How does cocaine cause thrombotic microangiopathy (TMA)?

From the Guidelines

Cocaine causes thrombotic microangiopathy through multiple mechanisms, including endothelial damage, vasoconstriction, and induction of a hypercoagulable state, as evidenced by the most recent study 1. The pathophysiology of cocaine-induced thrombotic microangiopathy involves several key mechanisms:

• Endothelial damage: Cocaine directly injures the endothelial cells lining blood vessels, disrupting their normal protective function and activating platelets and the coagulation cascade, leading to inappropriate clot formation in small blood vessels 1.
• Vasoconstriction: Cocaine causes intense vasoconstriction by blocking the reuptake of norepinephrine, which further damages vessel walls and reduces blood flow to tissues 1.
• Hypercoagulable state: Cocaine induces a hypercoagulable state by increasing levels of procoagulant factors while decreasing natural anticoagulants, leading to widespread formation of microthrombi throughout small blood vessels 1.
• Inflammation and oxidative stress: Cocaine triggers inflammation and oxidative stress, which exacerbate endothelial injury and contribute to the development of thrombotic microangiopathy 1. These combined mechanisms result in tissue ischemia, organ damage, and the clinical manifestations of thrombotic microangiopathy, including hemolytic anemia, thrombocytopenia, and organ dysfunction, particularly affecting the kidneys and brain 1. Some of the key factors that contribute to the development of thrombotic microangiopathy in cocaine users include:
• Increased platelet activation and aggregation
• Elevated levels of procoagulant factors, such as fibrinogen and von Willebrand factor
• Decreased levels of natural anticoagulants, such as protein C and protein S
• Endothelial dysfunction and damage
• Inflammation and oxidative stress Overall, the evidence suggests that cocaine use is a significant risk factor for the development of thrombotic microangiopathy, and that the mechanisms involved are complex and multifactorial 1.

From the Research

Mechanisms of Cocaine-Induced Thrombotic Microangiopathy

• Cocaine use can lead to thrombotic microangiopathy (TMA) through various mechanisms, including endothelial damage and complement activation 2, 3.
• The activation of complements by cocaine may contribute to the development of TMA, as evidenced by reduced serum complement C3 and normal complement C4 levels in a patient with cocaine-induced TMA 2.
• Endothelial injury and platelet activation may also play important roles in the pathogenesis of cocaine-induced TMA, leading to microvascular occlusion and tissue ischemia 3.

Pathophysiology of Cocaine-Induced Thrombosis

• Cocaine use can cause a widespread prothrombotic state, involving both arterial and venous circulations, and leading to significant morbidity 4.
• The complex pathophysiology of cocaine-induced thrombosis includes endothelial damage, increased fibrinogen and Von Willebrand factor, and platelet aggregation and clot formation 4.
• Cocaine-induced venous thrombosis can lead to potentially fatal complications, such as pulmonary embolism, highlighting the need for further studies to identify patients at higher risk for these complications 4.

Treatment of Cocaine-Induced Thrombotic Microangiopathy

• While there is limited evidence on the treatment of cocaine-induced TMA, studies on drug-induced TMA suggest that eculizumab, a terminal complement inhibitor, may be effective in achieving hematologic and renal recovery in refractory cases 5, 6.
• Eculizumab has been shown to be safely tolerated and effective in treating chemotherapy-induced TMA, and its use may be considered in severe or refractory cases of cocaine-induced TMA 5, 6.