The research, led by Erens Spiff Ekprikpo, Stella Urekweru Ken-Ezihuo, and Zaccheaus Awortu Jeremiah and published in PLOS Global Public Health, enrolled 220 participants aged 20 to 65 years. The cohort was divided evenly into four groups of 55 people each: healthy controls, individuals with confirmed malaria, individuals with mild COVID-19, and individuals co-infected with both pathogens. Each group was deliberately balanced by sex, containing 22 females and 33 males, a design choice that allowed the investigators to probe whether biological sex modified the hemostatic response rather than simply averaging over it. The study followed STROBE reporting guidelines, the international standard for observational studies, lending additional rigor to its design and analysis.

The technical core of the investigation rested on two families of measurements. Platelet indices—including platelet count, mean platelet volume, and platelet distribution width, abbreviated PDW—were obtained using a Sysmex XP-300 automated hematology analyzer. PDW reflects the variability in platelet size within a blood sample; a wider distribution suggests the bone marrow is releasing a heterogeneous population of platelets, often a sign of accelerated platelet turnover or activation. D-dimer and fibrinogen, meanwhile, were quantified with a sandwich enzyme-linked immunosorbent assay. D-dimer is a degradation fragment produced when the body dissolves a fibrin clot, so elevated levels signal active clot formation and breakdown, while fibrinogen is the soluble protein precursor that polymerizes into fibrin strands during clotting. Together, these markers span both the cellular and protein arms of hemostasis.

The headline finding was remarkably consistent: PDW was significantly elevated in every infected group compared with healthy controls. Controls averaged 13.27 plus or minus 1.20 femtoliters, while the malaria group averaged 15.19 plus or minus 1.47 fL, the COVID-19 group 15.17 plus or minus 1.51 fL, and the co-infected group 15.58 plus or minus 1.45 fL. The differences across groups were highly significant, with an F statistic of 25.850 and a p value below 0.001. In practical terms, all three infection states—viral, parasitic, and combined—pushed platelet size variability upward by a similar margin, suggesting a shared pathway of platelet activation and turnover regardless of which pathogen triggered it.

D-dimer told a more nuanced story. Levels climbed across the infected groups but peaked in the co-infected participants, who averaged 552.80 plus or minus 402.46 nanograms per milliliter, a difference that reached statistical significance with F equal to 2.816 and p equal to 0.040. This pattern implies that the fibrinolytic system—the machinery that dissolves clots—was working hardest when both pathogens were present simultaneously. Clinicians in endemic regions have long suspected that malaria and COVID-19 could compound each other’s prothrombotic effects, and these numbers offer quantitative support for that suspicion even among patients whose illnesses never became severe.

Perhaps the most intriguing results emerged from the two-way analysis of variance, which tested whether infection group and sex interacted in shaping each marker. For the platelet indices themselves, no significant group-by-sex interaction appeared, meaning platelet responses were broadly similar between men and women. But for fibrinogen the interaction was emphatic, with F equal to 18.42 and p below 0.001, and for D-dimer it was also significant, with F equal to 3.14 and p equal to 0.026. In other words, the protein side of the clotting system responded differently depending on whether the patient was male or female, even when the infection itself was comparable.

Sex-stratified comparisons sharpened that picture. PDW was significantly higher in females than males within the malaria group, with p equal to 0.012, and within the co-infected group, with p equal to 0.033. D-dimer, by contrast, was significantly higher in males only in the malaria group, with p equal to 0.021. These divergent patterns hint at underlying biological differences—possibly involving hormones, iron status, or sex-specific regulation of inflammation and coagulation—that deserve closer study. They also carry a practical warning: interpreting a single cutoff value for these markers without accounting for the patient’s sex could mislead clinicians working in malaria-endemic areas.

One negative finding is equally important for interpreting the study. The researchers observed no significant correlations between the platelet indices and the fibrinolytic markers, meaning that a patient’s platelet size variability did not predict their D-dimer or fibrinogen levels. This statistical independence suggests that platelet activation and fibrin turnover are governed by at least partly separate mechanisms in these mild infections. Rather than being redundant, the two marker families may therefore offer complementary information about different limbs of the hemostatic response, and measuring both could yield a richer clinical picture than either alone.

