scholarly journals Adenovirus-Vectored COVID-19 Vaccine–Induced Immune Thrombosis of Carotid Artery: A Case Report

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012576
Author(s):  
Uwe Walter ◽  
Mario Fuchs ◽  
Annette Grossmann ◽  
Michael Walter ◽  
Thomas Thiele ◽  
...  
Keyword(s):  
Elevated Serum ◽  
Igg Antibodies ◽  
Laboratory Findings ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Carotid Bulb ◽  
Arterial Thromboembolic Events ◽  
Favorable Clinical Outcome ◽  
Acute Headache ◽  
Carotid Arterial

Objective:Venous thromboses and thrombocytopenia after vaccination with the adenovirus-vectored COVID-19 vaccine ChAdOx1 nCov-19 (AstraZeneca) have been linked to serum antibodies against platelet factor 4 (PF4)–polyanion complexes. We here report vaccine-induced isolated carotid arterial thrombosis.Methods:Imaging and laboratory findings, treatment decisions and outcome of this case are presented.Results:Eight days after having received the first dose of ChAdOx1 nCov-19 vaccine, a 31-year-old man was admitted to our stroke unit with acute headache, aphasia, and hemiparesis. D-dimers were slightly elevated, but platelet count and fibrinogen level were normal. MRI-confirmed mainstem occlusion of middle cerebral artery resolved within 1 hour after start of IV thrombolysis. A wall-adherent, non-occluding thrombus in the ipsilateral carotid bulb was identified as the source of embolism. Cardiac or paradoxical (venous) embolism was excluded. Screening for presence of heparin-induced thrombocytopenia-related antibodies was positive, and highly elevated serum IgG antibodies against PF4–polyanion complexes were subsequently proven. Treatment with aspirin and subcutaneous danaparoid, followed by phenprocoumon, led to thrombus shrinkage and dissolution within 19 days, and favorable clinical outcome.Discussion:Vaccine history is important in patients not only with venous but also with arterial thromboembolic events. Vaccine-induced immune thrombosis of brain-supplying arteries may well be handled.

Prediction of Heparin Induced Thrombocytopenia: Validation of an Experience-Based Computer Model.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3226-3226
Author(s):  
Nicole L. Whitlatch ◽  
David F. Kong ◽  
Thomas L. Ortel
Keyword(s):  
Predictive Accuracy ◽  
Medical Center ◽  
Confirmatory Test ◽  
Multivariate Logistic Regression Model ◽  
Clinical Value ◽  
Laboratory Findings ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Duke University ◽  
Heparin Exposure

Abstract Background: Diagnosis of heparin-induced thrombocytopenia (HIT) requires certain clinical features along with the detection of platelet activating antibodies induced by heparin interaction with platelet factor 4 (PF4). Although the PF4 enzyme-linked immunoassay (ELISA) is a highly sensitive laboratory test, it is not specific. Adding excess heparin to the sample can confirm a positive PF4 ELISA result when it decreases antibody binding by 50% or more, potentially improving the specificity of the assay. We sought to determine the clinical value of the PF4 ELISA and confirmatory test by developing a predictive algorithm for HIT. Methods: We retrospectively identified 116 patients with positive anti-PF4/heparin antibodies at Duke University Medical Center in 2005. We collected data on all patients to allow for clinical classification as HIT positive or HIT negative. HIT positive patients had at least a 30% decline in platelet count after 4–14 days of heparin exposure, or within 48 hours if recent (within last 100 days) heparin exposure. Anti-PF4/heparin antibody titers were determined by ELISA using a confirmatory step with excess heparin. A multivariate logistic regression model was fitted to the 2005 data, to estimate the relationship between patient characteristics (including age, gender, race, and clinical service), laboratory findings (including peak PF4 titer, confirmatory positive status), and clinical HIT status (HIT positive versus HIT negative). The model was then validated on an independent sample of 97 patients with positive anti-PF4/heparin antibodies retrospectively identified at Duke University Medical Center from January to July of 2006. Results: We found no significant relationship between age, race, or gender and clinical HIT status. In multivariate analysis, the peak PF4 titer and confirmatory positive status were independent predictors of HIT. Figure 1 depicts median, 25th, and 75th percentiles of the predicted probabilities for the HIT-positive and HIT-negative patients in the 2005 training and 2006 test populations. The predictive accuracy on the 2005 training set (c-index 0.783, Somer’s Dyx 0.566) was maintained when the algorithm was applied to the independent 2006 test population (c-index 0.799, Somer’s Dyx 0.597). Figure 2 depicts the ROC curves for both patient populations. Conclusions: This is the first study to our knowledge that has demonstrated the clinical utility of the Heparin/PF4 ELISA confirmatory test for the diagnosis of HIT. Based upon the PF4 ELISA and confirmatory assays, a predictive computer algorithm can distinguish patients likely to have HIT from those who are not. Accurate predicted probabilities of HIT will enable clinicians to more rapidly initiate appropriate therapy. Figure Figure Figure Figure

