Perioperative Plasma Exchange and Intravenous Immunoglobulin Use for Refractory Heparin-Induced Thrombocytopenia in a Liver Transplant Recipient

Background

Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening complication of heparin therapy, which can lead to a life-threatening prothrombotic state [1]. It is divided into 2 types. HIT type 1 is characterized by a mild and transient drop in platelet count within the first 4 days of heparin treatment, which spontaneously recovers without intervention. HIT type 2 is characterized by immune-mediated thrombocytopenia 4–15 days after initial heparin exposure, which is caused by antibodies against platelet factor 4 (PF4) bound to heparin. This paradoxically leads to a prothrombotic state [1–3]. The diagnosis can be challenging in some cases. To aid in the diagnosis of HIT, the 4T score, which is a clinical scoring system, is used along with confirmatory laboratory tests such as heparin-PF4 antibodies and serotonin release assays (SRAs). Unlike heparin-PF4 antibodies, SRA detects platelet activation and is considered the functional criterion standard test for HIT diagnosis [3–5].

Treatment of HIT requires the immediate cessation of all heparin products and initiation of non-heparin anticoagulants and/or potent antiplatelet agents (such as cangrelor) to prevent thromboembolic events [3]. Bivalirudin and argatroban are 2 direct thrombin inhibitors commonly used in HIT, since their onset of action is immediate and their elimination half-life is short (25 and 60 min, respectively) [6]. Typically, 7 days of non-heparin anticoagulation permits platelet recovery in 90% of cases [6,7]. However, in rare cases, despite appropriate HIT treatment, platelet-activating antibodies persist for more than 7 days after heparin is discontinued and cause “persisting/refractory HIT” [4]. These patients have more severe and prolonged thrombocytopenia, with a higher risk of developing disseminated intravascular coagulation (DIC) [4,8]. Since refractory HIT is refractory to conventional anticoagulation therapy, it necessitates advanced treatments such as plasma exchange (PLEX) and intravenous immunoglobulin (IVIG) [8,9]. PLEX removes anti-PF4 antibodies, while IVIG blocks Fcγ receptors on platelets, subsequently reduces platelet activation (decreases SRA), stabilizes platelet count, and reduces the risk thromboembolic events [10–12].

HIT is more common after major surgeries, particularly orthopedic, vascular, and cardiac surgeries. This is likely due to the activation of endothelial cells, the release of PF4 from intraoperatively activated platelets, and the perioperative administration of heparin [8,11]. For this reason, non-urgent or elective surgeries should be postponed until antibodies are undetectable and the platelet count has recovered. In patients with persistent positive antibody assay and in cases where significant bleeding precludes the use of therapeutic anticoagulation, HIT management becomes even more challenging [4,6,11]. Investigators recently focused on treating HIT with high-dose IVIG in these groups of patients, since IVIG inhibits

HIT reaction, has no additional bleeding risk, and its effect lasts more than approximately 1 week and thereby covers the critical early postoperative period [13].

Herein we report our experience in managing a case of refractory HIT in a liver transplant recipient that did not tolerate argatroban treatment (due to GI bleeding) and did not respond to PLEX and IVIG. Previously, perioperative PLEX and IVIG were used a few times for the treatment of refractory HIT. Nevertheless, our patient is the first reported experience of perioperative PLEX and IVIG administration for the treatment of refractory HIT in a liver transplant recipient. This case report along with previously reported cases may guide clinicians to find a proper treatment for refractory HIT in urgent surgery candidates.

Case Report

A 57-year-old man with a past medical history of hypertension, diabetes mellitus type 2, complicated alcoholic cirrhosis, and hepatocellular carcinoma underwent deceased donor liver transplantation (DDLT) in December 2022. The postoperative course was complicated with acute kidney injury that required hemodialysis and atrial fibrillation with a rapid ventricular response that required cardioversion. He was also severely hypotensive and diagnosed with septic shock that required broad-spectrum antibiotics and vasopressor infusion. An extensive clinical assessment did not detect any clear source of infection and the transplant team decided to perform an exploratory laparotomy, abdominal washout, and liver biopsy. The pathology report revealed moderate portal mixed inflammation with neutrophilic infiltrate, mild duct injury with marked ductular proliferation, cholestasis, and focal portal venulitis, suggesting mild acute cellular rejection with rejection activity index (RAI) 3 of 9, but no morphological features of antibody-mediated rejection.

