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Abstract: Platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies and anti-PF4 antibodies cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombocytopenia and thrombosis (VITT), respectively. Diagnostic and treatment considerations differ somewhat between HIT and VITT. We identified patients with thrombocytopenia and thrombosis without proximate heparin exposure or adenovirus-based vaccination who tested strongly positive by PF4/polyanion enzyme-immunoassays and negative/weakly positive by heparin-induced platelet activation (HIPA) test but strongly positive by PF4-induced platelet activation (PIPA) test (ie, VITT-like profile). We tested these patients by a standard chemiluminescence assay that detects anti-PF4/heparin antibodies found in HIT (HemosIL AcuStar HIT-IgG(PF4-H)) as well as a novel chemiluminescence assay for anti-PF4 antibodies found in VITT. Representative control sera included an exploratory anti-PF4 antibody-positive but HIPA-negative/weak cohort obtained before 2020 (n = 188). We identified 9 patients with a clinical-pathological profile of a VITT-like disorder in the absence of proximate heparin or vaccination, with a high frequency of stroke (arterial, n = 3; cerebral venous sinus thrombosis, n = 4), thrombocytopenia (median platelet count nadir, 49 × 109/L), and hypercoagulability (greatly elevated D-dimer levels). VITT-like serological features included strong reactivity by PIPA (aggregation <10 minutes in 9/9 sera) and positive testing in the novel anti-PF4 chemiluminescence assay (3/9 also tested positive in the anti-PF4/heparin chemiluminescence assay). Our exploratory cohort identified 13 additional patient sera obtained before 2020 with VITT-like anti-PF4 antibodies. Platelet-activating VITT-like anti-PF4 antibodies should be considered in patients with thrombocytopenia, thrombosis, and very high D-dimer levels, even without a proximate exposure to heparin or adenovirus vector vaccines., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Rapid diagnosis and treatment has improved outcome of patients with vaccine-induced immune thrombocytopenia and thrombosis (VITT). However, after the acute episode, many questions on long-term management of VITT remained unanswered., Objectives: To analyze, in patients with VITT, the long-term course of anti-platelet factor 4 (PF4) antibodies; clinical outcomes, including risk of recurrent thrombosis and/or thrombocytopenia; and the effects of new vaccinations., Methods: 71 patients with serologically confirmed VITT in Germany were enrolled into a prospective longitudinal study and followed for a mean of 79 weeks from March 2021 to January 2023. The course of anti-PF4 antibodies was analyzed by consecutive anti-PF4/heparin immunoglobulin G enzyme-linked immunosorbent assay and PF4-enhanced platelet activation assay., Results: Platelet-activating anti-PF4 antibodies became undetectable in 62 of 71 patients (87.3%; 95% CI, 77.6%-93.2%). In 6 patients (8.5%), platelet-activating anti-PF4 antibodies persisted for >18 months. Five of 71 patients (7.0%) showed recurrent episodes of thrombocytopenia and/or thrombosis; in 4 of them (80.0%), alternative explanations beside VITT were present. After further COVID-19 vaccination with a messenger RNA vaccine, no reactivation of platelet-activating anti-PF4 antibodies or new thrombosis was observed. No adverse events occurred in our patients subsequently vaccinated against influenza, tick-borne encephalitis, varicella, tetanus, diphtheria, pertussis, and polio. No new thrombosis occurred in the 24 patients (33.8%) who developed symptomatic SARS-CoV-2 infection following recovery from acute VITT., Conclusion: Once the acute episode of VITT has passed, patients appear to be at low risk for recurrent thrombosis and/or thrombocytopenia., Competing Interests: Declaration Of Competing Interests A.G. reports grants and nonfinancial support from Aspen, Boehringer Ingelheim, Merck-Sharp and Dome, Bristol-Myers Squibb (BMS), Paringenix, Bayer Healthcare, Gore Inc, Rovi, Sagent, and Biomarin/Prosensa; personal fees from Aspen, Boehringer Ingelheim, Merck-Sharp and Dome, Macopharma, BMS, Chromatec, and Instrumentation Laboratory; and nonfinancial support from Boehringer Ingelheim, Portola, Ergomed, and GTH e.V., outside the submitted work. T.T. reports personal fees and other from BMS, personal fees and other from Pfizer, personal fees from Bayer, personal fees and other from Chugai Pharma, other from Novo Nordisk, personal fees from Novartis, other from Daichii Sankyo, and other from Laboratoire français du Fractionnement et des Biotechnologies, outside the submitted work. E.L.