scholarly journals FcγRIIA H/R131 Polymorphism, Subclass-Specific IgG Anti-Heparin/Platelet Factor 4 Antibodies and Clinical Course in Patients With Heparin-Induced Thrombocytopenia and Thrombosis

Blood ◽  
1997 ◽  
Vol 89 (2) ◽  
pp. 370-375 ◽  
Author(s):  
Gowthami Arepally ◽  
Steven E. McKenzie ◽  
Xiao-Ming Jiang ◽  
Mortimer Poncz ◽  
Douglas B. Cines
Keyword(s):  
Amino Acid ◽  
Disease Susceptibility ◽  
Clinical Course ◽  
Platelet Factor 4 ◽  
Cross Linking ◽  
Functional Polymorphism ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Receptor Isoforms ◽  
Specific Igg

Abstract The explanation why only a subset of patients with heparin-induced thrombocytopenia (HIT) develop clinically apparent thromboses (HITT) remains uncertain. It has been proposed that platelet activation induced by cross-linking of FcγRIIA by anti-heparin/platelet factor 4 (PF4) antibodies is central to the pathogenesis of thrombosis. The observation that a common functional polymorphism of FcγRIIA, involving either an arginine (R) or histidine (H) at amino acid 131, may underlie disease susceptibility prompted us to investigate the prevalence of receptor isoforms in patients with HIT and HITT. Furthermore, because these isoforms reportedly differ in their avidity for immune complexes containing human IgG2 , we also analyzed sera from patients with HIT and HITT for the prevalence of various subclass-specific IgG anti-heparin/PF4 antibodies. No difference in the allele frequency of FcγRIIA-H131 or R131 was identified among 13 patients with HIT or 23 with HITT compared with 102 controls (χ2 = 1.21, P = .8). Furthermore, although most patients had IgG2 antibodies (62%), IgG1 was the predominant subclass in 30 of the 34 patients with IgG anti-heparin/PF4 antibodies and in 12 was the exclusive subclass found. Also, there was no association between the concordance of IgG2 anti-heparin/PF4 antibodies and the expression of FcγRIIA-H131 in patients with HITT compared with patients with thrombocytopenia alone. These results make it unlikely that the FcγRIIA-H131 isoform or IgG2 anti-heparin/PF4 antibodies are required to develop HITT, suggesting that factors in addition to cross-linking of FcγRIIA receptors contribute to the pathogenesis of thrombosis in patients with heparin-dependent antiplatelet antibodies.

scholarly journals A Case of Heparin-Induced Thrombocytopenia That Developed in the Therapeutic Course of Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis

2019 ◽  
Vol 2019 ◽  
pp. 1-4
Author(s):  
Taketoshi Nonaka ◽  
Makoto Harada ◽  
Masahiko Sumi ◽  
Wataru Ishii ◽  
Tohru Ichikawa ◽  
...  
Keyword(s):  
Clinical Course ◽  
Systemic Vasculitis ◽  
Platelet Factor 4 ◽  
Organ Injury ◽  
Platelet Factor ◽  
Immunological Mechanism ◽  
Heparin Induced Thrombocytopenia ◽  
Vein Thrombosis ◽  
Leg Edema ◽  
Rapidly Progressive Renal Failure

Background. Heparin-induced thrombocytopenia (HIT) causes thrombocytopenia via an immunological mechanism, resulting in severe organ injury due to arterial-venous thrombosis. HIT often develops in hemodialysis patients owing to heparin use. Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic vasculitis, and cases of AAV complicated with HIT are rare. In addition, it mostly occurs in patients undergoing hemodialysis. Case Presentation. An 87-year-old woman presented with rapidly progressive renal failure and severe leg edema. She was diagnosed with AAV and treated with glucocorticoid and heparin calcium to prevent deep vein thrombosis. Eight days after the start of heparin calcium, her platelet count decreased and the anti-platelet factor 4-heparin complex antibody was strongly positive (>5.0 U/mL; the cutoff point of the anti-platelet factor 4-heparin complex antibody evaluated by the latex turbidity assay is 1.0 U/mL). She was diagnosed with HIT and treated with argatroban. Subsequently, her platelet counts increased gradually. Conclusion. We encountered a case of HIT that developed prior to the induction of hemodialysis in the clinical course of AAV. When AAV clinical course presents thrombocytopenia, the possibility of HIT should be considered.

