Reduced β2-GPI is associated with increased platelet aggregation and activation in patients with prolonged isolated thrombocytopenia after allo-HSCT
|
摘要
We aimed to measure platelet function and its relationship with β2-GPI in prolonged isolated thrombocytopenia(PT) after allogeneic hematopoietic stem cell transplantation(allo-HSCT). Fifty-six patients with PT and 60 allo-HSCT recipients without PT(non-PT controls) were enrolled. Platelet aggregation and activation, β2-GPI and anti-β2-GPI antibody levels, vWF antigen,and vWF activity were analyzed. The effect of β2-GPI on platelet aggregation was also measured ex vivo. Results showed that ADP-induced platelet aggregation significantly increased(39%±7.5% vs. 23%±8.5%, P=0.032), and the platelet expression of both CD62 p(33.6%±11.6% vs. 8.5%±3.5%, P<0.001) and PAC-1(42.4%±7.6% vs. 6.8%±2.2%, P<0.001) was significantly higher in patients with PT than in those without PT. Significantly lower β2-GPI levels(164.2±12 μg m L–1 vs. 234.2±16 μg mL–1,P<0.001), higher anti-β2-GPI IgG levels(1.78±0.46 U mL–1 vs. 0.94±0.39 U mL–1, P<0.001), and increased vWF activity(133.06%±30.50% vs. 102.17%±25.90%, P<0.001) were observed in patients with PT than in those without PT. Both ADPinduced platelet aggregation(n=116, r~2=-0.5042, P<0.001) and vWF activity(n=116, r~2=-0.2872, P<0.001) were negatively correlated with β2-GPI levels. In summary, our data suggested that platelet aggregation and activation were significantly higher in patients with PT than in those without PT, which might be associated with reduced β2-GPI levels. The reduced β2-GPI levels might be due to the existence of anti-β2-GPI IgG.
We aimed to measure platelet function and its relationship with β2-GPI in prolonged isolated thrombocytopenia(PT) after allogeneic hematopoietic stem cell transplantation(allo-HSCT). Fifty-six patients with PT and 60 allo-HSCT recipients without PT(non-PT controls) were enrolled. Platelet aggregation and activation, β2-GPI and anti-β2-GPI antibody levels, vWF antigen,and vWF activity were analyzed. The effect of β2-GPI on platelet aggregation was also measured ex vivo. Results showed that ADP-induced platelet aggregation significantly increased(39%±7.5% vs. 23%±8.5%, P=0.032), and the platelet expression of both CD62 p(33.6%±11.6% vs. 8.5%±3.5%, P<0.001) and PAC-1(42.4%±7.6% vs. 6.8%±2.2%, P<0.001) was significantly higher in patients with PT than in those without PT. Significantly lower β2-GPI levels(164.2±12 μg m L–1 vs. 234.2±16 μg mL–1,P<0.001), higher anti-β2-GPI IgG levels(1.78±0.46 U mL–1 vs. 0.94±0.39 U mL–1, P<0.001), and increased vWF activity(133.06%±30.50% vs. 102.17%±25.90%, P<0.001) were observed in patients with PT than in those without PT. Both ADPinduced platelet aggregation(n=116, r~2=-0.5042, P<0.001) and vWF activity(n=116, r~2=-0.2872, P<0.001) were negatively correlated with β2-GPI levels. In summary, our data suggested that platelet aggregation and activation were significantly higher in patients with PT than in those without PT, which might be associated with reduced β2-GPI levels. The reduced β2-GPI levels might be due to the existence of anti-β2-GPI IgG.
