scholarly journals Studies on the Contact System of Coagulation during Therapy with High Doses of Recombinant IL-2: Implications for Septic Shock

1991 ◽  
Vol 65 (05) ◽  
pp. 497-503 ◽  
Author(s):  
C Erik Hack ◽  
John Wagstaff ◽  
Robert J M Strack Van Schijndel ◽  
Anke J M Eerenberg ◽  
Herbert M Pinedo ◽  
...  
Keyword(s):  
Septic Shock ◽  
Day Treatment ◽  
Interleukin 2 ◽  
Acute Phase Reactant ◽  
Contact System ◽  
Factor Xii ◽  
Protein Leakage ◽  
Sds Page ◽  
Plasma Factor ◽  
High Doses

SummaryPatients treated with high doses of interleukin-2 (IL-2) because of cancer, develop hemodynamic and vasopermeability changes, that resemble those observed in sepsis. These patients thus provide a unique opportunity to study the early events in the development of septic shock. We analysed the changes that occurred in the contact system of coagulation in plasma from 4 patients, who together received seven 12-day cycles of high doses of IL-2. Levels of factor XII and prekallikrein during the cycles progressively fell to 50 and 30% of their initial levels, respectively, whereas significant increases in plasma factor XIIa-and kallikrein-C1-inhibitor complexes were not observed (in 3 out of 211 samples slightly increased levels of both complexes were found). The reductions in factor XII and prekallikrein were only in part due to protein leakage, since levels were still significantly lower, i. e., 80 and 50%, respectively, when corrected for albumin decreases. Levels of high molecular weight kininogen (HMWK) also decreased during IL-2 therapy, however, this decrease paralleled that of albumin. SDS-PAGE analysis of plasma HMWK did not reveal increased cleavage of this protein. The reduction of factor XII and prekallikrein, corrected for protein leakage, significantly correlated with albumin levels and inversely with daily cumulative weight gain in the patients.Thus, we demonstrate that factor XII and prekallikrein decrease during IL-2 therapy. As these decreases, already observed after 1 day treatment, were disproportional to that of albumin, a negative acute phase reactant, and correlated with signs of the vascular leak syndrome, we favor the explanation that they reflected activation rather than a decreased synthesis of the contact system proteins. Further studies are needed to substantiate this hypothesis.

scholarly journals Quantification of plasma factor XIIa-Cl(-)-inhibitor and kallikrein-Cl(- )-inhibitor complexes in sepsis

Blood ◽  
1988 ◽  
Vol 72 (6) ◽  
pp. 1841-1848 ◽  
Author(s):  
JH Nuijens ◽  
CC Huijbregts ◽  
AJ Eerenberg-Belmer ◽  
JJ Abbink ◽  
RJ Strack van Schijndel ◽  
...  
Keyword(s):  
Septic Shock ◽  
Molar Ratio ◽  
Plasma Kallikrein ◽  
Factor Xii ◽  
Plasma Samples ◽  
Contact Activation ◽  
Highly Sensitive ◽  
Plasma Factor ◽  
Factor Xiia ◽  
Serial Samples

Abstract Considerable evidence indicates that activation of the contact system of intrinsic coagulation plays a role in the pathogenesis of septic shock. To monitor contact activation in patients with sepsis, we developed highly sensitive radioimmunoassays (RIAs) for factor XIIa-Cl(- )-inhibitor (Cl(-)-Inh) and kallikrein-Cl(-)-Inh complexes using a monoclonal antibody (MoAb Kok 12) that binds to a neodeterminant exposed on both complexed and cleaved Cl(-)-Inh. Plasma samples were serially collected from 48 patients admitted to the intensive care unit because of severe sepsis. Forty percent of patients on at least one occasion had increased levels of plasma factor XIIa-Cl(-)-Inh (greater than 5 x 10(-4) U/mL) and kallikrein-Cl(-)-Inh (greater than 25 x 10(- 4) U/mL), that correlated at a molar ratio of approximately 1:3. Levels of factor XII antigen in plasma and both the highest as well as the levels on admission of plasma factor XIIa-Cl(-)-Inh in 23 patients with septic shock were lower than in 25 normotensive patients (P = .015: factor XII on admission; P = .04: highest factor XIIa-Cl(-)-Inh; P = .01: factor XIIa-Cl(-)-Inh on admission). No significant differences in plasma kallikrein-Cl(-)-Inh or prekallikrein antigen were found between these patients' groups. Elevated Cl(-)-Inh complex levels were measured less frequently in serial samples from patients with septic shock than in those from patients without shock (P less than .0001). Based on these results, we conclude that plasma Cl(-)-Inh complex levels during sepsis may not properly reflect the extent of contact activation.

