PROC is activated on the endothelial cell membrane, necessitating two membrane receptors: endothelial PROC receptor and thrombomodulin [9, 10]. aPC mitigates thrombin generation by selectively proteolyzing activated factors V and VIIIa [1, 11]. While severe PROC deficiency (homozygous or compound heterozygous forms) is exceedingly rare (prevalence between 1/500,000 and 1/750,000), partial deficiencies (heterozygous forms) are relatively common (occurring in 1/200 to 1/500 individuals) [11, 12]. In our observed cases, patients exhibited two point mutations in the PROC gene (refer to Supplementary Table 1). Notably, despite the administration of large heparin doses for anticoagulation in patients with DVT, resistance to heparin was suspected. This suspicion prompted a switch to alternative anticoagulants, leading to a marked reduction in systemic blood clots and a decrease in reliance on ECMO and ventilatory support parameters (Fig. 1). Heparin resistance typically involves the need for unusually high heparin doses to maintain therapeutic aPTT (or ACT) levels, often due to enhanced heparin clearance or elevated factor VIII levels [13, 14]. In this context, PROC deficiency contributes to factor VIII elevation, potentially leading to heparin resistance. Consequently, we propose comprehensive thrombogenic screening in young patients presenting with unexplained multiple VTE. If new VTEs emerge despite high-dose anticoagulant therapy, consideration of heparin resistance should prompt a swift switch in anticoagulant medication.

A repeat CT of the head on 15th May, three days post-admission, revealed a progression in the extent of intracranial hemorrhage (Fig. 2). Despite this, continued ECMO was necessary, warranting anticoagulation to ensure circuit patency. Managing anticoagulation in this scenario posed a significant challenge. For veno-venous extracorporeal membrane oxygenation (VV-ECMO), standard practice involves administering a heparin loading dose (e.g., 5000U) prior to intubation, followed by a continuous intravenous infusion, with the aim of maintaining aPTT within 40–60 s. However, this anticoagulation protocol may be adjusted in cases with additional factors necessitating higher anticoagulation levels, such as venous thromboembolism, atrial fibrillation, or thrombosis, or if anticoagulation is contraindicated due to bleeding or procedural requirements [15, 16].

Studies have explored low-intensity anticoagulation in traumatic brain injury (TBI) patients, maintaining aPTT between 45 and 55 s without exacerbating intracranial hemorrhage [17]. In one study focusing on TBI patients undergoing VV-ECMO, a maintained aPTT between 45 and 55 s showed that among 29 patients (81%) undergoing repeat head CT during ECMO, only one exhibited hematoma enlargement and another developed a new bleeding site [18]. Conversely, in VA-ECMO cases without active bleeding, a higher aPTT target is often pursued due to increased risks of arterial embolism, left ventricular thrombosis, and circuit thrombosis, which are associated with arterial cannulation, retrograde arterial reinfusion, and lower blood flow rates compared to VV-ECMO. Thus, an aPTT range of 45 to 55 s is deemed safe for patients with cerebral hemorrhage. However, in our patient’s case, the target aPTT was not achieved during ECMO therapy, primarily due to a PROC gene defect leading to a degree of heparin resistance.

Currently, the management of severe PROC deficiency primarily involves the use of PROC substitutes and oral anticoagulants. Exogenous PROC can be administered either through fresh frozen plasma or as a concentrated pharmaceutical preparation derived from purified PROC [19, 20]. Another critical aspect of long-term management in these patients is the administration of long-term oral anticoagulants, such as non-vitamin K antagonist oral anticoagulants (NOACs) [21]. The selection between NOACs and traditional anticoagulants like warfarin depends on various factors, including the severity of thrombosis, patient preference, and adherence to treatment. Research indicates that indefinite anticoagulation is necessary for patients with PROC deficiency, particularly those with a significant family history of VTE [22].

In the case of our patient, warfarin was chosen as the anticoagulant. We conducted regular monitoring of the INR, evaluated for extremity venous thrombosis, and performed CTPA. The dosage of warfarin was adjusted based on these results, ensuring effective and tailored anticoagulation management.