scholarly journals Review and evolution of guidelines for diagnosis of COVID-19 vaccine induced thrombotic thrombocytopenia (VITT)

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Emmanuel J. Favaloro ◽  
Leonardo Pasalic ◽  
Giuseppe Lippi
Keyword(s):  
Infectious Disease ◽  
Severe Acute Respiratory Syndrome ◽  
Adverse Events ◽  
Platelet Activation ◽  
Platelet Factor 4 ◽  
Government Agencies ◽  
Platelet Factor ◽  
Or Management ◽  
Life Threatening ◽  
Development And Evolution

Abstract Coronavirus disease 2019 (COVID-19) is a life-threatening infectious disease caused by Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2). In response to the still ongoing pandemic outbreak, a number of COVID-19 vaccines have been quickly developed and deployed. Although minor adverse events, either local (e.g., soreness, itch, redness) or systematic (fever, malaise, headache, etc.), are not uncommon following any COVID-19 vaccination, one rare vaccine-associated event can cause fatal consequences due to development of antibodies against platelet factor 4 (PF4), which trigger platelet activation, aggregation, and possible resultant thrombosis, often at unusual vascular sites. Termed thrombosis with thrombocytopenia syndrome (TTS) by reporting government agencies, the term vaccine-induced (immune) thrombotic thrombocytopenia (VITT) is more widely adopted by workers in the field. In response to increasing reports of VITT, several expert groups have formulated guidelines for diagnosis and/or management of VITT. Herein, we review some key guidelines related to diagnosis of VITT, and also provide some commentary on their development and evolution.

Pathophysiology of Heparin-Induced Thrombocytopenia

2000 ◽  
Vol 124 (11) ◽  
pp. 1657-1666 ◽  
Author(s):  
Fabrizio Fabris ◽  
Sarfraz Ahmad ◽  
Giuseppe Cella ◽  
Walter P. Jeske ◽  
Jeanine M. Walenga ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Serotonin Release ◽  
Platelet Factor 4 ◽  
Thrombin Inhibitors ◽  
Platelet Factor ◽  
Cellular Activation ◽  
Heparin Induced Thrombocytopenia ◽  
New Information ◽  
Study Selection ◽  
Release Assay

Abstract Objective.—This review of heparin-induced thrombocytopenia (HIT), the most frequent and dangerous side effect of heparin exposure, covers the epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment of this disease syndrome. Data Sources and Study Selection.—Current consensus of opinion is given based on literature reports, as well as new information where available. A comprehensive analysis of the reasons for discrepancies in incidence numbers is given. The currently known mechanism is that HIT is mediated by an antibody to the complex of heparin–platelet factor 4, which binds to the Fc receptor on platelets. New evidence suggests a functional heterogeneity in the anti-heparin-platelet factor 4 antibodies generated to heparin, and a “superactive” heparin-platelet factor 4 antibody that does not require the presence of heparin to promote platelet activation or aggregation has been identified. Up-regulation of cell adhesion molecules and inflammatory markers, as well as preactivation of platelets/endothelial cells/leukocytes, are also considered to be related to the pathophysiology of HIT. Issues related to the specificity of currently available and new laboratory assays that support a clinical diagnosis are addressed in relation to the serotonin-release assay. Past experience with various anticoagulant treatments is reviewed with a focus on the recent successes of thrombin inhibitors and platelet GPIIb/IIIa inhibitors to combat the platelet activation and severe thrombotic episodes associated with HIT. Conclusions.—The pathophysiology of HIT is multifactorial. However, the primary factor in the mediation of the cellular activation is due to the generation of an antibody to the heparin-platelet factor 4 complex. This review is written as a reference for HIT research.

scholarly journals Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic Pathways

2020 ◽  
Vol 21 (7) ◽  
pp. 2556
Author(s):  
Elmira R. Mordakhanova ◽  
Tatiana A. Nevzorova ◽  
Gulnaz E. Synbulatova ◽  
Lubica Rauova ◽  
John W. Weisel ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Immune Complexes ◽  
Gel Filtration ◽  
Human Platelets ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Mitochondrial Membrane Depolarization ◽  
Low Platelet Count ◽  
Apoptotic Pathways

