Coordinated responses of natural anticoagulants to allogeneic stem cell transplantation and acute GVHD - A longitudinal study.

Beata Przybyla,Lotta Joutsi-Korhonen,Ann-Kristin Öhlin,Anne Pinomäki,Jari Petäjä,Andreas Hillarp,Liisa Volin,Riitta Lassila,Karin Strandberg,Tapani Ruutu

doi:10.1371/journal.pone.0190007

Beata Przybyla, Lotta Joutsi-Korhonen + Show 8 more

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https://doi.org/10.1371/journal.pone.0190007

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Abstract

BackgroundAllogeneic stem cell transplantation (SCT) enhances coagulation via endothelial perturbation and inflammation. Role of natural anticoagulants in interactions between coagulation and inflammation as well as in acute graft-versus-host disease (GVHD) are not well known. The purpose of this study was to define changes in natural anticoagulants over time in association with GVHD.Patients and methodsThis prospective study included 30 patients who received grafts from siblings (n = 19) or unrelated donors (n = 11). Eight patients developed GVHD. Standard clinical assays were applied to measure natural anticoagulants, represented by protein C (PC), antithrombin (AT), protein S (PS), complex of activated PC with its inhibitor (APC-PCI) and by markers of endothelial activation: Factor VIII coagulant activity (FVIII:C) and soluble thrombomodulin (s-TM) at 6–8 time points over three months.ResultsOverall, PC, AT and FVIII:C increased in parallel after engraftment. Significant correlations between PC and FVIII:C (r = 0.64–0.82, p<0.001) and between PC and AT (r = 0.62–0.81, p<0.05) were observed at each time point. Patients with GVHD had 21% lower PC during conditioning therapy and 55% lower APC-PCI early after transplantation, as well as 37% higher values of s-TM after engraftment. The GVHD group had also increases of PC (24%), FVIII: C (28%) and AT (16%) three months after transplantation.ConclusionThe coordinated activation of natural anticoagulants in our longitudinal study indicates the sustained ability of adaptation to endothelial and inflammatory activation during allogenic SCT treatment. The suboptimal control of coagulation by natural anticoagulants at early stage of SCT may contribute to onset of GVHD.

Highlights

Allogeneic stem cell transplantation (SCT) is the most efficient, and often the only curative treatment modality in various, usually malignant hematological disorders
Standard clinical assays were applied to measure natural anticoagulants, represented by protein C (PC), antithrombin (AT), protein S (PS), complex of activated PC with its inhibitor (APC-PCI) and by markers of endothelial activation: Factor VIII coagulant activity (FVIII:C) and soluble thrombomodulin (s-TM) at 6–8 time points over three months
The coordinated activation of natural anticoagulants in our longitudinal study indicates the sustained ability of adaptation to endothelial and inflammatory activation during allogenic SCT treatment

Summary

Introduction

Allogeneic SCT is the most efficient, and often the only curative treatment modality in various, usually malignant hematological disorders. Conditioning therapy is used to eradicate hematological cancers, but is mandatory to avoid rejection of the graft. This therapy causes vascular injury [1] leading to activation of coagulation. Coagulation is controlled by natural anticoagulants such as PC and AT. The key activator of coagulation pathway, activates PC by binding to endothelial TM. AT inhibits thrombin and other coagulation factors by binding active site, and this process is enhanced by endothelial heparan sulphate. Allogeneic stem cell transplantation (SCT) enhances coagulation via endothelial perturbation and inflammation. Role of natural anticoagulants in interactions between coagulation and inflammation as well as in acute graft-versus-host disease (GVHD) are not well known.

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