Table 2. Studies evaluating the effect... | American Society of Hematology

Table 2.

Studies evaluating the effect of histones on coagulation

Reference	Histone type	Study design	Main conclusions
Kheiri et al, 1996⁶⁶	Histone H1 from human acute myelogenous leukemia cells	Incubation in plasma	Prolonged PTT, aPTT and dilute Russell viper venom times, but not thrombin time
Xu et al, 2009⁶⁰	Mixture of calf thymus histones	Intravenous injection into mice	Lethality (75 mg/kg)
Xu et al, 2009⁶⁰	Mixture of calf thymus histones	Intravenous injection into mice	Sublethal dose induces endothelial damage and microthrombosis in lungs
Fuchs et al, 2011⁶¹	Mixture of calf thymus histones or individual recombinant human histones	Incubation with platelets	Platelet aggregation
Fuchs et al, 2011⁶¹		Intravenous injection of sublethal dose into mice	Thrombocytopenia, prolonged bleeding time, platelet aggregates in lungs
Semeraro et al, 2011⁶³	Mixture of calf thymus histones or individual recombinant human histones	Incubation with PRP or isolated platelets	Enhanced thrombin generation in PRP, platelet aggregation, expression of phosphatidylserine and FV/Va on platelets, enhanced prothrombinase activity on platelets
Ammollo et al, 2011⁶⁴	Mixture of calf thymus histones or individual recombinant human histones	Incubation with PPP, incubation with thrombin, thrombomodulin and protein C	Shortened clotting times measured by turbidimetry, enhanced thrombin generation in the presence of thrombomodulin; H1 impairs thrombin generation in PPP; histones impair thrombin-thrombomodulin-dependent activation of protein C
Abrams et al, 2013⁶²	Mixture of calf thymus or individual recombinant human histones	Tail vein injection of lethal dose into mice	Thrombosis in the lung and kidney, increased plasma TAT complexes
Barranco-Medina et al, 2013⁶⁵	Recombinant human histones H3 or H4	Incubation with purified coagulation proteins	Histone H4 but not H3 directly promotes prothrombin autoactivation to thrombin
Semeraro et al, 2014⁶⁷	Mixture of calf thymus histones or recombinant human histones H1, H2A, H2B, H3, and H4	Incubation with isolated red blood cells in suspension	Histone H4 induced phosphatidylserine exposure on red blood cells
Yang et al, 2016⁶⁹	Mixture of calf thymus histones and recombinant human histones H1, H2A, H2B, H3, or H4	Incubation with primary coronary artery endothelial cells, human umbilical vein endothelial cells, and murine macrophage-like RAW264.7 cells	Histones induced upregulation of tissue factor on endothelial cells and macrophages
Kim et al, 2016⁷⁰	Mixture of calf thymus histones	Incubation with EA.hy926 human endothelial cell line	Histones induced upregulation of tissue factor and protein-disulfide isomerase, and downregulation of thrombomodulin on endothelial cells
Gould et al, 2016⁷¹	Mixture of bovine histones or recombinant human histones H1, H2A, H2B, H3, and H4	Incubation with THP-1 cell line and human monocytes	Histones upregulated tissue factor expression and phosphatidylserine exposure by THP-1 cells and human monocytes
Noubouossie et al, 2017²⁴	Recombinant human histones H3 or H4	Incubation in PFP and PRP	Histones triggered thrombin generation in PRP but not in PFP
Kordbacheh et al, 2017⁶⁸	Mixture of calf thymus histones	Incubation in buffer with isolated human erythrocytes or intravenous injection of sublethal dose to mice	Histones induce erythrocyte aggregation, fragility to lysis under shear stress and reduce deformability; in vivo, histones induce thrombocytopenia, anemia and leukopenia

Reference	Histone type	Study design	Main conclusions
Kheiri et al, 1996⁶⁶	Histone H1 from human acute myelogenous leukemia cells	Incubation in plasma	Prolonged PTT, aPTT and dilute Russell viper venom times, but not thrombin time
Xu et al, 2009⁶⁰	Mixture of calf thymus histones	Intravenous injection into mice	Lethality (75 mg/kg)
Xu et al, 2009⁶⁰	Mixture of calf thymus histones	Intravenous injection into mice	Sublethal dose induces endothelial damage and microthrombosis in lungs
Fuchs et al, 2011⁶¹	Mixture of calf thymus histones or individual recombinant human histones	Incubation with platelets	Platelet aggregation
Fuchs et al, 2011⁶¹		Intravenous injection of sublethal dose into mice	Thrombocytopenia, prolonged bleeding time, platelet aggregates in lungs
Semeraro et al, 2011⁶³	Mixture of calf thymus histones or individual recombinant human histones	Incubation with PRP or isolated platelets	Enhanced thrombin generation in PRP, platelet aggregation, expression of phosphatidylserine and FV/Va on platelets, enhanced prothrombinase activity on platelets
Ammollo et al, 2011⁶⁴	Mixture of calf thymus histones or individual recombinant human histones	Incubation with PPP, incubation with thrombin, thrombomodulin and protein C	Shortened clotting times measured by turbidimetry, enhanced thrombin generation in the presence of thrombomodulin; H1 impairs thrombin generation in PPP; histones impair thrombin-thrombomodulin-dependent activation of protein C
Abrams et al, 2013⁶²	Mixture of calf thymus or individual recombinant human histones	Tail vein injection of lethal dose into mice	Thrombosis in the lung and kidney, increased plasma TAT complexes
Barranco-Medina et al, 2013⁶⁵	Recombinant human histones H3 or H4	Incubation with purified coagulation proteins	Histone H4 but not H3 directly promotes prothrombin autoactivation to thrombin
Semeraro et al, 2014⁶⁷	Mixture of calf thymus histones or recombinant human histones H1, H2A, H2B, H3, and H4	Incubation with isolated red blood cells in suspension	Histone H4 induced phosphatidylserine exposure on red blood cells
Yang et al, 2016⁶⁹	Mixture of calf thymus histones and recombinant human histones H1, H2A, H2B, H3, or H4	Incubation with primary coronary artery endothelial cells, human umbilical vein endothelial cells, and murine macrophage-like RAW264.7 cells	Histones induced upregulation of tissue factor on endothelial cells and macrophages
Kim et al, 2016⁷⁰	Mixture of calf thymus histones	Incubation with EA.hy926 human endothelial cell line	Histones induced upregulation of tissue factor and protein-disulfide isomerase, and downregulation of thrombomodulin on endothelial cells
Gould et al, 2016⁷¹	Mixture of bovine histones or recombinant human histones H1, H2A, H2B, H3, and H4	Incubation with THP-1 cell line and human monocytes	Histones upregulated tissue factor expression and phosphatidylserine exposure by THP-1 cells and human monocytes
Noubouossie et al, 2017²⁴	Recombinant human histones H3 or H4	Incubation in PFP and PRP	Histones triggered thrombin generation in PRP but not in PFP
Kordbacheh et al, 2017⁶⁸	Mixture of calf thymus histones	Incubation in buffer with isolated human erythrocytes or intravenous injection of sublethal dose to mice	Histones induce erythrocyte aggregation, fragility to lysis under shear stress and reduce deformability; in vivo, histones induce thrombocytopenia, anemia and leukopenia

aPTT, activated partial thromboplastin time; PFP, platelet-free plasma; PTT, prothrombin time; TAT, thrombin-antithrombin complexes.