Pathogenesis of heparin-induced thrombocytopenia

Arepally, Gowthami M.; Cines, Douglas B.

doi:10.1016/j.trsl.2020.04.014

Cited by 75 publications

(88 citation statements)

References 131 publications

(164 reference statements)

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“…These results indicate that CXCL4 has the ability to be recognized by T-cells in SSc; thus, we assumed that determinants of CXCL4 bind at least some MHC class II molecules. Overall, these data suggest that the generation of anti-CXCL4 antibodies may rely on T-cell help, as previously suggested in other contexts [ 14 , 16 ].…”

Section: Resultssupporting

confidence: 81%

“…These results, although obtained with an artificial anti-CXCL4–CXCL4–DNA complex, suggest that one of the effector functions of anti-CXCL4 antibodies could be to concentrate and/or more efficiently deliver CXCL4–DNA complexes to immune cells (i.e., to pDCs) and further amplify IFN-α production in SSc. This finding also suggests the interesting possibility that CXCL4–anti-CXCL4 immune complexes circulating in SLE (or in other disease) could be interferogenic because they contain nucleic acids [ 14 , 16 ].…”

Section: Resultsmentioning

confidence: 99%

“…It is worth noting that a rare disease called heparin-induced thrombocytopenia (HIT), in which CXCL4 becomes the target of anti-CXCL4 antibodies with pathogenic activity, is a severe condition in which heparin-dependent anti-CXCL4 antibodies are generated that exert pathogenic functions as they target CXCL4 attached to endogenous heparan-sulfate on endothelial cells, causing injury to these cells [ 14 ]. HIT antibodies can also bind independently of heparin to CXCL4–proteoglycan (chrondroitin sulfate) complexes and also cause normal platelets to aggregate and activate [ 14 ]. Of note, platelet activation is present in SSc [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…The ability of CXCL4 to bind cationic molecules including DNA, in the form of crystals, suggested to us that anti-CXCL4 antibodies could be easily generated in SSc. Indeed, formation of particulate structures, such as large molecular complexes and/or crystal structures containing self-molecules, confers greater antigenicity to otherwise less immunogenic proteins [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature

Lande

Mennella

Palazzo

et al. 2020

IJMS

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Systemic sclerosis (SSc) is characterized by skin/internal organ fibrosis, vasculopathy and autoimmunity. Chemokine (C-X-C motif) ligand 4 (CXCL4) is an SSc biomarker, predicting unfavorable prognosis and lung fibrosis. CXCL4 binds DNA/RNA and favors interferon (IFN)-α production by plasmacytoid dendritic cells (pDCs), contributing to the type I IFN (IFN-I) signature in SSc patients. However, whether CXCL4 is an autoantigen in SSc is unknown. Here, we show that at least half of SSc patients show consistent antibody reactivity to CXCL4. T-cell proliferation to CXCL4, tested in a limited number of patients, correlates with anti-CXCL4 antibody reactivity. Antibodies to CXCL4 mostly correlate with circulating IFN-α levels and are significantly higher in patients with lung fibrosis in two independent SSc cohorts. Antibodies to CXCL4 implement the CXCL4–DNA complex’s effect on IFN-α production by pDCs; CXCL4–DNA/RNA complexes stimulate purified human B-cells to become antibody-secreting plasma cells in vitro. These data indicate that CXCL4 is indeed an autoantigen in SSc and suggest that CXCL4, and CXCL4-specific autoantibodies, can fuel a harmful loop: CXCL4–DNA/RNA complexes induce IFN-α in pDCs and direct B-cell stimulation, including the secretion of anti-CXCL4 antibodies. Anti-CXCL4 antibodies may further increase pDC stimulation and IFN-α release in vivo, creating a vicious cycle which sustains the SSc IFN-I signature and general inflammation.

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Section: Resultssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature

Lande

Mennella

Palazzo

et al. 2020

IJMS

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“…286 For a broader discussion of HITT, readers are referred to the accompanying review on this topic in this journal. 292 Sickle cell disease. Sickle cell disease (SCD) is a group of inherited hemolytic anemias arising from mutation in b-globin gene resulting in an abnormal hemoglobin tetramer HbS.…”

Section: Clinical Overview Of Microvascular Thrombosismentioning

confidence: 99%

Microvascular thrombosis: experimental and clinical implications

Bray

Sartain

Gollamudi

et al. 2020

Translational Research

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A significant amount of clinical and research interest in thrombosis is focused on large vessels (eg, stroke, myocardial infarction, deep venous thrombosis, etc.); however, thrombosis is often present in the microcirculation in a variety of significant human diseases, such as disseminated intravascular coagulation, thrombotic microangiopathy, sickle cell disease, and others. Further, microvascular thrombosis has recently been demonstrated in patients with COVID-19, and has been proposed to mediate the pathogenesis of organ injury in this disease. In many of these conditions, microvascular thrombosis is accompanied by inflammation, an association referred to as thromboinflammation. In this review, we discuss endogenous regulatory mechanisms that prevent thrombosis in the microcirculation, experimental approaches to induce microvascular thrombi, and clinical conditions associated with microvascular thrombosis. A greater understanding of the links between inflammation and thrombosis in the microcirculation is anticipated to provide optimal therapeutic targets for patients with diseases accompanied by microvascular thrombosis.

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Application of a clinical decision rule and laboratory assays in pediatrics: Adult heparin‐induced thrombocytopenia

Cohen

Lange

Budnik

et al. 2022

Pediatric Blood & Cancer

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Background Heparin‐induced thrombocytopenia (HIT) is rare among pediatric patients. The diagnosis of HIT depends upon clinical decision tools to assess its pretest probability, supported by laboratory evidence of anti‐platelet factor 4 (anti‐PF4)/heparin antibodies. Aims To compare the use of the 4Ts score clinical decision tool, clinical characteristics, and laboratory findings between pediatric and adult patients with suspected HIT. Methods We compiled all pediatric patients in our center for whom HIT testing was performed during the years 2015–2021. These were compared with a cohort of consecutive adult patients. Laboratory diagnosis of HIT was performed with particle gel immunoassay (PaGIA) as screening test and confirmed by an automated latex‐enhanced immunoturbidimetric assay (LIA) and/or by functional flow cytometry assay (FCA). Results The cohort included 34 children (under 18 years) and 105 adults. Adults mostly received heparins for thromboembolism prophylaxis and treatment (72.4%, n = 76), and were more frequently treated with low‐molecular‐weight heparin (LMWH). Children were mostly exposed during cardiopulmonary bypass and extracorporeal membrane oxygenation (ECMO, 61.8%, n = 21), and were more frequently treated with unfractionated heparin (UFH). Compared with adults, children had significantly higher 4Ts scores. Nevertheless, adults had a slightly higher rate of a positive diagnosis of HIT. Six out of 16 adults with confirmed HIT presented with thrombosis (37.5%), whereas all three pediatric patients with HIT presented with thrombosis (p = .087). Conclusions 4Ts scores are higher in children compared with adult patients for whom laboratory tests for HIT were obtained. A potentially higher incidence of thrombosis in children with HIT may be attributable to the severity of underlying illness.

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Pathogenesis of heparin-induced thrombocytopenia

Cited by 75 publications

References 131 publications

Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature

Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature

Microvascular thrombosis: experimental and clinical implications

Application of a clinical decision rule and laboratory assays in pediatrics: Adult heparin‐induced thrombocytopenia

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