The study’s setting gives its conclusions particular weight. Most of what is known about COVID-19 coagulopathy comes from hospitalized patients in high-income countries, where severe disease dominates the clinical picture and malaria is rare. By focusing on mild cases in Port Harcourt, the investigators demonstrated that hemostatic perturbation is detectable even before patients become critically ill, and they did so in the exact environment where such knowledge is most needed. Automated hematology analyzers like the Sysmex XP-300 are widely available in district laboratories across sub-Saharan Africa, and D-dimer assays are increasingly accessible, making both markers realistic tools rather than laboratory luxuries.

The authors analyzed their data with SAS 9.4 and JMP 14.3, and the statistical framework—analysis of variance with sex as a factor—was well suited to the question at hand. Still, as a case-control study of mild disease, it cannot establish causation or track how these markers evolve as illness progresses, and the balanced but unequal sex composition of each group reflects the epidemiology of the infections themselves. Future longitudinal work could follow patients from infection through recovery to see whether elevated PDW and D-dimer normalize and whether early hemostatic changes predict later complications. For now, the study establishes that PDW and D-dimer are accessible, informative indicators of hemostatic alteration in mild COVID-19, malaria, and co-infection, and that sex must be part of the interpretive equation in tropical clinical practice.

Subject of Research: Sex-specific hemostatic responses measured by platelet distribution width and D-dimer in mild COVID-19, malaria, and co-infection in Nigeria

Article Title: Sex-specific hemostatic responses and alterations of Platelet Distribution Width (PDW) and D-dimer in mild COVID-19, Malaria, and co-infection in a tropical setting: A case-control study in Port Harcourt, Nigeria

Article References: Sex-specific hemostatic responses and alterations of Platelet Distribution Width (PDW) and D-dimer in mild COVID-19, Malaria, and co-infection in a tropical setting: A case-control study in Port Harcourt, Nigeria. (n.d.). https://doi.org/10.1371/journal.pgph.0007465

Image Credits: AI Generated

DOI: 10.1371/journal.pgph.0007465

Keywords: COVID-19, malaria, co-infection, platelet distribution width, D-dimer, fibrinogen, hemostasis, sex differences, Nigeria, case-control study, tropical medicine, platelet indices

The patient arrived at the emergency department with three days of high-grade fever, reaching 103 degrees Fahrenheit, accompanied by the classic hallmarks of dengue: headache, retro-orbital pain behind the eyes, and generalized body aches. He had no vomiting, diarrhea, cough, or any bleeding manifestations, and no chronic medical conditions, prior surgeries, or relevant family history. He did not smoke, drink alcohol, or use recreational drugs. On examination he appeared ill and febrile, with a pulse of 110 beats per minute and a blood pressure of 115/80 mmHg, but his heart, lungs, abdomen, and neurological status were otherwise unremarkable. In short, he presented as a textbook case of uncomplicated dengue.

Laboratory testing confirmed the diagnosis. The dengue NS1 antigen came back positive, malaria parasites were absent, and ELISA-based serology ruled out other viral infections. His hemoglobin stood at 13 g/dL and his platelet count at 192,000 per microliter, well within the normal range, which would later prove to be one of the most instructive features of the case. His leukocyte count was initially elevated at 12,000 per microliter before settling to 4,600. More ominous was the coagulation picture: while his standard coagulation profile was normal, his D-dimer, a breakdown product of cross-linked fibrin that serves as a molecular flag for active clot formation and dissolution, was dramatically elevated at 9,968 ng/mL, later declining to 4,068 ng/mL. Inflammatory markers told a similar story of a body under siege, with C-reactive protein at 142 mg/L against a normal threshold of 10, procalcitonin at 0.57 ng/mL, and an erythrocyte sedimentation rate of 54 mm/h.

