Early thrombin generation and impaired fibrinolysis after SCT associate with acute GVHD

Abstract

The evolution of coagulation and fibrinolysis has not been thoroughly evaluated in allogeneic SCT. In this pilot study, we characterized the adaptive mechanisms of coagulation and fibrinolysis during allogeneic SCT and 3-month followup and studied possible associations with outcome, including acute GVHD. Thirty patients underwent SCT for a haematological malignancy after myeloablative conditioning. Nineteen patients received the transplant from an HLAidentical sibling and 11 from an unrelated donor. GVHD prophylaxis consisted of CYA and MTX, with methylprednisolone in sibling transplants. Serial coagulation and fibrinolytic activity markers were assessed, including prothrombin fragments 1 þ 2 (F1 þ 2), thrombin time, D-dimer, tissue-type plasminogen-activator (tPA) and plasminogenactivator inhibitor (PAI-1). Early during conditioning therapy, F1 þ 2 and D-dimer increased threefold indicating thrombin generation and fibrin turnover. TPA activity peaked before engraftment, concurring with diminished PAI-1. At 10 days after transplantation shortened thrombin time (o15 s), F1 þ 2 exceeding 0.7 nmol/L and PAI-1 3.0 IU/mL were associated with the development of GVHD. In conclusion, early maladaptation, that is, upregulated thrombin generation and inhibition of fibrinolysis, occurred in one-third of the SCT patients associating with the development of GVHD, a finding suggesting an interplay between coagulation and immunology during SCT.

Efficacy of Recombinant Human Soluble Thrombomodulin in Treating Disseminated Intravascular Coagulation Complicating Allogeneic Hematopoietic Stem Cell Transplantation

“…The mortality rate of patients with hemorrhagic complications was found to be 25% higher than in patients who did not bleed [9]. It has been reported that upregulated thrombin generation and fibrinolysis inhibition occur in one-third of allo-HSCT patients and that this is associated with the development of aGVHD [10]. These findings suggest an interplay between coagulation and immunology following allo-HSCT.…”

Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking

“…On the other hand, increased tPA levels have been reported during sepsis in mice and the early phase of HSCT in humans. 5,[47][48][49] We found that plm is activated during the early phase of aGVHD and endotoxin shock, causing severe tissue destruction. YO-2 can block excessive circulating plm thereby blocking fibrinolysis, without the requirement of binding to the lysine-binding site of the plg molecule-binding fibrin as other plm inhibitors.…”

“…3 The 'cytokine storm' drives the systemic inflammatory response observed in septic shock and aGVHD, accelerates the coagulation/fibrinolytic system and generates an imbalance between coagulation and fibrinolysis. 4,5 Plasmin (plm), a serine protease, is generated by conversion from plasminogen (plg) by two plasminogen activators (PA), such as tissue-type PA (tPA) and urokinase-type PA (uPA). Although tPA has a dominant role in the resolution of fibrin clots (fibrinolysis), uPA can activate extracellular proteolysis during inflammatory processes.…”

The Preventative Effects of Recombinant Thrombomodulin on Transplantation-Associated Coagulopathy after Allogeneic Hematopoietic Stem Cell Transplantation

“…It is thought that the risk for TAC includes many factors, such as age of the patient, basal disease or the degree of disease remission before HSCT [7,8]. Additionally, previous reports have documented the effect of conditioning regimens that included TBI or not [9].…”