Heparin-induced thrombocytopenia in extracorporeal membrane oxygenation-supported patients: a systematic review and meta-analysis.

BACKGROUND: In recent years, extracorporeal membrane oxygenation (ECMO) has been increasingly used in critically ill patients with respiratory or cardiac failure. Heparin is usually used as anticoagulation therapy during ECMO support. However, heparin-induced thrombocytopenia (HIT) in ECMO-supported patients, which results in considerable morbidity and mortality, has not yet been well described. This meta-analysis and systematic review aimed to thoroughly report the incidence of HIT on ECMO, as well as the characteristics and outcomes of HIT patients. METHODS: We searched the PubMed, Embase, Cochrane Library, and Scopus databases for studies investigating HIT in adult patients supported by ECMO. All studies conforming to the inclusion criteria were screened from 1975 to August 2023. Nineteen studies from a total of 1,625 abstracts were selected. The primary outcomes were the incidence of HIT and suspected HIT. RESULTS: The pooled incidence of HIT in ECMO-supported patients was 4.2% (95% CI: 2.7-5.6; 18 studies). A total of 15.9% (95% CI: 9.0-22.8; 12 studies) of patients on ECMO were suspected of having HIT. Enzyme-linked immunosorbent assay (ELISA) is the most commonly used immunoassay. The median optical density (OD) of the ELISA in HIT-confirmed patients ranged from 1.08 to 2.10. In most studies, the serotonin release assay (SRA) was performed as a HIT-confirming test. According to the subgroup analysis, the pooled incidence of HIT in ECMO patients was 2.7% in studies whose diagnostic mode was functional assays, which is significantly lower than the incidence in studies in which the patients were diagnosed by immunoassay (14.5%). Argatroban was most commonly used as an alternative anticoagulation agent after the withdrawal of heparin. Among confirmed HIT patients, 45.5% (95% CI: 28.8-62.6) experienced thrombotic events, while 50.1% (95% CI: 24.9-75.4) experienced bleeding events. Overall, 46.6% (95% CI: 30.4-63.1) of patients on ECMO with HIT died. CONCLUSION: According to our study, the pooled incidence of HIT in ECMO-supported patients is 4.2%, and it contributes to adverse outcomes. Inappropriate diagnostic methods can easily lead to misdiagnosis of HIT. Further research and development of diagnostic algorithms and laboratory assays are warranted.

A Rare Case of Argatroban-Induced Anaphylaxis in a Patient With Intermediate-High Risk Pulmonary Embolism.

Heparin-induced thrombocytopenia is a rare and potentially devastating complication of heparin therapy. Patients with an absolute indication for anticoagulation, such as those with significant pulmonary embolism, must be switched to a different anticoagulant, such as argatroban, a direct thrombin inhibitor. We report a case of anaphylaxis to argatroban in a patient who was initially on heparin for intermediate-high risk pulmonary embolism but developed suspected type II heparin-induced thrombocytopenia. This case highlights the significance of recognizing and treating anaphylactic reactions and the diagnostic challenges associated with heparin-induced thrombocytopenia.

Usefulness of bicarbonate-based Impella purge solution in a patient with heparin-induced thrombocytopenia: the first case report of long-term management in Japan.

Percutaneous mechanical circulatory support utilizing micro-axial flow pumps, such as the Impella group of devices, has become a life-saving technique in the treatment of refractory cardiogenic shock, with ever-increasing success rates. A 30-year-old man presented with acute decompensated heart failure and a severely reduced left ventricular ejection fraction (17%). Despite initial treatment with inotropic drugs and intra-aortic balloon pump support, his hemodynamic status remained unstable. Transition to Impella CP mechanical circulatory support was made on day 6 owing to persistently low systolic blood pressure. A significant decline in platelet count prompted suspicion of heparin-induced thrombocytopenia (HIT), later confirmed by positive platelet-activated anti-platelet factor 4/heparin antibody and a 4Ts score of 6 points. Argatroban was initially used as the purge solution, but owing to complications, a switch to Impella 5.0 and a bicarbonate-based purge solution (BBPS) was performed. Despite additional veno-arterial extracorporeal membrane oxygenation support on day 24, the patient, aiming for ventricular assist device treatment and heart transplantation, died from infection and multiple organ failure. Remarkably, the Impella CP continued functioning normally until the patient's demise, indicating stable Impella pump performance using BBPS. This case highlights the usefulness of BBPS as an alternative to conventional Impella heparin purge solution when HIT occurs.