The patient received subcutaneous heparin for deep venous thrombosis (DVT) prophylaxis before and after surgery. The baseline platelet count was 92×103/μL (ref 150–450×103/μL) prior to DDLT, which dropped to 9×103/μL on the eighth day after surgery. He did not have any petechiae but had scattered bruising on his extremities and episodic oozing at vascular access sites. Thrombocytopenia was thought to be multifactorial from splenic sequestration, bone marrow suppression due to septic shock, and prolonged alcohol consumption, and adverse effects of medications such as antibiotics and immunosuppressants. Other notable laboratory findings included prothrombin time 19.9 s (ref 9.6–12.4 s), activated partial thromboplastin time 78.1 s (ref 23.0–32.0 s), fibrinogen 65 mg/dL (ref 150–440 mg/dL), and D-dimer 6.9 (ref <0.50 mg/L FEU). He received several units of blood product transfusions. Peripheral blood smear showed rare schistocytes, spur cells, and low platelet count with no platelet clumping or giant platelets. Ultimately, he was diagnosed with DIC and HIT based on a 4T score of 5 points and positive confirmatory tests including heparin-induced platelet antibody (HIPA) and SRA. HIPA was strongly positive with an optic density (OD) of 2.76 and SRA of 95% and 97% with 0.1 and 0.5 IU/mL of unfractionated heparin, respectively (normal value <20%). For this reason, heparin was stopped immediately and argatroban was initiated after the diagnosis of HIT.

On day 20 after his first transplant surgery, further assessment revealed he had also developed DVT involving the right femoral vein and bilateral pulmonary embolism. Unfortunately, severe thrombocytopenia persisted and the presence of anti-PF4 antibodies continued despite the cessation of heparin and initiation of argatroban (platelets count was 15 000/μL on day 23 after surgery). Therefore, he was diagnosed with refractory HIT. Meanwhile, total bilirubin and liver enzymes gradually increased. Repeated liver biopsy showed moderate inflammation with mixed populations of lymphocytes and neutrophils and significant cholestasis. Trichrome stain highlighted portal fibrous expansion and focal bridging fibrosis (stages 2–3 of 4). He was treated for liver rejection with 1 dose of methylprednisolone 500 mg IV followed by a taper over 7 days. However, an abdominal ultrasound did not visualize hepatic arterial flow, and abdomen computed tomography angiography (CTA) confirmed hepatic artery thrombosis, which subsequently resulted in failure of the transplanted liver (Figure 1).

After a multidisciplinary team assessment, the decision was made to proceed with a second DDLT 30 days after the first transplant. Meanwhile, ongoing refractory HIT necessitated advanced therapeutic interventions and he underwent 2 sessions of PLEX before surgery to decrease the level of HIPA in the blood. He also received 1 dose of IVIG 1 g/kg 1 day before and an additional dose during the surgery. Postoperative SRA was negative, and HIPA was initially negative on postoperative day 1, then was weakly positive 1 week afterward. Argatroban was continued, but it was stopped when he had melena and hemoglobin drop to 4.2 g/dl (ref 12–16 g/dl). The patient underwent esophagogastroduodenoscopy (EGD), which did not identify the source of the bleeding. The abrupt elevation of liver enzymes and total bilirubin was a concern for recurrent hepatic artery thrombosis. Abdominal CTA demonstrated hepatic artery stenosis with multiple subcapsular hypodense areas consistent with liver infarct. Therefore, he underwent urgent catheter-directed intra-arterial thrombolysis and started another course of IVIG 0.5 gr/kg/day for 4 doses, but there was minimal improvement in arterial flow. Despite all available therapeutic interventions, the hepatic artery thrombosis resulted in liver transplant failure for the second time. The patient developed hemorrhagic shock and required a massive blood transfusion and a maximum dose of 3 vasopressors. He eventually had a cardiac arrest and died 1 month after his second liver transplant.

Discussion

Thromboembolic events (including hepatic vein thrombosis) have been previously reported as a complication of HIT [14]. However, our patient is the first reported case of hepatic artery thrombosis as a complication of persistent HIT in a liver transplant recipient. The American Society of Hematology (ASH) guidelines [15] recommend argatroban and bivalirudin as the best anticoagulant options in acute HIT. In the case of argatroban use, the ASH guideline suggests dose adjustment to achieve aPTT 1.5–3.0 times baseline (ref 25–32 s), as well as dose reduction in patients with liver dysfunction (bilirubin >1.5 mg/dL). Nevertheless, there are no published recommendations for the treatment of patients with refractory HIT, and the treatment strategies recently used in this group of patients are limited to PLEX and IVIG [16].