Detection of Activation of the Contact System of Coagulation In Vitro and In Vivo: Quantitation of Activated Hageman Factor-C1-Inhibitor and Kallikrein-C1-Inhibitor Complexes by Specific Radioimmunoassays

1987 ◽  
Vol 58 (02) ◽  
pp. 778-785 ◽  
Author(s):  
J H Nuijens ◽  
C C M Huijbregts ◽  
M Cohen ◽  
G O Navis ◽  
A de Vries ◽  
...  
Keyword(s):  
Contact System ◽  
Factor Xii ◽  
Plasma Samples ◽  
C1 Inhibitor ◽  
Hageman Factor ◽  
Plasma Factor ◽  
Factor Xiia ◽  
Kallikrein Activity

SummaryRadioimmunoassays (RIAs) for the detection of C1-inhihitor (C1-Inh) complexed to either kallikrein or activated Hageman factor (factor XIIa) are described. Kallikrein-C1-Inh or factor XIIa-C1-Inh complexes were bound to Scpharosc to which monospecific antibodies against (pre)kallikrein or factor XII, respectively, were coupled. Bound complexes were subsequently detected by an incubation with affinity purified 125I-labeled antibodies against Ci-Inh. These RIAs were used to detect activation of the contact system of coagulation in vitro and in vivo. Addition of dextran sulfate (DXS) (20 μg/ml) to fresh plasma resulted at 37° C in the rapid generation of amidolytic kallikrein activity, which was maximal after 1 to 2 min of incubation and subsequently decreased within a few minutes. The generation of kallikrein activity coincided with the appearance of both kallikrein-C1-Inh and factor XIIa-C1-Inh complexes. However, in contrast to kallikrein activity, both types of complexes remained detectable in the incubation mixtures during the incubation period. Experiments with purified kallikrein, C1-Inh and partly purified β-factor XIIa, and activation experiments in plasmas deficient in either factor XII or prekallikrein, demonstrated the specificity of both RIAs. The minimal amount of DXS that resulted in the generation of measurable amounts of both types of complexes in plasma was 2-3 μg per ml. Similar experiments with kaolin showed that with limiting amounts of activator (1-2 mg/ ml), only kallikrein-C1-Inh complexes were detected in plasma. When larger amounts of kaolin were added to plasma, factor XIIa-C1-Inh complexes were additionally detected in plasma. In plasma samples obtained from healthy donors under conditions that prevented activation of the contact system in vitro, very low levels of both factor XIIa-C1-Inh and kallikrein-C1-Inh complexes were measured, representing approximately 0.3% activation of both factor XII and prekallikrein. In serial plasma samples from a patient with adult respiratory distress syndrome, increased levels of both types of complexes were detected. The radioimmunoassays described in this paper provide useful tools to detect activation of the contact system in vitroas well as in vivo.

scholarly journals Quantification of plasma factor XIIa-Cl(-)-inhibitor and kallikrein-Cl(- )-inhibitor complexes in sepsis

