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.

Following the current guidelines, immunoassays for the diagnosis of heparin-induced thrombocytopenia (HIT) are interpreted dichotomously, with test results categorized as either positive or negative. However, the extent to which test results hold diagnostic significance across the entire dynamic range remains unclear.

We utilized data from the prospective towards precise and rapid diagnosis of heparin-induced thrombocytopenia study, comprising 1393 consecutive patients with suspected HIT, to assess the diagnostic significance of 2 heparin/platelet factor 4 immunoassay test results across their respective dynamic ranges: HemoSil Acustar HIT IgG (chemiluminescence immunoassay [CLIA]) and Lifecodes PF4 immunoglobulin G (enzyme-linked immunosorbent assay [ELISA]).

HIT diagnosis was determined by a washed platelet heparin-induced platelet activation assay. For each measurement point in the dataset, we computed likelihood ratios (LRs), sensitivities, and specificities. To provide posttest probabilities for individual test results, we calculated interval-specific LRs and integrated them into a web-based calculator.

The prevalence of HIT was 8.5% (n = 119). An LR of ≥10 was first achieved at 0.3% of the dynamic range (0.4 U/mL; CLIA) and then at 16% (0.64 optical density; ELISA). An LR of ≥100 was present at 9.4% (12 U/mL; CLIA) and 75.0% (3.0 optical density; ELISA). The slope of the linear regression line (LR ∼ dynamic range) was 9.5 (CLIA) and 0.9 (ELISA).

Despite both immunoassays showing an association between results and diagnostic significance, the strength of the association varies by assay. CLIA has a larger increase per measurement unit. Posttest probabilities for individual patients can be estimated using a web-based calculator: https://pcd-research.shinyapps.io/BayesianCalculator/.

Thrombocytopenia frequently occurs in patients before, during, and after admission to Pediatric Intensive Care Units (PICUs). In critically ill children, it is often due to multifactorial causes and can be a sign of significant organ dysfunction. This review summarizes the potential causes/mechanisms of thrombocytopenia in acutely ill children, their identification, and treatments, with special attention paid to septic patients. The mechanisms of thrombocytopenia include decreased production and sequestration, but the most common reason is increased destruction or consumption. This review specifically reviews and compares the presentation, pathogenesis, and treatment of disseminated intravascular coagulation (DIC) and the thrombotic microangiopathic spectrum (TMA), including thrombocytopenia-associated multiorgan failure (TAMOF), hemolytic uremic syndrome, and other diagnoses. The other etiologies discussed include HLH/MAS, immune thrombocytopenia, and dilutional thrombocytopenia. Finally, this review analyzes platelet transfusions, the various thresholds, and complications.

Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening adverse drug reaction with numerous diagnostic challenges. Diagnosis of HIT begins with 4T score clinical assessment, followed by laboratory testing for those not deemed low risk. Laboratory testing for HIT includes screening [enzyme-linked immunosorbent assay (ELISA)] and confirmatory [serotonin release assay (SRA)] assays, wherein SRA testing can be pursued following a positive ELISA result. These tests aid diagnosis of HIT, but also introduce interpretive challenges, additional costs, and delays in clinical intervention.

A retrospective review of 1011 HIT ELISA and 169 SRA tests performed over 5 years was conducted. ELISA percent inhibition and ELISA low-heparin optical density (OD) were evaluated for positive predictive value (PPV). Based on these findings, HIT ELISA reporting and management algorithm changes were implemented and metrics compared for 5 months pre- and post-intervention to assess intervention success.

Equivocal and positive HIT ELISA interpretation showed poor PPV based on percent inhibition (0.20 and 0.32, respectively). However, rising low-heparin OD correlated with increasing PPV (PPV of 0.00 for OD values 0.40-1.00, 0.29 for values 1.00-1.99, and 0.91 for values >2.00). Data-driven intervention decreased ELISA positivity rates (13% to 5%), decreased rates of SRA confirmatory testing overall (13% to 9%), decreased SRA testing rates for patients with non-negative ELISAs (78% to 43%), and increased heparin resumption (20% to 57%). Hematology consults remained relatively stable (78% and 86%).

Low-heparin OD-based HIT ELISA interpretation yielded enhanced PPV compared with percent inhibition-based interpretation. Implementation of data-driven changes improved testing stewardship and clinical management for patients with non-negative ELISAs.

The increased interest in anti-platelet factor 4 (PF4)-heparin complex (anti-PF4/H) antibodies following the COVID-19 pandemic has established them as crucial players in immunothrombosis.

We aimed to investigate the involvement of anti-PF4/H antibodies during COVID-19 and after vaccination, particularly in patients with systemic inflammatory disease (SID).

This retrospective study analyzed the presence of anti-PF4/H antibodies and their ability to induce platelet activation in COVID-19 patients with and without suspected heparin-induced thrombocytopenia (HIT), vaccine-induced immune thrombotic thrombocytopenia (VITT) patients, and in controls and SID patients following COVID-19 vaccination.

