Bleeding and Thrombosis¶
Chapter 69 | Part 2: Cardinal Manifestations and Presentation of Diseases
KEY CLINICAL POINTS¶
- Hemostasis involves a balance between procoagulant (platelet adhesion/aggregation, fibrin clot formation) and anticoagulant (natural inhibitors, fibrinolytic system) mechanisms.
- Macrophage activation syndrome (MAS-HLH) is a life-threatening complication of autoimmune diseases, characterized by cytokine storm and hemophagocytosis, with mortality rates 5–10% in children and 10–15% in adults.
- Thrombosis risk factors include genetic predispositions (Factor V Leiden, prothrombin G20210A) and acquired conditions (malignancy, antiphospholipid syndrome, immobilization).
- Diagnostic workup for bleeding disorders includes PT, aPTT, platelet count, and mixing studies to differentiate factor deficiencies from inhibitors.
- Anticoagulant therapy requires monitoring (INR for vitamin K antagonists) and awareness of drug interactions (e.g., NSAIDs, direct Xa inhibitors).
1. DEFINITION & OVERVIEW¶
Bleeding and thrombosis represent extremes of hemostatic regulation. Hemostasis is a dynamic process balancing procoagulant and anticoagulant forces to prevent excessive bleeding or clot formation. Disruption of this balance leads to either hemorrhagic or thrombotic disorders.
Table 69-1: Primary Hemostatic (Platelet Plug) Disorders¶
| Defect Type | Examples |
|---|---|
| Defects of Platelet Adhesion | von Willebrand disease, Bernard-Soulier syndrome |
| Defects of Platelet Aggregation | Glanzmann’s thrombasthenia, afibrinogenemia |
| Defects of Platelet Secretion | Decreased cyclooxygenase activity, drug-induced (NSAIDs) |
| Defect of Platelet Coagulant Activity | Scott’s syndrome |
Table 69-2: Risk Factors for Thrombosis¶
| Category | Examples |
|---|---|
| Inherited | Factor V Leiden, Prothrombin G20210A, Antithrombin deficiency |
| Acquired | Age, Obesity, Immobilization, Malignancy, Antiphospholipid syndrome |
| Venous and Arterial | Hormonal therapy, Polycythemia vera, Heparin-induced thrombocytopenia |
1.1 Macrophage Activation Syndrome (MAS-HLH)¶
MAS-HLH is a severe complication of autoimmune diseases, characterized by uncontrolled macrophage and T-cell activation, leading to systemic inflammation, hemophagocytosis, and multiorgan failure. It is classified as a secondary form of hemophagocytic lymphohistiocytosis (HLH) and is associated with cytokine storm (elevated IL-18).
1.2 Hemostatic System Overview¶
The hemostatic system comprises platelets, plasma coagulation factors, and the vascular wall. Platelet plug formation (primary hemostasis) is followed by fibrin clot formation (secondary hemostasis). Anticoagulant mechanisms (e.g., antithrombin, protein C) and fibrinolytic pathways (plasmin) prevent excessive clotting.
2. EPIDEMIOLOGY¶
MAS-HLH is the third most common form of HLH in adults and the second most common in children. In children, it is most frequently associated with systemic juvenile idiopathic arthritis (sJIA) (10% of cases) and systemic lupus erythematosus (SLE). In adults, SLE is the most common cause, followed by adult-onset Still’s disease.
2.1 Thrombosis Risk Factors¶
Venous thrombosis risk factors include immobility, surgery, malignancy, obesity, and hormonal therapy. Arterial thrombosis is linked to atherosclerosis. Genetic thrombophilias (e.g., Factor V Leiden) modestly increase risk, especially in elderly patients undergoing high-risk surgery.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
MAS-HLH is driven by cytokine storm (IL-18, TNF- α ) and uncontrolled T-cell/macrophage activation. Thrombosis results from endothelial damage, platelet activation, and coagulation cascade dysregulation. Anticoagulant mechanisms (antithrombin, protein C) are impaired in liver disease or vitamin K deficiency.
