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Vaccine-induced immune thrombotic thrombocytopaenia (VITT) is a rare adverse effect of COVID-19 adenoviral vector vaccines 1 – 3 . VITT resembles heparin-induced thrombocytopaenia (HIT) in that it is associated with platelet-activating antibodies against platelet factor 4 (PF4) 4 ; however, patients with VITT develop thrombocytopaenia and thrombosis without exposure to heparin. Here we sought to determine the binding site on PF4 of antibodies from patients with VITT. Using alanine-scanning mutagenesis 5 , we found that the binding of anti-PF4 antibodies from patients with VITT ( n  = 5) was restricted to eight surface amino acids on PF4, all of which were located within the heparin-binding site, and that the binding was inhibited by heparin. By contrast, antibodies from patients with HIT ( n  = 10) bound to amino acids that corresponded to two different sites on PF4. Biolayer interferometry experiments also revealed that VITT anti-PF4 antibodies had a stronger binding response to PF4 and PF4–heparin complexes than did HIT anti-PF4 antibodies, albeit with similar dissociation rates. Our data indicate that VITT antibodies can mimic the effect of heparin by binding to a similar site on PF4; this allows PF4 tetramers to cluster and form immune complexes, which in turn causes Fcγ receptor IIa (FcγRIIa; also known as CD32a)-dependent platelet activation. These results provide an explanation for VITT-antibody-induced platelet activation that could contribute to thrombosis. Alanine-scanning mutagenesis is used to identify the PF4 epitope that is recognized by anti-PF4 antibodies in patients with vaccine-induced immune thrombotic thrombocytopaenia, revealing that the epitope corresponds to the heparin-binding site on PF4.

Heparin-induced thrombocytopenia is a syndrome of antibody-mediated thrombocytopenia that paradoxically is often associated with thrombosis. 1 – 5 Most patients with this disorder produce IgG antibodies 6 , 7 against complexes of platelet factor 4 and heparin. 8 – 11 Platelet factor 4, a small peptide stored within the alpha granules of platelets, binds to heparin and is released into the blood during treatment with heparin. 12 In vitro, IgG–platelet factor 4–heparin complexes can activate platelets, 13 , 14 a finding that raises the possibility that platelet activation in vivo contributes to the thrombotic complications of heparin-induced thrombocytopenia. 15 , 16 Typically, heparin-induced thrombocytopenia begins with the appearance of thrombocytopenia about . . .

Coronavirus Disease 2019 (COVID-19) is a global pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While detection of SARS-CoV-2 by polymerase chain reaction with reverse transcription (RT-PCR) is currently used to diagnose acute COVID-19 infection, serological assays are needed to study the humoral immune response to SARS-CoV-2. Anti-SARS-CoV-2 immunoglobulin (Ig)G/A/M antibodies against spike (S) protein and its receptor-binding domain (RBD) were characterized in recovered subjects who were RT-PCR-positive (n = 153) and RT-PCR-negative (n = 55) using an enzyme-linked immunosorbent assay (ELISA). These antibodies were also further assessed for their ability to neutralize live SARS-CoV-2 virus. Anti-SARS-CoV-2 antibodies were detected in 90.9% of resolved subjects up to 180 days post-symptom onset. Anti-S protein and anti-RBD IgG titers correlated (r = 0.5157 and r = 0.6010, respectively) with viral neutralization. Of the RT-PCR-positive subjects, 22 (14.3%) did not have anti-SARS-CoV-2 antibodies; and of those, 17 had RT-PCR cycle threshold (Ct) values > 27. These high Ct values raise the possibility that these indeterminate results are from individuals who were not infected or had mild infection that failed to elicit an antibody response. This study highlights the importance of serological surveys to determine population-level immunity based on infection numbers as determined by RT-PCR.