scholarly journals Anti–platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3791-3796 ◽  
Author(s):  
Theodore E. Warkentin ◽  
Richard J. Cook ◽  
Victor J. Marder ◽  
Jo-Ann I. Sheppard ◽  
Jane C. Moore ◽  
...  
Keyword(s):  
Cross Reactivity ◽  
Platelet Factor 4 ◽  
Low Molecular Weight ◽  
Igg Antibodies ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Antithrombotic Prophylaxis ◽  
High Concentrations ◽  
To Receive

Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating IgG antibodies that recognize platelet factor 4 (PF4) bound to heparin. Immunogenicity of heparins differs in that unfractionated heparin (UFH) induces more anti–PF4/heparin antibodies than low-molecular-weight heparin (LMWH) and UFH also causes more HIT. Fondaparinux, a synthetic anticoagulant modeled after the antithrombin-binding pentasaccharide, is believed to be nonimmunogenic. We tested 2726 patients for anti–PF4/heparin antibodies after they were randomized to receive antithrombotic prophylaxis with fondaparinux or LMWH (enoxaparin) following hip or knee surgery. We also evaluated in vitro cross-reactivity of the IgG antibodies generated against PF4 in the presence of UFH, LMWH, danaparoid, or fondaparinux. We found that anti–PF4/heparin antibodies were generated at similar frequencies in patients treated with fondaparinux or enoxaparin. Although antibodies reacted equally well in vitro against PF4/UFH and PF4/LMWH, and sometimes weakly against PF4/danaparoid, none reacted against PF4/fondaparinux, including even those sera obtained from patients who formed antibodies during fondaparinux treatment. At high concentrations, however, fondaparinux inhibited binding of HIT antibodies to PF4/polysaccharide, indicating that PF4/fondaparinux interactions occur. No patient developed HIT. We conclude that despite similar immunogenicity of fondaparinux and LMWH, PF4/fondaparinux, but not PF4/LMWH, is recognized poorly by the antibodies generated, suggesting that the risk of HIT with fondaparinux likely is very low.

A New Approach in the Study of the Molecular and Cellular Events Implicated in Heparin-induced Thrombocytopenia

2001 ◽  
Vol 85 (06) ◽  
pp. 1090-1096 ◽  
Author(s):  
Mahnouch Khairy ◽  
Dominique Lasne ◽  
Brigitte Brohard-Bohn ◽  
Martine Aiach ◽  
Francine Rendu ◽  
...  
Keyword(s):  
Heparin Therapy ◽  
Dependent Manner ◽  
Common Complication ◽  
Igg Antibodies ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
New Approach ◽  
Cellular Events ◽  
Healthy Donors ◽  
Antigenic Complex