Association of Metal Cations with the Anti-PF4/Heparin Antibody Response in Heparin-Induced Thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated immune response against complexes of heparin and platelet factor 4 (PF4). The electrostatic interaction between heparin and PF4 is critical for the anti-PF4/heparin antibody response seen in HIT. The binding of metal cations to heparin induces conformational changes and charge neutralization of the heparin molecule, and cation-heparin binding can modulate the specificity and affinity for heparin-binding partners. However, the effects of metal cation binding to heparin in the context of anti-PF4/heparin antibody response have not been determined. Here, we utilized inductively coupled plasma mass spectrometry (ICP-MS) to quantify 16 metal cations in patient plasma and tested for correlation with anti-PF4/heparin IgG levels and platelet count after clinical suspicion of HIT in a cohort of heparin-treated patients. The average age of the cohort (n = 32) was 60.53 (SD = 14.31) years old, had a mean anti-PF4/heparin antibody optical density [OD405] of 0.93 (SD = 1.21) units and was primarily female (n = 23). Patients with positive anti-PF4/heparin antibody test results (OD405 ≥ 0.5 units) were younger, had increased weight and BMI, and were more likely to have a positive serotonin release assay (SRA) result compared to antibody negative patients. We observed statistical differences between antibody positive and negative groups for sodium and aluminum and significant correlations of anti-PF4/heparin antibody levels with sodium and silver. While differences in sodium concentrations were associated with antibody positive status and correlated with antibody levels, no replication was performed. Additional studies are warranted to confirm our observed association, including in vitro binding studies and larger observational cohorts.

Coagulation and platelet biology at the intersection of health and disease: illustrated capsules of the 11th Symposium on Hemostasis at the University of North Carolina.

The University of North Carolina Symposia on Hemostasis began in 2002, with The First Symposium on Hemostasis with a Special Focus on FVIIa and Tissue Factor. They have occurred biannually since and have maintained the primary goal of establishing a forum for the sharing of outstanding advances made in the basic sciences of hemostasis. The 2024 11th Symposium on Hemostasis will bring together leading scientists from around the globe to present and discuss the latest research related to coagulation factors and platelet biology. In keeping with the tradition of the conference, we expect novel cross-disciplinary collaborations to result from bringing together fundamental scientists and physician-scientists from different backgrounds and perspectives. The aim of these collaborations is to springboard the next generation of important advances in the field. This year's program was designed to discuss Coagulation and Platelet Biology at the Intersection of Health and Disease. The goal is to develop a better understanding of the pathophysiologic mechanisms leading to hemostatic and thrombotic disorders as this understanding is critical for the continued development of safe and efficacious therapeutics. Included in this review article are illustrated capsules provided by our speakers that highlight the main conclusions of the invited talks.

POCUS for Thrombus: Emphasizing the Importance of Initial Point-of-Care Ultrasound in the Management of Pulmonary Thromboembolism.

Pulmonary embolism (PE) constitutes a substantial health burden among individuals in the United States. It ranks as the third most common cause of cardiovascular death aside from stroke and myocardial infarction. Diagnostic errors are common with PE as patients can present with non-specific symptoms or could be completely asymptomatic with PE being an incidental finding. Diagnostic errors can result in missed or late diagnosis of PE, which, in turn, increases health care costs, morbidity, and mortality rates. Hence, early diagnosis is crucial. Computed tomography pulmonary angiography (CTPA) remains the gold standard in PE diagnosis, despite exposure to high doses of radiation. Point-of-care ultrasound (POCUS) is an underutilized, non-invasive technique that aids in the early diagnosis of PE and can safely reduce the radiation from CTPA in cases where contraindication exists. POCUS has been shown to have a high sensitivity and specificity for early diagnosis of PE.