Recent studies have recommended PLEX use in HIT [15] and more reports in the literature have indicated a trend toward increased IVIG and/or PLEX use in HIT over time [17]. Treatment of refractory HIT with PLEX and IVIG was associated with a higher likelihood of inpatient mortality, major bleeding, GI bleeding, and infection. However, this is confounded by the fact that these treatments are usually used in patients with more advanced diseases who are refractory to conventional treatments [13,17]. The optimal regimen for PLEX treatment is still unknown. Multiple PLEX sessions may be needed in the case of active thrombosis in the perioperative period and/or strongly positive HIPA, such as our patient experienced. Nevertheless, PLEX may have adverse effects such as hemodynamic instability that can limit its use [3].

The use of IVIG in severe HIT was first published by Frame et al [18] in 1989. They presented the case of a 62-year-old woman with severe HIT complicated by extensive venous thromboembolism, who had an excellent response 3 days after high-dose IVIG treatment. Although multiple studies later reported experiences of IVIG use in refractory HIT [2,8,9], they were single cases or small case series. The dosage of IVIG varied in different studies according to the patient’s characteristics and the risk of thrombosis, but the most common IVIG dose administered was 1 g/kg per day [9,12,19]. High-dose IVIG mostly resulted in an abrupt increase in platelet count to >100×103/μL in 50–70% of patients within 3 days, but the platelet-inhibitory effect of IVIG was transient, with a return to a strong positive SRA after 1 week [2,4,16,19,20].

Treatment of refractory HIT in patients undergoing urgent surgery is even more challenging since it requires a careful balance of bleeding and thrombotic risks. Recently IVIG has been used in patients with HIT undergoing various surgeries such as lung transplants [21], left ventricular assist device (LVAD) placement [3,22], vascular surgery [20], and heart transplant [11]. In 2018, Warkentin et al [20] presented the case of a 59-year-old man who developed refractory HIT after heparin exposure during vascular surgery, and he later required an urgent revascularization. Therefore, he received 1 dose of IVIG 9 h before surgery and a second dose was given during the surgery. The surgery was successful, without thrombotic complications or recurrent thrombocytopenia. Later, Mandernach et al [21] described another case of HIT in a patient with end-stage lung disease who needed an urgent lung transplant and intraoperative heparin use. Preoperative treatment with PLEX and IVIG led to successful lung transplantation without the development of subsequent HIT. In another study [23], the strategy of combined treatment with PLEX and IVIG was used in 3 consecutive patients with HIT on temporary mechanical circulatory support awaiting an urgent heart transplant. This approach allowed safer use of heparin during cardiopulmonary bypass.

Although most of the previously published experiences successfully treated cases with refractory HIT, most of these studies may have been under the influence of “positive-result bias,” in which studies with positive findings are more likely to be published than studies with negative or neutral results. This publication bias can confound interpretation of the efficacy and safety of treatments in case report [24]. In our patient with refractory HIT, there was insufficient time to await SRA negativity before surgery. Therefore, the multidisciplinary team planned multiple immunomodulatory therapies to reduce the risk of recurrent thrombosis.

Conclusions

This case report along with previous reported cases may guide clinicians who need to treat patients with HIT undergoing urgent surgeries. Few previous studies [3,11,20–22] have assessed the safety and efficacy of IVIG and/or PLEX use in this group of patients. However, to our knowledge, we are the first to report perioperative IVIG and PLEX use in liver transplant surgery. Although the refractory HIT persisted despite advanced treatment with PLEX and IVIG in our case, further investigation with more patients may be necessary to provide conclusive information. Cases should be selected cautiously since IVIG has a Food and Drug Administration (FDA) black box warning for increasing the risk of thrombosis in some of the potential predisposing states such as prolonged immobilization, and use of estrogens [7,25]. Nevertheless, the benefits of IVIG may outweigh the risks of thrombosis. Moreover, several previous HIT-related studies [4,9,25] revealed no thrombotic events using IVIG. Although our patient and some previous cases experienced a thrombosis after IVIG treatment, it is not clear whether these were adverse reactions to IVIG or a complication of prolonged refractory HIT.