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction characterized by thrombocytopenia and a high risk for venous or arterial thrombosis. HIT is caused by antibodies that recognize complexes of platelet factor 4 and heparin. The pathogenic mechanisms of this condition are not fully understood. In this study, we used flow cytometry, fluorimetry, and Western blot analysis to study the direct effects of pathogenic immune complexes containing platelet factor 4 on human platelets isolated by gel-filtration. HIT-like pathogenic immune complexes initially caused pronounced activation of platelets detected by an increased expression of phosphatidylserine and P-selectin. This activation was mediated either directly through the FcγRIIA receptors or indirectly via protease-activated receptor 1 (PAR1) receptors due to thrombin generated on or near the surface of activated platelets. The immune activation was later followed by the biochemical signs of cell death, such as mitochondrial membrane depolarization, up-regulation of Bax, down-regulation of Bcl-XL, and moderate activation of procaspase 3 and increased calpain activity. The results show that platelet activation under the action of HIT-like immune complexes is accompanied by their death through complex apoptotic and calpain-dependent non-apoptotic pathways that may underlie the low platelet count in HIT.

Management of Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Syndrome

1997 ◽  
Vol 3 (1_suppl) ◽  
pp. S53-S63 ◽  
Author(s):  
Jeanine M. Walenga ◽  
Bruce E. Lewis ◽  
Debra A. Hoppensteadt ◽  
Jawed Fareed ◽  
Mamdouh Bakbos
Keyword(s):  
Antibody Titer ◽  
Platelet Factor 4 ◽  
Positive Patient ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Comprehensive Account ◽  
Immune Mediated ◽  
Life Threatening ◽  
Pros And Cons ◽  
Sensitivity Specificity

Summary: Heparin-induced thrombocytopenia (HIT) is an immune mediated response to heparin in which antibody driven thrombosis can have a dramatic life-threatening expression. There is much interest on this subject including studies on the pathophysiologic mechanism, the clinical managements of the initial stages of HIT versus the HIT-positive patient requiring continued anticoagulation versus the HIT patient with thrombosis, the pros and cons of available alterr~aci~~ anticoagulants, and the laboratory assays to aid in the diagnosis of HIT with particular reference to the sensitivity/specificity of the new heparin-platelet factor 4 antibody titer assay. A comprehensive account of these timely issues is given in this article.

The Variability of β Thromboglobulin and Platelet Factor 4 in Healthy Subjects

1979 ◽  
Author(s):  
J. Zahavi ◽  
N.A.G. Jones ◽  
M. Dubiel ◽  
J. Leyton ◽  
V.V. Kakkar
Keyword(s):  
Platelet Activation ◽  
Healthy Subjects ◽  
Platelet Factor 4 ◽  
Vascular Changes ◽  
Platelet Activity ◽  
Platelet Factor ◽  
Platelet Concentration ◽  
The Mean ◽  
Age Range

Plasma β TC was measured by radioimmunoassay (RIA)in 202 healthy subjects (age range 12-103); 111 young (mean age 25.2) 34 middle aged (MA) (mean age 55.6) and 57 old (mean age 82.2). Their mean ±1SE plasma β TG levels in ng/ml were 28.3 ± 1.5 (range 3-74), 31.9-2-70 (range 7-65) and 49.99 ± 2.9 (range 14-95) respectively. Plasma βTG level was significantly raised in the old subjects compared to young or MA (p ⩽ 0.0005). Furthermore the ratio of plasma β TG to platelet concentration in whole blood (PC) was higher in the MA subjects compared to the young (p ⩽ 0.009). Plasma platelet factor 4 (PF4) was measured by RIA in 4l healthy subjects, 11 young and 30 old and correlated to plasma βTG. A significant correlation between the 2 proteins was found in the 2 groups (r = 0.8337 in the young and r = 0.0602 in the old subjects), indicating that both proteins are released in-vivo from the same pool and presumably at the same rate. The mean plasma PF4 level in ng/ml was 14.6 (range 6-48) in the young and 18.2 (range 7.7-50) in the old and the ratio of the plasma PF4 to PC was higher in the old subjects (p ⩽ 0.04), These results suggest that in-vivo platelet activation and “release reaction” are increased in old and MA subjects compared to young, presumably due to atherosclerotic vascular changes. This enhanced platelet activity may reflect a pre-thtombotic state.