Interventional Therapy for Upper Extremity Phlegmasia Cerulea Dolens in a Patient With Heparin-Induced Thrombocytopenia: A Case Report.

This article presents a case of a multimorbid 63-year-old woman with chronic kidney disease and heparin-induced thrombocytopenia (HIT). Following the insertion of a central venous catheter, she developed phlegmasia cerulea dolens (PCD) in her left arm, a rare and severe complication of deep vein thrombosis (DVT). Given the severity of the case, adapting to anticoagulant contraindications or unavailability, management with catheter-directed thrombolysis and mechanical thrombectomy was made. It is concluded that catheter-directed thrombolysis and mechanical thrombectomy are valuable therapeutic alternatives in critical situations where treatment options are limited.

Paradoxical Worsening of Cerebral Venous Sinus Thrombosis Due to Heparin-Induced Thrombocytopenia: A Case Report and Literature Review.

Development of cerebral venous sinus thrombosis (CVST) is a rare manifestation of heparin-induced thrombocytopenia (HIT). Herein, we present a case in which heparin administration for primary CVST caused paradoxical worsening of CVST secondary to HIT. A 53-year-old woman diagnosed with CVST was provided with intravenous unfractionated heparin therapy. After 12 days, the patient presented tonic convulsive seizures (TCS). Subsequent magnetic resonance image (MRI) scans revealed an exacerbation of cerebral edema with a subcortical hemorrhage on the left parietal lobe. Laboratory test results revealed a significant decline in platelet count. Heparin was immediately discontinued and replaced with argatroban. The definitive diagnosis of HIT was made through the presence of HIT antibodies. The present case, in which HIT caused the secondary CVST exacerbation, is distinctly rare. Our case provides an instructive example by highlighting the potential of TCS as the first sign of HIT development during CVST treatment.

Anti-PF4 ELISA-Negative, SRA-Positive Heparin-Induced Thrombocytopenia.

Heparin products are frequently used in the inpatient setting to prevent and treat venous thromboembolism, but they simultaneously put patients at risk of developing heparin-induced thrombocytopenia (HIT). The 4Ts score determines the pretest probability of HIT. Diagnosis is made with a screening antiplatelet factor (PF4) immunoassay and the serotonin-release assay (SRA) as a confirmatory test. Anti-PF4 assays have high sensitivity (98%) but lower specificity (50%) and result in frequent false-positive tests. We present a rare case from our institution of a patient with anti-PF4-Polyanion ELISA-negative, SRA-positive HIT and describe the challenges in making a timely diagnosis in this case.

How We Interpret Thrombosis with Thrombocytopenia Syndrome?

Platelets play an important role in hemostasis, and a low platelet count usually increases the risk of bleeding. Conditions in which thrombosis occurs despite low platelet counts are referred to as thrombosis with thrombocytopenia syndrome, including heparin-induced thrombocytopenia, vaccine-induced immune thrombotic thrombocytopenia, paroxysmal nocturnal hemoglobinuria, antiphospholipid syndrome, thrombotic microangiopathy (TMA), and disseminated intravascular coagulation. TMA includes thrombotic thrombocytopenic purpura, Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (HUS), and atypical HUS. Patients with these pathologies present with thrombosis and consumptive thrombocytopenia associated with the activation of platelets and the coagulation system. Treatment varies from disease to disease, and many diseases have direct impacts on mortality and organ prognosis if therapeutic interventions are not promptly implemented. Underlying diseases and the results of physical examinations and general laboratory tests as part of a thorough workup for patients should promptly lead to therapeutic intervention before definitive diagnosis. For some diseases, the diagnosis and initial treatment must proceed in parallel. Utilization of not only laboratory tests but also various scoring systems is important for validating therapeutic interventions based on clinical information.

Double Emergency: A Case of Concurrent Heparin-Induced Thrombocytopenia and Acute Promyelocytic Leukemia.