The turning point came on the sixth day of hospitalization, roughly the ninth day of illness, when the patient developed sudden painful swelling of the right lower limb extending from calf to thigh, together with progressive shortness of breath on exertion. The limb was visibly swollen up to the groin, red, warm, and tender, with increased calf and thigh circumference, though peripheral pulses remained intact. He remained hemodynamically stable apart from mild tachycardia, with a blood pressure of 105/70 mmHg and an oxygen saturation of 93 percent on room air. Doppler ultrasonography confirmed deep vein thrombosis, and because his dyspnea worsened, the team proceeded to CT pulmonary angiography. The scan revealed bilateral pulmonary emboli and dilatation of the right cardiac chambers, a sign that the clots lodging in the pulmonary arteries were forcing the right side of the heart to pump against dangerous resistance.

Imaging then uncovered a further puzzle. A chest radiograph showed a cavitary lesion in the right lung with mild cardiomegaly, and high-resolution computed tomography revealed that cavity surrounded by pneumonic consolidation, minimal bilateral pleural effusions, and basal atelectatic changes. Cavitary lung lesions typically raise the specter of tuberculosis, lung abscess, fungal infection, or malignancy, each of which could independently predispose a patient to clotting. The team therefore cast a wide diagnostic net: sputum examination, acid-fast bacilli smears, and GeneXpert testing were negative for Mycobacterium tuberculosis, blood cultures grew no bacterial or fungal pathogens, and bronchoscopy with bronchoalveolar lavage found only mucopurulent secretions with no organisms on Gram stain, no growth on culture, and no malignant cells on cytology. Transthoracic echocardiography showed preserved left ventricular function with an ejection fraction of 64 percent, no intracardiac vegetations, and a positive McConnell sign, a regional pattern of right ventricular dysfunction considered suggestive of acute pulmonary embolism.

The authors argue that the most likely explanation for the cavity is pulmonary infarction, tissue death downstream of the embolic obstruction, which can occasionally cavitate when vascular blockage is severe. The temporal relationship between the dengue infection and the thrombotic event, combined with a negative thrombophilia workup and the patient’s young age, pointed toward a transient, infection-associated prothrombotic state rather than an inherited clotting disorder or occult cancer. The differential diagnosis nonetheless included septic pulmonary emboli, secondary bacterial pneumonia, and malignancy, and the authors note that unexplained or recurrent venous thromboembolism should always prompt consideration of hidden malignancy, citing a prior report in which deep vein thrombosis was the presenting feature of uterine leiomyosarcoma.

The mechanistic picture emerging from the dengue literature is one of coordinated disruption of hemostasis. The authors outline several converging pathways: molecular mimicry between viral antigens and coagulation factors generating cross-reactive autoantibodies; direct endothelial dysfunction driven in part by the dengue NS1 protein; infection-induced upregulation of tissue factor in monocytes and endothelial cells; and a cytokine storm that amplifies both inflammation and coagulation activation. Critically, this case demonstrates that clinically significant thrombosis can occur even when platelet counts remain normal. Previous analyses have documented venous thrombosis in dengue patients with median platelet counts as low as 52,000 per cubic millimeter, but this patient never developed thrombocytopenia during hospitalization, underscoring that the absence of low platelets offers no reassurance against the thrombotic complication.

The timing also fits an emerging pattern. In an analysis of 19 previously reported cases of spontaneous venous thrombosis in dengue cited by the authors, the median onset of thrombosis was six days after fever began, with serious thrombotic events generally clustering between days 5 and 10 of illness, the transition from the acute phase to recovery. Lower limb deep vein thrombosis was the dominant manifestation, accounting for 68 percent of cases, most often involving the right side and the external iliac, common femoral, and popliteal veins. This patient’s right lower limb clot extending from calf to thigh, with bilateral pulmonary embolism on top, represents an unusually severe expression of that same tendency. His markedly elevated C-reactive protein also aligned with evidence that more intense inflammatory responses accompany severe dengue, where mean CRP levels of roughly 50 mg/L have been recorded against about 22 mg/L in non-severe disease.