No significant increase in anti-PF4/H antibody levels was observed during COVID-19 regardless of disease severity. Despite a 2-fold increase in HIT suspicion observed during the pandemic, there was no corresponding increase in HIT diagnoses. Additionally, no significant increase in anti-PF4/H levels was noted after vaccination, even in SID patients. None of the positive anti-PF4/H antibodies detected in COVID-19 or vaccination cohorts induced platelet activation, measured by soluble P-selectin levels and flow cytometry-based on platelet microvesicle generation. Finally, in VITT patients, unlike in HIT patients, anti-PF4/H levels were strongly associated with platelet microvesicle assay and moderately with soluble P-selectin levels.

Our study found no significant increase in anti-PF4/H antibodies in COVID-19 or after vaccination, including in SID patients. However, in VITT patients, but not in HIT patients, these antibodies were correlated with platelet activation. This finding suggests that anti-PF4/H antibodies play a different role in the pathophysiology of VITT but that their interest is limited outside clear contexts of HIT/VITT suspicion.

Although heparin-induced thrombocytopenia (HIT) presents management challenges for any population, it adds complexity to the management of certain patient populations, including those undergoing cardiac surgery and those with refractory HIT and/or acute bleeding. For each of these scenarios, we review alternative management strategies when standard therapies-heparin cessation and the initiation of a nonheparin anticoagulant-are either insufficient or not practicable. In patients with HIT undergoing cardiac surgery, we review the clinical experience for heparin reexposure using therapeutic plasma exchange (TPE) or antiplatelet therapy. In patients with refractory HIT despite adequate nonheparin anticoagulation, we address the use of intravenous immune globulin, TPE, and rituximab. Finally, in patients with active bleeding, we discuss bleeding management and the risks associated with platelet transfusion. Although they may facilitate a patient-centered approach, most of these strategies are supported by limited evidence.

We report a rare case of heparin-induced thrombocytopenia with thrombosis (HITT) following treatment for May-Thurner syndrome complicated by deep vein thrombosis (DVT), which resulted in venous stent thrombosis. A 27-year-old male with acute left lower-limb DVT successfully underwent thrombolysis and stenting for May-Thurner syndrome. However, the patient developed recurrent thrombosis and thrombocytopenia 3 days post-procedure. HITT was confirmed by a positive antiplatelet factor 4-heparin antibody test. After discontinuing heparin, the patient was successfully treated with fondaparinux, followed by repeat thrombectomy and thrombolysis, and then transitioned to warfarin. This is the second reported case of venous stent thrombosis due to HITT in May-Thurner syndrome. This case underscores the importance of early recognition and prompt management of HITT using alternative anticoagulants like fondaparinux to prevent complications such as venous limb gangrene. Further randomized controlled trials are required to evaluate the safety and efficacy of fondaparinux in HITT.

To investigate the safety and efficacy of direct oral anticoagulants (DOACs) in the treatment of the acute phase of heparin-induced thrombocytopenia (HIT).

A systematic review of the literature was conducted on PubMed, MEDLINE, Embase, and Web of Science Core Collection through July 2023. Search terms included "heparin-induced thrombocytopenia AND direct-oral-anticoagulants" in addition to a list of oral anticoagulants. Adult patients who used direct oral anticoagulants as the initial treatment for the acute phase of HIT were included. A total of 1,188 articles were initially identified, with 770 articles reviewed following removal of duplicates. Following the application of inclusion and exclusion criteria, 12 articles were ultimately included. Rivaroxaban was the most-utilized DOAC (28 patients), followed by apixaban (7 patients) and dabigatran (1 patient). All patients with thrombocytopenia demonstrated successful platelet recovery, with two patients presenting with normal platelet counts. One patient developed a deep venous thrombosis with no other new or recurrent thromboses. There were no reported clinically significant adverse events in any patient. Obstacles and deterrents to the use of the standards of care in the acute phase of HIT exist. Argatroban and bivalirudin require intravenous infusion and require close aPTT monitoring and dose adjustment. Fondaparinux requires injection and is contraindicated with body weight <50kg. DOACs would offer the novel ability for an oral treatment in the treatment of the acute phase HIT and allow for minimal monitoring and consistent dosing strategies. Therefore, DOACs are an intriguing choice for the treatment of the acute phase of HIT.

Data from 12 publications and across 36 patients suggests that the use of DOACs in the acute phase of HIT may be a safe and efficacious treatment option with favorable ease of monitoring and management.

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.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-Like Receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA (mtDNA).

We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially-available indirect inhibitors and a proprietary, selective direct small molecule inhibitor.

We employed two independent cohorts of patients with IPF, multiple in vitro fibroblast cell culture platforms, an in vivo mouse model, and an ex vivo human precision cut lung slices system to investigate the clinical and biologic significance of TLR9 in this disease.

In two independent IPF cohorts, plasma mtDNA activates TLR9 in a manner associated with the expression of MCP-1, IL-6, TNFα, and IP-10 and worsened transplant-free survival. Our cell culture platform showed that TLR9 mediates fibroblast activation via TGFβ1 and stiff substrates, and that its antagonism, particularly direct inhibition, ameliorates this process, including production of these TLR9 associated pharmacodynamic endpoints. We further demonstrated that direct TLR9 inhibition mitigates these fibroproliferative responses in our in vivo and ex vivo models of pulmonary fibrosis.

