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

<div><p>Background</p><p>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. The purpose of this study was to define changes in natural anticoagulants over time in association with GVHD.</p><p>Patients and methods</p><p>This 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.</p><p>Results</p><p>Overall, 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.</p><p>Conclusion</p><p>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. The suboptimal control of coagulation by natural anticoagulants at early stage of SCT may contribute to onset of GVHD.</p></div

Variability of APC-PCI between different time points during allogenic SCT.

<p>Activated protein C complexed with its inhibitor (APC-PCI) was measured at 6 time points. Data are presented as median values and error bars as the 25^th and 75^th percentiles; comparisons were with baseline values; d = transplantation/graft infusion day; * = p < 0.05; ** = p < 0.001.</p

Correlations between PC, FVIII and AT at different stages afte allogenic graft infusion.

<p>Correlations between PC, FVIII and AT at different stages afte allogenic graft infusion.</p

Natural anticoagulants and endothelial activation markers associated with aGVHD.

<p>Differences between the group of acute GVHD (aGVHD+, N = 8) and without GVHD (aGVHD-, N = 22), are depicted for (A) FVIII, (B) s-TM endothelial antigen, (C) protein C (PC) activity and (D) antithrombin. Data on panels (A) and (B) are presented as median values with error bars as the 25^th and 75^th percentiles; and on panels (C) and (D) as mean values and error bars as the standard errors; d = transplantation day; * = p < 0.05; ** = p < 0.01.</p

Longitudinal changes of endothelial activation markers and natural anticoagulants in allogenic SCT/graft infusion.

<p>Endothelial markers: (A) Factor VIII with coagulant activity (FVIII:C); (B) soluble thrombomodulin antigen (s-TM Ag); (C) soluble thrombomodulin activity (s-TM Act) are shown at 6–7 time points during allogenic SCT treatment. Activities of natural anticoagulants: (D) protein C; (E) antithrombin; and (F) protein S were measured at 7–8 time points. Data points represent median values and error bars—25^th and 75^th percentiles; comparisons were with baseline values. The horizontal line depicts lower and upper normal reference limits; d = transplantation /graft infusion day; * = p < 0.05; ** = p < 0.001.</p