Treatment required navigating a genuine therapeutic dilemma: anticoagulating a dengue patient in whom bleeding is the classically feared complication. The team initiated weight-based therapeutic enoxaparin at 60 mg subcutaneously twice daily for the approximately 60-kg patient, alongside intravenous paracetamol, fluids, broad-spectrum antimicrobials with meropenem and linezolid given concern for secondary bacterial infection, and nebulized bronchodilators and corticosteroids for respiratory symptoms. In the published series, 57.8 percent of patients received low-molecular-weight heparin, anticoagulation was tolerated even amid thrombocytopenia, and all patients recovered without incident. Yet the literature still lacks formal guidelines for managing dengue-associated pulmonary embolism, and the authors emphasize that the decision to anticoagulate remains difficult in the face of bleeding risk. This patient improved steadily, was discharged on day thirteen with apixaban 10 mg twice daily tapering to 5 mg twice daily for a total of six months of anticoagulation, and at four-week follow-up his dyspnea and leg swelling had resolved, repeat Doppler ultrasound showed interval improvement, and chest CT showed partial resolution of the cavitary lesion.

The case carries two forward-looking warnings. First, because the patient demonstrated right ventricular dysfunction from bilateral pulmonary emboli, he faces a risk of chronic thromboembolic pulmonary hypertension, a disabling late complication that demands extended monitoring. Second, and more broadly, the authors urge clinicians caring for dengue patients to stay alert for thrombotic symptoms during the recovery phase, when vague complaints such as unilateral limb swelling or exertional breathlessness may be the only clues to a clot that imaging will confirm. Early recognition, timely diagnosis with tools such as D-dimer measurement, Doppler ultrasound, and CT angiography, and prompt anticoagulation can prevent life-threatening outcomes in a complication that remains poorly recognized but is, as this case shows, very much preventable.

Subject of Research: Venous thromboembolism as a complication of dengue fever

Article Title: Post‐Dengue Deep Vein Thrombosis Complicated by Pulmonary Embolism: A Case Report

Article References: Nisar, S., Mushtaq, H., Khan, M. H., Sajjad, F., Afridi, A., Fatima, N. E., & Kamil, K. A. (2026). Post‐Dengue Deep Vein Thrombosis Complicated by Pulmonary Embolism: A Case Report. Clinical Case Reports, 14(10), Article e73642. https://doi.org/10.1002/ccr3.73642

Image Credits: AI Generated

DOI: 10.1002/ccr3.73642

Keywords: dengue, deep vein thrombosis, pulmonary embolism, venous thromboembolism, hypercoagulability, D-dimer, anticoagulation, enoxaparin, apixaban, NS1 antigen, pulmonary infarction, case report

D-dimer is far from a new player in stroke medicine. The molecule appears whenever the body forms a clot and then dissolves it, so elevated concentrations signal active coagulation and fibrinolysis. Previous studies had already linked high D-dimer levels after aneurysmal subarachnoid hemorrhage to poor outcomes, but the mechanism driving that early surge remained contested. Was the marker simply reflecting the size of the hemorrhage itself, or was it tracking deeper disturbances of hemostasis, systemic inflammation, or secondary complications such as delayed cerebral ischemia? Disentangling these possibilities requires detailed imaging data and sophisticated statistical modeling, both of which the Nanchang team brought to bear. Their study drew on the PROSAH-MPC cohort, a single-center database of 473 patients treated at the Second Affiliated Hospital of Nanchang University, each of whom had complete clinical, radiological, and laboratory records from the moment of admission.

The centerpiece of the analysis was a quantitative variable that few centers routinely measure: total bleeding volume. Using deep learning-based segmentation of non-contrast CT scans, the researchers computed the absolute volume of subarachnoid blood for every patient, an approach they had validated in earlier work. Rather than grading hemorrhage on the coarse modified Fisher scale, which lumps patients into broad categories, total bleeding volume offers a continuous, patient-specific measure of the initial insult. When the team stratified patients by admission D-dimer quartiles, a clear gradient emerged. Patients in the highest quartile were substantially more likely to suffer an unfavorable outcome, defined as a modified Rankin scale score of 3 to 6 at twelve months, meaning moderate to severe disability or death. Across the entire cohort, 125 patients, or 26.4 percent, experienced such unfavorable outcomes.