In this novel study, we found that direct TLR9 inhibition mitigates fibroproliferative responses in preclinical models of pulmonary fibrosis. Our work demonstrates the therapeutic potential of direct TLR9 antagonism in IPF and related fibrotic lung diseases.

Heparin-induced thrombocytopenia (HIT) is a life- and limb-threatening immune-mediated emergency classically associated with heparin therapy. This review focuses on type II HIT, characterized by the development of antibodies against platelet-factor 4 (PF4) bound to heparin after exposure, causing life-threatening thrombocytopenia, arterial thrombosis, and/or venous thrombosis. The high morbidity and mortality rates emphasize the need for early recognition and urgent intervention with discontinuation of heparin and initiation of non-heparin anticoagulation. We discuss the management of HIT with an emphasis on recent developments: (i) incorporating the phases of HIT (i.e., suspected, acute, subacute A and B, and remote) into its management, categorized according to platelet count, immunoassay, and functional assay results and (ii) direct-acting oral anticoagulants (DOACs), which are increasingly used in appropriate cases of acute HIT (off-label). In comparison to parenteral options (e.g., bivalirudin and danaparoid), they are easier to administer, are more cost-effective, and obviate the need for transition to an oral anticoagulant after platelet recovery. We also identify the knowledge gaps and suggest areas for future research.

Cardiogenic shock (CS) is associated with high mortality. Patients treated for CS mostly require heparin therapy, which may be associated with complications such as heparin-induced thrombocytopenia (HIT). HIT represents a serious condition associated with platelet decline and increased hypercoagulability and remains a poorly researched field in intensive care medicine. Primary purpose of this study was to: 1) determine HIT prevalence in CS, 2) assess the performance of common diagnostic tests for the workup of HIT, and 3) compare outcomes in CS patients with excluded and confirmed HIT.

Retrospective dual-center study including adult patients 18 years old or older with diagnosed CS and suspected HIT from January 2010 to November 2022.

Cardiac ICU at the Ludwig-Maximilians University hospital in Munich and the university hospital of Bonn.

In this retrospective analysis, adult patients with diagnosed CS and suspected HIT were included. Differences in baseline characteristics, mortality, neurologic and safety outcomes between patients with excluded and confirmed HIT were evaluated.

In cases of suspected HIT, positive screening antibodies were detected in 159 of 2808 patients (5.7%). HIT was confirmed via positive functional assay in 57 of 2808 patients, corresponding to a prevalence rate of 2.0%. The positive predictive value for anti-platelet factor 4/heparin screening antibodies was 35.8%. Total in-hospital mortality (58.8% vs. 57.9%; p > 0.999), 1-month mortality (47.1% vs. 43.9%; p = 0.781), and 12-month mortality (58.8% vs. 59.6%; p > 0.999) were similar between patients with excluded and confirmed HIT, respectively. Furthermore, no significant difference in neurologic outcome among survivors was found between groups (Cerebral Performance Category [CPC] score 1: 8.8% vs. 8.8%; p > 0.999 and CPC 2: 7.8% vs. 12.3%; p = 0.485).

HIT was a rare complication in CS patients treated with unfractionated heparin and was not associated with increased mortality. Also, HIT confirmation was not associated with worse neurologic outcome in survivors. Future studies should aim at developing more precise, standardized, and cost-effective strategies to diagnose HIT and prevent complications.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic condition induced by platelet-activating IgG antibodies that recognize PF4/heparin complexes. Diagnosis of HIT relies on enzyme immunologic assays (EIAs) and functional assays [serotonin release assay (SRA)]. Our institution uses a latex immunoturbidimetric assay (LIA), which has shown a positive-predictive value (PPV) of 55.6%, and a negative-predictive value (NPV) of 99.7%. The low PPV of EIAs/LIAs, in combination with the clinical delay in obtaining results of a SRA, commonly leads to a false-positive diagnosis of HIT and inappropriate treatment. We performed a single-institution retrospective study at a large tertiary center to assess patient management decisions and economic costs following a false-positive HIT (LIA) test. This study found an 89.5% incidence of false-positive HIT (LIA) tests. 97.4% of patients underwent anticoagulation changes. 69.6% of patients were switched to argatroban. Of patients with a false-positive HIT immunoassay (LIA), 42 (40.7%) patients were on a prophylactic dose of anticoagulation at the time of HIT (LIA) positivity, of which 22 (52.4%) were switched to full anticoagulation with either argatroban or fondaparinux. Of the 22 patients switched to full anticoagulation, 15 (68%) had low-probability 4T scores. Seven (8.8%) of patients had bleeding events after HIT (LIA) positivity. All seven patients were switched to argatroban from a full-dose heparin anticoagulation. Five of the seven patients were considered major bleeds. Utilization of argatroban incurred substantial costs, estimated at approximately $73 000 for false-positive HIT cases. False-positive HIT (LIA) tests contribute to unwarranted anticoagulation changes, increased bleeding risks, and substantial healthcare costs. Incorporating the 4T score into diagnostic algorithms may help mitigate these risks by guiding appropriate clinical decisions. Future research should focus on refining diagnostic approaches and standardizing management strategies to improve patient outcomes and cost-effectiveness in HIT diagnosis and management.