Complete Covalent Structure of Human Platelet Factor 4

1979 ◽  
Vol 42 (05) ◽  
pp. 1652-1660 ◽  
Author(s):  
Francis J Morgan ◽  
Geoffrey S Begg ◽  
Colin N Chesterman
Keyword(s):  
Amino Acids ◽  
Molecular Weight ◽  
Amino Acid ◽  
Amino Acid Sequence ◽  
Human Platelet ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Disulphide Bonds ◽  
Covalent Structure

SummaryThe amino acid sequence of the subunit of human platelet factor 4 has been determined. Human platelet factor 4 consists of identical subunits containing 70 amino acids, each with a molecular weight of 7,756. The molecule contains no methionine, phenylalanine or tryptophan. The proposed amino acid sequence of PF4 is: Glu-Ala-Glu-Glu-Asp-Gly-Asp-Leu-Gln-Cys-Leu-Cys-Val-Lys-Thr-Thr-Ser- Gln-Val-Arg-Pro-Arg-His-Ile-Thr-Ser-Leu-Glu-Val-Ile-Lys-Ala-Gly-Pro-His-Cys-Pro-Thr-Ala-Gin- Leu-Ile-Ala-Thr-Leu-Lys-Asn-Gly-Arg-Lys-Ile-Cys-Leu-Asp-Leu-Gln-Ala-Pro-Leu-Tyr-Lys-Lys- Ile-Ile-Lys-Lys-Leu-Leu-Glu-Ser. From consideration of the homology with p-thromboglobulin, disulphide bonds between residues 10 and 36 and between residues 12 and 52 can be inferred.

Prevalence, isotype, and functionality of antiheparin–platelet factor 4 antibodies in patients treated with heparin and clinically suspected for heparin-induced thrombocytopenia

2002 ◽  
Vol 105 (2) ◽  
pp. 117-123 ◽  
Author(s):  
Brian Untch ◽  
Sarfraz Ahmad ◽  
Walter P. Jeske ◽  
Harry L. Messmore ◽  
Debra A. Hoppensteadt ◽  
...  
Keyword(s):  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia

scholarly journals Structure of the rat platelet factor 4 gene: a marker for megakaryocyte differentiation.

1987 ◽  
Vol 7 (2) ◽  
pp. 898-904 ◽  
Author(s):  
T Doi ◽  
S M Greenberg ◽  
R D Rosenberg
Keyword(s):  
Amino Acid ◽  
Sequence Analysis ◽  
Genomic Library ◽  
Transcriptional Start Site ◽  
Platelet Factor 4 ◽  
Start Codon ◽  
Cdna Expression Library ◽  
Amino Acid Residues ◽  
Platelet Factor ◽  
Nuclease Mapping

A rat platelet factor 4 (PF4) cDNA has been isolated by immunoscreening a g lambda 11 rat megakaryocyte cDNA expression library. Sequence analysis of the rat PF4 cDNA revealed that this megakaryocyte protein is composed of a leader sequence of 29 amino acid residues and a mature protein sequence of 76 amino acid residues. The structure of rat PF4 derived from its cDNA shows a marked homology with the amino acid sequence of human PF4 obtained by classical protein chemistry techniques. This observation is particularly striking with regard to the carboxy-terminal region of rat and human PF4, where 28 of the last 31 C-terminal residues are identical. The rat PF4 gene was obtained from a rat genomic library by using rat PF4 cDNA as a hybridization probe. Sequence analysis showed that the gene is constructed of three exons and two short introns. The transcriptional start site is located 73 base pairs upstream of the translational start codon as judged by S1 nuclease mapping and primer extension. The 5' noncoding region of the gene also exhibited a sequence homologous to the TATA box at -31, as well as a series of direct and inverted repeat sequences and a cluster of 26 T residues at -155 to -218. This latter domain may be involved in regulating PF4 gene expression during megakaryocytopoiesis.

