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Bleeding andThrombosis

Chapter 69 | Part 2: Cardiovascular Diseases · Part 2 – Cardinal Manifestations & Presentation · Chapter 69

Key Clinical Points

  1. Hemostasis is a balance between procoagulant forces (platelet adhesion, fibrin clot) and anticoagulant forces (natural inhibitors).
  2. Macrophage Activation Syndrome (MAS-HLH) in children is defined as a febrile patient with ferritin >684 μg/L and any two of: platelet count ≤181 × 10^9/L, AST >48 U/L, triglycerides >1.76 mmol/L (156 mg/dL), and fibrinogen ≤3.6 g/L.
  3. d-Dimer assays are sensitive markers of blood clot formation and validated to exclude deep venous thrombosis (DVT) and pulmonary embolism in selected populations.
  4. The International Normalized Ratio (INR) is determined by INR = (PT / PT_normal_mean)^ISI and is used to assess stable anticoagulation.
  5. Bleeding score (ISTH Bleeding Assessment Tool) is recommended for screening von Willebrand disease (VWD) in primary care to avoid unnecessary testing.
  6. Heavy menstrual bleeding is quantitatively defined as >80 mL of blood per cycle.
  7. NSAIDs impair primary hemostasis by inhibiting cyclooxygenase 1 and can precipitate GI bleeding, particularly in patients with underlying bleeding disorders.
  8. Thrombotic risk increases with age, and a history of idiopathic venous thromboembolism (VTE) is the strongest predictor of recurrence in patients without underlying malignancy.
  9. Proper sample acquisition for coagulation assays requires filling citrate tubes to >90% of recommended volume to avoid erroneous results due to incorrect plasma-to-anticoagulant ratio.
  10. Activated protein C (APC) acts as an anticoagulant by cleaving and inactivating activated factors V and VIII, accelerated by cofactor protein S.

1. DEFINITION & OVERVIEW

• Hemostasis: A balance between procoagulant and anticoagulant forces. ◦ Procoagulant: Platelet adhesion/aggregation and fibrin clot formation. ◦ Anticoagulant: Natural inhibitors of coagulation and fibrinolysis. ◦ Components: (1) platelets and formed elements (monocytes, red cells); (2) plasma proteins (coagulation factors and inhibitors); (3) the vessel wall.

• Hemophagocytic Lymphohistiocytosis (HLH) & Macrophage Activation Syndrome (MAS): ◦ MAS-HLH: A life-threatening hyperinflammatory complication of rheumatic/autoimmune diseases; it is a secondary, acquired form of HLH. ◦ Clinical Presentation: Fever, liver dysfunction, cytopenia, hyperferritinemia, coagulopathy, CNS abnormalities. ◦ Diagnostic Criteria (Children): Ferritin >684 μg/L and any two of: platelet count ≤181 × 10^9/L, AST >48 U/L, triglycerides >1.76 mmol/L (156 mg/dL), and fibrinogen ≤3.6 g/L. ◦ Clinical Nuance: High serum IL-18 distinguishes it from other HLH forms; pulmonary disease has a high fatality rate (~50%).

2. ETIOLOGY & PATHOPHYSIOLOGY

• Coagulation Initiation: ◦ Trigger: Vascular damage exposes blood to Tissue Factor (TF) on subendothelial cells. ◦ Pathway: TF binds FVIIa → activates FIX and FX. ◦ Amplification: Thrombin activates FXI, FVIII, and FV. ◦ Regulation: TFPI inhibits the TF/FVIIa/FIX complex to ensure dependence on the amplification loop.

• Platelet Function: ◦ Adhesion: Mediated by von Willebrand factor (VWF) as 'molecular glue' and direct binding to subendothelial collagen. ◦ Activation: Triggered by thrombin, ADP, serotonin, and tissue factors. ◦ Aggregation: Gp IIb/IIIa complex converts to active form → binds fibrinogen and VWF to form an occlusive platelet plug.

