Risk factors for heparin-induced thrombocytopenia: Focus on Fcγ receptors

SummaryFcγ receptors have critical roles in the pathophysiology of heparin-induced thrombocytopenia (HIT), a severe immune-mediated complication of heparin treatment. Activation of platelets, monocytes and neutrophils by platelet-activating anti-PF4/heparin IgG antibodies results in thrombocytopenia, hypercoagulability and thrombosis in susceptible patients, effects that depend on FcγRIIA. In addition, FcγRIIIA receptors probably contribute to clearance of platelets sensitised by HIT immune complexes. FcγRI has also been reported to be involved in monocyte activation by HIT IgG antibodies and synthesis of tissue factor. This review focuses on the role of these FcγRs in HIT pathophysiology, including the potential influence of several gene variations associated with variable risk of HIT and related thrombosis. In particular, the 276P and 326Q alleles of CD148, a protein tyrosine phosphatase that regulates FcγRIIA signalling, are associated with a lower risk of HIT, and platelets from healthy donors expressing these alleles are hyporesponsive to anti-PF4/H antibodies. It was also recently demonstrated that the risk of thrombosis is higher in HIT patients expressing the R isoform of the FcγRIIA H131R polymorphism, with HIT antibodies shown to activate RR platelets more efficiently, mainly explained by an inhibitory effect of normal IgG2, which bound to the FcγRIIA 131H isoform more efficiently. Environmental risk factors probably interact with these gene polymorphisms affecting FcγRs, thereby increasing thrombosis risk in HIT.

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Heparin-induced thrombocytopenia: research and clinical updates

Hematology ◽

10.1182/asheducation-2016.1.262 ◽

2016 ◽

Vol 2016 (1) ◽

pp. 262-268 ◽

Cited By ~ 8

Author(s):

Oluwatoyosi Onwuemene ◽

Gowthami M. Arepally

Keyword(s):

Limited Data ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Diagnostic Strategies ◽

Immune Mediated ◽

Emerging Therapies ◽

Current Perspective ◽

Clinical Advances ◽

A Current

Abstract Heparin-induced thrombocytopenia (HIT) remains an important diagnosis to consider in hospitalized patients developing thrombocytopenia. HIT is an immune-mediated prothrombotic disorder caused by antibodies to platelet factor 4 (PF4) and heparin. Recent basic scientific studies have advanced our understanding of disease pathogenesis through studies of the PF4/heparin structure, immune mechanisms, and cellular basis of thrombosis. Clinical advances have also occurred in areas of HIT prevention, description of disease variants, and diagnostic strategies. Emerging anticoagulants with the potential to change HIT treatment are evolving, although with limited data. This review will provide a current perspective on HIT pathogenesis, disease features, diagnostic strategies, and role of emerging therapies for the management of HIT.

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

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615969 ◽

2001 ◽

Vol 85 (06) ◽

pp. 1090-1096 ◽

Cited By ~ 30

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.

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Low-affinity Fcγ receptors, autoimmunity and infection

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399409001161 ◽

2009 ◽

Vol 11 ◽

Cited By ~ 51

Author(s):

Lisa C. Willcocks ◽

Kenneth G.C. Smith ◽

Menna R. Clatworthy

Keyword(s):

B Cell ◽

Cell Activation ◽

Cell Receptor ◽

B Cell Receptor ◽

B Cell Activation ◽

Antibody Dependent Cellular Cytotoxicity ◽

Igg Antibodies ◽

Fcγ Receptors ◽

Susceptibility To Infection

Low-affinity Fcγ receptors (FcγRs) mediate the effects of immunoglobulin G (IgG) antibodies on leukocytes, including recruitment to inflammatory lesions, phagocytosis, antibody-dependent cellular cytotoxicity, release of inflammatory mediators and regulation of B cell activation. These functions are an important part of the mammalian response to infection, but if deployed inappropriately can cause autoimmune disease. Although most FcγRs are activatory, there is also an inhibitory FcγR that, when bound to IgG immune complexes, is able to downregulate the effects of both the activatory FcγRs and the B cell receptor. This review discusses the role of the low-affinity FcγRs in a balanced immune response and how perturbations in FcγR function result in susceptibility to infection or autoimmunity.