-L. has received lecture honoraria and advisory fees from Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Portola, CSL Behring, Viatris, Werfen, Norgine, and Aspen and institutional research support from Bayer AG, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, and CSL Behring for a different research project. L.S. receives a young investigator grant of the medical faculty of the Universitätsmedizin Greifswald. There are no other competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Life-threatening heparin-induced thrombocytopenia (HIT) is treated with the alternative nonheparin anticoagulants argatroban, lepirudin, or danaparoid. Frequently, the pentasaccharide fondaparinux is used off-label., Objectives: The authors sought to investigate the safety and efficacy of the different anticoagulants for treating HIT., Methods: In a national, multicenter registry study, hospitalized patients who were diagnosed with HIT, an at least intermediate clinical HIT-risk (4Ts score ≥4 points), and received treatment with ≥1 dose of the aforementioned anticoagulants were included. Main outcome measures were the incidences of HIT-specific complications (thromboembolic venous/arterial events, amputations, recurrent/persistent thrombocytopenia, skin lesions) and bleedings., Results: Of 195 patients, 46 (23.6%), 4 (2.1%), 61 (31.3%), and 84 (43.1%) had been treated first-line with argatroban, lepirudin, danaparoid, and fondaparinux, respectively. The composite endpoint of HIT-specific complications (thromboembolic events, amputation, skin necrosis) occurred in 11.7% of patients treated with approved alternative anticoagulation and in 0.0% of fondaparinux-treated patients. The all-cause in-hospital mortality rates were 14.4% during approved alternative anticoagulation and 0.0% during fondaparinux treatment. Bleeding complications occurred in alternatively anticoagulated patients and in fondaparinux-treated patients in 6.3% and 4.8%, respectively. Post hoc analysis of clinical and laboratory features confirmed "true" HIT in at least 74 of 195 (38.0%) patients; 35 of 74 (47.3%) were treated with fondaparinux., Conclusions: Fondaparinux is effective and safe in suspected acute HIT; no HIT-specific complications occurred in the fondaparinux-treated patients, even among those with a high clinical HIT probability. Further data from randomized controlled trials are urgently needed because lepirudin was recalled from the market; danaparoid access has been limited and is not approved in the United States; and argatroban is contraindicated in patients with impaired liver function, and activated partial thromboplastin time confounding may interfere with monitoring. (Retrospective Registry of Patients With Acute Heparin-induced Thrombocytopenia Type II; NCT01304238)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: In life-threatening immune heparin-induced thrombocytopenia (HIT), treatment with an approved non-heparin anticoagulant is essential. However, off-label use with fondaparinux has been reported in the literature. The study aim was to collect data on "real-life" management of patients with suspected acute HIT regarding diagnostic and therapeutic strategies., Patients and Methods: In a national multi-centre registry study, patients with a 4T's HIT-probability score of ≥ 4 points and treatment with at least one dose of (A)rgatroban, (L)epirudin, (D)anaparoid, or (F)ondaparinux were retrospectively evaluated., Results: Of 195 patients, the 4T's scores were 4/5/6/7/8 points in 46 (23.6%)/50 (25.6%)/74 (38.0%)/13 (6.7%)/7 (3.6%) patients, respectively. During heparin therapy, 47 (24.1%) thromboembolic events, 5 (2.6%) skin lesions, 1 (0.5%) amputation, 24 (12.3%) Hb-relevant bleedings, and 2 (1.0%) fatalities occurred. A functional heparin-induced platelet activation assay was performed in 96.9%, a platelet factor 4/heparin-dependent enzyme immunoassay in 89.2%, a particle gel immunoassay in 12.3%, and a serotonin-release assay in none of the patients. Argatroban was used in 16.4%, lepirudin in 2.1%, danaparoid in 23.6%, fondaparinux in 40.0% of the patients; the sequential therapy strata were: AF (5.6%), DA (5.6%), DF (2.6%), DL (2.1%), ADF (1.5%), and DFL (0.5%)., Conclusions: The current diagnostic laboratory strategy for suspected HIT is mostly (>96%) based on the recommended 2-step strategy (immunoassay plus functional assay). However, there is a wide fondaparinux off-label use (up to 50.3%) for suspected HIT, even in those patients with a high clinical pretest probability. Efficacy and safety of fondaparinux for HIT-treatment require further evaluation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Summary Background: Recently, there has been an increasing number of reports regarding adverse skin reactions to subcutaneous heparin administration. Case series have implied that heparin-induced skin lesions are predominantly associated with life-threatening heparin-induced thrombocytopenia (HIT) in at least 22% of patients. Skin lesions, therefore, have been included in clinical scores for HIT., Objectives: To determine the association of heparin-induced skin lesions with HIT. This would have a pivotal impact on further anticoagulatory management in patients with heparin-induced skin lesions., Patients/methods: In our observational cohort study, 87 consecutive patients with heparin-induced skin lesions (85 occurring during low-molecular-weight heparin administration) were evaluated using a standardized internal protocol, including HIT diagnostics (heparin-platelet factor 4-ELISA, heparin-induced platelet activation assay), platelet count monitoring, clinical/sonographical screening for thrombosis, skin allergy testing and, if necessary, histology., Results: None of the observed heparin-induced skin lesions was due to HIT; all lesions were caused by delayed-type IV-hypersensitivity reactions (DTH) instead. Even the cutaneous reaction in one patient with concomitant HIT could be classified histologically as DTH reaction, amounting to an association of heparin-induced skin lesions and HIT in 1.2% (1/87; 95% confidence interval, 0.00-0.06)., Conclusion: Heparin-induced skin lesions associated with use of low-molecular-weight heparins do not seem to be strongly associated with a systemic immunologic reaction in terms of HIT and might rather be due to DTH reactions than due to microvascular thrombosis. Hence, we propose refining existing pretest probability scores for HIT, unless underlying causes have been clarified.

Background: Little is known about the incidence and causes of heparin-induced skin lesions. The 2 most commonly reported causes of heparin-induced skin lesions are immune-mediated heparin-induced thrombocytopenia and delayed-type hypersensitivity reactions., Methods: We prospectively examined consecutive patients who received subcutaneous heparin (most often enoxaparin or nadroparin) for the presence of heparin-induced skin lesions. If such lesions were identified, we performed a skin biopsy, platelet count measurements, and antiplatelet-factor 4 antibody and allergy testing., Results: We enrolled 320 patients. In total, 24 patients (7.5%, 95% confidence interval [CI] 4.7%-10.6%) had heparin-induced skin lesions. Delayed-type hypersensitivity reactions were identified as the cause in all 24 patients. One patient with histopathologic evidence of delayed-type hypersensitivity tested positive for antiplatelet-factor 4 antibodies. We identified the following risk factors for heparin-induced skin lesions: a body mass index greater than 25 (odds ratio [OR] 4.6, 95% CI 1.7-15.3), duration of heparin therapy longer than 9 days (OR 5.9, 95% CI 1.9-26.3) and female sex (OR 3.0, 95% CI 1.1-8.8)., Interpretation: Heparin-induced skin lesions are relatively common, have identifiable risk factors and are commonly caused by a delayed-type hypersensitivity reaction (type IV allergic response).