We aimed to measure platelet function and its relationship with β2-GPI in prolonged isolated thrombocytopenia(PT) after allogeneic hematopoietic stem cell transplantation(allo-HSCT). Fifty-six patients with PT and 60 allo-HSCT recipients without PT(non-PT controls) were enrolled. Platelet aggregation and activation, β2-GPI and anti-β2-GPI antibody levels, vWF antigen,and vWF activity were analyzed. The effect of β2-GPI on platelet aggregation was also measured ex vivo. Results showed that ADP-induced platelet aggregation significantly increased(39%±7.5% vs. 23%±8.5%, P=0.032), and the platelet expression of both CD62 p(33.6%±11.6% vs. 8.5%±3.5%, P<0.001) and PAC-1(42.4%±7.6% vs. 6.8%±2.2%, P<0.001) was significantly higher in patients with PT than in those without PT. Significantly lower β2-GPI levels(164.2±12 μg m L–1 vs. 234.2±16 μg mL–1,P<0.001), higher anti-β2-GPI IgG levels(1.78±0.46 U mL–1 vs. 0.94±0.39 U mL–1, P<0.001), and increased vWF activity(133.06%±30.50% vs. 102.17%±25.90%, P<0.001) were observed in patients with PT than in those without PT. Both ADPinduced platelet aggregation(n=116, r~2=-0.5042, P<0.001) and vWF activity(n=116, r~2=-0.2872, P<0.001) were negatively correlated with β2-GPI levels. In summary, our data suggested that platelet aggregation and activation were significantly higher in patients with PT than in those without PT, which might be associated with reduced β2-GPI levels. The reduced β2-GPI levels might be due to the existence of anti-β2-GPI IgG.
引文
Berndt,M.,Shen,Y.,Dopheide,S.,Gardiner,E.,and Andrews,R.(2001).The vascular biology of the glycoprotein Ib-IX-V complex.Thromb Haemost 86,178-188.
Bielski,M.,Yomtovian,R.,Lazarus,H.M.,and Rosenthal,N.(1998).Prolonged isolated thrombocytopenia after hematopoietic stem cell transplantation:morphologic correlation.Bone Marrow Transplant 22,1071-1076.
Canobbio,I.,Balduini,C.,and Torti,M.(2004).Signalling through the platelet glycoprotein Ib-V-IX complex.Cell Signal 16,1329-1344.
de Laat,H.B.,Derksen,R.H.W.M.,Urbanus,R.T.,Roest,M.,and de Groot,P.G.(2004).2-glycoprotein I-dependent lupus anticoagulant highly correlates with thrombosis in the antiphospholipid syndrome.Blood104,3598-3602.
Du,X.(2007).Signaling and regulation of the platelet glycoprotein Ib-IX-V complex.Curr Opin Hematol 14,262-269.
First,L.R.,Smith,B.R.,Lipton,J.,Nathan,D.G.,Parkman,R.,and Rappeport,J.M.(1985).Isolated thrombocytopenia after allogeneic bone marrow transplantation:existence of transient and chronic thrombocytopenic syndromes.Blood 65,368-374.
Fu,Q.,Xu,L.,Zhang,X.,Wang,Y.,Chang,Y.,Liu,K.,and Huang,X.(2018).Platelet transfusion refractoriness after T-cell-replete haploidentical transplantation is associated with inferior clinical outcomes.Sci China Life Sci 61,569-577.
Galli,M.,Luciani,D.,Bertolini,G.,and Barbui,T.(2003).Anti-2-glycoprotein I,antiprothrombin antibodies,and the risk of thrombosis in the antiphospholipid syndrome.Blood 102,2717-2723.
Huang,X.J.,Liu,D.H.,Liu,K.Y.,Xu,L.P.,Chen,H.,Han,W.,Chen,Y.H.,Wang,J.Z.,Gao,Z.Y.,Zhang,Y.C.,et al.(2006).Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies.Bone Marrow Transplant 38,291-297.
Huang,X.J.,Xu,L.P.,Liu,K.Y.,Liu,D.H.,Wang,Y.,Chen,H.,Chen,Y.H.,Han,W.,Wang,J.H.,Chen,Y.,et al.(2009).Partially matched related donor transplantation can achieve outcomes comparable with unrelated donor transplantation for patients with hematologic malignancies.Clin Cancer Res 15,4777-4783.
Hulstein,J.J.J.,Lenting,P.J.,de Laat,B.,Derksen,R.H.W.M.,Fijnheer,R.,and de Groot,P.G.(2007).2-Glycoprotein I inhibits von Willebrand factor dependent platelet adhesion and aggregation.Blood 110,1483-1491.
