Mechanism of Bleeding in Ebola Hemorrhagic Fever
The primary mechanism of bleeding in Ebola hemorrhagic fever is tissue factor (TF) overexpression in monocytes/macrophages leading to disseminated intravascular coagulation (DIC), combined with impaired fibrinolysis and decreased coagulation factors due to liver damage.
Pathophysiological Mechanisms
Primary Mechanism: Tissue Factor Overexpression
- Ebola virus infection causes dramatic overexpression of tissue factor (TF) in infected monocytes and macrophages, which are early targets of viral infection 1
- This TF overexpression triggers the coagulation cascade, leading to widespread microvascular thrombosis and consumption of clotting factors
- Studies in primate models show increased TF transcripts by day 3 of infection, with dramatically increased TF protein levels by day 2 in infected human monocytes/macrophages 1
Coagulation Dysregulation
- Disseminated intravascular coagulation (DIC) is a prominent manifestation that develops early in the disease course 1
- Key laboratory findings include:
Endothelial Involvement
- Contrary to previous assumptions, direct viral cytolysis of endothelial cells is NOT the primary cause of hemorrhage 3
- Endothelial cells are not early targets of Ebola virus, with viral replication in these cells not consistently observed until day 5 after infection 3
- Endothelium remains relatively intact even at terminal stages of disease 3
- Hemorrhage occurs through immune-mediated mechanisms rather than direct viral damage to blood vessels
Immune System Dysregulation
- Dendritic cells in lymphoid tissues are early and sustained targets of Ebola virus, leading to immunosuppression 4
- Bystander lymphocyte apoptosis occurs early in the disease course, particularly affecting NK cells, impairing innate immunity 4
- Cytokine storm contributes to vascular instability and increased permeability 5
Clinical Manifestations of Hemorrhage
Hemorrhagic manifestations typically appear late in the disease course and include:
- Bleeding from injection sites
- Epistaxis (nose bleeds)
- Hematemesis (vomiting blood)
- Hematochezia (bloody stool)
- Melena (black, tarry stool)
- Gingival bleeding (bleeding gums) 2
Temporal Progression
Early phase (Days 1-3):
- Initial infection of monocytes/macrophages and dendritic cells
- Increased TF expression begins
- Bystander lymphocyte apoptosis starts
Middle phase (Days 3-5):
- DIC develops, preceding endothelial infection
- Consumption of clotting factors accelerates
- Protein C levels decrease rapidly
Late phase (Days 5+):
- Endothelial cells become infected
- Overt hemorrhagic manifestations appear
- Multi-organ failure develops
Clinical Implications
- Hemorrhage in Ebola is primarily due to coagulopathy rather than direct vessel damage
- Therapeutic approaches targeting TF overexpression may be beneficial in managing hemorrhagic complications 1
- Early supportive care with careful fluid management is critical
- Monitoring coagulation parameters (PT, PTT, platelets, fibrin degradation products) is essential for clinical management
Pitfalls and Caveats
- Do not assume direct endothelial damage: The traditional view that Ebola causes hemorrhage through direct damage to blood vessels is incorrect; immune-mediated mechanisms and coagulopathy are more important 3
- Do not delay supportive care: Waiting for hemorrhagic manifestations before aggressive supportive care is dangerous as coagulopathy begins early
- Avoid antiplatelet medications: Medications like aspirin can worsen bleeding tendency and should be avoided
- Monitor for occult bleeding: Not all bleeding is externally visible; internal hemorrhage can occur without obvious external signs
Understanding these mechanisms is crucial for developing effective therapeutic strategies that target the specific pathways involved in Ebola-induced hemorrhage, particularly approaches that might control TF overexpression.