When Stroke Strikes Without Cause: The Hidden Heart Clots of Cancer and Autoimmune Disease

Imagine a 56-year-old woman arriving at an emergency department with sudden weakness on one side of her body. She has no hypertension, no diabetes, no atrial fibrillation, no smoking history—none of the usual suspects behind ischemic stroke. Yet her brain scans reveal not one but multiple infarcts scattered across different vascular territories, and her heart valves are studded with sterile, fibrin-platelet vegetations. This is the clinical face of non-bacterial thrombotic endocarditis, or NBTE, a rare but devastating condition that has long lurked in the shadows of stroke medicine. Now, a comprehensive patient-level systematic review published in Frontiers in Stroke has assembled the largest synthesis to date of stroke in NBTE, drawing on 236 patients from 218 published studies to paint the most detailed portrait yet of this enigmatic disease.

NBTE, also known as marantic endocarditis, is a form of non-infective endocarditis characterized by the deposition of sterile vegetations—composed predominantly of fibrin and platelets—on the cardiac valves. Unlike bacterial endocarditis, these growths are not driven by microbial infection but by an underlying hypercoagulable state, most commonly advanced systemic malignancy. The vegetations are friable and prone to fragmentation, showering emboli into the systemic circulation. Ischemic cerebrovascular events rank among the most common clinical consequences of this embolization, yet the evidence base has remained fragmented across individual case reports and small case series for decades. The new review, led by Ahmed Aljabali and colleagues spanning institutions in Jordan, the United Arab Emirates, and the United States, set out to change that by systematically extracting patient-level data from every published account of NBTE-related stroke.

The research team searched PubMed, MEDLINE, Embase, Web of Science, and PsycINFO from database inception through August 2025, ultimately identifying 949 studies. After rigorous screening and removal of duplicates, 218 studies—comprising 142 case reports and 7 case series published between 1981 and 2025—provided sufficient clinical detail for 236 patients who experienced stroke within 30 days of NBTE diagnosis. Two authors independently screened titles and abstracts, followed by full-text assessment, while a third independently verified all extracted data. Quality was assessed using the Murad methodological tool adapted for case reports and series, with approximately 30% of studies rated low risk of bias, 61% intermediate, and 9% high. Multivariable logistic regression, adjusted for age, sex, etiology, anticoagulation, and valvular intervention, was then employed to explore factors associated with recurrent stroke and mortality.

The demographic profile of the cohort is striking. The median age was 56 years, with an interquartile range of 43 to 63, and 63% of patients were female. Most patients had few or no traditional vascular risk factors: hypertension was present in only 21%, dyslipidemia in 8%, diabetes in 8%, and atrial fibrillation in just 4%. Instead, 43% had a prior history of thrombotic events—deep vein thrombosis or pulmonary embolism—most occurring within days to weeks of the NBTE diagnosis. This pattern underscores a central clinical message: when stroke strikes a patient without conventional risk factors, particularly one with known cancer or autoimmune disease, NBTE should rise to the top of the differential diagnosis.

Neuroimaging findings proved equally distinctive. Approximately 65% of patients had ischemic infarcts affecting more than two vascular territories—a hallmark of cardioembolism from friable valve vegetations—while only 18% had infarcts confined to a single territory. Ischemic stroke dominated at 94.6% of cases, with just 0.4% showing purely hemorrhagic infarcts and 5% showing a combination of both. Systemic embolism was documented in 41% of patients, most commonly involving the spleen and kidneys, each affected in roughly a quarter of cases. Left hemispheric stroke syndromes predominated among clinical presentations at 27%, followed by right hemispheric syndromes at 23% and posterior circulation syndromes at 20%. Notably, 8% of patients were neurologically asymptomatic but showed evidence of acute ischemic infarcts on neuroimaging, highlighting the condition’s capacity for silent cerebral injury.

The etiological landscape of NBTE-related stroke is dominated by cancer. Malignancy accounted for 70% of cases, with 58% of those patients already harboring metastatic disease at the time of NBTE diagnosis. Non-small cell lung cancer and gastrointestinal cancers each represented 31% of malignancy cases, followed by breast and reproductive organ cancers at 22%. Autoimmune disorders—principally antiphospholipid syndrome, which comprised 81% of autoimmune etiologies—accounted for another 25%. Only 4% of cases remained idiopathic despite thorough investigation. On echocardiography, the mitral valve was most frequently involved (68%), followed by the aortic valve (42%), with multi-valve involvement in 15% of patients. Among those with documented vegetation characteristics, 73% had mobile vegetations—a feature that likely facilitates embolic fragmentation.