The use of high-dose intravenous immune globulin (IVIG) plus anticoagulation is recommended for the treatment of vaccine-induced immune thrombotic thrombocytopenia (VITT), a rare side effect of adenoviral vector vaccines against coronavirus disease 2019 (Covid-19). We describe the response to IVIG therapy in three of the first patients in whom VITT was identified in Canada after the receipt of the ChAdOx1 nCoV-19 vaccine. The patients were between the ages of 63 and 72 years; one was female. At the time of this report, Canada had restricted the use of the ChAdOx1 nCoV-19 vaccine to persons who were 55 years of age or older on the basis of reports that VITT had occurred primarily in younger persons. Two of the patients in our study presented with limb-artery thrombosis; the third had cerebral venous and arterial thrombosis. Variable patterns of serum-induced platelet activation were observed in response to heparin and platelet factor 4 (PF4), indicating the heterogeneity of the manifestations of VITT in serum. After the initiation of IVIG, reduced antibody-induced platelet activation in serum was seen in all three patients. (Funded by the Canadian Institutes of Health Research.) A rare side effect of ChAdOx1 nCoV-19 vaccination against Covid-19 — venous or arterial thrombosis, which has been termed vaccine-induced immune thrombotic thrombocytopenia — has been reported in recent months. In this Brief Report, investigators describe the use of intravenous immune globulin in the treatment of three such vaccine recipients in Canada.

Heparin-induced thrombocytopenia develops in a 57-year-old man who underwent knee-replacement surgery 7 days previously. Several agents are in clinical use for this condition, including parenteral direct thrombin inhibitors and parenteral factor Xa inhibitors. Foreword This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the authors' clinical recommendations. A 57-year-old man remains in the hospital after experiencing complications from knee-replacement surgery 7 days ago. Low-molecular-weight heparin prophylaxis is initiated on the first postoperative day. Compression ultrasonography performed for left leg swelling noted on day 7 shows a proximal deep-vein thrombosis. A complete blood count reveals that his platelet count has decreased from 300×10 9 per liter to 125×10 9 per liter, and an enzyme immunoassay for heparin-induced thrombocytopenia shows a high titer of antibodies against platelet factor 4 (PF4)–heparin complexes. The patient has normal renal function. The physician in the intensive care unit wonders about the best treatment. The Clinical Problem Heparin-induced thrombocytopenia is a prothrombotic disorder mediated by IgG antibodies that bind to conformational epitopes on PF4 when it is complexed with heparin. Typically, the platelet counts are only moderately reduced. 1 – 7 Occasionally, patients do not have thrombocytopenia, but their platelet counts decrease by 50% from pretreatment levels. 8 The risk of heparin-induced thrombocytopenia is related to characteristics of the patient, the type of heparin used, and the clinical setting. 1 , 2 , 9 Older patients and women are at increased risk. Surgical patients have a higher risk than medical patients, possibly because of the release of cytokines during tissue . . .

In patients with heparin-induced thrombocytopenia, pathogenic antibodies were found to be monoclonal, which challenges previous views of HIT as a polyclonal disorder and suggests new avenues for diagnosis and treatment.

Severe thrombocytopenia in an otherwise healthy neonate is an uncommon but important clinical finding 1 – 3 . Some infants with this condition have major bleeding, including intracranial hemorrhage, that may leave them with lifelong residual defects. Physicians have become highly aware of the risk of neonatal thrombocytopenia, and some have adopted an aggressive approach to treating the fetus with this potential problem. The issue is confounded by the fact that whereas severe thrombocytopenia is common among sick, premature infants (it occurs in as many as 15 percent of infants in a neonatal intensive care unit 4 , 5 ), the frequency of thrombocytopenia . . .

Congenital causes of venous thrombosis have gained increasing prominence with the description of the factor V Leiden mutation and the prothrombin gene mutation. More recently, the description of the association between increased levels of coagulation factors and venous thrombosis and the finding that patients with thrombophilia can harbor more than one prothrombotic state have further increased the clinical relevance of the congenital thrombophilic states. In this qualitative review, we summarize current knowledge of the congenital prothrombotic states and propose a simple classification system that divides the states into two broad groups: those associated with reduced levels of the inhibitors of the coagulation cascade and those associated with increased levels or function of the coagulation factors. The first group is less common than the second, but it is associated with a much higher risk for venous thrombosis. This review provides clinicians with an evidence-based, practical guide to the congenital prothrombotic states.

Febrile, nonhemolytic transfusion reactions are the most frequent adverse reactions to blood products. The risk of these reactions is highest with platelets; they occur in 5 to 30 percent of platelet transfusions, depending on the type of product 1 – 3 . Most of the reactions are mild, but some are life-threatening. The widespread practice of premedication with antipyretic agents often prevents fever, but not the other unpleasant side effects of the reactions 2 . The mechanism of reactions to transfused platelets is not well understood. It is generally assumed that they are caused by the interaction of antileukocyte alloantibodies in the recipient's . . .