A Multicenter Retrospective Evaluation of Direct Oral Anticoagulants for the Treatment of Heparin-Induced Thrombocytopenia

Davis, Kyle; Sebaaly, Jamie; Wooten, Leslie; Khouli, Courtney; Mihm, Alexandra E.; Nisly, Sarah A.

doi:10.1007/s40256-021-00519-0

Cited by 7 publications

(2 citation statements)

References 21 publications

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“…The standard treatment for HIT (nonheparin anticoagulants) reduces but does not eliminate thrombosis, while many patients experience major bleeding. [50][51][52][53] In support of our findings that both thrombin-PAR and immune complex-FcγRIIA interactions drive thrombosis, the combination of anticoagulation to block thrombin action with intravenous immunoglobulin to block FcγRIIA has been shown to be effective in the treatment of severe HIT and vaccine-induced thrombotic thrombocytopenia. 54,55 However, limits on cost and availability of intravenous immunoglobulin in addition to risks of continued thrombosis remain.…”

Section: Discussionsupporting

confidence: 61%

Novel Strategy to Combat the Procoagulant Phenotype in Heparin-Induced Thrombocytopenia Using 12-LOX Inhibition

Renna

Zhao

Kunapuli

et al. 2023

ATVB

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BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a major concern for all individuals that undergo cardiac bypass surgeries or require prolonged heparin exposure. HIT is a life- and limb-threatening adverse drug reaction with an immune response following the formation of ultra-large immune complexes that drive platelet activation through the receptor FcγRIIA. Thrombotic events remain high following the standard of care treatment with anticoagulants, while increasing risk of bleeding complications. This study sought to investigate a novel approach to treatment of HIT. Recent reports demonstrate increased procoagulant activity in HIT; however, these reports required analysis ex vivo, and relevance in vivo remains unclear. METHODS: Using human and mouse model systems, we investigated the cooperativity of PARs (protease-activated receptors) and FcγRIIA in HIT. We challenged humanized FcγRIIA transgenic mice with or without endogenous mouse Par4 (denoted as IIA-Par4 +/+ or IIA-Par4 − /− , respectively) with a well-established model IgG immune complex (anti [α]-CD9). Furthermore, we assessed the procoagulant phenotype and efficacy to treat HIT utilizing inhibitor of 12-LOX (12[S]-lipoxygenase), VLX-1005, previously reported to decrease platelet activation downstream of FcγRIIA and PAR4, using the triple allele HIT mouse model. RESULTS: IIA-Par4 +/+ mice given αCD9 were severely thrombocytopenic, with extensive platelet-fibrin deposition in the lung. In contrast, IIA-Par4 −/− mice had negligible thrombocytopenia or pulmonary platelet-fibrin thrombi. We observed that pharmacological inhibition of 12-LOX resulted in a significant reduction in both platelet procoagulant phenotype ex vivo, and thrombocytopenia and thrombosis in our humanized mouse model of HIT in vivo. CONCLUSIONS: These data demonstrate for the first time the need for dual platelet receptor (PAR [protease-activated receptor] and FcγRIIA) stimulation for fibrin formation in HIT in vivo. These results extend our understanding of HIT pathophysiology and provide a scientific rationale for targeting the procoagulant phenotype as a possible therapeutic strategy in HIT.

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Section: Discussionsupporting

confidence: 61%

Novel Strategy to Combat the Procoagulant Phenotype in Heparin-Induced Thrombocytopenia Using 12-LOX Inhibition

Renna

Zhao

Kunapuli

et al. 2023

ATVB

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“…Here, blood from a patient on dabigatran therapy only showed a soft clot after 80 min in a conventional blood collection tube; however, the presence of 0.15 mU rEcarin caused a firm clot in less than 5 min to produce high-quality serum. In addition to heparin, warfarin and dabigatran, a range of other anticoagulants, such as fondaparinux, apixaban and rivaroxaban, are used clinically [ 16 , 45 ]. Here, we further demonstrated the efficacy of rEcarin in clotting recalcified citrated whole blood spiked with these three anticoagulants at doses significantly higher than clinically used levels.…”

Section: Discussionmentioning

confidence: 99%

Potential Application of Recombinant Snake Prothrombin Activator Ecarin in Blood Diagnostics

et al. 2022

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We describe here the purification and cloning of a codon-optimized form of the snake prothrombin activator ecarin from the saw scaled viper (Echis carinatus) expressed in mammalian cells. Expression of recombinant ecarin (rEcarin) was carried out in human embryonic kidney cells (HEK) cells under conditions for the development and performance of a novel and scalable recombinant snake ecarin to industry standards. Clotting performance of the rEcarin was established in recalcified citrated whole blood, plasma, and fresh whole blood and found to be comparable to native ecarin (N-Ecarin). Furthermore, hemolysis was observed with N-Ecarin at relatively high doses in both recalcified citrated and fresh whole blood, while clotting was not observed with rEcarin, providing an important advantage for the recombinant form. In addition, rEcarin effectively clotted both recalcified citrated whole blood and fresh whole blood containing different anticoagulants including heparin, warfarin, dabigatran, Fondaparinux, rivaroxaban and apixaban, forming firm clots in the blood collection tubes. These results demonstrate that rEcarin efficiently clots normal blood as well as blood spiked with high concentrations of anticoagulants and has great potential as an additive to blood collection tubes to produce high quality serum for analyte analysis in diagnostic medicine.

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Heparin

2022

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A Multicenter Retrospective Evaluation of Direct Oral Anticoagulants for the Treatment of Heparin-Induced Thrombocytopenia

Cited by 7 publications

References 21 publications

Novel Strategy to Combat the Procoagulant Phenotype in Heparin-Induced Thrombocytopenia Using 12-LOX Inhibition

Novel Strategy to Combat the Procoagulant Phenotype in Heparin-Induced Thrombocytopenia Using 12-LOX Inhibition

Potential Application of Recombinant Snake Prothrombin Activator Ecarin in Blood Diagnostics

Heparin

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