When an Extra X Means Extra Risk: Venous Thromboembolism in Klinefelter Syndrome

Klinefelter syndrome (KS) is a common but frequently underdiagnosed sex chromosome aneuploidy that confers a markedly elevated risk of venous thromboembolism (VTE), yet it remains absent from major anticoagulation guidelines. We present a 41-year-old man with known KS on testosterone replacement who developed massive bilateral pulmonary embolism with concurrent deep vein thrombosis, presenting with syncope, dyspnea, and right heart strain on imaging. Hematocrit was 48.8% at admission, below the erythrocytosis threshold despite ongoing testosterone therapy. Serial laboratory data over 13 months consistently showed normal hematocrit values, implicating KS-intrinsic hypercoagulability rather than testosterone-induced erythrocytosis as the primary thrombotic driver. Thrombophilia testing was negative for factor V Leiden, prothrombin G20210A, and JAK2 mutations. The patient was managed with heparin bridged to apixaban and discharged on lifelong anticoagulation. This case highlights KS as a high-risk thrombophilic condition in which the underlying genetic syndrome, not testosterone therapy, is the primary driver of thrombosis. Early recognition and formal inclusion of KS in VTE management guidelines are needed to standardize care for this commonly underdiagnosed population.