SummaryHeparin-induced thrombocytopenia (HIT), a relatively common complication of heparin therapy, results of platelet activation, via the receptor for the Fc domain of IgG (FcγRIIa), by heparin-dependentantibodies, commonly directed against the heparin-platelet factor 4 (H-PF4) antigenic complex. Our strategy was to use whole blood allowing the study of leukocyte-platelet interactions. Experiments were performed with blood from healthy donors incubated with HIT patients’ plasma and different concentrations of heparin. We showed that 75% of the HIT patients’ plasma induced the formation of leukocyteplatelet-aggregates in a heparin-dependent-manner. The formation of leukocyteplatelet-aggregates induced by HIT plasma in the presence of heparin was (i) independent of the healthy blood donor FcγRIIa polymorphism, (ii) correlated with the levels of anti H-PF4 IgG antibodies contained in the patients’ plasma, and to a lesser extent to anti H-PF4 IgM antibodies, and (iii) was mediated by P-selectin. This report opens new prospects in the study of the molecular and cellular events implicated in HIT.

Serological features of antibodies to protamine inducing thrombocytopenia and thrombosis

2015 ◽  
Vol 53 (2) ◽  
Author(s):  
Simon Panzer ◽  
Arno Schiferer ◽  
Barbara Steinlechner ◽  
Ludovic Drouet ◽  
Jean Amiral
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Thromboembolic Event ◽  
Significant Proportion ◽  
Thromboembolic Events ◽  
Igg Antibodies ◽  
Binding Properties ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Blood Samples

AbstractA significant proportion of patients undergoing cardiopulmonary bypass develop anti-protamine antibodies, with or without the association of thromboembolic events.We extensively investigated the serological features of protamine antibodies, which developed in six patients who were clinically suspected to have heparin-induced thrombocytopenia (HIT). Three patients had thrombotic events. Sera were tested by four different commercially available immunoassays, a heparin-platelet aggregation test, and for their binding properties to heparin, platelet factor 4 (PF4), complex heparin-PF4, protamine, and protamine complex with heparin. Sera from four patients were also tested for the capability to induce platelet activation and the formation of platelet-monocyte heterotypic aggregates.The ELISA assay Zymutest HIA was strongly positive in all cases, the HPIA Asserachrome was borderline, and the gel centrifugation test PaDGIA was positive in two tested patients. Platelet aggregation tests were negative. Using a variation of the Zymutest HIA we demonstrate that IgG antibodies bound only to protamine or protamine complex with heparin, but not to heparin or PF4 only. Sera-induced platelet P-selectin expression and the formation of platelet-monocyte aggregates. Blood samples from one patient proofed positive concomitantly with the thromboembolic event. However, serological characteristics did not differ between antibodies associated with thromboembolic events from those without.These data show that protamine-induced antibodies are specific and may induce platelet activation, which explains their association with thromboembolic events.

Heparin-Induced Thrombocytopenia Antibody Is More Common in Patients with Active Bacterial Infections

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4678-4678
Author(s):  
Melody Smith ◽  
Prapti A. Patel ◽  
Jonathan E Dowell ◽  
Eugene P. Frenkel ◽  
Ravindra Sarode ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Subgroup Analysis ◽  
Bacterial Infections ◽  
Conflicts Of Interest ◽  
Igg Antibodies ◽  
Platelet Factor ◽  
Platelet Surface ◽  
Heparin Induced Thrombocytopenia ◽  
E Coli ◽  
Significant Difference