• Antithrombotic Mechanisms: ◦ Endothelial Cells: Produce prostacyclin, nitric oxide, and ectoADPase/CD39; produce heparin proteoglycans, TFPI, and thrombomodulin. ◦ Antithrombin: Major plasma protease inhibitor of thrombin and other clotting factors. ◦ Protein C System: Thrombin → interaction with thrombomodulin and EPCR → activation of Protein C. Activated Protein C (APC) + cofactor protein S → inactivates factors V and VIII. ◦ TFPI: Regulates the TF-induced extrinsic pathway by inhibiting the TF/FVIIa/FIX complex.

• Fibrinolytic System: ◦ Key Enzyme: Plasmin (converts fibrin to fibrin degradation products). ◦ Activators: tPA and uPA convert plasminogen to plasmin. ◦ Specificity: Plasminogen and tPA have specific affinity for fibrin; d-dimers are released from cross-linked fibrin and serve as specific markers of fibrin degradation.

Coagulation Cascade Pathway

  1. Initiation: TF + FVIIa → Activation of FIX and FX.
  2. Amplification Loop: Thrombin activates FXI, FVIII, and FV.
  3. Common Pathway: FX → FXa → Prothrombin (II) → Thrombin (IIa).
  4. Stabilization: Thrombin activates Factor XIII → Factor XIIIa → Cross-links fibrin.

3. CLINICAL FEATURES

• Clinical Presentation: ◦ Symptoms: Duration, family history, and site of bleeding/thrombosis. ◦ Bleeding Sites: Mucosal/joint (common in factor deficiencies) vs. skin/subcutaneous (can be non-coagulopathic). ◦ Hemarthroses: Hallmark of severe Factor VIII or IX deficiency.

• Reproductive Health: ◦ Heavy Menstrual Bleeding: Defined as >80 mL of blood per cycle. ◦ Risk Factors: Iron-deficiency anemia, clots >1 inch, pad change >1 hour. ◦ Pregnancy: VWD (Type 1) and Hemophilia A may show normalized factor levels during pregnancy.

Medications and Supplements

• NSAIDs: Inhibit COX-1 → impair primary hemostasis; can cause GI bleeding or unmask underlying disorders. ◦ Duration: Aspirin effect lasts for the life of the platelet (2–3 days). ◦ Thienopyridines: (e.g., clopidogrel) pose higher risk than NSAIDs. ◦ Other Factors: Identification of other agents like heparin or direct thrombin inhibitors in bleeding workups.

4. DIFFERENTIAL DIAGNOSIS

• Primary Hemostatic Disorders (Table 1): ◦ Adhesion: von Willebrand disease, Bernard-Soulier syndrome. ◦ Aggregation: Glanzmann’s thrombasthenia, Afibrinogenemia. ◦ Secretion: Decreased COX activity, Drug-induced (aspirin, NSAIDs, thienopyridines), Uremia, Platelet coating. ◦ Coagulant Activity: Scott’s syndrome.

• Thrombosis Risk Factors (Table 2): ◦ Venous Inherited: Factor V Leiden, Prothrombin G20110A, Antithrombin deficiency, Protein C deficiency, Protein S deficiency. ◦ Venous and Arterial Inherited: Homocystinuria, Dysfibrinogenemia. ◦ Venous Acquired: Age, Previous thrombosis, Immobilization, Major surgery, Pregnancy/puerperium, Hospitalization, Obesity, Infection, Smoking. ◦ Arterial Acquired: Malignancy, Antiphospholipid antibody syndrome, Hormonal therapy, Polycythemia vera, Essential thrombocythemia, Paroxysmal nocturnal hemoglobinuria, Thrombotic thrombocytopenic purpura, Heparin-induced thrombocytopenia, Disseminated intravascular coagulation (DIC), Infection. ◦ Unknown: Elevated factor II, VIII, IX, XI; Elevated TAFI levels; Low levels of TFPI.