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Heparin-Induced Thrombocytopenia

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.315445 ◽

2020 ◽

Author(s):

Gowthami M. Arepally ◽

Anand Padmanabhan

Keyword(s):

Risk Factors ◽

Immune Complexes ◽

Optimal Management ◽

Cellular Mechanisms ◽

Platelet Factor ◽

Thrombotic Risk ◽

Heparin Induced Thrombocytopenia ◽

Factors Associated ◽

Clinical Complications ◽

Immune Mediated

Heparin-induced thrombocytopenia is an immune-mediated disorder caused by antibodies that recognize complexes of platelet factor 4 and heparin. Thrombosis is a central and unpredictable feature of this syndrome. Despite optimal management, disease morbidity and mortality from thrombosis remain high. The hypercoagulable state in heparin-induced thrombocytopenia is biologically distinct from other thrombophilic disorders in that clinical complications are directly attributable to circulating ultra-large immune complexes. In some individuals, ultra-large immune complexes elicit unchecked cellular procoagulant responses that culminate in thrombosis. To date, the clinical and biologic risk factors associated with thrombotic risk in heparin-induced thrombocytopenia remain elusive. This review will summarize our current understanding of thrombosis in heparin-induced thrombocytopenia with attention to its clinical features, cellular mechanisms, and its management.

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Thrombosis risk in systemic lupus erythematosus: the role of thrombophilic risk factors

Scandinavian Journal of Rheumatology ◽

10.1080/03009740601089283 ◽

2007 ◽

Vol 36 (3) ◽

pp. 198-205 ◽

Cited By ~ 19

Author(s):

K. K. Sallai ◽

E. Nagy ◽

I. Bodó ◽

A. Mohl ◽

P. Gergely

Keyword(s):

Risk Factors ◽

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Systemic Lupus ◽

Thrombosis Risk

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Risk factors for thrombosis in patients with immune mediated heparin-induced thrombocytopenia

Journal of Internal Medicine ◽

10.1046/j.1365-2796.2002.01021.x ◽

2002 ◽

Vol 252 (2) ◽

pp. 149-154 ◽

Cited By ~ 42

Author(s):

F. Fabris ◽

G. Luzzatto ◽

B. Soini ◽

R. Ramon ◽

R. Scandellari ◽

...

Keyword(s):

Risk Factors ◽

Heparin Induced Thrombocytopenia ◽

Immune Mediated

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Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis

Thrombosis and Haemostasis ◽

10.1160/th04-12-0825 ◽

2005 ◽

Vol 94 (07) ◽

pp. 132-135 ◽

Cited By ~ 142

Author(s):

Beate Farner ◽

Hartmut Kroll ◽

Thomas Kohlmann ◽

Theodore E. Warkentin ◽

Petra Eichler ◽

...

Keyword(s):

Risk Factors ◽

Platelet Count ◽

Arterial Thrombosis ◽

Trauma Surgery ◽

Considerable Proportion ◽

Functional Assay ◽

Heparin Induced Thrombocytopenia ◽

Platelet Counts ◽

Immune Mediated ◽

Orthopedic Trauma Surgery

SummaryImmune mediated heparin induced thrombocytopenia (HIT) is a prothrombotic adverse effect of heparin. However, only a subgroup of patients with HIT develops thromboembolic complications. We aimed to identify risk factors for developing HITassociated thrombosis. We analyzed a registry of patients with clinical suspicion of HIT who tested positive using a sensitive functional assay. Patient information was obtained by a standardized questionnaire. By multivariate analysis the association of age, gender, type of patient population, and magnitude of the platelet count decline with the frequency, type (venous or arterial), and temporal pattern of thrombotic events was assessed. In 408 HIT patients we observed predominance of venous thrombosis (2.4:1), with 40% of patients developing a pulmonary embolism. However, in the subgroup of post-cardiovascular surgery patients there was predominance of arterial thrombosis (1:8.5). The type of arterial thrombosis (limb artery thrombosis > thrombotic stroke > myocardial infarction) was the converse of that observed with typical atherothrombotic clots in non-HIT populations. In 59.8% of patients HIT-related thrombosis manifested either on the same day a platelet count decrease >50% was documented (26.3%) or before the decrease in platelet counts (33.5%).The most important risk factors for thrombosis were orthopedic/trauma surgery and the magnitude of platelet count decrease. HIT-associated thrombosis occurs in a considerable proportion of patients before platelet counts decrease by more than 50%.