The statistical backbone of the study was multivariable logistic regression, adjusted for the standard confounders that muddy any observational analysis. Even after accounting for age, clinical severity as measured by the Hunt–Hess grade, radiological severity on the modified Fisher score, and other clinical variables, elevated admission D-dimer remained independently associated with poor functional outcome, with an adjusted odds ratio of 1.08 per unit increase and a 95 percent confidence interval of 1.02 to 1.16. That effect size may look modest, but in a condition where every percentage point of prognostic accuracy matters, the signal is clinically meaningful. More striking was the discovery of a statistically significant interaction between D-dimer and total bleeding volume, with a P value for interaction of 0.032. In plain terms, the prognostic impact of the blood marker depended on how much blood was actually present in the subarachnoid spaces, and vice versa.

This interaction finding is where the study moves beyond simple biomarker association and begins to touch on mechanism. One leading hypothesis, advanced by the authors in light of prior literature, is that large volumes of subarachnoid blood elevate intracranial pressure and physically stress the delicate neurovascular environment, while simultaneously releasing procoagulant and fibrinolytic products that drive D-dimer upward. The blood clot burden and the fibrin turnover it provokes may thus represent two faces of the same pathological process. An alternative interpretation is that acute microthrombosis within cortical vessels, a phenomenon increasingly documented after subarachnoid hemorrhage, generates both the biochemical signature and much of the delayed ischemic damage that destroys neurons in the days after the bleed. The new data cannot definitively adjudicate between these mechanisms, but they establish that the two variables are not redundant: each captures prognostic information the other misses.

To formalize these relationships into a practical prediction tool, the team turned to machine learning. Using the Boruta algorithm, an established wrapper method for feature selection that compares each candidate variable against randomized shadow features, they identified five top-ranked predictors: admission D-dimer, total bleeding volume, age, Hunt–Hess grade, and the modified Fisher score. Seven different machine learning architectures were then trained to predict twelve-month functional outcome. A composite of D-dimer, total bleeding volume, and Hunt–Hess grade achieved an area under the receiver operating characteristic curve of 0.867, outperforming any single variable alone, with D-dimer alone reaching 0.735, total bleeding volume 0.783, and the Hunt–Hess grade 0.833. Among the full algorithmic models, XGBoost, a gradient-boosted decision tree method celebrated for its performance on tabular clinical data, achieved the highest discriminative power with an AUC of 0.904 on the held-out internal test set.

What elevates this work above many machine learning studies in medicine is its commitment to interpretability. Black-box predictions are notoriously hard to trust in the intensive care unit, where clinicians must justify every decision. The researchers therefore applied SHapley Additive exPlanations, or SHAP, a technique rooted in cooperative game theory that assigns each feature a quantified contribution to every individual prediction. The SHAP analysis confirmed that D-dimer and total bleeding volume were among the dominant contributors to the model’s output, alongside the established severity scales. Crucially, SHAP interaction plots revealed a synergistic adverse effect: at higher D-dimer concentrations, increasing total bleeding volume pushed predictions steeply toward poor outcome, visually mirroring the statistical interaction term from the regression analysis. For individual patients, force plots showed exactly which variables drove a given forecast, offering clinicians a transparent rationale rather than an inscrutable score.

The clinical implications are tantalizing but must be tempered by the study’s design. As a retrospective, single-center cohort, the findings require external validation before admission D-dimer can be woven into formal prognostic scores or triage protocols. The study also complied with the STROBE reporting guidelines and used structured approaches such as the CHARMS checklist for prediction model appraisal, along with E-value sensitivity analyses to probe unmeasured confounding, all of which strengthen confidence in the internal validity. Nonetheless, the appeal of the approach lies in its practicality: D-dimer is already measured in virtually every emergency department in the world, costs pennies, and returns results within minutes. If combined with automated CT segmentation pipelines that are rapidly maturing, a bedside risk estimate could plausibly be generated within the first hour of hospital arrival, precisely the window when decisions about transfer, aneurysm securing, and blood pressure management are made.