5. INVESTIGATIONS & DIAGNOSIS

  1. D-dimer Assay: ◦ Use as a sensitive marker of blood clot formation. ◦ Clinical Utility: Validated to exclude DVT and pulmonary embolism in selected populations.
  2. INR Calculation: ◦ Formula: INR = (PT / PT_normal_mean)^ISI. ◦ Purpose: Assessment of stable anticoagulation.
  3. Coagulation Profile Interpretation (Table 3): ◦ aPTT Prolongation: ◦ No bleeding → ↓ Factor XII, HMWK, prekallikrein. ◦ Variable/Mild bleeding → ↓ Factor XI, mild ↓ Factor VIII and factor IX. ◦ Frequent/Severe bleeding → severe deficiencies of factors VIII and IX; Heparin and direct thromrin inhibitors. ◦ PT Prolongation: ◦ Factor VII deficiency. ◦ Vitamin K deficiency (early). ◦ Warfarin anticoagulation. ◦ Direct Xa inhibitors (Note: PT may be normal). ◦ Prolonged aPTT and PT: ◦ Factor II, V, X, or fibrinogen deficiency. ◦ Vitamin K deficiency (late). ◦ Prolonged Thrombin Time: ◦ Heparin or heparin-like inhibitors. ◦ Direct thrombin inhibitors (e.g., dabigatran, argatroban, bivalirudin). ◦ Abnormal Clot Solubility: ◦ Factor XIII deficiency; Inhibitors or defective cross-linking. ◦ Rapid Clot Lysis: ◦ Deficiency of α-antiplasmin or plasminogen activator inhibitor 1 (PAI-1).

Laboratory Sample Preparation

• Citrate Tubes: Must be filled to >90% of recommended volume → prevents errors in plasma-to-anticoagulant ratio.

6. MANAGEMENT & TREATMENT

  1. Medication Review: ◦ Identify and discontinue agents affecting primary hemostasis (NSAIDs, thienopyridines) or those causing coagulopathy.
  2. MAS-HLH Management: ◦ Early diagnosis is critical due to high mortality rates. ◦ Pulmonary complications: High fatality rate (~50%); treatment/prevention remains unknown.

7. PROGNOSIS & COMPLICATIONS

• CNS Bleeding: Major cause of death in patients with severe congenital factor deficiencies. ◦ Pulmonary Disease (MAS-HLH): High fatality rate (~50%). ◦ Thrombosis Risk: Increases with age; risk is cumulative based on genetic factors (e.g., Factor V Leiden) and transient triggers (surgery, immobilization).

8. SPECIAL CONSIDERATIONS

• Pregnancy/Reproduction: ◦ Women with VWD or Hemophilia A may have delayed postpartum hemorrhage due to normalization of factor levels during pregnancy. ◦ Risk of intraabdominal hemorrhage from ruptured ovarian cysts in patients with bleeding disorders.

9. KEY PEARLS & CLINICAL TRAPS

• D-dimer: Use as a sensitive marker for clot formation; useful for excluding DVT/PE. ◦ Factor XIII: Responsible for cross-linking fibrin; deficiency leads to abnormal clot solubility. ◦ Thrombin: Central protease of the coagulation system; converts fibrinogen to fibrin and activates Factor XIII. ◦ Primary Hemostatic Disorders (Table 1): ◦ Adhesion: VWD, Bernard-Soulier. ◦ Aggregation: Glanzmann’s thrombasthenia, Afibrinogenemia. ◦ Secretion: Decreased COX activity, Drug-induced (NSAIDs, thienopyridines), Uremia, Platelet coating. ◦ Thrombin Time: Specific for detecting heparin or direct thrombin inhibitors.

10. WHAT TO LOOK FOR — DIAGNOSTIC CLUES

• D-dimer: High sensitivity for clot formation; used to rule out DVT/PE. ◦ Thrombin Time: Useful for identifying heparin or direct thrombin inhibitors. ◦ Factor XIII Deficiency: Identified by abnormal clot solubility.

