Plasma Protein Z and Protein C Inhibitors and Their Role in Hypercoagulability of Thalassemia

Vecchio, Giovanni Carlo Del; Nigro, Antonia; Giordano, Paola; Schettini, F; Altomare, Maria; Pietrapertosa, Anna; Mattia, Domenico De

doi:10.1159/000107924

Cited by 7 publications

(7 citation statements)

References 49 publications

(33 reference statements)

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“…Previous studies have reported decreased PC and PS activity in β-TM [15,19,21] and Hb E/β-thal [22], and decreased PC in β-TI [23]. We observed a significant decrease of PC and PS activity in α-TI and α + β-thal and the PC deficiency was consistent with Type II abnormalities.…”

Section: Discussionsupporting

confidence: 79%

Alterations of anticoagulant proteins and soluble endothelial protein C receptor in thalassemia patients of Chinese origin

Huang¹,

Yuan²,

Deng

et al. 2018

Thrombosis Research

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Background: Thalassemia is characterized by a hypercoagulable state in which the protein C (PC) pathway controls thrombosis. We investigated changes in PC, protein S (PS), antithrombin III (AT III) and soluble endothelial protein C receptor (sEPCR) in thalassemia. Methods: A group of 129 patients with β-thalassemia major (β-TM), β-thalassemia intermedia (β-TI), α-thalassemia intermedia (α-TI) and combined α-/β-thalassemia (α + β-thal) were compared with 32 gender-and age-matched controls. PC, PS, AT III, sEPCR, thrombin-antithrombin complex (TAT), and intercellular adhesion molecule1 (ICAM-1) antigens were measured by enzyme-linked immunosorbent assay. PC, AT III, and PS activity were assayed by substrate chromatography and a prothrombin time (PT)-based free protein S assay. Results: PC deficiency was seen in 95.3% of the patients and PS deficiency was seen in 77.5%. Concomitant reductions in PC and AT III antigen and activity were observed in β-TM, β-TI, and α-TI than in controls (p < 0.005). PC activity was lower in β-TM than in α-TI (p = 0.004). PS antigen was elevated in β-TM (p = 0.011) and sEPCR was elevated in α-TI (p = 0.018). Nonsplenectomized patients had lower PC (p = 0.001) and PS (p = 0.006) and higher sEPCR (p = 0.021) than postsplenectomy patients. Transfusion dependent thalassemia (TDT) patients had lower PC levels (p < 0.005) than those with nontransfusion dependent thalassemia (NTDT). ICAM-1 was increased in patient subgroups (p < 0.001), especially those with splenectomies (p = 0.009), and TAT was increased in all patient subgroups compared with controls (p < 0.001) except for α + β-thal. Conclusions: Deficiencies of anticoagulant proteins and elevated sEPCR contributed to chronic hypercoagulability in these thalassemia patients of Chinese origin. Splenectomy alleviated these alterations in this patient cohort with the median duration since splenectomy of two years. Blood transfusion was not ideal for avoiding thrombosis. 1. Introduction Mutations or deletions of globin genes in thalassemia result in an imbalance of globin synthesis, decreased erythropoiesis, and extravascular hemolysis. Hypercoagulability states are common occurrences in thalassemia patients in southeast Asia, the Mediterranean, and the Middle East regions [1-3]. The prevalence of β-thalassemia is approximately 4.91% and that of α-thalassemia is about 14.13% in the Guangxi province of China, and the various causes of coagulation disorders deserve investigation [4]. Accumulation of unmatched globin chains results in premature destruction of erythrocyte precursors in bone marrow, hemolysis of erythrocytes in the peripheral blood, and the appearance of abnormal red blood cells (RBCs). Loss of deformability impairs passage of RBCs through capillaries [5], and the resulting hemostasis may elicit a procoagulant condition [6]. Other reasons may include endothelial injury, platelet activation, increased plasma microparticles, impaired nitric oxide bioavailability, increased blood oxidants, and phosphatidylserine exposure on the outer ...

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Section: Discussionsupporting

confidence: 79%

Alterations of anticoagulant proteins and soluble endothelial protein C receptor in thalassemia patients of Chinese origin

Huang¹,

Yuan²,

Deng

et al. 2018

Thrombosis Research

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“…Influenceo fr enal insufficiencyand haemodialysis is not clear:inarecent study, asignificant decrease(p=0.022) of PZ wasobservedin46patients with chronic renal diseaseeitheronhaemodialysis or without dialysis (59).H owever,t he difference wasn ot statisticallys ignificant when patients are divided in groups on haemodialysis (23 cases) or without haemodialysis (23 cases).N os ignificant variations were previouslyd escribed in afirst limiteds tudy on 12 adults with glomerulonephritis without nephrotic syndrome and noton haemodialysis (60).Incontrast to the study of Blyth et al 59, PZ levels were found to be enhanced in patients on haemodialysis (60).The main difference betweenthe twogroups of patients on haemodialysis is thatinone study (59),CRP wasslightlyincreased,whereasitwas in anormal range in the other one (60). Peritoneal dialysis doesnot seemtomodify PZ levels (60,61) In addition to the well-known PC deficiencyinthalassemia, ac lear decreaseo fP Zi sa lso observed ( 62). PZ levels are decreased (50.8% )i np atients with malignant tumours, and the deficiencywas morepronounced in the most advanced stages of the tumours (63).…”

