The State of the Globe: Deep-vein Thrombosis in Dengue Fever – A Rare or Protective Association?

Dengue fever is one of the most widespread arboviral infections globally and has emerged as a major public health challenge in the tropical and subtropical regions. Caused by the dengue virus (DENV), a flavivirus transmitted primarily by Aedes aegypti mosquitoes, it now threatens nearly half of the world’s population. According to the World Health Organization, an estimated 390 million dengue infections occur every year, of which approximately 96 million manifest clinically.[1] While the majority of these infections are asymptomatic or present with mild febrile illness, a significant minority develop severe and potentially fatal complications, such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS).

Interestingly, despite the profound disturbances in vascular integrity, platelet function, and coagulation that characterize dengue, reports of thrombotic events such as deep-vein thrombosis (DVT) remain exceedingly rare. The current issue of the Journal of Global Infectious Diseases presents a systematic review of this phenomenon, drawing attention to a surprising gap between the expected and observed incidence of thrombosis in dengue patients.[2]

The pathogenic cascade of dengue begins when the virus enters the human cells through the mosquito bite. The virus primarily infects dendritic cells, monocytes, macrophages, and endothelial cells.[3] Within these cells, DENV undergoes replication, leading to viremia and systemic immune activation. Infected cells release interferons and proinflammatory cytokines, which account for the hallmark symptoms of dengue fever, headache, retro-orbital pain, rash, and severe myalgia.[3]

Dengue demonstrates organ-specific tropism. Skin, liver, and gastrointestinal tissues are the most frequently affected, whereas the spleen, thymus, and lymph nodes harbor lower viral loads in autopsy studies.[3] Severe disease manifestations, however, revolve around the microvasculature. Vascular leakage, culminating in DSS, is the principal cause of death in dengue patients.[4,5]

The direct infection of endothelial cells by DENV remains controversial. Early biopsy studies suggested that the virus was absent in endothelial cells themselves, being more commonly localized to perivascular cells.[6] More recent research indicates that susceptibility of endothelial cells may differ across vascular beds. For instance, pulmonary and abdominal vasculature often demonstrates selective apoptosis, leading to localized vascular leakage that typifies DHF/DSS.[6]

Pathogenesis is further complicated by widespread complement activation,[3] antibody-dependent enhancement during secondary infection with a different serotype,[3] and direct bone marrow suppression. These mechanisms, along with immune-mediated platelet destruction, contribute to the profound thrombocytopenia observed in dengue.[3] Collectively, these processes drive a hemorrhagic phenotype, rather than a prothrombotic one.

Given the degree of vascular injury, endothelial activation, and platelet abnormalities seen in dengue, one might expect thrombotic complications such as DVT to occur with significant frequency. However, the evidence suggests the opposite.

Globally, in 2024 alone, there were approximately 96 million clinically manifest dengue cases.[3] However, a systematic review of case reports has identified only 19 cases of DVT associated with dengue infection to date.[2] This number is strikingly small when compared to the baseline incidence of DVT in the general population, estimated at 5 per 10,000 person-years.[7] Extrapolating this incidence rate to the dengue population would predict at least 48,000 DVT cases annually, regardless of infection status.[1,7] The discrepancy between the expected and reported cases is therefore remarkable.

The review also highlights that the median age of dengue patients who developed DVT was 39 years. In this age group (30–49 years), the background incidence of DVT is estimated at ~20 per 10,000 person-years,[7] further strengthening the argument that these cases may have had additional risk factors for thrombosis independent of dengue infection. Traditional contributors such as immobility, dehydration, surgery, malignancy, or inherited thrombophilia may have been responsible, rather than dengue itself.

Several hypotheses may explain the apparent protection from thrombosis in dengue infection:

1. Profound thrombocytopenia – Severe reductions in platelet counts, often below 50,000/mm³, make clot formation unlikely in many patients

2. Endothelial disruption leading to leak rather than clot – The dominant pathological outcome of endothelial injury in dengue is plasma leakage and hemorrhage, not thrombosis

3. Immune-mediated anticoagulant environment – Cytokine release and complement activation may tip the hemostatic balance toward bleeding rather than clotting

4. Under-reporting – In the resource-limited settings, the clinical focus is usually on managing shock and bleeding; subtle thrombotic events may go undiagnosed

5. Protective viral-host interactions – It is possible that DENV or its immune responses downregulate prothrombotic pathways, although this requires further research.

For clinicians, the key message is that thrombotic complications in dengue patients are exceedingly rare. The priority remains the timely recognition and management of plasma leakage, shock, and hemorrhage. Prophylactic anticoagulation is not recommended in dengue, given the much higher risk of bleeding.

From a research perspective, however, the disparity between expected and observed cases of DVT is intriguing. It raises the question of whether DENV infection exerts a protective influence against venous thrombosis. This could have broader implications for understanding the interplay between viral infections, immunity, and coagulation biology.

To conclude, despite extensive endothelial dysfunction, vascular leakage, and coagulation abnormalities, DVT is not a recognized complication of dengue infection. The extraordinarily low number of reported cases worldwide is only 19, against an expected burden in the tens of thousands, suggests that dengue may even confer protection against thrombosis.

Further large-scale and population-based studies are needed to confirm whether this association is real and to uncover the biological mechanisms underlying it. Until then, DVT in dengue should be regarded as a rare coincidence rather than a direct complication

Research quality and ethics statement

The authors followed applicable EQUATOR Network (https://www.equator-network.org/) guidelines, notably the CARE guideline, during the conduct of this report.