Abstract Abstract 4678 Heparin mobilizes and binds to platelet factor 4 (PF4), forming a heparin-PF4 complex on the platelet surface. Rarely, IgG antibodies recognize and bind to the immune complex, causing platelet activation and thrombin generation, resulting in heparin induced thrombocytopenia (HIT). There is evidence that PF4 has a role in antibacterial host defense and can concurrently prime the immune system with IgG antibodies that can cross-react with the heparin-PF4 complex (Krauel et al, Blood 2011). In the setting of a bacterial infection, the PF4 molecules interact with the bacterial cell wall and induce antibody production. These antibodies are able to recognize any bacteria coated in PF4, resulting in phagocytosis. In the setting of heparin, this antibody can cross react with the heparin-PF4 complex and result in HIT. In vitro studies suggest that E. coli, S. pneumo, and S. aureus coated in PF4 cross-react with human heparin induced anti-PF4/heparin antibodies. We have collected a database of patients being tested for HIT at our institution and performed a retrospective analysis of the incidence of bacterial infections. We hypothesize that patients who have a bacterial infection will be more likely to develop HIT due to anti-bacterial antibodies that cross-react with the heparin-PF4 complex. We collected culture data from 54 patients with positive HIT antibody by ELISA and 178 patients with negative HIT antibody. The incidence of positive cultures and active infections in described in table 1. In the HIT negative patients, 61/178 (34.3%) had positive cultures, compared to 28/54 (51.9%) in the HIT positive patients (p=0.0198). Given that there is data to support E. coli, S. pneumo, and S. aureus-induced antibody cross-reactivity, we performed a subgroup analysis of the incidence of these specific bacterial infection in HIT positive and negative patients (33.3% versus 19.7%, p=0.0357). There is a statistically significant difference noted in the active infections, subgroup analysis, as well presence of any positive cultures in the HIT positive patients as compared to the HIT negative patients.Table 1Colonized Infections (%)Active Infections (%)E. coli, S. pneumo, S. aureus (%)Any + culture (%)HIT negative (n=178)15 (8.4)61 (34.3)35 (19.7)66 (37.1)HIT positive (n=54)2 (3.7)28 (51.9)18 (33.3)29 (53.7)p value0.2420.01980.03570.0293 This data supports that in the setting of active infection, particularly with E. coli, S. pneumo, and S. aureus, HIT antibody results should be carefully evaluated. Patients with positive cultures are likely to have thrombocytopenia from infection or sepsis, regardless of the presence of a HIT antibody. Thus, additional factors, such as the patient's 4T score and the presence of thrombosis should be considered prior to initiating treatment for HIT. Disclosures: No relevant conflicts of interest to declare.

A Human Antibody, Cloned from a Patient with Heparin-Induced Thrombocytopenia, That Binds Heparin/Platelet Factor 4 Complexes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 58-58
Author(s):  
Scott K. Dessain ◽  
Katherine E. Rybinski ◽  
Sharad P. Adekar ◽  
Lubica Rauova ◽  
Bruce S. Sachais ◽  
...  
Keyword(s):  
B Cells ◽  
Venous Thrombosis ◽  
Cell Line ◽  
Platelet Factor 4 ◽  
Human Antibody ◽  
Fusion Partner ◽  
Igg Antibodies ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Human Antibodies