Section: Physiopathological Variationsofplasma Pzmentioning

confidence: 99%

Protein Z, a protein seeking a pathology

Vasse¹

2008

Thromb Haemost

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SummaryProtein Z (PZ) is a vitamin K-dependent factor identified in human plasma in 1984 characterized by an homology with other vitamin K-dependent factors (factor VII, IX, X, protein C). In contrast to these factors, PZ does not possess any enzymatic activity but is involved as a cofactor in the down-regulation of coagulation by forming a complex with the protein Z-dependent protease inhibitor (ZPI). ZPI inhibits the activated factor X (FXa) on phospholipid surface. In mice, the disruption of PZ gene is asymptomatic, but the association with the factor V Leiden mutation leads to a quasi complete mortality during the neonatal period with microvascular thrombosis. In humans, PZ is characterized by an unusual wide distribution in plasma, and a major decrease induced by warfarin. Isolated PZ deficiency does not seem to constitute a risk for venous thrombosis, but a severe PZ deficiency could increase the risk of well recognized venous thrombotic risk factors such as factor V Leiden, G20210A mutation or hyperhomocysteinemia. Unexpectedly, a relationship between PZ deficiency and ischemic arterial diseases such as stroke, acute coronary syndromes or peripheral arterial disease was described but not confirmed by all studies. PZ deficiency could be also a risk factor for early fetal losses, and increases the arterial risk in antiphospholipid syndrome. This review analyzes the different studies so far published and discusses the various results obtained in order to understand whether or not protein Z deficiency could be considered as an arterial ischemic risk factor.

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“…In the current study, a significant difference in PZ and ZPI levels was found in patients with thalassemia rather than the control subjects. In contrast, Del Vecchio et al in 2007 have shown reduced levels of PZ in thalassemic patients rather than in healthy subjects by ELISA method [18]. In addition, Gris et al in 2002 andBretelle et al in 2005 have suggested that low serum levels of PZ were associated with thrombosis risk in patients with pregnancy complications by ELISA method [19,20].…”

Section: Discussionmentioning

confidence: 96%

“…It has been suggested that PS acts as a recognition signal of damaged RBCs by phagocytes of 1.53 ± 0.48 0.5 ± 0.24 p = 0.001 PZ, ng/mL (mean ± 2SE) 1031 ± 230 621 ± 156 p = 0.004 NO. number, PZ protein Z, ZPI protein Z-dependent protease inhibitor [18]. Therefore, these damaged cells remain in circulation in splenectomized subjects.…”

Section: Discussionmentioning

confidence: 99%

Plasma Concentrations of Protein Z and Protein Z-Dependent Protease Inhibitor in Thalassemia Major Patients

Ghazanfari

Far

Shirali

et al. 2019

SN Compr. Clin. Med.

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Thalassemia is the most common congenital hemolytic disorder by a partial or complete deficiency in globin chain synthesis. Recent investigations have suggested a correlation between protein Z (PZ) and protein Z-dependent protease inhibitor (ZPI) deficiency and thrombosis. So, the aim of this study was to evaluate the PZ and ZPI levels in beta (β)-thalassemia patients. In this study, 40 patients with thalassemia major and 40 control subjects were selected. PZ and ZPI serum levels were measured by sandwich ELISA technique. PZ and ZPI were significantly higher in thalassemic patient group than control group. Also, PZ levels and PLT and Hb counts were significantly higher in splenectomized thalassemic patients than non-splenectomized ones. The exact mechanism of increased PZ and ZPI have an impact on hypercoagulable state in β-thalassemia major could not be found in our study. More studies are still needed to understand these challenges in β-thalassemia major patients.Keywords Thalassemia major . Protein Z . Protein Z-dependent protease inhibitor . Plasma . Coagulability state Highlights • PZ and ZPI levels were significantly increased in β-thalassemia major group than control group • PZ levels, PLT and Hb counts were significantly increased in splenectomized thalassemic patients than non-splenectomized • PZ and ZPI increased levels did not show the exact influence on coagulability in thalassemia major patients This article is part of the Topical Collection on Medicine.

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Plasma Protein Z and Protein C Inhibitors and Their Role in Hypercoagulability of Thalassemia

Cited by 7 publications

References 49 publications

Alterations of anticoagulant proteins and soluble endothelial protein C receptor in thalassemia patients of Chinese origin

Alterations of anticoagulant proteins and soluble endothelial protein C receptor in thalassemia patients of Chinese origin

Protein Z, a protein seeking a pathology

Plasma Concentrations of Protein Z and Protein Z-Dependent Protease Inhibitor in Thalassemia Major Patients

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