Kang,I.,Raghavachari,M.,Hofmann,C.M.,and Marchant,R.E.(2007).Surface-dependent expression in the platelet GPIb binding domain within human von Willebrand factor studied by atomic force microscopy.Thromb Res 119,731-740.
Kong,Y.,Hu,Y.,Zhang,X.H.,Wang,Y.Z.,Mo,X.D.,Zhang,Y.Y.,Wang,Y.,Han,W.,Xu,L.P.,Chang,Y.J.,et al.(2014).Association between an impaired bone marrow vascular microenvironment and prolonged isolated thrombocytopenia after allogeneic hematopoietic stem cell transplantation.Biol Blood Marrow Transplant 20,1190-1197.
Labrador,J.,López-Corral,L.,Vazquez,L.,Sánchez-Guijo,F.,Guerrero,C.,Sánchez-Barba,M.,Lozano,F.S.,Alberca,I.,Del Ca?izo,M.C.,Caballero,D.,et al.(2015).Incidence and risk factors for lifethreatening bleeding after allogeneic stem cell transplant.Br J Haematol169,719-725.
Middelburg,R.A.,Carbaat-Ham,J.C.,Hesam,H.,Ragusi,M.A.A.D.,and Zwaginga,J.J.(2016).Platelet function in adult ITP patients can be either increased or decreased,compared to healthy controls,and is associated with bleeding risk.Hematology 21,549-551.
Morigi,M.,Galbusera,M.,Gastoldi,S.,Locatelli,M.,Buelli,S.,Pezzotta,A.,Pagani,C.,Noris,M.,Gobbi,M.,Stravalaci,M.,et al.(2011).Alternative pathway activation of complement by Shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis.JImmunol 187,172-180.
Nimpf,J.,Wurm,H.,and Kostner,G.M.(1987).β2-glycoprotein-I(apo-H)inhibits the release reaction of human platelets during ADP-induced aggregation.Atherosclerosis 63,109-114.
Ozaki,Y.,Asazuma,N.,Suzuki-Inoue,K.,and Berndt,M.C.(2005).Platelet GPIb-IX-V-dependent signaling.J Thromb Haemost 3,1745-1751.
Przepiorka,D.,Weisdorf,D.,Martin,P.,Klingemann,H.G.,Beatty,P.,Hows,J.,and Thomas,E.D.(1995).1994 consensus conference on acute GVHD grading.Bone Marrow Transplant 15,825-828.
Ruggeri,Z.M.(2003).Von Willebrand factor,platelets and endothelial cell interactions.J Thromb Haemost 1,1335-1342.
Shi,T.,Giannakopoulos,B.,Yan,X.,Yu,P.,Berndt,M.C.,Andrews,R.K.,Rivera,J.,Iverson,G.M.,Cockerill,K.A.,Linnik,M.D.,et al.(2006).Anti-β2-glycoprotein I antibodies in complex withβ2-glycoprotein Ican activate platelets in a dysregulated manner via glycoprotein Ib-IX-V.Arthritis Rheum 54,2558-2567.
Tedesco,F.,Pausa,M.,Nardon,E.,Introna,M.,Mantovani,A.,and Dobrina,A.(1997).The cytolytically inactive terminal complement complex activates endothelial cells to express adhesion molecules and tissue factor procoagulant activity.J Exp Med 185,1619-1628.
van Lier,M.,Lee,F.,Farndale,R.W.,Gorter,G.,Verhoef,S.,OhnoIwashita,Y.,Akkerman,J.W.N.,and Heijnen,H.F.G.(2005).Adhesive surface determines raft composition in platelets adhered under flow.JThromb Haemost 3,2514-2525.
van Velzen,J.F.,Laros-van Gorkom,B.A.P.,Pop,G.A.M.,and van Heerde,W.L.(2012).Multicolor flow cytometry for evaluation of platelet surface antigens and activation markers.Thromb Res 130,92-98.