Abstract In heparin-induced thrombocytopenia (HIT), patients receiving heparin develop IgG antibodies that bind complexes formed between heparin and platelet factor 4 (PF4). Most patients are asymptomatic, but some develop life- and limb-threatening arterial or venous thrombosis. We previously described a transgenic mouse model of HIT that demonstrated four factors are necessary and sufficient to recapitulate the clinical manifestations of HIT with thrombosis: heparin, human PF4, a heparin/PF4 antibody, and platelet activation via FcγRIIA. We hypothesize that specific quantitative and qualitative characteristics of heparin/PF4 antibodies determine which patients with HIT will develop thrombosis. Because heparin/PF4 antibodies isolated from patients with HIT are generally polyclonal and heterogeneous, it has been impossible to directly test this hypothesis. We recently developed a novel means of cloning human antibodies, in which we fuse primary human B-cells to a murine cell line that ectopically expresses human telomerase (hTERT) and murine interleukin-6 (mIL-6). This method readily generates heterohybridoma cells that stably secrete human antibodies. We have used this method to clone human heparin/PF4 antibodies from patients with HIT and thrombosis. We identified a patient with clinical HIT, exhibiting a heparin-dependent drop in platelet counts, plasma heparin/PF4 IgG antibodies by ELISA, and a deep venous thrombosis. We fused peripheral blood lymphocytes from this patient to our novel fusion partner cell line, and isolated 2 independent hybridomas that express IgM antibodies that strongly bind heparin/PF4 complexes. We assayed the specificity of the cloned antibodies by testing serial dilutions for heparin/PF4 binding activity by ELISA. Each cloned antibody bound heparin/PF4 with an absorbance >2X background at dilutions that ranged from 1:32–1:64, whereas three negative control antibodies gave no detectable binding at dilutions of 1:2 or greater. cDNA sequencing indicated that both antibodies have the same heavy chain sequences, including a novel CDR3 region, suggesting that the antibodies were derived from post-germinal center memory B-cells rather than from naive B-cells. Using recombinant DNA techniques and ectopic expression in CHO cells, we produced an IgG1 version of one of these antibodies (8E5). By ELISA, the 8E5 IgG1 antibody binds human PF4 at optimal ratio of 10 μg/ml to 0.4 U/ml of heparin (see Figure). We are currently exploring the nature of the 8E5 IgG/heparin/PF4 complex and its platelet activating/thrombotic potential. Figure Figure

A New Enzyme Immuno-Assay That Only Detects IgG Antibodies to Heparin-PF4 Complexes (Zymutest HIA IgG®) Improves the Specificity of the Diagnosis of HIT without Loss of Sensitivity.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2096-2096
Author(s):  
Claire Pouplard ◽  
Sandra Regina ◽  
Jean Baptiste Valentin ◽  
Yves Gruel
Keyword(s):  
Platelet Activation ◽  
High Specificity ◽  
Serotonin Release ◽  
Igg Antibodies ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Release Assay ◽  
Immuno Assay ◽  
Enzyme Immuno Assay ◽  
Test Probability

Abstract Heparin-induced thrombocytopenia (HIT) is associated in most patients with the development of antibodies to heparin-modified platelet factor 4 (PF4). Commercial immuno-assays frequently detect these antibodies after cardiac surgery but only few patients develop clinical HIT. Therefore, platelet activation tests such as serotonin release assay (SRA) are necessary to ensure the diagnosis of HIT with high specificity. Another approach to increase diagnosis specificity could be to detect IgG antibodies which are of major clinical relevance since they are the only class able to directly activate platelets in the presence of heparin. Therefore, we evaluated the performances of a new commercial immuno-assay specific to IgG for the diagnosis of HIT Abs (Zymutest HIA IgG®, Hyphen Biomed, Neuville sur Oise, France). Samples from 101 patients with suspected HIT were analysed. 40 cases had developed significant levels of Abs to PF4 measured with PVS/PF4 ELISA (HAT45®,GTI, Brookfiled, WI, USA) and the diagnosis of HIT had been confirmed since SRA was positive. Every sample was then tested with a global assay named Zymutest HIA G/A/M® as followed: each diluted plasma (200 μl) was incubated for 1 hour with 50 μl of platelet lysate providing PF4 into wells previously coated with unfractionated heparin. After washings and incubation (1 hour) with anti IgG/A/M-HRP immunoconjugate, the enzyme activity was developed and absorbance was read at 450nm. In case of positive result (A450 ≥ 0.5), the isotype distribution was analysed with a specific and standardized assay using monospecific anti-IgG-, anti-IgA- and anti IgM-HRP conjugates (Zymutest HIA-IgG® or -IgA® or -IgM®). A450 values ≥ 0.5 were also considered as positive. GTI assay that detected IgG/A/M Abs to PVS/PF4 complexes in the 40 patients with HIT (Ss 100%) was also positive in 30 of the 61 cases with no HIT (Sp 50.8%). Comparatively, Zymutest HIA® global assay was positive in 39 of the 40 patients with HIT (Ss 97.5%) and in 14 of 61 cases without HIT (Sp 77%). On the other hand, significant levels of heparin-dependent IgG antibodies were also measured in these 39 HIT patients using Zymutest HIA IgG® assay (mean A450: 1.81; range A450: 0.5 – 2.76), and only in 6 patients without HIT (Sp: 90%). However, IgG levels measured in patients without HIT were significantly lower (mean A450: 0.60; range A450: 0.08 – 2.20) than in those with HIT (p < 0.0001). In addition, IgA or IgM heparin-dependent antibodies were only present, i.e. without IgG, in samples from patients for whom the diagnosis of HIT had been ruled out (n = 3). In conclusion, this study supports that the detection of significant levels of IgG heparin-dependent antibodies improves the diagnosis specificity in patients with a suspicion of HIT without loss of sensitivity. Nonetheless, whether IgG-specific immunoassays could avoid to perform platelet activation tests in patients with a strong pre-test probability of HIT warrant further study.