Blood ◽  
1988 ◽  
Vol 72 (6) ◽  
pp. 1841-1848 ◽  
Author(s):  
JH Nuijens ◽  
CC Huijbregts ◽  
AJ Eerenberg-Belmer ◽  
JJ Abbink ◽  
RJ Strack van Schijndel ◽  
...  
Keyword(s):  
Septic Shock ◽  
Molar Ratio ◽  
Plasma Kallikrein ◽  
Factor Xii ◽  
Plasma Samples ◽  
Contact Activation ◽  
Highly Sensitive ◽  
Plasma Factor ◽  
Factor Xiia ◽  
Serial Samples

Considerable evidence indicates that activation of the contact system of intrinsic coagulation plays a role in the pathogenesis of septic shock. To monitor contact activation in patients with sepsis, we developed highly sensitive radioimmunoassays (RIAs) for factor XIIa-Cl(- )-inhibitor (Cl(-)-Inh) and kallikrein-Cl(-)-Inh complexes using a monoclonal antibody (MoAb Kok 12) that binds to a neodeterminant exposed on both complexed and cleaved Cl(-)-Inh. Plasma samples were serially collected from 48 patients admitted to the intensive care unit because of severe sepsis. Forty percent of patients on at least one occasion had increased levels of plasma factor XIIa-Cl(-)-Inh (greater than 5 x 10(-4) U/mL) and kallikrein-Cl(-)-Inh (greater than 25 x 10(- 4) U/mL), that correlated at a molar ratio of approximately 1:3. Levels of factor XII antigen in plasma and both the highest as well as the levels on admission of plasma factor XIIa-Cl(-)-Inh in 23 patients with septic shock were lower than in 25 normotensive patients (P = .015: factor XII on admission; P = .04: highest factor XIIa-Cl(-)-Inh; P = .01: factor XIIa-Cl(-)-Inh on admission). No significant differences in plasma kallikrein-Cl(-)-Inh or prekallikrein antigen were found between these patients' groups. Elevated Cl(-)-Inh complex levels were measured less frequently in serial samples from patients with septic shock than in those from patients without shock (P less than .0001). Based on these results, we conclude that plasma Cl(-)-Inh complex levels during sepsis may not properly reflect the extent of contact activation.

Activation of the Intrinsic Pathway of Coagulation in Children with Meningococcal Septic Shock

1995 ◽  
Vol 74 (06) ◽  
pp. 1436-1441 ◽  
Author(s):  
Walter A Wuillemin ◽  
Karin Fijnvandraat ◽  
Bert H F Derkx ◽  
Marjolein Peters ◽  
Willem Vreede ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Septic Shock ◽  
Intensive Care ◽  
Contact System ◽  
Morbidity And Mortality ◽  
Factor Xii ◽  
C1 Inhibitor ◽  
Intrinsic Pathway ◽  
Factor Xi ◽  
Meningococcal Septic Shock

SummaryMeningococcal septic shock (MSS) is complicated by activation of coagulation, fibrinolytic, and complement systems. We studied the contact system of the intrinsic pathway of coagulation in thirteen children with MSS. Activation was assessed upon admittance to the intensive care unit and 48 h thereafter, based on the measurement of factor XII- (FXII), prekallikrein- and factor XI (FXI) antigen levels, as well as on the detection of FXIa-FXIa inhibitor, FXIIa-C1-inhibitor, and kallikrein-C1-inhibitor complexes, respectively. Levels of FXII, prekallikrein and FXI were reduced to about 50% in all patients on admission, and were significantly higher 48 h later. FXIIa-C1-inhibitor complexes were elevated in 7 patients, and kallikrein-C1-inhibitor complexes in 2 patients. FXIa-α1-antitrypsin complexes were elevated in all patients, FXIa-C1-inhibitor complexes in nine, and FXIa-anti-thrombin III complexes in one patient. We conclude that patients with MSS have activation of the contact system, which may contribute to activation of coagulation, and thus to morbidity and mortality.