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Ultrasensitive Interferons quantification in idiopathic inflammatory myopathies serve as biomarkers of activity in dermatomyositis and anti-synthetase syndrome

10.21203/rs.2.23943/v1 ◽

2020 ◽

Author(s):

BOLKO Loïs ◽

Celine Anquetil ◽

Alba llibre ◽

Solene Maillard ◽

Damien Amelin ◽

...

Keyword(s):

Disease Activity ◽

Predictive Accuracy ◽

Serum Levels ◽

Type I ◽

Detection Technology ◽

Immune Mediated ◽

Healthy Donors ◽

Ifn Γ ◽

Α Level

Abstract Objectives Inflammatory idiopathic myopathies (IIM) are a heterogeneous group of disorders, ranging from a muscle-specific autoimmune disease to a systemic one that are difficult to assess. Recent insights into IIM pathogenesis highlighted the role of interferon (IFN) in the pathophysiology. The aim of this study was to test if IFN serum levels can a use as a biomarker of disease activity in IIM. Methods IFN type I and II were measured using an ultrasensitive detection technology and assess the potential of IFN. Results One hundred and fifty-two patients (dermatomyositis (DM); n=50, anti-synthetase syndrome (ASyS); n=46, immune-mediated necrotizing myopathy (IMNM); n=32, inclusion body myositis (IBM); n=24) and 33 age-matched healthy donors were included. IFN-α levels were higher only in DM (0.07 pg/ml [0.03-0.23], p<0.005) and ASyS groups (0.07 [0.02-0.16], p<0.05) compared with controls (0.02 [0.01-0.05]). IFN-β was increased only in DM and IFN-γ among all IIM. IFN-α levels were correlated with disease activity in DM (r=0.76, p<0.0001). The predictive accuracy of IFN-α level to discriminate active and non-active disease was excellent as reflected by an area under the ROC-curve of 0.88. Using an IFN-α level cut-off above 0.11 pg/ml, the sensitivity was 75% and the specificity was 96% in DM patient. IFN-α and IFN-γ were correlated with disease activity in ASyS groups (r=0.55 and r=0.46 p<0.05)). Conclusions IFNs are promising biomarker for DM and ASyS disease activity.

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Incidence, Outcomes and Risk Factors of Heparin-Induced Thrombocytopenia After Total Joint Arthroplasty: A National Inpatient Sample Database Study

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/10760296211042938 ◽

2021 ◽

Vol 27 ◽

pp. 107602962110429

Author(s):

Yuhang Chen ◽

Jian Wang ◽

Zhan-jun Shi ◽

Yang Zhang ◽

Qinfeng Yang ◽

...

Keyword(s):

Risk Factors ◽

Racial Minority ◽

Negative Consequences ◽

National Inpatient Sample ◽

Inpatient Mortality ◽

Heparin Induced Thrombocytopenia ◽

Immune Mediated ◽

Hospital Stays ◽

Comorbidity Index ◽

Heparin Exposure

Backgrounds: Heparin-induced thrombocytopenia (HIT) is a severe immune-mediated complication of heparin exposure, leading to negative consequences after total hip (THA) and knee arthroplasty (TKA). Materials and Methods: A retrospective study was conducted using the National Inpatient Sample (NIS) database from 2005 to 2014. The incidence and outcomes of HIT after THA or TKA were documented. Logistic regression analysis was performed to identify the postoperative HIT risk factors. Results: A total of 59 3045 patients who underwent THA and 1228 707 patients who underwent TKA were identified. The cumulative incidences were 0.02% and 0.01%, respectively. The HIT group presented significantly higher Charlson Comorbidity Index and Elixhauser Comorbidity Index scores, longer hospital stays (LOS), and higher medical costs. HIT led to a significantly higher mortality rate after THA (2.17% vs 0.16%, P = .0091). In THA, the HIT risk factors were racial minority, AIDS, pulmonary circulation disorders (PCD), psychoses, and hypertension. In TKA, the HIT risk factors were racial minority, PCD, and weight loss. Conclusion: The incidence of HIT after THA and TKA is relatively low; however, HIT significantly increases inpatient mortality, LOS, and medical cost.

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