A 48-year-old woman presented to the hospital with acute pulmonary embolism in the setting of presumed apixaban failure and was transitioned to heparin. Rapidly progressive pancytopenia prompted workup with suspicion for heparin-induced thrombocytopenia (HIT) as well as peripheral blood smear concerning for acute promyelocytic leukemia (APL). She was emergently started on non-heparin anticoagulation and transferred to start APL-directed treatment. Both HIT and APL were confirmed with serotonin release assay (SRA) and promyelocytic leukemia/retinoic acid receptor alpha (PML-RARA) fusion assay, respectively. We present this case to remark on the novelty of these two acute diseases occurring together. Each of these entities is a hematologic emergency requiring immediate treatment before disease confirmation. We explore the mechanisms by which HIT occurs and outline the parameters for managing APL in the acute setting. Furthermore, this case serves to examine the treatment considerations for needing to carefully balance the thrombotic and hemorrhagic risk of both HIT and APL, which are clinically well-known for coagulopathy. Fortunately, HIT in this patient recovered on anticoagulation without bleeding or worsening thrombosis. Furthermore, following induction and consolidation treatment for APL, she remained negative for residual disease.

High-Dose Immunoglobulin Therapy for Multiple Thromboembolism in Persisting Heparin-Induced Thrombocytopenia.

This report presents a case of an 81-year-old male with acute respiratory distress syndrome secondary to aspiration pneumonia who developed heparin-induced thrombocytopenia (HIT). His platelet count remained persistently low despite discontinuing unfractionated heparin and initiating intravenous argatroban. Multiple thromboembolisms, including a new aortic mural thrombus in the descending aorta, were observed on contrast-enhanced computed tomography (CT), resulting in a diagnosis of autoimmune HIT (aHIT). Subsequent high-dose intravenous immunoglobulin (IVIG) therapy substantially improved the platelet count and resolved thromboembolisms. This case is notable owing to the improvement of aHIT complicated by multiple thromboembolisms, including an aortic mural thrombus, following high-dose IVIG therapy. In recent years, a growing number of reports have documented the effectiveness of high-dose IVIG therapy for aHIT. However, reports on whether high-dose IVIG therapy could improve an aortic mural thrombus complicating aHIT are lacking. The successful use of high-dose IVIG therapy in the current case highlights its potential efficacy in treating aHIT complicated by multiple thromboembolisms. Further studies are required to clarify the role of IVIG in the management of aHIT with thromboembolism.

Bivalirudin as a substitute for heparin in neurointervention for patients with heparin-induced thrombocytopenia.

OBJECTIVES: Heparin-induced thrombocytopenia is a known complication of heparin exposure with potentially life-threatening sequelae. Direct thrombin inhibitors can be substituted for heparin in patients with heparin-induced thrombocytopenia that require anticoagulation. However, the use of direct thrombin inhibitors as a substitute for heparin has not been widely reported in the neuroendovascular literature. MATERIALS AND METHODS: Here we report the first use of the direct thrombin inhibitor bivalirudin in a neuroendovascular procedure as a substitute for heparin in a patient with a ruptured pseudoaneurysm and heparin-induced thrombocytopenia, and review the literature on the use of bivalirudin and argatroban for such patients. RESULTS: Bivalirudin was safely and effectively used in the case reported, with no thrombotic or hemorrhagic complications. Our literature review revealed a paucity of studies on the use of heparin alternatives, including bivalirudin, in neuroendovascular procedures in patients with heparin-induced thrombocytopenia. CONCLUSIONS: Heparin-induced thrombocytopenia is an important iatrogenic disease process in patients undergoing neuroendovascular procedures, and developing protocols to diagnose and manage heparin-induced thrombocytopenia is important for healthcare systems. While further research needs to be done to establish the full range of anticoagulation options to substitute for heparin, our case indicates bivalirudin as a potential candidate.

Challenges in the Monitoring of Therapeutic Plasma Exchange during Acute Heparin-Induced Thrombocytopenia in Adults under ECMO.

