Antigen and substrate withdrawal in the management of autoimmune thrombotic disorders

Cines, Douglas B.; McCrae, Keith R.; Zheng, X. Long; Sachais, Bruce S.; Prak, Eline T. Luning; Siegel, Don L.

doi:10.1182/blood-2012-06-389445

Cited by 6 publications

(7 citation statements)

References 102 publications

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“…Formation of platelet-activating immune complexes depends on availability of the PF4 target antigen, and the risk of HIT is therefore highest in settings characterized by intense PF4 release. It is logical that minimizing the availability of PF4 or otherwise preventing formation of PF4/heparin complexes would be strategies to abrogate the risk of immunogenesis and pathogenesis of HIT antibodies [149]. …”

Section: Reviewmentioning

confidence: 99%

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Emphasis on the Role of PF4 in the Incidence, Pathophysiology and Treatment of Heparin Induced Thrombocytopenia

Prechel

Walenga

2013

Thrombosis J

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Heparin Induced Thrombocytopenia (HIT) is caused by antibodies that recognize platelet factor 4 (PF4) associated with polyanionic glycosaminoglycan drugs or displayed on vascular cell membranes. These antibodies are elicited by multimolecular complexes that can occur when heparin is administered in clinical settings associated with abundant PF4. Heparin binding alters native PF4 and elicits immune recognition and response. While the presence of heparin is integral to immunogenesis, the HIT antibody binding site is within PF4. Thus HIT antibodies develop and function to cause thrombocytopenia and/or thrombosis only in the presence of PF4. Future emphasis on understanding the biology, turnover and regulation of PF4 may lead to insights into the prevention and treatment of HIT.

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Section: Reviewmentioning

confidence: 99%

“…Complexes of variant PF4 and heparin were poorly recognized by HIT antibodies [151], and PF4 antagonist molecules inhibited HIT antibody-mediated platelet activation [152]. These studies demonstrate that strategies to alter or diminish the PF4 target antigen may lead to novel therapeutic approaches for treatment of HIT [149,153]. …”

Section: Reviewmentioning

confidence: 99%

Emphasis on the Role of PF4 in the Incidence, Pathophysiology and Treatment of Heparin Induced Thrombocytopenia

Prechel

Walenga

2013

Thrombosis J

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“…The emergent VITT phenotype shares many clinical, laboratory and immunological features with HIT, the latter of which is well reviewed elsewhere [ 10 ]. These features include thrombocytopenia, unusual strokes (including venous strokes) and the presence of anti-PF4 autoantibodies [ 41 ]. It is well established that HIT is an autoimmune disease that nearly always develops following heparin therapy, though VITT cases have not been generally exposed to heparin.…”

Section: Introductionmentioning

confidence: 99%

“…PF4 is a heparin-binding protein and is the target of autoimmunity in HIT, with the electrochemical interplay between negatively charged heparin and positively charged PF4 being crucial to this interaction [ 41 , 44 ]. Native heparin is well known for its immunomodulatory properties in vivo [ 45 ], but large heparin-PF4 complexes, analogous to PF4-bacterial complexes, render PF4 immunogenic through potential conformational changes in the molecule [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Immunothrombosis in Vaccine-Induced Thrombotic Thrombocytopenia (VITT) Compared to Natural SARS-CoV-2 Infection

McGonagle

Marco

Bridgewood

2021

Journal of Autoimmunity

139

128

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Herein, we consider venous immunothrombotic mechanisms in SARS-CoV-2 infection and anti-SARS-CoV-2 DNA vaccination. Primary SARS-CoV-2 infection with systemic viral RNA release (RNAaemia) contributes to innate immune coagulation cascade activation, with both pulmonary and systemic immunothrombosis - including venous territory strokes. However, anti-SARS-CoV-2 adenoviral-vectored-DNA vaccines -initially shown for the ChAdOx1 vaccine-may rarely exhibit autoimmunity with autoantibodies to Platelet Factor-4 (PF4) that is termed Vaccine-Induced Thrombotic Thrombocytopenia (VITT), an entity pathophysiologically similar to Heparin-Induced Thrombocytopenia (HIT). The PF4 autoantigen is a polyanion molecule capable of independent interactions with negatively charged bacterial cellular wall, heparin and DNA molecules, thus linking intravascular innate immunity to both bacterial cell walls and pathogen-derived DNA. Crucially, negatively charged extracellular DNA is a powerful adjuvant that can break tolerance to positively charged nuclear histone proteins in many experimental autoimmunity settings, including SLE and scleroderma. Analogous to DNA-histone interactons, positively charged PF4-DNA complexes stimulate strong interferon responses via Toll-Like Receptor (TLR) 9 engagement. A chain of events following intramuscular adenoviral-vectored-DNA vaccine inoculation including microvascular damage; microbleeding and platelet activation with PF4 release, adenovirus cargo dispersement with DNA-PF4 engagement may rarely break immune tolerance, leading to rare PF4-directed autoimmunity. The VITT cavernous sinus cerebral and intestinal venous territory immunothrombosis proclivity may pertain to venous drainage of shared microbiotal-rich areas of the nose and in intestines that initiates local endovascular venous immunity by PF4/microbiotal engagement with PF4 autoantibody driven immunothrombosis reminiscent of HIT. According to the proposed model, any adenovirus-vectored-DNA vaccine could drive autoimmune VITT in susceptible individuals and alternative mechanism based on molecular mimicry, vaccine protein contaminants, adenovirus vector proteins, EDTA buffers or immunity against the viral spike protein are secondary factors. Hence, electrochemical DNA-PF4 interactions and PF4-heparin interactions, but at different locations, represent the common denominator in HIT and VITT related autoimmune-mediated thrombosis.

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“…Novel therapeutics for hereditary or acquired TTP has been evaluated in animal models or clinical trials with some success. These novel modalities include the use of anti-platelet glycoprotein 1b (GP1b) monoclonal antibody, nanobody to GP1b, anti-VWF A1 aptamer, and N-acetylcysteine [ 24 ]. All these strategies involve in a direct disruption of the interaction between VWF and platelets, which is the pathologic hallmark of TTP and other related arterial thrombotic disorders.…”

Section: Descriptionmentioning

confidence: 99%

ADAMTS13, TTP and Beyond

Zheng¹

2013

Hereditary Genetics

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Antigen and substrate withdrawal in the management of autoimmune thrombotic disorders

Abstract: Prevailing approaches to manage autoimmune thrombotic disorders, such as heparin-induced thrombocytopenia, antiphospholipid syndrome and thrombotic thrombocytopenic purpura, include immunosuppression and systemic anticoagulation, though neither provides optimal outcome for many patients.

Cited by 6 publications

References 102 publications

Emphasis on the Role of PF4 in the Incidence, Pathophysiology and Treatment of Heparin Induced Thrombocytopenia

Emphasis on the Role of PF4 in the Incidence, Pathophysiology and Treatment of Heparin Induced Thrombocytopenia

Mechanisms of Immunothrombosis in Vaccine-Induced Thrombotic Thrombocytopenia (VITT) Compared to Natural SARS-CoV-2 Infection

ADAMTS13, TTP and Beyond

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