We report the case of a 61-year-old female who developed heparin-induced thrombocytopaenia following treatment of a submassive pulmonary embolism, and who then required an above knee amputation for critical limb ischaemia. Heparin-induced thrombocytopaenia is a rare, immune-mediated complication associated with an in-hospital mortality rate of 10%. It is more common in surgical patients, with patients undergoing orthopaedic surgery more likely to develop it than patients undergoing cardiac surgery, but heparin-dependent immunoglobulin G antibodies are more likely to be formed in the latter. Peri-operative management remains a challenge. Ideally, it is preferable to wait for the platelet count to improve; but in certain cases, surgery cannot be delayed. Heparin-induced thrombocytopaenia is usually managed with direct thrombin inhibitors, such as argatroban and bivalirudin. Newer therapeutic modalities, such as plasmapheresis and intravenous immunoglobulin, as used in this case, can rapidly remove antibodies, but the certainty of evidence is low. Our case adds to the literature regarding the use of these modalities and highlights the multidisciplinary team approach required to manage such complex cases.

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.

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.

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.

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.

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.

Heparin-induced thrombocytopenia can occur in obese subjects. The medical comorbidities associated with obesity may contribute to the pathogenesis of this disease. It is unknown, however, which specific medical comorbidities and if higher odds of thrombosis are present in obese heparin-induced thrombocytopenia patients. We sought to determine whether obese heparin-induced thrombocytopenia subjects had higher odds of both comorbidities and thrombosis, hypothesizing that this patient population would have higher odds of both these conditions.

This was a multi-center retrospective study utilizing TriNetX©, an electronic health record database, in subjects aged 18-99 years diagnosed with heparin-induced thrombocytopenia. The cohort was divided into two groups (1) non-obese (body mass index < 30 kg/m2) and (2) obese (body mass index ⩾ 30 kg/m2). We evaluated patient characteristics, diagnostic, laboratory, medication, and procedure codes.

A total of 1583 subjects (696 (44.0%) non-obese and 887 (56.0%) obese) were included. Obese subjects had higher odds of diabetes with complications (OR = 1.73, 95% CI = 1.35-2.22, p < 0.001) and without complications (OR = 1.81, 95% CI = 1.47-2.22, p < 0.001). This association was still present after correcting for demographic and clinical factors. There were no increased odds of thrombosis observed in the obesity group.

Our study found that obese heparin-induced thrombocytopenia subjects had higher odds of having a diabetes mellitus comorbidity, but did not have higher odds of thrombosis. Given obesity is considered a hypercoagulable state, further study may be needed to understand why obese subjects diagnosed with heparin-induced thrombocytopenia do not have higher rates of thrombosis.

Cardiac surgery is a high-risk setting for heparin-induced thrombocytopenia (HIT). However, large differences in its incidence, rate of thrombotic complications, and mortality have been reported in this context. Few studies address the pharmacologic management of HIT specifically in this setting.

To describe the incidence, outcomes, and management of patients with HIT in our cohort and to compare them with patients presenting platelet factor 4/heparin antibodies but without platelet-activating capacity.

A retrospective observational study was conducted over a period of 10 years and 6 months on 13,178 cardiac operations in a single high-volume cardiac surgery center.

HIT was diagnosed in 0.22% of patients. HIT with associated thromboembolic complications occurred in 0.04% of cases. Two deaths at 30 days were registered, both in patients with associated thrombosis. The 4T score showed a 99.9% negative predictive value. The immunoglobulin G-specific chemiluminescence test positivity rate was highly predictive of HIT. Warfarin was often started early after surgery, and although it was rarely stopped when the diagnosis of HIT was made, no new thromboembolic complications subsequently occurred. Thrombocytopenia appeared to be a poor prognostic sign, whatever the cause.

Although rare, HIT is characterized by high mortality in this setting, especially if thrombotic complications occur. Large multicentric studies or an international registry should be created to enhance the scientific evidence on HIT diagnosis and management in this context.

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).

Only some studies have directly compared and analyzed the roles of activated partial thromboplastin time (aPTT) and activated clotting time (ACT) in coagulation monitoring during argatroban administration.

This study aims to assess the correlation of argatroban dose with ACT and aPTT values and to identify the optimal coagulation test for argatroban dose adjustment.

We evaluated 55 patients on extracorporeal membrane oxygenation (ECMO) who received argatroban for more than 72 hours. The correlation between argatroban dose and aPTT and ACT values was evaluated. To compare argatroban dose and bleeding events according to liver dysfunction, the patients were divided into 2 groups based on alanine aminotransferase and total bilirubin.