scholarly journals Genetic Variants in Platelet Factor 4 Modulate Inflammatory and Platelet Activation Biomarkers

2012 ◽  
Vol 5 (4) ◽  
pp. 412-421 ◽  
Author(s):  
Pallav Bhatnagar ◽  
Xiaochun Lu ◽  
Michele K. Evans ◽  
Thomas A. LaVeist ◽  
Alan B. Zonderman ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Genetic Variants ◽  
Platelet Factor 4 ◽  
Platelet Factor

Functional Microparticles Are up Regulated in Patients with Anti-Heparin/Platelet Factor 4 Antibodies: A Potential Mechanism of Thrombogenesis in the Heparin-Induced Thrombocytopenia Syndrome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2105-2105
Author(s):  
Josephine Cunanan ◽  
Michelle Kujawski ◽  
He Zhu ◽  
Margaret Prechel ◽  
Jeanine Walenga ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Medical Center ◽  
Annexin V ◽  
Platelet Factor 4 ◽  
Cellular Damage ◽  
Clinical Samples ◽  
Limiting Factor ◽  
Therapeutic Effects ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia

Abstract Heparin-induced thrombocytopenia (HIT) is one of the most catastrophic adverse effects of heparin therapy, representing a complex syndrome involving immunopathologic and hemostatic disorders. Vascular and blood cellular damage results in the generation of microparticles (MP). These MP are formed from stress conditions/cellular disruption and apoptosis. Cellular MP mediated pathophysiologic responses include platelet activation, up regulation of adhesion molecules, monocyte activation, up regulation of tissue factor and endothelial dysfunction. Several methods based on flow cytometric and other immunologic probes have been used to measure MP in the HIT syndrome. Recently, a functional method based on the complexation of MP with annexin V promoting the generation of factor Xa and thrombin has become available (Hyphen Biomedical, Neuville-Oise, France). To validate the hypothesis that functional MP are elevated in the HIT syndrome, this method was utilized for the quantitation of MP in sera ELISA positive for anti-heparin/platelet factor 4 (HIT) antibodies. Specimens (n = 53) were selected from archived samples that had been referred to Loyola University Medical Center for the laboratory diagnosis of HIT by quantitating anti-heparin/PF4 antibodies by ELISA and by evaluating HIT antibody induced platelet activation using the 14C Serotonin Release Assay (SRA). All selected specimens were positive for HIT antibodies in the GTI PF4 Enhanced ELISA with a broad range of antibody titers (absorbance range of 0.4 – 2.5). Eleven of these specimens were positive in the SRA. In addition, serial samples from HIT patients treated with argatroban (from the ARG-911 clinical study) were included (n = 23). The normal samples represented control sera obtained from healthy human volunteers (n = 25) and processed in the same manner as the clinical samples. Test samples were added to microtiter plates coated with streptavidin and biotinylated annexin V. MP present in the test sample bound to annexin V via exposed surface phospholipids. Following incubation and washing steps, a FXa – FVa mixture containing calcium and prothrombin was added. The assay was optimized so that MP associated phospholipid was the limiting factor for the generation of thrombin. In normal non-HIT sera, the MP levels ranged 5.6 – 10.1 nM (6.1 ± 2.8 nM). The pre-treatment, baseline levels of circulating MP in the suspected HIT patients ranged from 4.2 – 26.8 nM (15.8 ± 7.3 nM). Interestingly, SRA positive/ELISA positive samples had relatively higher levels of MP (19.9 ± 7.7 nM; range 11.5 – 29.8 nM) than SRA negative/ELISA positive samples (14.2± 4.6; range 6.8–21.2). In the ARG-911 study, sequential blood samples exhibited MP levels at the baseline ranging from 8.2 – 38.6 nM (21.8 ± 10.8 nM), whereas after 3 days of argatroban treatment were reduced to 5.1 – 19.2 nM (12.6 ± 6.3). The results of these studies suggest that circulating functional MP are increased in patients with ELISA positive HIT antibodies. Anticoagulation with such direct thrombin agents as argatroban effectively decreases the circulating functional MP levels. Since the elevated MP levels may mediate thrombin and FXa generation, the therapeutic effects of these drugs in HIT may be related to the decreased activation of coagulation and related thrombogenic processes.