Heparin-induced thrombocytopenia (HIT) appears rarely in pregnant patients who are being treated with heparin. When HIT is suspected, heparin treatment should be discontinued and alternative anticoagulation should be started. The heparinoid danaparoid appears to be the drug of choice for acute treatment and prophylaxis because of its low placental permeability. Between the 12th and 36th weeks of pregnancy, either danaparoid may be continued or warfarin may be used after recovery of platelet counts. Before and during delivery, danaparoid should be preferred over warfarin in order to avoid bleeding complications in mother and infant. Hirudin should only be used when either cross-reactivity with heparin-induced antibodies or cutaneous allergy against heparinoids are observed. Postpartum warfarin seems to be the treatment of choice because breast-feeding can be continued. Alternative treatment with either danaparoid or hirudin is possible, but data on treatment with these reagents in lactating mothers are very limited.

Dispositional risk factors for developing the immune-type of heparin-induced thrombocytopenia (HIT) are yet unclear. This article presents a long-term follow-up of patients with HIT to define possible risk factors that may increase the risk of HIT. The clinical course of acute HIT was analyzed retrospectively in 52 patients with HIT. Thirteen patients died; 8 due to HIT. A follow-up investigation was performed in 28 of the remaining 39 patients 29 +/- 12 months after the onset of HIT, including genotyping for the factor V G1691A- and the prothrombin G20210A-mutation, measurement of antithrombin, protein C, protein S, factor VIII, and factor XII activity as well as the concentration of antiphospholipid antibodies. The results were compared to an age- and sex-matched control group. New thromboembolic events and re-exposure to heparin were also documented. No difference between patients and controls was observed concerning the factor V Leiden mutation, the prothrombin mutation, factor XII, antithrombin, protein S, or protein C deficiency and antiphospholipid antibodies. Increased factor VIII activity was found in 16 of 21 HIT patients compared to 4 of 21 controls (p=0.0005). New thromboembolic events developed in 5 patients within 9 months after HIT. One patient had been re-exposed to heparin 9 months after acute HIT without any complications. Increased factor VIII activity was frequently observed in patients in whom HIT developed. Thromboembolic complications within the first months after onset of HIT occurred often.

Only a few patients with heparin-induced antibodies develop heparin-induced thrombocytopenia (HIT). In this study, we investigated whether different immunglobulin classes can be used to differentiate between antibody-positive patients with and without HIT. Four different patient populations were investigated: 32 patients with the immune type of HIT with thromboembolic complications, 13 patients with HIT without thromboembolism, 24 patients with heparin-platelet factor 4 (PF4) antibodies without clinical symptoms of HIT, and 20 heparin-treated patients with thrombocytopenia caused by other reasons. In all patients the immunglobulin mixture of IgG, IgM and IgA, and the single immunglobulin classes of heparin-PF4 antibodies, were investigated. No significant differences between HIT patients with thromboembolic complications and patients with isolated HIT were found concerning the different immunglobulin classes. Antibody-positive patients with HIT had significantly higher levels of IgG antibodies than those without HIT (P < 0.05), while they did not differ concerning IgM and IgA antibodies. By determining IgG antibodies, the specificity of the enzyme-linked immunosorbent assay (ELISA) system was increased without loss of sensitivity. Heparin-PF4-IgG antibodies can identify patients at risk of developing life-threatening HIT. Future ELISAs should only include this immunglobulin class, as the determination of the antibody mixture may lead to overestimation of HIT.

The heparin-platelet factor 4-antibody assay, polyanion-platelet factor 4-antibody assay and heparin-induced platelet activation test are used for laboratory diagnosis of the immune form of heparin-induced thrombocytopenia. Fifty consecutive patients receiving heparin treatment for more than 5 days after vascular surgery were prospectively screened for heparin-induced thrombocytopenia antibodies, thrombocytopenia (daily platelet counts), deep-vein thrombosis (color-coded duplex sonography), and arterial reocclusion (clinical assessment). None of the patients developed thrombocytopenia or thrombosis in association with formation of heparin-induced thrombocytopenia antibodies. Despite the absence of clinical evidence of heparin-induced thrombocytopenia, many patients formed heparin-induced thrombocytopenia antibodies: 34% of the patients were positive in the heparin-platelet factor 4-antibody assay, 28% in the polyanion-platelet factor 4-antibody assay, 14% in the heparin-induced platelet activation test, and 54% with any of these tests. Patients predominantly developed IgM (24%) and IgA antibodies (16%), whereas IgG antibodies were found in 12% of patients. Whereas the majority of patients with positive ELISA assays had IgM and IgA antibodies, patients with a positive functional assay (heparin-induced platelet activation test) predominantly had IgG antibodies. We conclude that a high percentage of patients develop heparin-induced antibodies after vascular surgery without any clinical symptoms of heparin-induced thrombocytopenia. None of the assays therefore is predictive of the clinical manifestation of heparin-induced thrombocytopenia in asymptomatic patients. Therefore, the diagnostic specificity of both antigen and activation assays for heparin-induced thrombocytopenia appears to be relatively low in the vascular surgery patient population.

