Heparin-Induced Thrombocytopenia After Revascularization of Gustilo-Anderson Type IIIC Open Lower Leg Fracture: A Case Report of Subsequent Ischemic Limb Salvage Failure

Introduction

Heparin-induced thrombocytopenia (HIT) is a condition in which the immune response elicited by heparin administration results in thrombocytopenia owing to platelet activation and thromboembolism owing to hypercoagulability. This prothrombotic action makes early recognition of HIT very important [1]. The severity of trauma has been reported to strongly influence the risk of HIT antibody production [2]. However, in patients with severe trauma, the causes of thrombocytopenia vary. Despite the high risk of HIT, its recognition, evaluation, and appropriate treatment are infrequent and delayed [3]. Gustilo-Anderson Grade type IIIC open fractures of the extremities are defined as open fractures with arterial injuries that require repair [4]. In particular, Gustilo-Anderson type IIIC open tibial fractures are commonly associated with serious complications, such as soft tissue loss and arterial injury, which particularly affect the amount of acute blood loss [5]. The treatment of this type of fracture is challenging. A meta-analysis demonstrated that the use of systemic anticoagulants in the context of vascular trauma is significantly associated with a reduction in the rates of arterial patency failure and amputation, as well as a reduced risk of VTE development [6]. Therefore, we also used heparin after vascular anastomosis in Gustilo-Anderson type IIIC open fractures; however, the patient developed HIT, which led to lower-extremity ischemia. In the management of Gustilo-Anderson type IIIC open lower leg fractures, it is crucial to differentiate wasting thrombocytopenia associated with bleeding caused by heparin-induced thrombocytopenia. We report our experience with this case of HIT after revascularization of a Gustilo-Anderson type IIIC open fracture in the lower leg.

Case Report

The patient was a 48-year-old man who was attempting to get into his car when another vehicle struck it, pinning his lower right leg against the door and injuring him. He had no comorbidities or relevant medical history, but he had a personal history of smoking. Upon arrival at our hospital emergency room, he had 2 open wounds on the medial and lateral sides of the right lower leg, and the skin color of his foot was pale (Figure 1A, 1B). Laboratory data showed a hemoglobin level of 13.1 g/dl and a platelet count of 170 000/µl. Radiography revealed a segmental fracture (AO/OTA 42 C3) in the distal one-third of the tibia (Figure 2A), and contrast-enhanced computed tomography (CT) showed disruption of all 3 branches of the main artery at the fracture site, leading to the diagnosis of a Gustilo-Anderson type IIIC open fracture of the right lower leg. Emergency surgery was performed, with debridement, external fixation, and vascular anastomosis of the anterior and posterior tibial arteries. Postoperatively, heparin (12 000 U/day) continuous infusion and prostaglandin (alprostadil 40 μg×2 times/day) were administered intravenously to prevent thrombus formation in the vascular anastomosis location and deep veins of the lower extremities. Wound care was performed on days 2 and 5 after the injury, and internal fixation of the tibial fracture with an intramedullary nail was performed on day 7. At this time, the bone defect in the tibial diaphysis was filled with antibiotic-loaded cement (Figure 2B). A free flap was subsequently scheduled, but pallor appeared in the right foot on the 9th day after injury (Figure 3A). Because of suspected thrombus formation at the site of the vascular anastomosis, angiography of the right lower limb was performed, which revealed poor circulation in the anterior tibial artery and interruption of the blood flow at the site of anastomosis of the posterior tibial artery (Figure 3B). We determined that thrombus occlusion had occurred at the suture site and attempted to urgently revascularize the anterior and posterior tibial arteries using a vein graft on the same day. However, despite local heparin administration from the femoral artery, the patient developed an anastomotic thrombus immediately after vascular anastomosis (Figure 3C), revascularization was abandoned, and the operation was terminated. Ten days after the injury, the patient’s FDP and D-dimer levels were elevated (95.8 μg/ml and 48.1 μg/ml, respectively) and contrast CT was performed, which revealed a right inferior pulmonary artery thrombus (Figure 4) and a deep vein thrombus below the left knee. Rechecking the blood test trends, we suspected HIT because of the progressive drop in the platelet count (76 000/µl) and the elevation of FDP (8.2 μg/ml) from day 7 after the injury (Figure 5). On day 11 after the injury, a HIT antibody test was administered, heparin was discontinued, and subcutaneous fondaparinux injection (7.5 mg/day) was started. On day 13 after injury, the platelet count began to rise, and the FDP/D-dimer ratio began to fall. On the 14th day after the injury, amputation of the ischemic right lower leg was performed, after which the numerical rating scale became 1; however, it was 10 for the Gustilo-Anderson Grade IIIC open fracture injury. Subsequently, the patient was found to be positive for HIT antibodies using immunoassays. Postoperatively, the patient was switched to edoxaban 60 mg, and anticoagulation therapy was continued for 3 months. Thereafter, the patient experienced no new thrombus occlusion or wound trouble, and was able to walk on a prosthetic leg and return to daily life. Written informed consent was obtained from the patient for anonymized information and the accompanying images to be published in this article.