For patients and families, the difference between a 70 percent and a 90 percent accurate prognosis on day one can shape everything from the intensity of neurocritical care to the timing of family conversations. For researchers, the study adds to a growing body of evidence that hemostatic activation is not an epiphenomenon of aneurysmal subarachnoid hemorrhage but a central axis of injury, one that intersects with bleeding volume, intracranial pressure, and delayed cerebral ischemia. Whether interventions targeting coagulation or fibrinolysis could one day improve outcomes remains an open question, and the authors are careful not to overclaim therapeutic implications. What their work does establish, with unusual statistical rigor and computational transparency, is that the humble fibrin fragment measured on admission encodes genuine, quantifiable information about a patient’s twelve-month trajectory. In a disease where early brain injury unfolds within hours, that information, delivered through interpretable machine learning models, may prove to be exactly the early warning system neurointensivists have been seeking.

Subject of Research: Prognostic value of admission D-dimer and total bleeding volume in aneurysmal subarachnoid hemorrhage using interpretable machine learning.

Article Title: Prognostic Value of Admission D-dimer Levels and Total Bleeding Volume in Aneurysmal Subarachnoid Hemorrhage: A Retrospective Cohort Study with Machine Learning-Based Modeling

Article References: Wu, Y., Hu, P., Yang, X., Liao, Q., Chen, Z., Zhang, S., Xiao, B., Lv, S., Wu, M., Yan, T., Zhu, X., Ye, M., & Tu, W. (2026). Prognostic Value of Admission D-dimer Levels and Total Bleeding Volume in Aneurysmal Subarachnoid Hemorrhage: A Retrospective Cohort Study with Machine Learning-Based Modeling. Neurocritical Care. https://doi.org/10.1007/s12028-026-02558-4

Image Credits: AI Generated

DOI: 10.1007/s12028-026-02558-4

Keywords: aneurysmal subarachnoid hemorrhage, D-dimer, total bleeding volume, machine learning, XGBoost, SHAP, prognosis, biomarkers, neurocritical care, stroke, CT imaging, functional outcomes

The epidemiological data assembled in the review are striking. Active cancer is present in roughly 5 to 10 percent of patients presenting with ischemic stroke, a proportion that rises among those with embolic stroke of undetermined source, the cryptogenic category in which no conventional mechanism can be identified. In 3 to 5 percent of such patients, the stroke actually precedes the cancer diagnosis by up to two years, making it the first clinical manifestation of an occult malignancy. Occult cancer is detected in about 5.3 percent of patients with embolic stroke of undetermined source, with the highest detection rate occurring in the early period after the stroke, at 14.3 per 1,000 person-months. Among cancer patients who do stroke, cancer-associated coagulopathy is the most frequent cause, accounting for 39.8 percent of cases, while traditional mechanisms such as large-artery atherosclerosis and cardioembolism from atrial fibrillation are comparatively less common.

Timing emerges as one of the most consistent signatures of the condition. The risk of hypercoagulability-related stroke peaks within the first six months after a cancer diagnosis, and many patients have already reached metastatic disease by the time the stroke occurs. Arterial thromboembolism more broadly shows a characteristic temporal pattern, with incidence peaking in the first year after cancer diagnosis, and stroke represents the majority of these arterial events at 71.6 percent. Although the risk declines after the first year, it remains elevated above that of the general population for as long as a decade. Histologically, adenocarcinoma dominates, with lung and pancreatic cancer most frequently implicated, followed by colorectal, breast and prostate malignancies. The interval between cancer diagnosis and stroke is particularly short in pancreatic and colorectal cancer, underscoring their especially potent thrombotic potential.