Wang,Y.,Liu,Q.F.,Xu,L.P.,Liu,K.Y.,Zhang,X.H.,Ma,X.,Fan,Z.P.,Wu,D.P.,and Huang,X.J.(2015).Haploidentical vs identical-sibling transplant for AML in remission:a multicenter,prospective study.Blood 125,3956-3962.
Yamazaki,R.,Kuwana,M.,Mori,T.,Okazaki,Y.,Kawakami,Y.,Ikeda,Y.,and Okamoto,S.(2006).Prolonged thrombocytopenia after allogeneic hematopoietic stem cell transplantation:associations with impaired platelet production and increased platelet turnover.Bone Marrow Transplant 38,377-384.
Zhang,X.,Fu,H.,Xu,L.,Liu,D.,Wang,J.,Liu,K.,and Huang,X.(2011).Prolonged thrombocytopenia following allogeneic hematopoietic stem cell transplantation and its association with a reduction in ploidy and an immaturation of megakaryocytes.Biol Blood Marrow Transplant 17,274-280.
Zhang,X.H.,Wang,G.X.,Zhu,H.H.,Liu,Y.R.,Xu,L.P.,Han,W.,Chen,H.,Chen,Y.H.,Wang,F.R.,Wang,J.Z.,et al.(2015a).Recruitment of CD8+T cells into bone marrow might explain the suppression of megakaryocyte apoptosis through high expression of CX3CR1+in prolonged isolated thrombocytopenia after allogeneic hematopoietic stem cell transplantation.Ann Hematol 94,1689-1698.
Zhang,X.H.,Wang,Q.M.,Zhang,J.M.,Feng,F.E.,Wang,F.R.,Chen,H.,Zhang,Y.Y.,Chen,Y.H.,Han,W.,Xu,L.P.,et al.(2015b).Desialylation is associated with apoptosis and phagocytosis of platelets in patients with prolonged isolated thrombocytopenia after allo-HSCT.J Hematol Oncol 8,116-131.
Zhang,X.H.,Wang,Q.M.,Chen,H.,Chen,Y.H.,Han,W.,Wang,F.R.,Wang,J.Z.,Zhang,Y.Y.,Mo,X.D.,Chen,Y.,et al.(2016).Clinical characteristics and risk factors of Intracranial hemorrhage in patients following allogeneic hematopoietic stem cell transplantation.Ann Hematol 95,1637-1643.
Zhang,W.,Gao,F.,Lu,D.,Sun,N.,Yin,X.,Jin,M.,and Liu,Y.(2016).Anti-β2 glycoprotein I antibodies in complex withβ2 glycoprotein Iinduce platelet activation via two receptors:apolipoprotein E receptor 2′and glycoprotein I bα.Front Med 10,76-84.
Bielski,M.,Yomtovian,R.,Lazarus,H.M.,and Rosenthal,N.(1998).Prolonged isolated thrombocytopenia after hematopoietic stem cell transplantation:morphologic correlation.Bone Marrow Transplant 22,1071-1076.
Canobbio,I.,Balduini,C.,and Torti,M.(2004).Signalling through the platelet glycoprotein Ib-V-IX complex.Cell Signal 16,1329-1344.
de Laat,H.B.,Derksen,R.H.W.M.,Urbanus,R.T.,Roest,M.,and de Groot,P.G.(2004).2-glycoprotein I-dependent lupus anticoagulant highly correlates with thrombosis in the antiphospholipid syndrome.Blood104,3598-3602.
Du,X.(2007).Signaling and regulation of the platelet glycoprotein Ib-IX-V complex.Curr Opin Hematol 14,262-269.
First,L.R.,Smith,B.R.,Lipton,J.,Nathan,D.G.,Parkman,R.,and Rappeport,J.M.(1985).Isolated thrombocytopenia after allogeneic bone marrow transplantation:existence of transient and chronic thrombocytopenic syndromes.Blood 65,368-374.
