Activation of Coagulation and Fibrinolysis Following OKT3 Administration to Renal Transplant Recipients: Association with Distinct Mediators

Abstract

SummaryTreatment with OKT3 induces cytokine release and activates the complement system. Since both phenomena may affect coagulation and fibrinolysis we studied these systems in 8 renal transplant recipients during OKT3 treatment. In 8 of 9 patients a similar pattern was observed: plasma thrombin-antithrombin-III-complex, tissue-type plasminogen-activator and plasmin-α2-antiplasmin-complex levels were increased as compared to pretreatment levels (p <0.05) at 15 min after the first OKT3 dose and reached peak values at 1 h. No significant changes were observed upon subsequent OKT3 administrations or in a control group of 8 patients. In one patient upon the first OKT3 administration only complement activation, and no cytokine release was observed, whereas plasma thrombin-antithrombin-III-complex, tissue-type plasminogen-activator and plasmin-α2-antiplasmin-complex levels increased only at 15 min.In conclusion, we demonstrate a biphasic activation of coagulation and fibrinolysis upon the first OKT3 dose; the initial phase seems to be associated with complement activation, the later phase with cytokine release.

In vivo effects of IgA and IgG2a anti-CD3 isotype switch variants.

“…In contrast, T3.G2a induces a rapid activation offibrinolysis, as evidenced by increased levels oftPA and PAPc at 1 h, followed by a gradual activation ofthe common pathway of coagulation, as evidenced by slightly increased levels of F1 + 2 at 6 h. In our opinion, the elevated baseline values of F1 + 2 in our patients can be ascribed to recent surgery (renal transplantation). Our results are in agreement with other reports in which activation of fibrinolysis and coagulation have been described after the administration of TNF to healthy humans (40,50), and after the administration of OKT3 to renal transplant recipients (24). Considering the recently described dose-dependent increased incidence of thrombotic complications after OKT3 treatment (26), the absence of effects on coagulation and fibrinolysis may offer an additional advantage to T3.A.…”

“…Prothrombin activation fragment Fl + 2 was determined with a commercially available ELISA (Behringwerke AG, Marburg, Germany). Levels of tissue-type plasminogen activator (tPA) and plasmin-a2-antiplasmin complex (PAPc) were measured as described previously (24,34). The upper limit of values in plasma of 20 healthy controls, defined as mean + 2 SD was 40 pg/ml (TNF-a), 13 pg/ml (IL-6), 1 U/ml (y-IFN), 5 nmol/l (C3a-desarg), 55 nmol/l (C4b/c), 424 ng/ml (lactoferrin), 117 ng/ml (elastase-a,-AT), 1.1 nmol/l (F 1 + 2), 10,ug/l (tPA) and 7 nmol/l (PAPc).…”

Monoclonal Antibody Therapy and Renal Transplantation: Focus on Adverse Effects

“…Additionally, in most cases this syndrome may be, also, associated with: nephropathy as consequence of the enhanced cytokines synthesis and a decrement in the intra-renal prostaglandin synthesis [ 111 ]; pulmonary edema , due to the concomitant complement-related vascular endothelium damage [ 112 ]; central nervous system (CNS) complications associated to an activation of T-cells that directly attack specific CNS elements; activation of coagulation and fibrinolysis due to complement activation and cytokine release itself leading to graft thrombosis [ 113 , 114 , 115 ].…”

Acute Thrombosis of the Renal Transplant Artery after a Single Dose of OKT3

“…However, the first injection of OKT3 results in massive leukocyte activation, leading to the well-known OKT3 first-dose cytokine release syndrome [16,17]. OKT3 has been associated with an increased incidence of early irreversible intragraft thrombosis, leading to graft loss [18][19][20]. These thrombotic events occur most often during the course of the 1st posttransplant week and involve either renal arteries, veins, or glomerular capillaries [18].…”

“…These thrombotic events occur most often during the course of the 1st posttransplant week and involve either renal arteries, veins, or glomerular capillaries [18]. The procoagulant effects of OKT3 are through induction of the expression of a procoagulant molecule, tissue factor, at the surface of both monocytes [21][22][23] and endothelial cells [22] which activates the extrinsic coagulation pathway [19,20]. OKT3 also triggers the systemic release of tumor necrosis factor alpha, interleukin 2, and interferon gamma [16,19], tumor necrosis factor alpha inducing tissue factor mediated procoagulant activity [19].…”