Injectable pentosan polysulfate: A novel cause of heparin-induced thrombocytopenia and stroke

Abstract Introduction: We describe a rare and diagnostically challenging presentation of heparin-induced thrombocytopenia (HIT) leading to acute ischemic stroke in a young female, highlighting the critical importance of a comprehensive medication history that includes unconventional exposures. Case Description: A 36-year-old female with history of T6–T9 syrinx and bladder spasms presented to the Emergency Department with nausea, vomiting, fatigue, and transient word-finding difficulty. Neurologic examination was non-focal, and her symptoms improved during evaluation. Laboratory testing revealed thrombocytopenia (platelets 31x10³/μL). She was ultimately discharged with recommended outpatient Hematology follow up. She returned the next day with chest pressure, diaphoresis, diffuse weakness, new-onset right lower facial droop, diplopia with downward gaze, and intermittent dysarthria. Brain MRI demonstrated a right frontal FLAIR hyperintensity with diffusion restriction, consistent with an acute cortical infarction. CT angiography and bilateral lower extremity duplex studies were negative for thromboembolism. Transthoracic echocardiogram with agitated saline contrast revealed a moderate patent foramen ovale (PFO). Aspirin and Atorvastatin were initiated, and Clopidogrel was deferred due to continued thrombocytopenia. Due to the unusual presentation of ischemic stroke and isolated thrombocytopenia in a young female without traditional risk factors, a comprehensive diagnostic evaluation was pursued. Autoimmune workup including antinuclear antibodies and antiphospholipid antibodies were negative. Hypercoagulable panel including Factor V Leiden, prothrombin gene mutation, and protein C and S levels were unremarkable. Peripheral smear showed no schistocytes or evidence of microangiopathy. Bilateral upper extremity duplex ultrasound revealed superficial venous thrombi, raising concern for a systemic prothrombotic process. A 4T's score of 6 and a positive anti-platelet factor 4 (PF4) antibody ELISA suggested high probability of HIT. Serotonin release assay (SRA) was performed using both low-dose and high-dose porcine heparin. The test demonstrated strong platelet activation at low-dose heparin (82%) with suppression at high-dose heparin (0%), consistent with a positive SRA and diagnostic of HIT, despite no known heparin exposure. On detailed history review, the patient had self-administered an injectable medication, Pentosan Polysulfate (PPS), for bladder spasms, which she had purchased online. PPS is a semisynthetic pentasaccharide with anticoagulant properties similar to low molecular weight heparin. While an oral formulation is FDA-approved for interstitial cystitis, injectable PPS is not approved for human use and is restricted to veterinary medicine, primarily for canine osteoarthritis. The patient injected two doses in the preceding week, the second immediately before symptom onset. PPS was therefore identified as the likely HIT trigger and the patient was treated with Argatroban and transitioned to Apixaban, with platelet count recovery to 204x10³/μL. Discussion: This case illustrates the importance of maintaining a broad differential when encountering unexplained thrombocytopenia and thrombosis, as HIT may arise from unconventional exposures. Obtaining a detailed medication history, which includes unregulated and non-prescribed medications, is essential to identifying a diagnosis.