Among the 55 patients, a total of 459 doses and coagulation tests were evaluated. The aPTT and ACT values showed a weak correlation with argatroban dose, with the Pearson correlation coefficients of 0.261 (P < 0.001) and 0.194 (P = 0.001), respectively. The agreement between the target 150 to 180 seconds for ACT and 55 to 75 seconds for aPTT was observed in 140 patients (46.1%). Twenty-four patients (43.6%) had liver dysfunction when they started argatroban. The median argatroban dose was lower in the liver dysfunction group than in the control group (0.094 mcg/kg/min vs 0.169 mcg/kg/min, P = 0.020). Difference was not observed between the 2 groups in the amount of red blood cell (0.47 vs 0.43 pack, P = 0.909) and platelet (0.60 vs 0.08 pack, P = 0.079) transfusion per day.

A weak correlation was observed between argatroban dose and the aPTT and ACT values. However, the agreement between aPTT and ACT was only 46.1% regarding the scope of target range. Further research is necessary to determine how to assess the optimal argatroban dose for patients administered argatroban while undergoing ECMO at the intensive care unit.

Heparin-induced thrombocytopenia (HIT) is a life-threatening condition that requires urgent diagnostic clarification. However, knowledge of the diagnostic utility of the recommended diagnostic tests is limited in clinical practice.

To evaluate the current diagnostic practice for managing the suspicion of HIT.

This prospective diagnostic study was conducted from January 2018 to May 2021 among consecutive patients with suspected HIT from 11 study centers in Switzerland, Germany, and the United States. Detailed clinical data and laboratory information were recorded. Platelet factor 4/heparin antibodies were quantified using an automated chemiluminescent immunoassay (CLIA). A washed-platelet heparin-induced platelet activation (HIPA) test was used as a reference standard to define HIT.

Suspicion of HIT.

The primary outcome was the diagnostic accuracy of the 4Ts score, the CLIA, and the recommended algorithm serially combining both tests.

Of 1448 patients included between 2018 and 2021, 1318 were available for the current analysis (median [IQR] age, 67 [57-75] years; 849 [64.6%] male). HIPA was positive in 111 patients (prevalence, 8.4%). The most frequent setting was intensive care unit (487 [37.0%]) or cardiovascular surgery (434 [33.0%]). The 4Ts score was low risk in 625 patients (46.8%). By 2 × 2 table, the numbers of patients with false-negative results were 10 (9.0%; 4Ts score), 5 (4.5%; CLIA), and 15 (13.5%; recommended diagnostic algorithm). The numbers of patients with false-positive results were 592 (49.0%; 4Ts score), 73 (6.0%; CLIA), and 50 (4.1%; recommended diagnostic algorithm), respectively.

In this diagnostic study of patients suspected of having HIT, when the recommended diagnostic algorithm was used in clinical practice, antibody testing was required in half the patients. A substantial number of patients were, however, still misclassified, which could lead to delayed diagnosis or overtreatment. Development of improved diagnostic algorithms for HIT diagnosis should be pursued.

We present a unique case of delayed-onset, profound eptifibatide-induced thrombocytopenia that occurred 5 days after initiation of the drug.

Eptifibatide is a platelet glycoprotein IIb/IIIa receptor inhibitor with indications for use in patients with acute coronary syndromes. Eptifibatide-induced thrombocytopenia is uncommon but well studied and typically occurs within 24 hours of initiation of the drug. In the case described here, a 62-year-old male with a past history of coronary artery disease (including percutaneous coronary intervention within the past 12 months) was started on eptifibatide at a dosage of 2 µg/kg per minute for management of significant thrombus burden prior to a planned cardiac revascularization procedure; heparin for anticoagulation was also initiated. About 5 days after initiation of eptifibatide, the patient developed severe thrombocytopenia, with the platelet count dropping precipitously from 249 × 103/µL on admission to less than 1 × 103/µL. After eptifibatide and heparin therapy were discontinued and the patient was switched to argatroban, the platelet count recovered to 38 × 103/µL over the next 2 days. An eptifibatide platelet antibody assay was positive for IgG-mediated reactions consistent with eptifibatide-induced thrombocytopenia. Scoring of this case with the Naranjo scale yielded a score of 4, suggesting a possible adverse reaction to eptifibatide.

This is the first published case report of profound eptifibatide-induced thrombocytopenia occurring more than 24 hours after eptifibatide initiation and serves to bring awareness that a delayed reaction can occur.

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.

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.

(1) Background: Extracorporeal membrane oxygenation (ECMO) is a complex procedure affecting both the risk of thrombosis and bleeding. High-quality data to personalize anticoagulation management in ECMO are lacking, resulting in a high variability in practice among centers. For this reason, we review coagulation methods and monitoring and share a pragmatic proposal of coagulation management, as performed in our high-volume ECMO Referral Centre; (2) Methods: We revised the anticoagulation options and monitoring methods available for coagulation management in ECMO through PubMed search based on words including "anticoagulation," "coagulation assays," "ECMO," "ELSO," and "ISTH"; (3) Results: Actual revision of the literature was described as our routine practice regarding ECMO anticoagulation and monitoring; (4) Conclusions: No coagulation test is exclusively predictive of bleeding or thrombotic risk in patients undergoing ECMO support. An approach that allows for a tailored regimen of anticoagulation (regardless of agent used) and monitoring is mandatory. To accomplish this, we propose that the titration of anticoagulation therapies should include multiple laboratory tests, including anti-Xa, aPTT, ACT, viscoelastic tests, AT levels, platelet count, fibrinogen, and FXIII levels. Anticoagulation regimens should be tailored to a specific patient and personalized based on this complex array of essays.

