Generation of the Complement Activation Product C5a Precedes Interleukin-2-Induced Capillary Leakage Syndrome

Heying

Burdach

et al. 1997

Annals of Hematology

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The prognosis of patients with severe capillary leakage syndrome (CLS) after bone marrow transplantation (BMT) is dismal despite aggressive use of intensive care therapy. Because the activated classical pathway of complement and relatively low levels of C1 esterase inhibitor (C1 INH) activity are known features in these patients, we evaluated the efficacy of a therapy using purified, human C1 INH concentrate. Severe CLS was defined as increase in body weight by more than 3% within 24 h combined with generalized edema, impaired hemodynamic system (tachycardia and/or decreased blood pressure), and non-responsiveness to furosemide. Of 142 patients, 22 developed severe CLS. The first seven patients whom we diagnosed with this complication were assessed as control patients. Fifteen patients with severe CLS were treated with C1 INH concentrate using a cumulative dose of 180 units/kg body wt. (initial dose: 60 units/kg, followed by two doses at 30 units/kg and four doses at 15 units/kg, every 12 h). The survival rate of patients with CLS was 57% at 1 year after BMT in the C1 INH treatment group, compared with 14% in the control group (p = 0.008). Eight of 15 treated patients are alive at a median of 9 months (range: 4-55) after BMT. The plasma levels of the complement activation parameters C4d and C5a were 3 +/- 1.1 mg/dl (mean +/- S.D.) and 0.3 +/- 0.1 microgram/l, respectively, prior to BMT, increasing to 8.2 +/- 2.1 mg/dl and 1.3 +/- 0.4 micrograms/l, respectively, at diagnosis of CLS. After infusion of C1 INH concentrate the plasma levels of C5a and C4d normalized. The activity of C1 INH rose to 139 +/- 10% of normal human plasma NHP pool (mean +/- S.D.) after infusion. The CH50 values were not significantly altered. The fluid status normalized within 11 days in 14 of 15 treated patients. The results of this study suggest that therapy with C1 INH concentrate improves the prognosis of patients with CLS after BMT. This has to be confirmed in a randomized, controlled trial.

Section: Laboratory Methodsmentioning

confidence: 99%

“…C1 INH activity [10] and hemolytic activity of the classical pathway (CH50) [18] were measured using chromogenic assays as previously desbribed [21]. There was no parameter available to us for assessing direct-contact activation; instead, prekallikrein activity was determined using a chromogenic assay system [22]. …”

Section: Laboratory Methodsmentioning

confidence: 99%

C1 esterase inhibitor concentrate for capillary leakage syndrome following bone marrow transplantation

Heying

Burdach

et al. 1997

Annals of Hematology

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“…Activated endothelial cells undergo structural changes which expose subendothelial structures to plasma proteins and may induce activation of the complement system [21]. Increased plasma levels of the complement activation product C5a, which is an inductor of edema, have been reported in CLS after BMT [15] and after IL-2 therapy [16].…”

Section: Discussionmentioning

confidence: 99%

Risk factors for capillary leakage syndrome after bone marrow transplantation

Willers

Burdach

et al. 1997

Annals of Hematology

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Age, hematopoietic growth factors, cyclosporin A, mode of bone marrow transplantation (BMT) (autologous, allogeneic-related, unrelated), and underlying disease were assessed as potential risk factors for capillary leakage syndrome (CLS) in 96 patients after BMT. CLS was defined as unexplained weight gain of > 3% within 24 h and nonresponsiveness to furosemide. CLS occurred in 9/21 patients after unrelated compared with 2/33 after allogeneic-related BMT (p = 0.0017) for hematopoietic disorders (n = 54) and in 6/7 patients after allogeneic-related compared with 3/35 after autologous BMT (p = 0.001) for solid tumors (n = 42). Hematopoietic growth factors and cyclosporin A were no significant risk factors on their own. We conclude that unrelated BMTs or high-intensity conditioning regimens used in combination with allogeneic-related BMT are the main risk factors for CLS.

“…Regarding the pathophysiology of CLS, we measured the C5a level as a significant parameter for complement activation in these patients. 8 Because the VOD treatment (anticoagulants) does not influence the associated vascular hyperpermeability, we intended to inhibit complement activation by C1-INH-C. 4,8 C5a levels decreased from 2.4 g/l on day +14 to 0.94 g/l on day +19. We observed clinical resolution of the symptoms as decreased weight to baseline, improved jaundice and cardiovascular function during therapy with rt-PA and C1-INH-C.…”

Section: 3mentioning

confidence: 99%

“…An activation of the complement system via the classical pathway has been described in CLS after interleukin-2 therapy as well as after BMT. 5,8 Because the above mentioned treatment of VOD does not address the problem of complement activation, further to rt-PA, our patient received C1 esterase inhibitor (C1-INH-C) as the main physiological inhibitor of the classical pathway of the complement system. 5 VOD is divided into mild, moderate and severe forms with respect to severity of jaundice, weight gain, edema and ascites.…”

mentioning

confidence: 99%

Hepatic veno-occlusive disease with severe capillary leakage after peripheral stem cell transplantation: treatment with recombinant plasminogen activator and C1-esterase inhibitor concentrate

Heying

Spiekerkötter

et al. 1998

Bone Marrow Transplant

Summary:Severe veno-occlusive disease (VOD), characterised by elevated serum bilirubin levels, is a known complication in the first 3 weeks after peripheral blood stem cell transplantation (PBSCT). Severe VOD is associated with capillary leakage and multiple organ dysfunction and leads to high mortality. We report a 17-year-old male, who developed VOD with capillary leakage (CL) after allogeneic PBSCT. The patient presented with a maximum serum bilirubin of 25.4 mg/dl, weight gain (10% of baseline weight), generalized edema, cardiovascular insufficiency, complement activation, jaundice and a decreased AT and protein C functional activity. After VOD and CL were diagnosed the patient was treated with recombinant human plasminogen activator (rt-PA) and C1 esterase-inhibitor concentrate (C1-INH-C). The clinical symptoms resolved and the patient's status stabilized. The patient was in an adequate clinical state 5 months after transplantation. We noted that the combined therapy with rt-PA and C1-INH-C in this high-risk situation led to a resolution of VOD with CL. Keywords: veno-occlusive disease; capillary leakage; rt-PA; C1 esterase inhibitor Hepatic VOD is a complication after peripheral blood stem cell transplantation which presents with different degrees of severity. Liver damage caused by obliteration of the hepatic venules by fibrin material and sinusoidal congestion is suggested as the pathophysiological cause.1,2 Therefore the usual therapy for severe VOD is based on the principle of anticoagulation with heparin, recombinant plasminogen activator (rt-PA) and antithrombin (AT) substitution. 2,3A condition of vascular hyperpermeability classified as systemic capillary leak syndrome (CLS) is known as associated with or isolated from VOD.1,4 Hypovolemic shock and organ dysfunction are the clinical consequences of a fluid and protein shift from the intravascular to the interCorrespondence: Dr R Heying,