The pathophysiology described in the review is a layered interplay of tumor biology and hemostasis. Adenocarcinomas produce mucin, a heavily glycosylated molecule that, although largely cleared by the liver, can engage the adhesion molecules P-selectin and L-selectin to trigger the formation of platelet-rich microthrombi. Tumor cells also overexpress tissue factor, a transmembrane receptor that activates the coagulation cascade through the extrinsic pathway, and this expression is upregulated by oncogenic events such as inactivation of the p53 tumor suppressor and activating mutations in the K-ras oncogene. More recently, alterations in K-ras and the STK11 tumor suppressor gene have been linked to arterial thromboembolism risk, with hazard ratios of 2.22 and 3.48 respectively for stroke among individuals carrying versus lacking these alterations. A recent in vitro study in human pancreatic cancer cell lines further showed that thrombosis induced by tissue factor-expressing microvesicles depends predominantly on coagulation factors VIII and IX, with von Willebrand factor playing a lesser role.

Beyond mucins and tissue factor, the review highlights two additional mechanisms that have reshaped understanding of cancer-driven thrombosis. Circulating extracellular vesicles secreted by tumor cells have been measured by flow cytometry, and levels of cancer cell-derived vesicles are higher in patients with cancer-related stroke than in other groups, correlating with D-dimer levels but not with vesicle-associated tissue factor, which points to prothrombotic pathways beyond the canonical tissue factor route. In vitro experiments also found that vesicles from adenocarcinoma cell lines shorten clotting times more than those from squamous cell carcinoma, consistent with the clinical predominance of adenocarcinoma. Separately, neutrophil extracellular trap formation, or NETosis, has emerged as a key mediator: cancers sensitize peripheral neutrophils toward NET release via granulocyte colony-stimulating factor, and in stroke patients with cancer, NET-specific biomarkers such as plasma DNA, nucleosomes and citrullinated histone H3 are significantly elevated and correlate with D-dimer and thrombin-antithrombin complex levels. A post-mortem histopathological study even demonstrated widespread microvascular thrombosis in the brain, with H3Cit-positive cells embedded in multiple cerebral thrombi.

Clots physically retrieved from patients during thrombectomy provide direct confirmation of this biology. Thrombi from stroke patients with active cancer are platelet-rich and erythrocyte-poor, a composition most pronounced in those with non-bacterial thrombotic endocarditis, and immunohistochemical analysis shows significantly higher content of von Willebrand factor and citrullinated histone H3 in clots from patients with cancer. Proteomic studies have added further markers, identifying elevated levels of proteins associated with active cancer and immune responses, such as IGHG1 and vitronectin, in cancer-related clots. This distinctive composition has a practical radiological consequence: the absence of the susceptibility vessel sign on susceptibility-weighted imaging in patients with large-vessel occlusion is associated with active cancer, with a reported sensitivity of 27 percent and specificity of 85 percent, reflecting the fibrin- and platelet-heavy, red-cell-poor nature of the thrombus.

On brain imaging, the review identifies a pattern that should raise immediate suspicion. The hallmark of cancer-associated coagulopathy stroke is multiple ischemic lesions spanning more than two vascular territories on diffusion-weighted MRI, with microembolic dispersion seen in 78 percent of patients and prior silent infarcts in half. The most specific finding is the so-called three territories sign, defined by simultaneous bilateral lesions in three vascular territories spanning both anterior and posterior circulation. In the absence of infective endocarditis, this sign is highly specific for cancer-related stroke, and among patients with three-territory infarcts and no identifiable embolic source, approximately 75 percent of cases are malignancy-related. The number of affected territories independently predicts occult malignancy in cryptogenic stroke. Cortical and subcortical regions are most frequently affected, followed by the cerebellar hemispheres and corpus callosum, while deep structures and the brainstem are rarely involved.