Discussion

In the present case, the patient developed HIT after revascularization of a Gustilo-Anderson type IIIC open fracture and the lower extremity could not be salvaged. It took time from the time of admission to recognize the onset of HIT due to prolonged thrombocytopenia associated with trauma and surgery. In addition, surgical intervention alone cannot solve the problem of thrombus occlusion after vascular suturing unless treatment is initiated based on the pathophysiology of HIT. Therefore, it is a complication that requires more attention in Gustilo-Anderson type IIIC open fractures requiring revascularization. This patient required emergency surgery for revascularization of the right lower leg. Although he was continuously treated with heparin from the time of admission to prevent thrombus formation, ischemic changes in the right lower extremity due to thrombus occlusion occurred on day 9 after the injury. Thrombocytopenia and thromboembolism associated with HIT often occur 5–10 days after heparin initiation [1], which is consistent with the timing of the onset of this case. Prospective studies of trauma patients who received heparin for more than 5 days reported an increased risk of HIT antibody production in patients who underwent major surgery [2]. Patients with severe trauma who receive heparin for thromboprophylaxis or anticoagulation after vascular repair, as in our case, are considered to be at a very high risk of HIT and should be carefully monitored for the development of HIT during acute management. The 4T score is often used to diagnose HIT [7]. Scoring is based on the degree and timing of thrombocytopenia, presence of thrombosis, and other causes of thrombocytopenia, and a low score is almost always considered to rule out HIT. On the other hand, the antibody test by immunoassay is very sensitive [8], so combining the 4T score with the antibody test is useful for making a diagnosis [9]. The American Society of Hematology guidelines recommend that if HIT is suspected, the 4T score should be calculated first, and if it is above intermediate risk (4 points or higher), heparin should be discontinued, alternative anticoagulation therapy should be started, and antibody testing should be added. If the test is positive, treatment should be continued [10]. Since patients with trauma are often complicated by thrombocytopenia due to wasting in association with bleeding, the assumption that these are processes associated with trauma has also led to delays in the diagnosis of HIT. In our case, the patient’s platelet count had been decreasing since day 7, even though the platelet count had been rising gradually due to a state of exhaustive thrombocytopenia. In the post-trauma period, platelet levels reach a nadir at 2–4 days, after which they reactively increase [1]; therefore, the possibility of HIT should be considered when platelets decline after an initial increase. The American College of Chest Physician guidelines also recommend that platelet levels should be monitored every 2–3 days in high-risk groups for HIT [11]. The FDP in our case also showed an increasing trend during the same period, suggesting that a new thrombus may have already developed at that time. If so, the 4T score of 6 was already high on day 7, antibody testing should have been added at this stage, and the discontinuation of heparin and initiation of alternative anticoagulation therapy should have been considered.

Gustilo-Anderson type IIIC open fractures are serious trauma that require vascular repair. Although HIT would have been prevented if heparin had not been used, a meta-analysis of extremity vascular injuries due to trauma also found that anticoagulation reduces intraoperative and postoperative complications [6], suggesting that heparin is necessary for revascularization. Furthermore, in severe trauma, heparin use may help prevent deep vein thrombosis, and in this case, the use was prolonged. Gustilo-Anderson type IIIC open tibial fractures are frequently associated with complex fracture patterns, heavy soft tissue destruction, and exsanguinating arterial hemorrhage [5]. In this case, the preconception that wasting thrombocytopenia is associated with bleeding may have masked the existence of HIT and caused delays in its diagnosis. Although it is a rare pathology, we speculate that amputation may have been performed in many cases of HIT without reaching a diagnosis. When heparin is used for Gustilo-Anderson type IIIC open fractures that require vascular anastomosis, complications of HIT should be considered.

In free-flap surgery requiring vascular anastomosis, flap necrosis due to venous or arterial thrombus caused by the onset of postoperative HIT has been reported [12]. These cases took a long time from onset to diagnosis, suggesting that once HIT develops, salvage is difficult. In a case where the flap could be salvaged [13], the patient was able to discontinue heparin and start argatroban before thrombotic symptoms developed. In patients with HIT, the American College of Chest Physicians suggests the use of argatroban, lepirudin, or danaparoid [11]. In recent years, fondaparinux has also been reported to be effective and safe in cases of suspected acute HIT [14]. The American Society of Hematology guidelines demonstrated that discontinuing heparin therapy and switching to a non-heparin anticoagulant is a critical step in the management of HIT and provides weak conditional support for direct oral anticoagulants as alternative anticoagulants (DOACs) in cases with confirmed or suspected HIT [10]. However, recent studies have shown that DOACs after platelet count recovery are widely accepted by clinicians and scientific experts in the field of platelet immunology [15]. In our case, we also opted to discontinue heparin and administer fondaparinux after the diagnosis of HIT, and we initiated oral treatment with edoxaban at a dose of 60 mg/day after platelet count recovery.

A limitation of our case report is that it is based on a single specific experience, which limits the generalizability of our findings. There may be insufficient evidence to support non-heparin anticoagulant therapy for patients with Gustilo-Anderson Grade IIIC open fractures of the extremities. Further research is needed to identify a safe anticoagulant regimen to rescue ischemic limbs in patients with Gustilo-Anderson Grade IIIC open fractures of the extremities.

Conclusions

We encountered a case of HIT after revascularization of a Gustilo-Anderson type IIIC open-leg fracture. It is important to consider the possibility of HIT as soon as possible when thrombocytopenia appears in patients receiving heparin after vascular anastomosis because it is difficult to save the limb if the diagnosis of HIT is delayed. Early diagnosis and treatment are essential to prevent ischemic tissue complications associated with HIT.