Therapeutic plasma exchange (TPE) has been proposed to remove heparin-induced thrombocytopenia (HIT) antibodies before planned thoracic surgery in patients with acute HIT and to allow brief re-exposure to heparin during surgery. In patients on extracorporeal membrane oxygenation (ECMO), simultaneous administration of TPE and alternative nonheparin anticoagulant therapies is challenging. We report 2 patients on ECMO with acute HIT who underwent repeated TPE to enable cardiothoracic surgery with the use of heparin. In both cases, serial monitoring of HIT antibody titer and heparin-induced platelet activation assay (HIPA) was performed. The effect of adding exogenous platelet factor 4 (PF4) in the HIPA was also tested. Negative anti-PF4/H IgG levels were achieved after 5 and 3 TPE sessions, respectively and patients could beneficiate from surgery with brief heparin re-exposure without any thrombotic complication. Negative HIPA results were obtained before negative anti-PF4/H IgG in one patient but remained positive in the other despite very low antibody titers. The addition of PF4 in HIPA led to more contrasted results for the two patients. Serial HIT screening including immunological and functional assays is necessary to closely monitor TPE in acute HIT patients on ECMO who require surgery. The addition of PF4 in HIPA could help detect clinically relevant platelet-activating antibodies and guide re-exposure to heparin.

A career in solving clinical-pathological conundrums: Heyde syndrome, anti-platelet factor 4 disorders, and microvascular limb ischemic necrosis.

Hematology is a clinical specialty with strong roots in the laboratory; accordingly, the lab can help solve perplexing clinical problems. This review highlights clinical-pathological conundrums addressed during my 35-year hematology career at McMaster University. Heyde syndrome is the association between aortic stenosis and bleeding gastrointestinal (GI) angiodysplasia where the bleeding is usually cured by aortic valve replacement; the chance reading of a neonatal study showing reversible deficiency of high-molecular-weight (HMW) multimers of von Willebrand factor (vWF) following surgical correction of congenital heart disease provided the key insight that a subtle deficiency of HMW multimers of vWF explains Heyde syndrome. The unusual immunobiology of heparin-induced thrombocytopenia (HIT)-a highly prothrombotic, antibody-mediated, anti-platelet factor 4 (PF4) disorder featuring rapid appearance and then disappearance (seroreversion) of the pathological heparin-dependent platelet-activating antibodies-permitted identification of key clinical features that informed development of a scoring system (4Ts) to aid in HIT diagnosis. Atypical clinical presentations of HIT prompted identification of heparin-independent anti-PF4 antibodies, now recognized as the explanation for vaccine-induced immune thrombotic thrombocytopenia (VITT), as well as VITT-like disorders triggered by adenovirus infection. Another unusual feature of HIT is its strong association with limb ischemia, including limb necrosis secondary to deep-vein/microvascular thrombosis (venous limb gangrene). The remarkable observation that supratherapeutic warfarin anticoagulation predisposes to HIT- and cancer-associated venous limb gangrene provided insight into disturbed procoagulant/anticoagulant balance; these concepts are relevant to microvascular thrombosis in critical illness (symmetrical peripheral gangrene), including a pathophysiological role for proximate "shock liver" (impaired hepatic synthesis of natural anticoagulants).

Key considerations in navigating ticagrelor's reported effect on heparin-induced thrombocytopenia functional assays in a landscape of limited data.

PURPOSE: This article discusses key considerations regarding ticagrelor's reported effect on heparin-induced thrombocytopenia functional assays, such as literature gaps and possible management strategies. SUMMARY: Limited data indicate that ticagrelor may induce false-negative results in functional assays used in the diagnosis of heparin-induced thrombocytopenia. False-negative functional assays for heparin-induced thrombocytopenia could have catastrophic consequences. The manufacturer labeling of ticagrelor now includes a warning for this potential drug-laboratory interaction. This article suggests areas that would benefit from further research and strategies in navigating this possible interaction. CONCLUSION: Clinicians should exercise caution when evaluating functional assays for heparin-induced thrombocytopenia in patients receiving ticagrelor. This article offers suggestions for future areas of research and potential management strategies.

Anti-PF4 antibodies and their relationship with COVID infection.