Biomarker evidence converges on D-dimer as the single most useful test, despite its lack of specificity. Proposed diagnostic thresholds vary, with one study suggesting a cutoff of 5.5 micrograms per milliliter yielding 99.7 percent specificity and 92.9 percent positive predictive value, and a later study proposing 2.785 micrograms per milliliter with 50.9 percent sensitivity and 98.5 percent specificity. The authors caution, however, that different analytical platforms and reporting units, fibrinogen-equivalent versus D-dimer units, preclude a universal cutoff. D-dimer remains the only biomarker consistently associated with recurrent stroke and mortality in this population, and elevated levels after anticoagulant therapy predict early recurrence. Supporting markers include C-reactive protein above 20 milligrams per liter and fibrinogen above 600 milligrams per deciliter, both highly specific for occult malignancy in cryptogenic stroke, along with CA-125, elevated neutrophil-to-lymphocyte ratio above 15, and transcranial Doppler microembolic signals, though the latter show limited specificity. The NORSTROKE score, combining age, D-dimer, hemoglobin and smoking status, offers a probabilistic approach, estimating a 53 percent probability of active cancer in a patient under 75 with cryptogenic stroke, D-dimer above 3 milligrams per liter, hemoglobin below 12 grams per deciliter and a smoking history.

Treatment remains the weakest link in the evidence chain. Low-molecular-weight heparin and direct oral anticoagulants are the most commonly used secondary prevention strategies, with low-molecular-weight heparin generally preferred in gastrointestinal malignancies because of the higher bleeding risk of direct oral anticoagulants in that setting, while vitamin K antagonists are less effective. Comparative studies have shown broadly similar outcomes between agents: enoxaparin versus aspirin, direct oral anticoagulants versus enoxaparin, apixaban versus aspirin in a post hoc analysis of the ARCADIA trial, and oral edoxaban versus subcutaneous enoxaparin all failed to show significant differences in major bleeding, thromboembolism or survival. A recent retrospective study found no mortality or recurrence difference between anticoagulant and antiplatelet therapy, and a 2026 American Heart Association scientific statement concluded there is insufficient evidence to choose between anticoagulation and antiplatelet therapy for this indication. Current guidelines for cancer-associated thrombosis recommend at least three to six months of anticoagulation, extended when cancer remains active.

The prognosis statistics explain why the authors frame this as an urgent, underrecognized problem. Thirty-day mortality ranges from 25 to 50 percent, compared with 14 percent in stroke patients without cancer, and more than half of deaths occur within six months. The median modified Rankin Scale score at discharge is 3, and at three months 75.6 percent of patients remain at least moderately disabled. Recurrence rates reach 13.6 percent, roughly three times that of patients without cancer, with cumulative rates of 7 percent at one month and 16 percent at six months. When stroke is the first manifestation of occult malignancy, median survival is only 58 days, and median survival in cancer patients with cryptogenic stroke ranges from 62 to 365 days, versus 590 days for stroke of other causes. In patients with non-bacterial thrombotic endocarditis, up to 90 percent die or suffer recurrent stroke within six months. The review’s authors acknowledge limitations, including the predominance of retrospective observational data, the absence of prospective protocol registration, marked heterogeneity that prevented meta-analysis, and language restrictions to English and Spanish. They call for prospective multicenter cohorts, standardized D-dimer assays, external validation of the NORSTROKE score and randomized trials comparing low-molecular-weight heparin, direct oral anticoagulants and antiplatelet therapy. As cancer incidence rises and survival improves, they warn, the burden of this devastating stroke subtype will only grow, making earlier recognition and personalized antithrombotic strategies a clinical imperative.

Subject of Research: Ischemic stroke caused by cancer-associated coagulopathy, including its epidemiology, mechanisms, biomarkers, imaging features and treatment

Article Title: Stroke secondary to cancer-associated coagulopathy: a systematic review

Article References: Stroke secondary to cancer-associated coagulopathy: a systematic review. (n.d.). https://doi.org/10.1007/s00415-026-14119-y

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14119-y

Keywords: stroke, cancer-associated coagulopathy, Trousseau syndrome, adenocarcinoma, D-dimer, hypercoagulability, three territories sign, anticoagulation, low-molecular-weight heparin, direct oral anticoagulants, neutrophil extracellular traps, tissue factor