C1-inhibitor substitution therapy in septic shock and in the vascular leak syndrome induced by high doses of interleukin-2

1993 ◽  
Vol 19 (S1) ◽  
pp. S19-S28 ◽  
Author(s):  
C. E. Hack ◽  
A. C. Ogilvie ◽  
B. Eisele ◽  
A. J. M. Eerenberg ◽  
J. Wagstaff ◽  
...  
Keyword(s):  
Septic Shock ◽  
Interleukin 2 ◽  
C1 Inhibitor ◽  
Vascular Leak Syndrome ◽  
Substitution Therapy ◽  
Vascular Leak ◽  
High Doses

Plasma Prekallikrein Activity in Patients with Total Hip Arthroplasty

1987 ◽  
Vol 58 (04) ◽  
pp. 1040-1042
Author(s):  
J J M L Hoffmann ◽  
J H J P M Kortmann
Keyword(s):  
Total Hip Arthroplasty ◽  
Hip Arthroplasty ◽  
Hip Prosthesis ◽  
Contact System ◽  
Factor Xii ◽  
Total Hip ◽  
Activity Factor ◽  
Patient Groups ◽  
Kallikrein Activity

SummaryThe behaviour of the contact system was studied in 40 patients with total hip arthroplasty, by measuring plasma prekallikrein, spontaneous kallikrein activity and factor XII. In the literature it had been shown that patients with complications from this operation had decreased prekallikrein and increased kallikrein activity (M. Nakahara. Acta orthop scand 1982; 53: 591-6). In the present study, comprising patients with and without pain and proven loosening of the hip prosthesis, these findings could only partially be confirmed. Patients with a loosened prosthesis had significantly lower prekallikrein (mean 0.78 ± 0.28 U/ml; p <0.01) than patients without problems, but no detectable kallikrein activity in plasma. Patients with pain but no loosening had normal prekallikrein (1.04 ±0 0.26 U/ml) and also no demonstrable kallikrein activity. Factor XII was normal in all patient groups. It is concluded that decreased prekallikrein is limited to patients with a loosened hip prosthesis, with or without pain.

Plasma Factor XIII and Platelet Factor XIII in Hyperlipaemia

1976 ◽  
Vol 36 (03) ◽  
pp. 542-550 ◽  
Author(s):  
Mircea P. Cucuianu ◽  
K Miloszewski ◽  
D Porutiu ◽  
M. S Losowsky
Keyword(s):  
Factor Xiii ◽  
Significant Contribution ◽  
Quantitative Assay ◽  
Factor Xii ◽  
Platelet Factor ◽  
Type Iv ◽  
Plasma Factor ◽  
Hepatic Synthesis

SummaryPlasma factor XIII activity measured by a quantitative assay was found to be significantly higher in hypertriglyceridaemic patients (type IV and combined hyperlipoproteinaemia), as compared to normolipaemic controls. No such elevation in plasma factor XIII activity was found in patients with type IIa hyperlipaemia. Plasma pseudocholinesterase was found to parallel the elevated factor XIII activity in hypertriglyceridaemic subjects.In contrast, platelet factor XIII activity was not raised in hyperlipaemic subjects, and plasma factor XIII was found to be normal in a normolipaemic subject with throm-bocythaemia.It was concluded that there is no significant contribution from platelets to plasma factor XIII activity, and that the observed increase in plasma factor XII in hypertriglyceridaemia results from enhanced hepatic synthesis of the enzyme.

Western Blot Analyses of Prekallikrein and its Activation Products in Human Plasma

1991 ◽  
Vol 65 (04) ◽  
pp. 382-388 ◽  
Author(s):  
Dulce Veloso ◽  
Robert W Colman
Keyword(s):  
Complex Formation ◽  
Western Blot ◽  
Human Plasma ◽  
Contact System ◽  
Plasma Activation ◽  
Normal Plasma ◽  
Sds Page ◽  
Activation Products ◽  
Major Antigen ◽  
Formation Of Complexes

