normal range: 11–14 seconds) and International Normalized Ratio (INR).

3. Common Pathway:

   • Factor Xa complexes with activated cofactor Factor Va, calcium, and phospholipid to form the "prothrombinase complex". Prothrombinase cleaves Prothrombin (Factor II) into active Thrombin (Factor IIa). Thrombin then cleaves soluble Fibrinogen (Factor I) into insoluble Fibrin monomers (Factor Ia). Finally, Factor XIIIa (fibrin-stabilizing factor, activated by thrombin) covalently crosslinks fibrin polymers via isopeptide bonds, cementing the stable hemostatic clot.
   • Crucial Diagnostic Rule: Deficiencies, consumptive loss, or pharmacological inhibition of common pathway factors (X, V, II, or I) produce prolongation of BOTH the PT and the aPTT.

• Clinical Manifestations of Secondary Hemostatic Defects: Deep tissue bleeding: Spontaneous haemarthroses (bleeding into joints, especially knees, elbows, ankles), intramuscular haematomas, retroperitoneal haemorrhage, and characteristically delayed bleeding hours or days following trauma or surgical interventions.

2. Inherited Bleeding Disorders

Haemophilia A & B

• Genetics: Both are X-linked recessive disorders, predominantly affecting males. Females are usually asymptomatic carriers (although extreme lyonization / skewed X-chromosome inactivation can result in mild clinical bleeding in females).
  • Haemophilia A: Deficiency of Factor VIII (accounts for ~80% of all haemophilia cases; incidence ~1 in 5,000 live male births).
  • Haemophilia B (Christmas Disease): Deficiency of Factor IX (incidence ~1 in 30,000 live male births).
• Laboratory Profile: Isolated prolongation of the aPTT with completely normal PT/INR, normal platelet count, and normal bleeding time / PFA-100.
• 50:50 Mixing Study: Mixing patient plasma 1:1 with normal pooled plasma results in complete correction of the prolonged aPTT, confirming an intrinsic factor deficiency (failure to correct indicates a circulating inhibitor or lupus anticoagulant).
• Clinical Classification by Baseline Factor Activity:
  • Severe (<1% normal activity / <0.01 IU/mL): Characterized by frequent spontaneous haemarthroses (starting at walking age) and deep muscle haematomas. Recurrent joint bleeding leads to chronic haemophilic arthropathy (synovial hypertrophy, cartilage loss, joint destruction).
  • Moderate (1–5% activity): Bleeding occurs with minor trauma or minor surgery; rare spontaneous bleeds.
  • Mild (5–40% activity): Often diagnosed late in adulthood following major trauma, dental extractions, or major surgery.
• Management:
  • On-demand or regular prophylactic replacement with recombinant Factor VIII or Factor IX.
  • Emicizumab: A humanized, bispecific monoclonal antibody that binds simultaneously to activated Factor IXa and Factor X, mimicking the cofactor activity of Factor VIII. Administered subcutaneously every 1–4 weeks; highly effective for Haemophilia A prophylaxis, including in patients with neutralizing anti-Factor VIII alloantibodies (inhibitors).
  • Mild Haemophilia A responds to Desmopressin (DDAVP), which stimulates the release of endogenous Factor VIII stores from endothelial Weibel-Palade bodies.

von Willebrand Disease (vWD)

• Epidemiology & Genetics: The most common inherited bleeding disorder in humans (estimated prevalence ~1% of the general population). Primarily autosomal dominant (Types 1 and 2), with rare severe autosomal recessive inheritance (Type 3).
• Dual Physiological Role of vWF:
  1. Facilitates primary hemostasis by anchoring platelets to subendothelial collagen (via GpIb);
  2. Facilitates secondary hemostasis by acting as the specific carrier protein for circulating Factor VIII, protecting it from rapid proteolytic degradation (extending Factor VIII half-life from ~2 hours to >12 hours).
• Classification:
  • Type 1 (75–80%): Autosomal dominant quantitative partial reduction of structurally normal vWF. Mild-to-moderate mucocutaneous bleeding.
  • Type 2 (15–20%): Qualitative functional defects in vWF (subtypes 2A, 2B, 2M, 2N).
  • Type 3 (<5%): Autosomal recessive virtually complete absence of vWF; manifests with severe mucocutaneous bleeding AND spontaneous haemarthroses (because Factor VIII levels drop to <5%).
• Laboratory Features: Bleeding time / PFA-100 is prolonged; PT is strictly normal; aPTT is normal or prolonged (prolongation depends on whether Factor VIII levels are reduced below 30–40%); platelet count is normal (except in type 2B, where gain-of-function induces mild thrombocytopenia).
• Diagnostic Panel: Plasma vWF antigen (quantitative), vWF ristocetin cofactor activity (vWF:RCo; functional ability to agglutinate platelets), and Factor VIII coagulant activity.
• Therapeutic Strategy:
  • Tranexamic acid (antifibrinolytic; competitive inhibitor of plasminogen activation) for mild mucosal bleeding, menorrhagia, and dental procedures.
  • Desmopressin (DDAVP): Stimulates rapid exocytosis of pre-formed endogenous vWF and Factor VIII stored in endothelial Weibel-Palade bodies. Effective in Type 1 vWD. CONTRAINDICATED in Type 2B vWD (triggers catastrophic intravascular platelet clumping and profound thrombocytopenia); INEFFECTIVE in Type 3 vWD (no intracellular stores exist).
  • Intermediate-purity, plasma-derived Factor VIII/vWF concentrates (e.g. Haemate-P, Voncento) or recombinant vWF for Type 3 vWD, severe Type 2, or major surgery.