Treatment and outcomes form the most sobering chapter of this story. Anticoagulation was initiated or continued in 70% of patients after stroke diagnosis, with unfractionated or low-molecular-weight heparin used in 53%, vitamin K antagonists in 16%, a heparin-then-VKA sequence in 20%, and direct oral anticoagulants in 11%. Valvular surgery was performed in 21% of patients. Despite these interventions, stroke recurred in 43% of patients over a median follow-up of just 2.0 months, and 59% of those recurrences occurred despite ongoing anticoagulation. Death claimed 49% of the cohort, with 83% of deaths occurring during the initial hospitalization and a median time to death of only one month. These figures paint NBTE-related stroke as a condition with an extraordinarily narrow therapeutic window.

The regression analyses yielded findings that are both informative and cautiously framed. Malignant etiology was independently associated with a dramatically increased odds of all-cause mortality (adjusted odds ratio 10.3, P < 0.001), as was the presence of metastases (aOR 3.9, P < 0.001). Conversely, autoimmune etiology (aOR 0.1, P < 0.001) and vitamin K antagonist therapy (aOR 0.08, P < 0.001) were associated with lower mortality, and valvular surgery also conferred a survival benefit (aOR 0.4, P = 0.013). For recurrent stroke, malignancy (aOR 2.8, P < 0.001) and metastases (aOR 2.3, P = 0.006) increased risk, while DOAC use was associated with a strikingly elevated odds of recurrent ischemic infarction (aOR 5.2, P = 0.012). Among patients on anticoagulation, recurrent stroke occurred in 56% of those receiving DOACs, compared with 29% on heparins and 18% on VKAs.

The authors are careful to emphasize that these anticoagulant-class findings must be interpreted as hypothesis-generating rather than definitive treatment guidance. Treatment allocation was not randomized and was likely influenced by malignancy status, thrombotic burden, bleeding risk, prognosis, and survivorship bias. The DOAC finding is particularly constrained by the small number of patients who received these agents after NBTE and stroke diagnosis—just 18 patients—and by possible misclassification. Moreover, a recent large retrospective cohort study of approximately 3,100 NBTE patients by Tran and colleagues found no statistically significant differences in thromboembolic outcomes across anticoagulant classes, underscoring the need for prospective comparative studies before any firm conclusions can be drawn about optimal anticoagulation strategy.

Nevertheless, the review’s limitations are candidly acknowledged. Reliance on case reports introduces publication and selection bias, with poorer outcomes more likely to be reported. The protocol was not prospectively registered, though eligibility criteria and data extraction fields were predefined and PRISMA recommendations were followed. Inconsistent reporting of follow-up duration resulted in a short median follow-up of 2.0 months, likely biasing findings toward acute inpatient outcomes. The regression models did not account for cancer staging or performance status, which may have driven differential outcomes between malignancy-related and autoimmune-related cases. Despite these constraints, the review delivers a clear clinical directive: NBTE belongs on the differential for stroke patients with minimal vascular risk factors, multifocal infarcts, and underlying malignancy or autoimmune disease. For clinicians navigating this diagnostic minefield, the message is unambiguous—look at the heart valves, look for the cancer, and act fast, because in NBTE-related stroke, time is not merely brain; it may be life itself.

Subject of Research: Clinical characteristics, management, and outcomes of stroke in non-bacterial thrombotic endocarditis

Article Title: Stroke in non-bacterial thrombotic endocarditis: a patient-level systematic review of clinical characteristics, management, and outcomes

Article References: Aljabali, A., Alhayali, D., Taylor-Wedge, H., Laffaye, T. A., Al-Ahmed, M., Harahsheh, A., Alamoush, M., Dweik, K., Osundiji, M. A., Mbonde, A. A., O'Carroll, C. B., Demaerschalk, B. M., & Harahsheh, E. (2026). Stroke in non-bacterial thrombotic endocarditis: a patient-level systematic review of clinical characteristics, management, and outcomes. Frontiers in Stroke, 5, Article 1915602. https://doi.org/10.3389/fstro.2026.1915602

Image Credits: AI Generated

DOI: 10.3389/fstro.2026.1915602

Keywords: non-bacterial thrombotic endocarditis, marantic endocarditis, ischemic stroke, malignancy, anticoagulation, systematic review, cardioembolism, antiphospholipid syndrome, DOACs, vitamin K antagonists, recurrent stroke, neuroimaging