SummaryPrekallikrein (PK), a zymogen of the contact system, and its activation products, kallikrein (KAL), KAl-inhibitor complexes and fragments containing KAL epitope(s) have been detected in human plasma by immunoblotting with a monoclonal anti-human plasma PK antibody, MAb 13G1L. Detection of antigen-MAb 13G11 complexes with peroxidase-conjugated anti-IgG showed that the two variants of PK (85- and 88-kDa) are the only major antigen species in normal, non-activated plasma. Upon plasma activation with kaolin, the intensity of the PK bands decreased with formation of complexes of KAL with CL inhibitor (C1 INH) and α2-rrtzcroglobulin (α2M) identical to those formed by the purified proteins. Immunoblots of normal plasma showed good correlation between the PK detected and the amount of plasma assayed. Increasing amounts of KAL incubated with a constant volume of PK-deficient plasma showed increasing amounts of KAL and of KAL-C1 INH and KAL-α2M complexes. Complexes of KALantithrombin III (ATIII) and the ratio of KALα2M/ KAL-CL INH were higher in activated CL INH-deficient plasmas than in activated normal plasmas. Protein resolution by 3-12% gradient SDS-PAGE and epitope detection with [125I]MAb 13G11 showed four KALα2M species and a 45-kDa fragment(s) in both surface-activated normal plasma and complexes formed by purified KAL and α2M. Immunoblots of activated plasma also showed bands at the position of KALCL INH and KALATIII complexes. When α1-antitrypsin Pittsburgh (cα1-AT, Pitts) was added to plasma before activation, KAL-α1-ALPitts was the main complex. The non-activated normal plasma revealed only an overloaded PK band. This is the first report of an antibody that recognizes KAL epitope(s) in KAL-α2M, KALATIII and KALa1-α1Pitts complexes and in the 45-kDa fragment(s). Therefore, MAb 13G11 should be useful for studying the structure of these complexes as well as the mechanism of complex formation. In addition, immunoblotting with MAb 13G11 would allow detection of KAl-inhibitor complexes in patient plasmas as indicators of activation of the contact system.

Plasma Contact Activation and Decrease of Factor V Activity on Negatively-Charged Polyelectrolytes

1984 ◽  
Vol 51 (01) ◽  
pp. 061-064 ◽  
Author(s):  
M C Boffa ◽  
B Dreyer ◽  
C Pusineri
Keyword(s):  
Time Dependent ◽  
Initial Contact ◽  
Factor Xii ◽  
Factor V ◽  
Contact Activation ◽  
Polyelectrolyte Complexes ◽  
Plasma Factor ◽  
Fresh Plasma ◽  
Direct Adsorption

SummaryThe effect of negatively-charged polymers, used in some artificial devices, on plasma clotting and kinin systems was studied in vitro using polyelectrolyte complexes.Contact activation was observed as an immediate, transient and surface-dependent phenomenon. After incubation of the plasma with the polymer a small decrease of factor XII activity was noticed, which corresponded to a greater reduction of prekallikrein activity and to a marked kinin release. No significant decrease of factor XII, prekallikrein, HMW kininogen could be detected immunologically. Only the initial contact of the plasma with the polyelectrolyte lead to activation, subsequently the surface became inert.Beside contact activation, factor V activity also decreased in the plasma. The decrease was surface and time-dependent. It was independent of contact factor activation, and appeared to be related to the sulfonated groups of the polymer. If purified factor V was used instead of plasma factor V, inactivation was immediate and not time-dependent suggesting a direct adsorption on the surface. A second incubation of the plasma-contacted polymer with fresh plasma resulted in a further loss of Factor V activity.

Interleukin-2 acutely induces protein leakage from the microcirculation

1991 ◽  
Vol 50 (6) ◽  
pp. 609-615 ◽  
Author(s):  
Michael J. Edwards ◽  
Dale A. Schuschke ◽  
Deanna L. Abney ◽  
Frederick N. Miller
Keyword(s):  
Interleukin 2 ◽  
Protein Leakage
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