The aim of this study was to determine an optimal cutoff value for the newly available HemosIL-AcuStar-HIT-IgG assay (AcuStar) for the diagnosis of heparin-induced thrombocytopenia (HIT).

We evaluated the performance of AcuStar using serotonin release assay (SRA) as the gold standard and incorporated 4T score calculation in a cohort of suspected HIT cases. Statistical analysis was performed to determine optimal cutoff value for the diagnosis of HIT.

A diagnosis of HIT can be excluded with a platelet factor 4 (PF4) value of <0.4 U/mL by AcuStar and 4T score in the low-risk category (≤3). All other cases will require confirmation with a functional test.

Our study resulted in the implementation of a diagnostic algorithm for laboratory diagnosis of HIT, which incorporates pretest calculation of 4T score and AcuStar as a screening test, with reflex confirmation by SRA. This new algorithm resulted in extended hours of test availability and a more rapid turnaround time in reporting PF4 results.

Heparin-induced thrombocytopenia (HIT) an immunologically mediated reaction to heparin products, can lead to severe thrombocytopenia and potentially life-threatening thrombotic events. In microsurgery, a missed or delayed diagnosis of HIT can cause complications requiring revision operations, flap loss, or limb loss. Surgeons must remain vigilant for this uncommon yet potentially devastating condition and keep abreast of management strategies.

CPT and ICD-10 codes in electronic medical records were used to collect demographic information, clinical courses, and outcomes for patients with a HIT diagnosis who underwent lower extremity free tissue transfer in one institution.

The authors' institution performed 415 lower extremity free flaps in 411 patients during the 10-year study period. Flap salvage rate was 71% for compromised lower extremity flaps without HIT, and 25% in those with HIT. Four patients (four flaps) met study inclusion criteria during the study period. Three of the four flaps failed and were later debrided; one was rescued after a takeback for anastomosis revision. Two patients successfully underwent a delayed second free flap procedure after recovery, and one was salvaged with a pedicled muscle flap.

Surgeons should monitor for HIT by establishing coagulation panel and platelet count baselines and trending these values in the early post-operative period for patients treated with heparin products. The 4T score can be used to screen for HIT with high clinical suspicion. Arterial thrombosis or poor flap perfusion despite sound microvascular technique could suggest HIT. Surgical and medical management including strict heparin avoidance can prevent adverse events for these patients.

We report the case of a woman who developed post-transfusion purpura following complicated cardiac surgery requiring multiple blood product transfusions and extracorporeal life support. This case highlights the challenges of managing thrombocytopenia in patients supported with prolonged mechanical cardiovascular and renal support with ongoing blood product transfusion requirements. The differential diagnoses are broad, varied and may overlap. Whilst post-transfusion purpura is very rare, clinical signs may prompt consideration and further specific diagnostic testing. Once confirmed, management is then specific, with some aspects which are at direct variance with standard intensive care and extracorporeal life support guidelines for the management of non-specific thrombocytopenia. Consideration of the diagnosis of post-transfusion purpura early in the clinical course could help anticipate and prevent a vicious cycle of bleeding, transfusion and autoimmune-mediated platelet disruption, and may improve clinical outcomes.

Thrombocytopenia is a rare but serious complication of the intravenous glycoprotein IIb/IIIa (GPIIb/IIIa; integrin αIIbβ3) receptor inhibitors (GPIs), abciximab, eptifibatide, and tirofiban. The thrombocytopenia ranges from mild (50 000-100 000 platelets/μL), to severe (20 000 to <50 000/μL), to profound (<20 000/μL). Profound thrombocytopenia appears to occur in <1% of patients receiving their first course of therapy. Thrombocytopenia can be either acute (<24 hours) or delayed (up to ~14 days). Both hemorrhagic and thrombotic complications have been reported in association with thrombocytopenia. Diagnosis requires exclusion of pseudothrombocytopenia and heparin-induced thrombocytopenia. Therapy based on the severity of thrombocytopenia and symptoms may include drug withdrawals and treatment with steroids, intravenous IgG, and platelet transfusions. Abciximab-associated thrombocytopenia is most common and due to either preformed antibodies or antibodies induced in response to abciximab (delayed). Readministration of abciximab is associated with increased risk of thrombocytopenia. Evidence also supports an immune basis for thrombocytopenia associated with the 2 small molecule GPIs. The latter bind αIIbβ3 like the natural ligands and thus induce the receptor to undergo major conformational changes that potentially create neoepitopes. Thrombocytopenia associated with these drugs is also immune-mediated, with antibodies recognizing the αIIbβ3 receptor only in the presence of the drug. It is unclear whether the antibody binding depends on the conformational change and whether the drug contributes directly to the epitope. Zalunfiban, a second-generation subcutaneous small molecule GPI, does not induce the conformational changes; therefore, data from studies of zalunfiban will provide information on the contribution of the conformational changes to the development of GPI-associated thrombocytopenia.