An 84-year-old patient with heparin-induced thrombocytopenia (HIT), global cardiac decompensation, and acute renal failure underwent a cardiosurgical intervention using an extracorporeal circuit. For systemic anticoagulation danaparoid (Orgaran) was applied as a heparin substitute preoperatively and maintained for systemic anticoagulation during ECC despite it being eliminated by the kidney. The postoperative recovery was prolonged due to bleeding complications. During cardiopulmonary bypass (216 min) the target level of anti-factor Xa was 1.5 UI/ml. This required continuous infusion and an occasional bolus of danaparoid. Coagulation in the extracorporeal circuit was observed twice at plasma levels below 1.4 IU/ml. There were no thromboembolic or neurologic events. We did not retransfuse blood from the extracorporeal circuit or the cardiotomy reservoir after bypass, but because elimination of danaparoid was impaired in this patient and there is no neutraliser available antifactor Xa postoperatively exceeded 0.6 IU/ml for 30 hours. Diffuse bleeding with tamponade resulted. Weaning the patient from the respirator was achieved 12 hours after the last re-exploration. From the 4th postoperative day 750 IU of danaparoid were administered twice daily subcutaneously for thrombosis prevention. On the 6th postoperative day discharge from the ICU was possible. We conclude that the application of danaparoid for cardiopulmonary bypass in patients suffering from acute renal failure may be complicated by hemorrhage.

Summary: Background: Heparins are widely prescribed for prevention and therapy of arterial and venous thromboembolic diseases. Heparin‐induced skin lesions are the most frequent adverse effect of subcutaneous heparin treatment in non‐surgical patients (7.5%‐39.8%); no data exist on surgical patients. Commonly, they are due to a delayed‐type hypersensitivity reaction (DTH), but may also be a manifestation of life‐threatening heparin‐induced thrombocytopenia (HIT). Lesions of both entities resemble initially. The risk of HIT is highest among heparin‐anticoagulated orthopedic surgery patients. Objective: To determine incidence and causes of heparin‐induced skin lesions in major orthopedic surgery patients. Methods: In a prospective cohort study, consecutive patients with subcutaneous low‐molecular‐weight heparin (LMWH) treatment were examined for cutaneous adverse effects. Further diagnostics (skin biopsy, clinical/laboratory assessment for thrombosis, bleeding, HIT, cross‐allergies) were performed. Results: Six of 316 enrolled patients (1.9%; 95% CI: 0.4%‐3.4%) developed heparin‐induced skin lesions. All were caused by a DTH reaction, and none was due to HIT or other rare heparin‐associated skin diseases. Therapeutic use (dosage) of LMWH was identified as only risk factor (odds ratio: 3.1, 95% CI: 1.4‐4.9; P = .00141). In addition to DTH, 5 thromboembolic, 4 major bleeding complications but no cases of HIT or cross‐allergies were observed. Conclusions and Clinical Relevance: Orthopedic surgery patients have—unlike non‐surgical patients—a low risk for heparin‐induced skin lesions during LMWH treatment; all lesions were due to a DTH reaction. The risk for DTH differs considerably between individual patient cohorts. No association with HIT was observed. These data help to tailor anticoagulatory treatment individually and to increase patient safety. [ABSTRACT FROM AUTHOR]