scholarly journals Injection Site Erythema in a Patient on Therapeutic Anticoagulation with Low Molecular Weight Heparin after Mechanical Aortic Valve Replacement: A Rare Presentation of Heparin- and Protamine-Induced Thrombocytopenia

2020 ◽  
Vol 2020 ◽  
pp. 1-3 ◽  
Author(s):  
Caroline Holaubek ◽  
Paul Simon ◽  
Sabine Eichinger-Hasenauer ◽  
Franz Gremmel ◽  
Barbara Steinlechner
Keyword(s):  
Skin Necrosis ◽  
Clinical Presentation ◽  
Clinical Symptoms ◽  
Clinical Manifestations ◽  
Low Molecular Weight ◽  
Igg Antibodies ◽  
Rare Presentation ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Therapeutic Anticoagulation

Previous exposition to heparin and protamine in patients undergoing cardiopulmonary bypass and postoperative therapeutic anticoagulation with LMWH may lead to the development of heparin-induced thrombocytopenia (HIT) and/or protamine-induced thrombocytopenia (PIT). This case deals with a rare clinical presentation of circulating IgG antibodies against heparin/platelet factor 4 complexes and heparin/protamine complexes after cardiac surgery. Ensuing purpura and skin necrosis (blisters) at the injection sites of LMWH and clinical symptoms improved rapidly after replacement of LMWH by an alternative anticoagulant. The aim of this report is to draw attention to the several different clinical manifestations of heparin- and/or protamine-induced thrombocytopenia and shows a possible course of treatment and recovery.

scholarly journals Heparin-induced thrombocytopenia

Blood ◽  
2017 ◽  
Vol 129 (21) ◽  
pp. 2864-2872 ◽  
Author(s):  
Gowthami M. Arepally
Keyword(s):  
Disease Susceptibility ◽  
Clinical Manifestations ◽  
Heparin Therapy ◽  
Laboratory Findings ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Laboratory Features ◽  
Life Threatening ◽  
Pathogenic Antibodies ◽  
Heparin Exposure

Abstract Heparin-induced thrombocytopenia (HIT) is an immune complication of heparin therapy caused by antibodies to complexes of platelet factor 4 (PF4) and heparin. Pathogenic antibodies to PF4/heparin bind and activate cellular FcγRIIA on platelets and monocytes to propagate a hypercoagulable state culminating in life-threatening thrombosis. It is now recognized that anti-PF4/heparin antibodies develop commonly after heparin exposure, but only a subset of sensitized patients progress to life-threatening complications of thrombocytopenia and thrombosis. Recent scientific developments have clarified mechanisms underlying PF4/heparin immunogenicity, disease susceptibility, and clinical manifestations of disease. Insights from clinical and laboratory findings have also been recently harnessed for disease prevention. This review will summarize our current understanding of HIT by reviewing pathogenesis, essential clinical and laboratory features, and management.

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