Thrombocytopenia in ill children is common; accurately diagnosing the underlying etiology is challenging and essential for appropriate management. Triggers for accelerated consumption of platelets are numerous; common downstream mechanisms of clearance include platelet trapping in microvascular thrombi, phagocytosis, and platelet activation. Thrombocytopenia with microangiopathic hemolytic anemia (MAHA) is frequently due to disseminated intravascular coagulation. Thrombotic microangiopathy (TMA) is a subgroup of MAHA. Specific TMA syndromes include thrombotic thrombocytopenic purpura, complement-mediated TMA (CM-TMA), and Shiga toxin-mediated hemolytic uremic syndrome. Isolated thrombocytopenia is characteristic of immune thrombocytopenia; however, concomitant cytopenias are frequent in critically ill patients, making the diagnosis difficult. Immune thrombocytopenia with large vessel thrombosis is a feature of heparin-induced thrombocytopenia and antiphospholipid antibody syndrome. In addition, thrombocytopenia is common with macrophage activation, which is characteristic of hemophagocytic lymphohistiocytosis. While thrombocytopenia in ill patients can be driven by hypoproliferative processes such as myelosuppression and/or bone marrow failure, this review will focus on consumptive thrombocytopenia due to immune and nonimmune causes.

To identify risk factors and develop a pretest scoring system to differentiate patients with heparin-induced thrombocytopenia (HIT) in the mechanical circulatory support (MCS) population. The authors present a modified "4TMCS" scoring system, which considers the "type of mechanical circulatory support" that may help identify patients at risk for developing postoperative HIT.

A retrospective cohort study. Patients who underwent cardiac surgery were categorized into 3 groups: (1) normal platelet count, (2) thrombocytopenia with a negative HIT test, and (3) thrombocytopenia with a positive HIT test. A comparison of diagnostic accuracy between the 4Ts and 4TMCS probability scores was performed.

At a single adult tertiary-care center.

A total of 5,314 patients who underwent cardiac surgery between May 1, 2008 and December 31, 2016.

None.

In total, 125 out of 5,314 patients (2.4%) were diagnosed with HIT, of whom 75 out of 5,314 (1.4%) had clinical evidence of thrombosis. Overall, in-hospital mortality was 25.6%, 11.7%, and 1.5% in the HIT(+), HIT(-), and control groups, respectively (p < 0.001). Mechanical circulatory support was associated with a significantly increased risk for HIT, with an incidence of 5.9% in patients receiving MCS versus 1.9% in those without (p < 0.001). Area under the receiver operator curve (AUC) analysis demonstrated improved diagnostic accuracy of the 4TMCS score compared with the 4Ts (AUC = 0.83 v 0.77, p < 0.044). The 4TMCS score had higher sensitivity than the 4Ts, using the guideline-recommended score cutoff of ≥4 (95.2% v 85.7%).

Heparin-induced thrombocytopenia is associated with worse outcomes and increased morbidity and mortality in the MCS population. Awareness of patient risk factors and the application of a modified 4TMCS probability score may allow for more accurate screening and treatment of HIT in the MCS population.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated drug reaction that can cause thromboembolism in the setting of thrombocytopenia. An enzyme-linked immunosorbent assay (ELISA)-based assay to screen for HIT antibodies (HAb) is available but has relatively low specificity and a correspondingly high false positive rate. The 4Ts score has been validated to determine the pretest probability of HIT. The authors hypothesized that an electronic health record (EHR)-based clinical decision support (CDS) tool incorporating the 4Ts score would reduce the volume of HAb orders.

After implementing a CDS tool into the EHR, the researchers retrospectively evaluated the impact from November 2019 to October 2021, compared to a preintervention period (January to October 2019). The primary outcome was average tests per month. Secondary outcomes included rates of tests ordered per total inpatient encounters and proportion of HAb sent despite low 4Ts score in the postintervention study period.

Of 1,833 HAb sent during the study period, 1,217 occurred in the postintervention period. In the postintervention period compared with the preintervention period, the average orders per month was 50.5 (standard deviation [SD] 9.7) vs. 61.6 (SD 7.2) (p = 0.003), and the order incidence rate was 8.0 per 1,000 patient encounters postintervention vs. 9.2 per 1,000 patient encounters preintervention (rate ratio [RR] 0.87, 95% confidence interval [CI] 0.79-0.96, p = 0.002). Postintervention, 252 (20.7%) had a 4Ts score calculated as low probability, 759 (62.4%) as intermediate probability, and 131 (10.8%) as high probability, and 75 had no associated 4Ts score.

Implementation of a simple CDS tool reduced the rate of HAb orders, reducing unnecessary HAb testing.

Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of heparin therapy (both unfractionated heparin and low-molecular-weight heparin). In our study, we examined a group of 122 patients with suspected HIT. The samples of all patients were analyzed in the first step using an immunoassay (ID-PaGIA Heparin/PF4, Hemos1L-Acustar HIT IgG, ZYMUTEST HIA Monostrip IgG) to detect the presence of antibodies against heparin-PF4 complexes (platelet factor 4). When the immunoassay was positive, the sample was subsequently analyzed for HIT with a functional flow cytometry assay, the HITAlert kit, the purpose of which was to demonstrate the ability of the antibodies present to activate platelets. A diagnosis of HIT can be made only after a positive functional test result. In this article, we present an overview of our practical experience with the use of the new functional method of analysis, HIT, with flow cytometry. In this work, we compared the mutual sensitivity of two functional tests, SRA and the flow cytometry HITAlert kit, in patients perceived as being at risk for HIT. This work aims to delineate the principle, procedure, advantages, pitfalls, and possibilities of the application of the functional test HITAlert using flow cytometry.

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated immune response against platelet factor 4 (PF4) bound to heparin anticoagulants. A priori identification of patients at-risk for HIT remains elusive and a number of risk factors have been identified, but these associations and their effect sizes have limited validation in large cohorts of suspected HIT patients. The aim of this study was to investigate existing anti-PF4/heparin antibody thresholds and model the relationship of demographic variables and anti-PF4/heparin antibody levels with functional assay positivity across multiple institutions in the absence of detailed clinical data. In a large collection of suspected HIT patients (n = 8904), we tested for associations between laboratory and demographic variables and functional assay positive status as well as anti-PF4/heparin antibody levels. We also tested for correlation between IgG-specific and polyspecific (IgG/IgA/IgM) anti-PF4/heparin antibody values and their ability to predict functional assay positive status using area under the receiver operating characteristic (AUROC). Logistic regression identified increasing anti-PF4/heparin antibody OD levels (OR = 51.84 [37.27-74.34], p < 2.0 × 10-16) and female sex (OR = 1.47 [1.19-1.82], p = 3.5 × 10-4) as risk factors for positive functional assay in the largest cohort with consistent effect sizes in two other cohorts. In a subset of 1175 patients, polyspecific and IgG-specific anti-PF4/heparin antibody values were heterogeneous (mean coefficient of variation = 31.9 %), but strongly correlated (rho = 0.878; p < 2 × 10-16) with similar prediction of functional assay positivity (polyspecific AUROC = 0.976 and IgG-specific AUROC = 0.980). Thus, we recapitulate previously identified risk factors of functional assay positivity, providing precise effect sizes in a large observational population of suspected HIT patients. Our data reinforce the necessity of functional assay confirmation and suggest that, despite heterogeneity, polyspecific and IgG-specific anti-PF4/heparin antibody assays predict functional assay positive status similarly, even in the absence of 4Ts scores and detailed clinical data.

Heparin-induced thrombocytopenia (HIT) is a life-threatening, immune-mediated complication following heparin exposure and is considered to be the most severe adverse reaction to heparin treatment that is not associated with bleeding. Development of autoantibodies against platelet factor 4 (PF4) - heparin complex constitutes the basis of the pathophysiological changes in patients suffering from HIT, which then binds to the surface of platelets and monocytes, thus provoking their activation and subsequent aggregation, ultimately leading to the formation of thrombosis. Formation of arterial and venous thrombosis is aggravated by the simultaneous activation of platelets and monocytes with a substantial mortality rate. The incidence of HIT is reported to be significantly lower in pediatric patients compared with adults. Diagnosis of HIT in pediatric population remains a clinical entity supplemented by laboratory evaluation. The positive predictive value of laboratory evaluation is further elevated by the use of scoring systems and predictive models used for hastening the diagnosis of HIT. Use of alternative anticoagulants like direct thrombin inhibitors and factor Xa inhibitors form the mainstay of treatment in cases of HIT, however, more prospective studies would be required in the pediatric population to delineate definitive guidelines for proper management of patients in this age-group. This article delivers diagnostic and treatment approach in case of patients with HIT, wherein the pathophysiology, clinical manifestations, diagnostic approach and the management of patients with HIT has been described.

Avacopan is a novel C5a receptor antagonist recently approved for the treatment of microscopic polyangiitis and granulomatosis with polyangiitis. To our knowledge, thrombocytopenia induced by avacopan has not been reported. We report a case of a 78-year-old man with microscopic polyangiitis who developed rapidly progressive glomerulonephritis (RPGN) and vasculitis neuropathy. After developing RPGN, he was treated with prednisolone, which was ineffective. As the dosage of corticosteroids was decreased, he developed impaired dorsiflexion of the left ankle, tingling and numbness in his feet, consistent with vasculitis neuropathy. After a 3-day administration of methylprednisolone, we started avacopan and prednisolone 20 mg/d to reduce the corticosteroid dosage. One week after starting avacopan, platelet counts began to decrease, eventually leading to the cessation of the drug. The possibility of thrombotic microangiopathy and heparin-induced thrombocytopenia was considered unlikely given the clinical course and laboratory studies. After 3 weeks of avacopan cessation, platelet counts began to increase, suggesting avacopan as the most probable cause of thrombocytopenia. Our case highlights the importance of postmarketing surveillance of avacopan to identify its adverse events that were not reported in clinical trials to ensure its safe use. Clinicians should carefully monitor platelet counts when using avacopan.