• D-dimer: A negative result in appropriate populations helps exclude DVT and pulmonary embolism. ◦ Normal PT/aPTT: Helps rule out common pathway deficiencies (II, V, X, I) or specific factor deficiencies (e.g., Factor VII for PT).

Reference Tables

TABLE 69-1 Primary Hemostatic (Platelet Plug) Disorders Defects of Platelet Adhesion von Willebrand disease…

Harrison's 22e, p.472

  • Defects of Platelet Adhesion
  • von Willebrand disease
  • Bernard-Soulier syndrome (absence or dysfunction of platelet Gp Ib-IX-V)
  • Defects of Platelet Aggregation
  • Glanzmann’s thrombasthenia (absence or dysfunction of platelet glycoprotein
    [Gp] IIb/IIIa)
  • Afibrinogenemia
  • Defects of Platelet Secretion
  • Decreased cyclooxygenase activity
  • Drug-induced (aspirin, nonsteroidal anti-inflammatory agents, thienopyridines)
  • Inherited
  • Granule storage pool defects
  • Inherited
  • Acquired
  • Nonspecific inherited secretory defects
  • Nonspecific drug effects
  • Uremia
  • Platelet coating (e.g., paraprotein, penicillin)
  • Defect of Platelet Coagulant Activity
  • Scott’s syndrome

TABLE 69-2 Some Risk Factors for Thrombosis VENOUS Inherited

Harrison's 22e, p.473

VENOUS VENOUS AND ARTERIAL
Inherited
Factor V Leiden
Prothrombin G20210A
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Acquired
Age
Previous thrombosis
Immobilization
Major surgery
Pregnancy and puerperium
Hospitalization
Obesity
Infection
Smoking		 Inherited
Homocystinuria
Dysfibrinogenemia
Acquired
Malignancy
Antiphospholipid antibody syndrome
Hormonal therapy
Polycythemia vera
Essential thrombocythemia
Paroxysmal nocturnal hemoglobinuria
Thrombotic thrombocytopenic purpura
Heparin-induced thrombocytopenia
Disseminated intravascular coagulation
Infection
Unknowna
Elevated factor II, VIII, IX, XI
Elevated TAFI levels
Low levels of TFPI

TABLE 69-3 Hemostatic Disorders and Coagulation Test Abnormalities Prolonged Activated Partial Thromboplastin Time…

Harrison's 22e, p.475

  • Prolonged Activated Partial Thromboplastin Time (aPTT)
  • No clinical bleeding—↓ factor XII, high-molecular-weight kininogen,
    prekallikrein
  • Variable, but usually mild, bleeding—↓ factor XI, mild ↓ factor VIII and factor IX
  • Frequent, severe bleeding—severe deficiencies of factors VIII and IX
  • Heparin and direct thrombin inhibitors
  • Prolonged Prothrombin Time (PT)
  • Factor VII deficiency
  • Vitamin K deficiency—early
  • Warfarin anticoagulation
  • Direct Xa inhibitors (rivaroxaban, edoxaban, apixaban—note PT may be normal)
  • Prolonged aPTT and PT
  • Factor II, V, X, or fibrinogen deficiency
  • Vitamin K deficiency—late
  • Direct thrombin inhibitors
  • Prolonged Thrombin Time
  • Heparin or heparin-like inhibitors
  • Direct thrombin inhibitors (e.g., dabigatran, argatroban, bivalirudin)
  • Mild or no bleeding—dysfibrinogenemia
  • Frequent, severe bleeding—afibrinogenemia
  • Prolonged PT and/or aPTT Not Corrected with Mixing with Normal
    Plasma
  • Bleeding—specific factor inhibitor
  • No symptoms, or clotting and/or pregnancy loss—lupus anticoagulant
  • Disseminated intravascular coagulation
  • Heparin or direct thrombin inhibitor
  • Abnormal Clot Solubility
  • Factor XIII deficiency
  • Inhibitors or defective cross-linking
  • Rapid Clot Lysis
  • Deficiency of α-antiplasmin or plasminogen activator inhibitor 1
    2
  • Treatment with fibrinolytic therapy