Prevalence of Anti-Heparin Platelet Factor 4 Antibodies in Patients with Disseminated Intravascular Coagulation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2094-2094
Author(s):  
Jawed Fareed ◽  
He Zhu ◽  
Josephine Cunanan ◽  
Walter Jeske ◽  
Debra Hoppensteadt ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Disseminated Intravascular Coagulation ◽  
Conflicts Of Interest ◽  
Platelet Factor 4 ◽  
Additional Analysis ◽  
Plasma Samples ◽  
Platelet Factor ◽  
Intravascular Coagulation ◽  
Activation Products ◽  
Low Levels

Abstract Abstract 2094 Poster Board II-71 Disseminated intravascular coagulation (DIC) represents a complex syndrome with multiple pathophysiologic components. Most patients with DIC exhibit thrombocytopenic responses due to endogenous consumption of platelets. A systematic study on the prevalence on anti-heparin platelet factor 4 (AHPF4) antibodies and HIT syndrome in DIC patients has not been presented. To determine the prevalence of AHPF4 antibodies in patients with suspected DIC syndrome a total of 25 plasma samples were retrospectively analyzed utilizing the two commercially available methods (GTI, Brookfield, WI and Hyphen Biomedical, Paris, France). Out of 25 patients, 24 samples were positive for the AHPF4 antibody in the GTI method (OD>0.400), whereas only 16 were positive in the Hyphen Biomedical assay (OD>0.500). Interestingly, only 9 samples were positive in both of these assays. None of the positive samples in either the GTI or the Hyphen assay exhibited a positive 14C serotonin response. Additional analysis of these samples revealed that only 8 of these patients were previously exposed to heparin. Only 4 of the baseline samples were found to contain low levels of heparin as measured by anti-Xa method (< 0.2 U/ml). Additional analysis of these samples revealed the presence of platelet activation products such as platelet factor 4 (PF4), selectin and p-selectin. These studies suggest that circulating AHPF4 antibodies are non-functional and do not produce any thrombocytopenic responses. The elevated circulating PF4 levels and other cytokines may be contributory to the generation of these antibodies in the DIC patients. Disclosures: No relevant conflicts of interest to declare.

Influence of Protein Tyrosine Phosphatase Polymorphisms on the Development of Antibodies to Platelet Factor 4 and the Risk of Heparin-Induced Thrombocytopenia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3683-3683
Author(s):  
Jerôme Rollin ◽  
Claire Pouplard ◽  
Dorothee Leroux ◽  
Marc-Antoine May ◽  
Yves Gruel
Keyword(s):  
Immune Response ◽  
Platelet Activation ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Platelet Factor 4 ◽  
Control Group ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Protein Tyrosine ◽  
Significant Difference

