Thrombosis in rare bleeding disorders: a bleeding phenotype does not fully preclude thrombotic risk- frequency, clinical contexts, and management in a large Iranian cohort.

backgroundBleeding is the dominant clinical feature of rare bleeding disorders (RBDs), yet thrombotic events have occasionally been reported. Available evidence is limited and mostly based on case reports. Thrombotic events tend to occur in high-risk clinical contexts and may be influenced by replacement therapy and coexisting risk factors. We aimed to estimate the frequency of imaging-confirmed thrombosis and describe associated clinical contexts and potential predisposing factors in an unselected RBD cohort.

methodsThis single-center retrospective study was conducted on all patients with confirmed diagnoses of RBDs, including rare coagulation factor deficiencies, von Willebrand disease, and inherited platelet function disorders, under care at our center between January and December 2025. Data were extracted from medical and laboratory records and imaging archives. Variables included age, sex, type and severity of deficiency, comorbidities, prothrombotic triggers (e.g., pregnancy, surgery, infection, and immobility), exposure to replacement therapy, and thrombophilia profile. Thrombotic events were verified through imaging.

resultsAmong 1,251 patients (682 FXIII, 127 FVII, 130 FV, 23 FX, 12 FII, 28 afibrinogenemia, 131 von Willebrand disease, 62 Glanzmann thrombasthenia, 26 FXI deficiency, 19 combined FV and FVIII deficiency, and 11 Bernard-Soulier syndrome), 12 (0.96%; 95% CI, 0.50-1.67%) had at least one lifetime imaging-confirmed thrombotic event. Events were exclusively venous. Events occurred mainly as deep vein thrombosis (50%) or cerebral venous thrombosis (41.7%), with other sites less common, most often in high-risk contexts such as pregnancy (4 cases), surgery, infection, or exposure to prothrombin complex concentrate (PCC). Thrombosis was more frequent in afibrinogenemia (7.1%) and FII deficiency (8.3%) than in FXIII deficiency (0.7%), although interpretation is limited by small numbers. In a sensitivity analysis excluding events associated with pregnancy, surgery, and exposure PCC, the proportion decreased to 0.48% (6/1,251; 95% CI, 0.18-1.04%). Thrombotic events were treated with therapeutic anticoagulation, most commonly initial low-molecular-weight heparin (LMWH) with transition to a Direct Oral Anticoagulant (DOAC) in selected non-pregnant adult patients; when replacement therapy was required, dosing was individualized to maintain minimum effective hemostatic levels and avoid full factor normalization.

conclusionsThrombosis in RBDs was rare and largely associated with major transient high-risk contexts and/or treatment exposure. Prospective multicenter studies are needed to improve the evidence base for clinical decision making regarding thrombotic risks in this vulnerable population.