3.1 Hemostatic Pathways¶
Coagulation proceeds via extrinsic (tissue factor) and intrinsic pathways, amplified by factor VIII and IX. Fibrin clot formation is stabilized by factor XIII. Anticoagulant pathways (protein C, antithrombin) and fibrinolytic systems (plasmin) prevent clot propagation.
4. CLINICAL FEATURES¶
MAS-HLH presents with fever, liver dysfunction, cytopenias, and neurological symptoms. Thrombosis manifests as DVT, pulmonary embolism, or arterial occlusion. Bleeding disorders include mucocutaneous hemorrhages, hemarthroses, and postpartum hemorrhage.
4.1 Bleeding Manifestations¶
Epistaxis, easy bruising, and prolonged bleeding after trauma/surgery are common. Hemarthroses (joint bleeding) indicate severe factor VIII/IX deficiency. Postpartum hemorrhage is a red flag for underlying coagulopathy.
5. DIFFERENTIAL DIAGNOSIS¶
Differential diagnoses for MAS-HLH include infections, autoimmune diseases, and malignancies. For thrombosis, consider venous vs. arterial causes, and differentiate from drug-induced bleeding (e.g., NSAIDs, anticoagulants).
6. INVESTIGATIONS & DIAGNOSIS¶
Laboratory tests include PT, aPTT, platelet count, and mixing studies. d-Dimer assays detect fibrinolysis. Genetic testing for thrombophilias (Factor V Leiden) is indicated in recurrent VTE. MAS-HLH diagnosis uses criteria like ferritin >684 µg/L and ≥ 2 of: platelet count ≤ 181×10 I /L, AST >48 U/L, fibrinogen ≤ 3.6 g/L.
6.1 Coagulation Testing¶
PT assesses factors II, V, VII, X; aPTT evaluates intrinsic/common pathways. Mixing studies differentiate factor deficiencies from inhibitors. INR monitoring is critical for vitamin K antagonists.
7. MANAGEMENT & TREATMENT¶
MAS-HLH is treated with corticosteroids (methylprednisolone 30 mg/kg), cyclosporin A, and anakinra. Thrombosis management includes anticoagulation (heparin, LMWH, direct Xa inhibitors) and thrombolysis. Bleeding disorders require factor replacement (e.g., factor VIII for hemophilia).
7.1 MAS-HLH Treatment Algorithm¶
- Initiate high-dose corticosteroids (IV methylprednisolone 30 mg/kg). 2. Add cyclosporin A (2–7 mg/kg/d) and anakinra (2–6 mg/kg/d). 3. Use etoposide (50–100 mg/m² weekly) if CNS involvement persists. 4. Consider ruxolitinib or emapalumab for refractory cases.
8. PROGNOSIS & COMPLICATIONS¶
MAS-HLH mortality is 5–10% in children, 10–15% in adults. Complications include irreversible neurological damage and pulmonary alveolar proteinosis. Thrombosis risks include pulmonary embolism (50% fatality rate in severe cases) and recurrent VTE in thrombophilic patients.
9. SPECIAL CONSIDERATIONS¶
Pregnancy increases thrombosis risk (especially in antiphospholipid syndrome) and may delay postpartum hemorrhage resolution. Elderly patients with liver disease have variable coagulation factor levels. Pediatric cases often involve sJIA or SLE.
10. KEY POINTS & CLINICAL PEARLS¶
- MAS-HLH is a life-threatening complication of autoimmune diseases, requiring prompt corticosteroid and immunomodulatory therapy.
- d-Dimer assays are sensitive for excluding DVT but increase with age.
- Anticoagulation with direct Xa inhibitors (e.g., apixaban) does not prolong PT.
- Genetic testing for thrombophilias should be limited to patients with strong family history of thrombosis.
- Platelet counts >50,000/ µ L rarely cause bleeding, but thrombocytopenia with coagulopathy increases risk.