scholarly journals Heparin-induced thrombocytopenia: in vitro studies on the interaction of dabigatran, rivaroxaban, and low-sulfated heparin, with platelet factor 4 and anti-PF4/heparin antibodies

Blood ◽  
2012 ◽  
Vol 119 (5) ◽  
pp. 1248-1255 ◽  
Author(s):  
Krystin Krauel ◽  
Christine Hackbarth ◽  
Birgitt Fürll ◽  
Andreas Greinacher
Keyword(s):  
Factor Xa ◽  
Platelet Factor 4 ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Alternative Anticoagulation ◽  
Heparin Complexes ◽  
History Of

Abstract Heparin is a widely used anticoagulant. Because of its negative charge, it forms complexes with positively charged platelet factor 4 (PF4). This can induce anti-PF4/heparin IgG Abs. Resulting immune complexes activate platelets, leading to the prothrombotic adverse drug reaction heparin-induced thrombocytopenia (HIT). HIT requires treatment with alternative anticoagulants. Approved for HIT are 2 direct thrombin inhibitors (DTI; lepirudin, argatroban) and danaparoid. They are niche products with limitations. We assessed the effects of the DTI dabigatran, the direct factor Xa-inhibitor rivaroxaban, and of 2-O, 3-O desulfated heparin (ODSH; a partially desulfated heparin with minimal anticoagulant effects) on PF4/heparin complexes and the interaction of anti-PF4/heparin Abs with platelets. Neither dabigatran nor rivaroxaban had any effect on the interaction of PF4 or anti-PF4/heparin Abs with platelets. In contrast, ODSH inhibited PF4 binding to gel-filtered platelets, displaced PF4 from a PF4-transfected cell line, displaced PF4/heparin complexes from platelet surfaces, and inhibited anti-PF4/heparin Ab binding to PF4/heparin complexes and subsequent platelet activation. Dabigatran and rivaroxaban seem to be options for alternative anticoagulation in patients with a history of HIT. ODSH prevents formation of immunogenic PF4/heparin complexes, and, when given together with heparin, may have the potential to reduce the risk for HIT during treatment with heparin.

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 Cloning and characterization of platelet factor 4 cDNA derived from a human erythroleukemic cell line

Blood ◽  
1987 ◽  
Vol 69 (1) ◽  
pp. 219-223 ◽  
Author(s):  
M Poncz ◽  
S Surrey ◽  
P LaRocco ◽  
MJ Weiss ◽  
EF Rappaport ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cell Line ◽  
Genomic Dna ◽  
Cdna Probe ◽  
Leader Sequence ◽  
Platelet Factor 4 ◽  
Coding Region ◽  
Platelet Factor ◽  
Amino Acid Homology

Abstract We report the isolation of a platelet factor 4 (PF4) cDNA clone from a lambda gt11 expression cDNA library which was derived from a human erythroleukemic (HEL) cell line. The sequence of the DNA insert includes the 3′-untranslated region, the entire amino acid coding region for the mature PF4 protein, and a 5′ region containing coding information for an additional 18 amino acids. In addition, supplemental genomic DNA sequencing shows that the full-length leader sequence is 30 amino acids long plus an initial methionine and codes for a hydrophobic signal-like sequence which is probably involved in transmembrane transport. A single species mRNA of approximately 800 nucleotides was detected on blots of HEL cell poly(A) + RNA using a labeled PF4 cDNA probe. The human PF4 leader sequence shares some DNA, but no amino acid, homology with the 15 amino acids at the N-terminus of mature bovine PF4, suggesting rapid divergence in this region of PF4 between these two species. Sequence comparison of the coding regions of mature PF4 and gamma IP-10, a protein induced in a variety of cells following treatment with gamma-interferon, shows a corrected divergence of 76%. The divergence of a common ancestor protein into PF4 and gamma IP-10 may have accompanied the development of sophisticated immune and coagulation systems in vertebrates. The availability of cDNA and genomic DNA information for these genes in other species will be useful in studying the evolution of the coagulation and immune systems.

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