Fu,Q.,Xu,L.,Zhang,X.,Wang,Y.,Chang,Y.,Liu,K.,and Huang,X.(2018).Platelet transfusion refractoriness after T-cell-replete haploidentical transplantation is associated with inferior clinical outcomes.Sci China Life Sci 61,569-577.
Galli,M.,Luciani,D.,Bertolini,G.,and Barbui,T.(2003).Anti-2-glycoprotein I,antiprothrombin antibodies,and the risk of thrombosis in the antiphospholipid syndrome.Blood 102,2717-2723.
Huang,X.J.,Liu,D.H.,Liu,K.Y.,Xu,L.P.,Chen,H.,Han,W.,Chen,Y.H.,Wang,J.Z.,Gao,Z.Y.,Zhang,Y.C.,et al.(2006).Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies.Bone Marrow Transplant 38,291-297.
Huang,X.J.,Xu,L.P.,Liu,K.Y.,Liu,D.H.,Wang,Y.,Chen,H.,Chen,Y.H.,Han,W.,Wang,J.H.,Chen,Y.,et al.(2009).Partially matched related donor transplantation can achieve outcomes comparable with unrelated donor transplantation for patients with hematologic malignancies.Clin Cancer Res 15,4777-4783.
Hulstein,J.J.J.,Lenting,P.J.,de Laat,B.,Derksen,R.H.W.M.,Fijnheer,R.,and de Groot,P.G.(2007).2-Glycoprotein I inhibits von Willebrand factor dependent platelet adhesion and aggregation.Blood 110,1483-1491.
Kang,I.,Raghavachari,M.,Hofmann,C.M.,and Marchant,R.E.(2007).Surface-dependent expression in the platelet GPIb binding domain within human von Willebrand factor studied by atomic force microscopy.Thromb Res 119,731-740.
Kong,Y.,Hu,Y.,Zhang,X.H.,Wang,Y.Z.,Mo,X.D.,Zhang,Y.Y.,Wang,Y.,Han,W.,Xu,L.P.,Chang,Y.J.,et al.(2014).Association between an impaired bone marrow vascular microenvironment and prolonged isolated thrombocytopenia after allogeneic hematopoietic stem cell transplantation.Biol Blood Marrow Transplant 20,1190-1197.
Labrador,J.,López-Corral,L.,Vazquez,L.,Sánchez-Guijo,F.,Guerrero,C.,Sánchez-Barba,M.,Lozano,F.S.,Alberca,I.,Del Ca?izo,M.C.,Caballero,D.,et al.(2015).Incidence and risk factors for lifethreatening bleeding after allogeneic stem cell transplant.Br J Haematol169,719-725.
Middelburg,R.A.,Carbaat-Ham,J.C.,Hesam,H.,Ragusi,M.A.A.D.,and Zwaginga,J.J.(2016).Platelet function in adult ITP patients can be either increased or decreased,compared to healthy controls,and is associated with bleeding risk.Hematology 21,549-551.
Morigi,M.,Galbusera,M.,Gastoldi,S.,Locatelli,M.,Buelli,S.,Pezzotta,A.,Pagani,C.,Noris,M.,Gobbi,M.,Stravalaci,M.,et al.(2011).Alternative pathway activation of complement by Shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis.JImmunol 187,172-180.
Nimpf,J.,Wurm,H.,and Kostner,G.M.(1987).β2-glycoprotein-I(apo-H)inhibits the release reaction of human platelets during ADP-induced aggregation.Atherosclerosis 63,109-114.
Ozaki,Y.,Asazuma,N.,Suzuki-Inoue,K.,and Berndt,M.C.(2005).Platelet GPIb-IX-V-dependent signaling.J Thromb Haemost 3,1745-1751.
Przepiorka,D.,Weisdorf,D.,Martin,P.,Klingemann,H.G.,Beatty,P.,Hows,J.,and Thomas,E.D.(1995).1994 consensus conference on acute GVHD grading.Bone Marrow Transplant 15,825-828.
Ruggeri,Z.M.(2003).Von Willebrand factor,platelets and endothelial cell interactions.J Thromb Haemost 1,1335-1342.