Abstract Abstract 3683 Introduction. Heparin-induced thrombocytopenia (HIT) results from an atypical immune response to platelet factor 4/heparin complexes (PF4/H), with rapid synthesis of platelet-activating IgG antibodies that activate platelets via FcgRIIa receptors. The reasons explaining why only a subset of patients treated with heparin develop IgG to PF4/H complexes, and why most patients who synthesize these antibodies do not develop HIT, have not been fully defined. The immune response in HIT involves both B and T cells, and protein tyrosine kinases (PTKs) and phosphatases (PTPs) are crucial for regulating antigen receptor-induced lymphocyte activation. Moreover, some PTPs such as CD148 and low-molecular-weight PTP (LMW-PTP) could also have a critical role in platelet activation. Dysregulation of the equilibrium between PTK and PTP function could therefore have pathologic consequences and influence the pathogenesis of HIT. Aim of the study. To investigate an association between polymorphisms affecting genes encoding 4 different PTPs i.e. CD45 (PTPRC), CD148 (PTPRJ), LYP (PTPN22) and LMW-PTP (ACP1) and the development of heparin-dependent antibodies to PF4 and HIT. Patients and methods. A cohort of 89 patients with definite HIT (positive PF4-specific ELISA and positive serotonin release assay) and two control groups were studied. The first control group (Abneg) consisted of 179 patients who had undergone cardiopulmonary bypass (CBP) with high doses of heparin and who did not develop Abs to PF4 post-operatively. The second control group (Abpos) consisted of 160 patients who had also undergone cardiac surgery with CPB and heparin, who had all developed significant levels of PF4-specific antibodies but without HIT. Genotypes of PTPRC 77C/G (rs17612648), PTPN22 1858C/T (rs2476601), PTPRJ 2965 C/G (rs4752904) and PTPRJ 1176 A/C (rs1566734) were studied by a PCR-HRM method using the LightCycler 480 (Roche). In addition, the ACP1 A, B, C alleles were defined by combining the analysis of T/C transition at codon 43 of exon 3 (rs11553742) and T/C transition at codon 41 of exon 4 (rs11553746). Results. The frequency of PTPRC 77G and PTPN22 1858T alleles was not different in HIT patients and controls, whether they had developed antibodies to PF4 or not. The third PTP gene analyzed was ACP1, in which three alleles (A, B and C) were previously associated with the synthesis of distinct active LMW-PTP isoforms exhibiting different catalytic properties. The percentage of subjects in our study carrying the AC, BB and BC genotypes was significantly higher in the HIT and the Abpos groups than in patients without antibodies to PF4 after CPB (Abneg). In addition, the ACP1 A allele was less frequent in patients with antibodies to PF4, whether they had developed HIT (25%) or not (27.5% in Abpos controls), than in Abneg subjects (37%). The AC, BB and BC genotypes (associated in Caucasians with the highest LMW-PTP enzyme activity) therefore appeared to increase the risk of antibody formation in heparin-treated patients (OR 1.8; 95% CI 1.2–2.6, p=0.004 after comparing Abpos + HIT vs. Abneg). We also evaluated 2 SNPs affecting PTPRJ encoding CD148. No significant difference was found concerning the 2965 C/G polymorphism, but the frequency of PTPRJ 1176 AC and CC genotypes was significantly lower in the HIT (17%) than in the Abneg and Abpos groups (35%, p=0.003 and 29.5%, p=0.041, respectively). The C allele therefore appeared to provide a significant protection from the risk of HIT (OR 0.52; 95%CI 0.29–0.94, p=0.041) in patients with antibodies to PF4. Discussion-Conclusion. Recent studies have demonstrated that CD148 is a positive regulator of platelet activation by maintaining a pool of active SFKs in platelets. This non-synonym PTPRJ 1176 A/C SNP is associated with a Q276P substitution inducing a torsional stress of a fibronectin domain that is critical for the activity of CD148 and may influence the pathogenic effects of HIT Abs. This study supports the hypothesis that PTPs such as LMW-PTP and CD148 influence the immune response to heparin and the risk of HIT in patients with antibodies to PF4. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Rivaroxaban Treatment for Heparin-Induced Thrombocytopenia: A Case Report and a Review of the Current Experience

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Mohamed Aon ◽  
Omar Al-Shammari
Keyword(s):  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Autoantibody Production ◽  
Heparin Induced Thrombocytopenia ◽  
Good Safety Profile ◽  
Good Patient Compliance ◽  
Life Threatening ◽  
Current Experience

Heparin-induced thrombocytopenia is a life-threatening complication of exposure to heparin. Heparin-induced thrombocytopenia results from an autoantibody directed against platelet factor 4 in complex with heparin. Heparin-induced thrombocytopenia is traditionally treated with bivalirudin, argatroban, danaparoid, or fondaparinux. Recently, direct oral anticoagulants administration to treat heparin-induced thrombocytopenia has been reported. Direct oral anticoagulants do not cause platelet activation in the presence of heparin-platelet factor 4 antibodies, nor do they provoke autoantibody production. Direct oral anticoagulants offer advantages such as consistent and predictable anticoagulation, oral administration with good patient compliance, and a good safety profile. We report a case of heparin-induced thrombocytopenia with deep venous thrombosis successfully treated with rivaroxaban and review the current experience with rivaroxaban for the treatment of heparin-induced thrombocytopenia.

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