How does Covid-19 cause blood clots?

How COVID-19 Causes Blood Clots

COVID-19 causes blood clots primarily through an inflammatory response rather than direct viral effects, triggering endothelial dysfunction, cytokine storm, neutrophil extracellular trap formation, and disruption of the renin-angiotensin system—all of which shift the vascular environment to a pro-thrombotic and pro-adhesive state. 1

Primary Mechanism: Inflammation-Driven Coagulopathy

The coagulopathy in COVID-19 is not a direct viral effect but rather a consequence of the subsequent inflammatory response that creates a hypercoagulable state. 1 This represents a distinct pathophysiological process compared to typical disseminated intravascular coagulation (DIC).

Key Inflammatory Pathways

Cytokine Storm and Immune Dysregulation:

• Elevated pro-inflammatory cytokines (TNF-α, IL-6, IL-1, IFN-γ) are particularly prominent in critically ill COVID-19 patients admitted to intensive care units. 1
• Increased neutrophil counts in critically ill patients contribute to thrombosis through specific mechanisms. 1
• T cell numbers are reduced in severe COVID-19, with remaining cells showing increased activation markers and higher percentages of pro-inflammatory Th17 cells. 1

Neutrophil Extracellular Traps (NETs):

• Autopsy reports demonstrate that COVID-19 induces formation of neutrophil extracellular traps—web-like structures of DNA and proteins secreted by neutrophils to capture pathogens. 1
• These NETs directly contribute to cytokine storm, vascular thrombosis, and acute respiratory distress syndrome (ARDS). 1

Endothelial Dysfunction and Vascular Injury

Endothelial Transformation to Pro-Thrombotic State:

• The endothelium, which expresses ACE2 receptors, becomes dysregulated due to inflammatory cytokines shifting it to a pro-adhesive and pro-thrombotic state. 1
• Post-mortem samples from multiple organs demonstrate inflammatory cell infiltration of vessel walls, apoptosis, and endothelial cell death. 1
• This endothelial dysfunction is characterized by localized inflammatory response with increased oxidative stress, infiltration of inflammatory cells, and a pro-thrombotic state. 1

Renin-Angiotensin System (RAS) Dysregulation

ACE2 Downregulation and Its Consequences:

• Loss of ACE2 (an antithrombotic enzyme) occurs via viral internalization or enhanced shedding, which exacerbates the coagulopathy. 1
• Reduced ACE2 leads to higher levels of Angiotensin II (Ang II), which potently upregulates plasminogen activator inhibitor-1 (PAI-1) expression and other pro-coagulant actions. 1
• The RAS plays a direct role in COVID-19-associated coagulopathy through inflammation-induced endothelial injury. 1

Clinical Manifestations of Thrombosis

Types of Thrombotic Events:

• High rates of venous thrombosis, arterial thrombosis, and microvascular thrombosis occur in COVID-19 patients. 1
• Numerous cases of limb ischemia, pulmonary emboli, and strokes have been reported in otherwise young, healthy individuals. 1
• Venous thromboembolic disease in COVID-19 often occurs despite appropriate prophylactic anticoagulation measures. 1
• Up to 31-49% of critically ill patients develop thrombotic complications even with systematic thromboprophylaxis. 1

Laboratory Markers:

• D-dimer levels are markedly increased in COVID-19 patients. 1
• Prothrombin times and activated partial thromboplastin times are longer in patients with worse outcomes. 1
• Additional pro-coagulant profile features include increased clot strength and hyperfibrinogenemia. 1
• Microthrombi are frequently reported in autopsy studies. 1

Critical Pitfalls in Understanding COVID-19 Coagulopathy

Distinguishing Features from Classic DIC:

• COVID-19-associated coagulopathy has distinct features: markedly elevated D-dimers with nearly normal activated partial thromboplastin time, prothrombin time, and platelet count. 2
• This differs from typical consumptive coagulopathy patterns seen in other conditions.

Heparin Resistance Concerns:

• Acute phase reactants (fibrinogen, C-reactive protein) are elevated in COVID-19 and can create heparin resistance. 1
• Hyperfibrinogenemia is a key factor causing heparin resistance, defined as requiring UFH doses exceeding 35,000 units/day to achieve therapeutic range. 1
• Heparin binds to acute-phase plasma proteins, activated macrophages, and endothelial cells—all increased in COVID-19. 1

Lupus Anticoagulant Presence:

• The aPTT may be prolonged in some COVID-19 patients due to presence of lupus anticoagulant (reported in up to 45% of patients in some series). 1
• Whether these antiphospholipid antibodies are pathogenic and result in thrombosis remains under investigation. 1

Algorithmic Summary of Thrombotic Mechanisms

1. SARS-CoV-2 infection → Inflammatory response activation
2. Cytokine storm (IL-6, TNF-α, IL-1) → Endothelial activation and injury
3. Neutrophil activation → NET formation → Direct vascular thrombosis
4. ACE2 downregulation → Increased Ang II → PAI-1 upregulation → Impaired fibrinolysis
5. Endothelial dysfunction → Pro-adhesive and pro-thrombotic state
6. Result: Macro- and microvascular thrombosis despite prophylactic anticoagulation

This mechanistic understanding explains why COVID-19 patients develop thrombotic complications at rates exceeding other critically ill populations, including those with influenza, and why standard prophylactic anticoagulation may be insufficient in severe cases. 1