Shi,T.,Giannakopoulos,B.,Yan,X.,Yu,P.,Berndt,M.C.,Andrews,R.K.,Rivera,J.,Iverson,G.M.,Cockerill,K.A.,Linnik,M.D.,et al.(2006).Anti-β2-glycoprotein I antibodies in complex withβ2-glycoprotein Ican activate platelets in a dysregulated manner via glycoprotein Ib-IX-V.Arthritis Rheum 54,2558-2567.
Tedesco,F.,Pausa,M.,Nardon,E.,Introna,M.,Mantovani,A.,and Dobrina,A.(1997).The cytolytically inactive terminal complement complex activates endothelial cells to express adhesion molecules and tissue factor procoagulant activity.J Exp Med 185,1619-1628.
van Lier,M.,Lee,F.,Farndale,R.W.,Gorter,G.,Verhoef,S.,OhnoIwashita,Y.,Akkerman,J.W.N.,and Heijnen,H.F.G.(2005).Adhesive surface determines raft composition in platelets adhered under flow.JThromb Haemost 3,2514-2525.
van Velzen,J.F.,Laros-van Gorkom,B.A.P.,Pop,G.A.M.,and van Heerde,W.L.(2012).Multicolor flow cytometry for evaluation of platelet surface antigens and activation markers.Thromb Res 130,92-98.
Wang,Y.,Liu,Q.F.,Xu,L.P.,Liu,K.Y.,Zhang,X.H.,Ma,X.,Fan,Z.P.,Wu,D.P.,and Huang,X.J.(2015).Haploidentical vs identical-sibling transplant for AML in remission:a multicenter,prospective study.Blood 125,3956-3962.
Yamazaki,R.,Kuwana,M.,Mori,T.,Okazaki,Y.,Kawakami,Y.,Ikeda,Y.,and Okamoto,S.(2006).Prolonged thrombocytopenia after allogeneic hematopoietic stem cell transplantation:associations with impaired platelet production and increased platelet turnover.Bone Marrow Transplant 38,377-384.
Zhang,X.,Fu,H.,Xu,L.,Liu,D.,Wang,J.,Liu,K.,and Huang,X.(2011).Prolonged thrombocytopenia following allogeneic hematopoietic stem cell transplantation and its association with a reduction in ploidy and an immaturation of megakaryocytes.Biol Blood Marrow Transplant 17,274-280.
Zhang,X.H.,Wang,G.X.,Zhu,H.H.,Liu,Y.R.,Xu,L.P.,Han,W.,Chen,H.,Chen,Y.H.,Wang,F.R.,Wang,J.Z.,et al.(2015a).Recruitment of CD8+T cells into bone marrow might explain the suppression of megakaryocyte apoptosis through high expression of CX3CR1+in prolonged isolated thrombocytopenia after allogeneic hematopoietic stem cell transplantation.Ann Hematol 94,1689-1698.
Zhang,X.H.,Wang,Q.M.,Zhang,J.M.,Feng,F.E.,Wang,F.R.,Chen,H.,Zhang,Y.Y.,Chen,Y.H.,Han,W.,Xu,L.P.,et al.(2015b).Desialylation is associated with apoptosis and phagocytosis of platelets in patients with prolonged isolated thrombocytopenia after allo-HSCT.J Hematol Oncol 8,116-131.
Zhang,X.H.,Wang,Q.M.,Chen,H.,Chen,Y.H.,Han,W.,Wang,F.R.,Wang,J.Z.,Zhang,Y.Y.,Mo,X.D.,Chen,Y.,et al.(2016).Clinical characteristics and risk factors of Intracranial hemorrhage in patients following allogeneic hematopoietic stem cell transplantation.Ann Hematol 95,1637-1643.
Zhang,W.,Gao,F.,Lu,D.,Sun,N.,Yin,X.,Jin,M.,and Liu,Y.(2016).Anti-β2 glycoprotein I antibodies in complex withβ2 glycoprotein Iinduce platelet activation via two receptors:apolipoprotein E receptor 2′and glycoprotein I bα.Front Med 10,76-84.