Hemostasis and complement in allogeneic hematopoietic stem cell transplantation: clinical significance of two interactive systems

Abstract

Hematopoietic stem cell transplantation (HCT) represents a curative treatment option for certain malignant and nonmalignant hematological diseases. Conditioning regimens before HCT, the development of graft-versus-host disease (GVHD) in the allogeneic setting, and delayed immune reconstitution contribute to early and late complications by inducing tissue damage or humoral alterations. Hemostasis and/or the complement system are biological regulatory defense systems involving humoral and cellular reactions and are variably involved in these complications after allogeneic HCT. The hemostasis and complement systems have multiple interactions, which have been described both under physiological and pathological conditions. They share common tissue targets, such as the endothelium, which suggests interactions in the pathogenesis of several serious complications in the early or late phase after HCT. Complications in which both systems interfere with each other and thus contribute to disease pathogenesis include transplant-associated thrombotic microangiopathy (HSCT-TMA), sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), and GVHD. Here, we review the current knowledge on changes in hemostasis and complement after allogeneic HCT and how these changes may define clinical impact.

Fig. 1. Simplified scheme of the coagulation (left panel) and complement (right panel) cascades active on a fictitious endothelial lesion.

A dotted line separates the illustration of the two biological systems only for better understanding. The endothelial bed as a common ground upon which they develop, binds the systems functionally and can promote activation and bilateral interaction of both mechanisms, depending on the nature or the intensity of the triggering event. LEFT PANEL: Va, Xa, VII, IX, XI, XII: coagulation enzymes, PreK: precallikrein, TF: tissue factor, Ca + +: calcium ions, green arrows: activation of the extrinsic pathway of coagulation, red arrow: activation of the intrinsic pathway of coagulation, bluish arrows: activation of the common pathway. RIGHT PANEL: Activation of the complement system over three distinct pathways going over to a common amplification loop and thus triggering humoral and/or cellular innate immunity reactions [7, 16].

Fig. 2. Simplified scheme of the coagulation (left panel) and complement (right panel) cascades on a fictitious common endothelial lesion.

Horizontal arrows depict interactions of components of the two systems illustrating how hemostasis can activate complement and vice versa (Va, Xa, VII, IX, XI, XII: coagulation enzymes, PreK: precallikrein, TF: tissue factor, Ca + +: calcium ions, MASP-2: mannose-binding protein-associated serine protease-2, MAC: membrane attack complex, C3a-C3b-C5a: complement factors). LEFT PANNEL: Red arrows illustrate how components of the coagulation system can activate complement at various levels of the cascade implicating the impact of coagulation on innate immunity reactions. RIGHT PANNEL: Grey arrows illustrate how complement components can activate coagulation reactions at variable levels of the cascade linking inflammatory reactions to thrombotic events [7, 16].

Fig. 3

Simplified scheme of the complement cascade and mode of action of drugs in clinical use or development as complement inhibitors in the HSCT setting (MASP-2: mannose-binding protein-associated serine protease-2, C1-C3-C5: Complement factors, conv.: convertase) [16].