Detecting anti-PF4 antibodies remains the golden diagnostic method for heparin-induced thrombocytopenia (HIT) diagnosis with high sensitivity and specificity. Various lab tests detect anti-PF4 antibodies, including immunoassays and functional assays. Even with positive detection of the anti-PF4 antibody, several factors are involved in the result. The concept of anti-PF4 disorders was recently brought to light during the COVID pandemic since the development of vaccine-induced thrombotic thrombocytopenia (VITT) with the adenovirus-vectored-DNA vaccine during the pandemic. Circumstances that detect anti-PF4 antibodies are classified as anti-PF4 disorders, including VITT, autoimmune HIT and spontaneous HIT. Some studies showed a higher percentage of anti-PF4 antibody detection among the population infected by COVID-19 without heparin exposure and some supported the theory that the anti-PF4 antibodies were related to the disease severity. In this review article, we provide a brief review of anti-PF4 disorders and summarize the current studies of anti-PF4 antibodies and COVID-19 infection.

Acute coronary thrombosis due to heparin-induced thrombocytopenia following improved COVID-19 pneumonia: A case report.

A 45-year-old male with anteroseptal myocardial infarction was referred to our hospital. The patient was previously admitted to another hospital with coronavirus disease-2019 pneumonia for 2 weeks; he was discharged 2 weeks before presentation to our institution. He received conventional treatment for coronavirus disease-2019, including administration of heparin. A moderate decrease in platelet count was observed on admission, and emergent angiography was performed under a definitive diagnosis of acute coronary syndrome. The angiography revealed occlusion of the left anterior descending artery. Percutaneous coronary intervention was performed; however, the occlusion did not improve owing to persistent thrombosis in the distal left anterior descending artery. Therefore, we induced intra-aortic balloon pumping to improve coronary blood flow and obtained Thrombolysis in Myocardial Infarction grade 2 flow. Following percutaneous coronary intervention, we detected a further decrease in platelets and positivity for heparin-induced thrombocytopenia antibody, leading to the diagnosis of heparin-induced thrombocytopenia. Subsequently, oral anticoagulation was introduced, and the symptoms did not recur. Learning objective: Treatment with heparin is indicated for patients with coronavirus disease-2019 (COVID-19) because of derangement of the coagulation system. However, this approach contributes to the development of heparin-induced thrombocytopenia (HIT). We report a case of acute coronary syndrome due to HIT with COVID-19. HIT is commonly reported in patients with COVID-19. Thus, attentive monitoring of the platelet count and considering the possibility of HIT are indispensable when treating acute coronary syndrome in patients with previous history of COVID-19.

Heparin-Induced Thrombocytopenia: A Case Report Four Years After the Initiation of Maintenance Hemodialysis.

Heparin-induced thrombocytopenia type II (HIT) is a rare and serious complication of heparin exposure and is always a potential risk in hemodialysis patients who routinely receive heparin. It is particularly likely to occur during the induction phase of dialysis. However, it is known to be less prevalent in long-term maintenance dialysis. In the present study, we experienced a maintenance dialysis patient who developed HIT four years after starting dialysis. After careful diagnosis with antibodies assay and clinical scores, the patient was treated with immediate heparin interruption, argatroban administration followed by nafamostat, and simple plasma exchange, which resulted in remission. Therefore, even in the maintenance phase of hemodialysis, it is important to consider HIT in the differential diagnosis of thrombocytopenia.

Diagnosis and management of heparin-induced thrombocytopenia: third edition

This guideline updates and widens the scope of the previ-ous British Society for Haematology (BSH) Clinical guide-lines for Diagnosis and Management of Heparin-Induced Thrombocytopenia: Second Edition1 to include functional assays in the diagnosis of heparin-induced thrombocytope-nia (HIT), when to use direct-acting oral anti-coagulants, and the role of intravenous (IV) immunoglobulins and plasma exchange in the management of HIT and spontane-ous HIT.HIT is an immune-mediated, highly pro-thrombotic dis-order of platelet activation caused by pathogenic antibodies against a platelet factor 4 (PF4)­heparin complex. It is the most frequent drug-induced immune thrombocytopenia and may lead to life-threatening thrombosis. There are two distinct forms of HIT: type I, also known as heparin-asso-ciated thrombocytopenia, which is a non-immunological response to heparin treatment, mediated by a direct interac-tion between heparin and circulating platelets causing plate-let clumping or sequestration, and type II, which is immune mediated.