Zika and Chikungunya Virus and Risk for Venous Thromboembolism

Introduction: Zika virus (ZIKV) and Chikungunya virus (CHIKV) infections are transmitted by various species of aedes mosquitoes. A fair number of young patients suspicious of the virus presented to the hospital with unusual edema of upper or lower limbs which was initially thought to be due to systemic inflammation. Although for ZIKV infected patients the disease is typically self-limiting, cases of neurologic manifestations and Guillain-Barré syndrome have been described in infected patients in Brazil. Reports of high D-dimer levels (greater than 15.00 µg/mL FEU) in a Guillain-Barré syndrome patient in the ICU suggested the possibility of linking this infection to the development of venous thromboembolism (VTE).

Methods: Following informed consent, serum and plasma was prepared from blood samples collected from 172 patients with symptoms of ZIKV or CHIKV infection. Viral RNA was extracted from serum using the QIAamp Viral RNA Mini kit (QIAGEN, Germany) and subjected to reverse transcription (SuperScript® III Platinum® kit, Invitrogen). Samples with a threshold number (CT) ≤ 38 were considered positive for infection caused by the Zika and Chikungunya viruses. D-dimer levels were measured in plasma samples by ELISA (Hyphen BioMed, France). The reference concentration of D-dimer was less than 0.5 µg/mL fibrinogen-equivalent units (FEU). We also report two cases of DVT events associated with ZIKV infection.

Results: PCR confirmed that of the 172 patients studied, 31 were infected with ZIKV and 141 were infected with CHIKV. Although D-dimer levels were elevated above the reference range in 19.4% of 31 patients with ZIKV and in 63.8% of 141 patients with CHIKV, none of the patients had developed symptomatic VTE at the time of the study. Case 1 : In early January 2016, a 46-year-old female previously healthy arrived at the emergency room of the University Hospital of Sergipe with history of 3 days with high fever (>39°C), joint pain, arthralgia, and a red cutaneous rash. She was treated with hydration and discharged with a paracetamol prescription. She returned to the emergency room 4 days later with right upper extremity painful edema. An upper limb duplex scan revealed right brachial vein thrombosis. She was treated with unfractionated heparin followed by vitamin K antagonists (VKA). PCR test confirmed ZIKV infection. Case 2: In the subsequent month, a 53-year-old male presented to the same emergency room with fever, asthenia, headache, and arthralgia with onset 5 days previously. The arthralgia had increased in intensity and was accompanied by pain in the left calf and bilateral edema of the ankles, more intense on the left. Color Doppler ultrasonography examination confirmed thrombosis of the left popliteal vein. Patient was treated with low-molecular weight heparin and VKA therapy and had a full recovery. He tested positive for ZIKV.

Conclusions: A relationship between systemic viral infection with H1N1, HIV and hepatitis and inflammatory/hypercoagulable states has previously been demonstrated. Although the mechanism behind this interplay is not yet well elucidated, factors such as direct endothelial injury, increased expression of tissue factor and the release of microparticles might be involved. A better understanding of the pathophysiology underlying the association of viral infections and coagulation disorders is crucial for developing therapeutic strategies. Patients at high risk of VTE with viral infections may be good candidates for VTE prophylaxis with current anticoagulants.