scholarly journals Inhibition of Factor XI by Myeloma Protein M.

1977 ◽  
Author(s):  
A. Rimon ◽  
I. Raz ◽  
M. Lahav

Waldenstrom’s macroglobulinemia sometimes involves hemostatic disorders. It has been assumed that this may be due to interaction of the myeloma protein with soom blood coagulation factor(s). In the present investigation the sera of seven myeloma patients were studied for a possible interaction between the myeloma protein and clotting factors II, VIM, IX and XI.Normal human plasma was incubated for 30 mi η at 37°C with different dilutions of patients’ serum or of purified myeloma proteins. The ability of this mixture to restore the clotting times of various deficient plasmas was tested by the partial thromboplastin time test.Factor XI activity of normal plasma was substantially inhibited upon incubation with patient’s serum or with purified myeloma protein M. This effect seems to be specific for myeloma protein M since it was neither observed with myeloma proteins G or A, nor with normal IgM. Other coagulation factors investigated so far were not inhibited by myeloma protein M. It is concluded that this protein is specifically affine to factor XI resulting in hindering the latter’s activity.

Blood ◽  
1979 ◽  
Vol 54 (4) ◽  
pp. 850-862 ◽  
Author(s):  
RJ Jr Mandle ◽  
AP Kaplan

Human coagulation factor XI has been purified, and upon activation with Hageman factor fragments, was found to convert the fibrinolytic proenzyme plasminogen to plasmin. This proactivator activity was shown to be functionally and antigenically distinct from prekallikrein. When the gamma-globulin fractions of plasma deficient in Hageman factor, prekallikrein and factor XI were isolated, factor-XI-deficient plasma possessed two-thirds of the plasminogen proactivator activity of the Hageman-factor-deficient plasma, while prekallikrein deficient plasma had only one-third of the plasminogen proactivator activity. Thus, the Hageman-factor-dependent plasminogen proactivator previously reported to be present in the gamma-globulin fraction of normal human plasma is a function of prekallikrein and factor XI, while the activity observed in prekallikrein-deficient plasma is attributable to factor XI. When compared utilizing digestion of iodinated fibrin, prekallikrein and factor XIa had similar potency per active site; they were, however, far less active than urokinase.


2021 ◽  
Vol 20 (4) ◽  
pp. 209-213
Author(s):  
S. A. Volkova ◽  
D. A. Kudlay ◽  
M. D. Bogomolova ◽  
E. A. Sirotkin ◽  
Yu. A. Sorokina

The prolongation of survival and the improvement of quality of life in patients with hemophilia A and B are only possible if hemostatic disorders caused by coagulation factor VIII and IX deficiency are managed effectively. Recombinant coagulation factors are playing an ever-increasing role in the preventive care of affected patients. The development, production and use of domestic recombinant coagulation factors opened up new treatment opportunities and improved access to preventive care for hemophilia patients. The results of clinical studies on the efficacy and safety of the Russian recombinant factors showed that they had similar efficacy and safety compared to the plasma derived clotting factors. 


Blood ◽  
1979 ◽  
Vol 54 (4) ◽  
pp. 850-862 ◽  
Author(s):  
RJ Jr Mandle ◽  
AP Kaplan

Abstract Human coagulation factor XI has been purified, and upon activation with Hageman factor fragments, was found to convert the fibrinolytic proenzyme plasminogen to plasmin. This proactivator activity was shown to be functionally and antigenically distinct from prekallikrein. When the gamma-globulin fractions of plasma deficient in Hageman factor, prekallikrein and factor XI were isolated, factor-XI-deficient plasma possessed two-thirds of the plasminogen proactivator activity of the Hageman-factor-deficient plasma, while prekallikrein deficient plasma had only one-third of the plasminogen proactivator activity. Thus, the Hageman-factor-dependent plasminogen proactivator previously reported to be present in the gamma-globulin fraction of normal human plasma is a function of prekallikrein and factor XI, while the activity observed in prekallikrein-deficient plasma is attributable to factor XI. When compared utilizing digestion of iodinated fibrin, prekallikrein and factor XIa had similar potency per active site; they were, however, far less active than urokinase.


Blood ◽  
1977 ◽  
Vol 49 (2) ◽  
pp. 219-231 ◽  
Author(s):  
R Egbring ◽  
W Schmidt ◽  
G Fuchs ◽  
K Havemann

To show whether direct proteolysis of coagulation factors may play a role in patients with so-called consumption coagulopathy, granulocytic neutral proteases in the plasma of patients with acute myelocytic leukemia and septicemia were assayed by one- and two-dimensional Laurell electrophoresis. Complexes between serum alpha1-antitrypsin and elastase-like granulocytic protease could be demonstrated in those patients with acute myelocytic leukemia and septicemia who also had moderate or severe coagulation defects. Despite the presence of a high antiprotease potential, addition of the elastase-like enzyme to normal plasma resulted in coagulation defects in vitro comparable to those seen in the patients. These results and the ability of the elastase- like protease to destroy isolated clotting factors suggested that in certain types of coagulation factor deficiencies direct proteolysis rather than consumption of clotting factors due to disseminated intravascular coagulation may be operational.


1988 ◽  
Vol 59 (02) ◽  
pp. 151-161 ◽  
Author(s):  
Bernhard Lämmle ◽  
Bruce L Zuraw ◽  
Mary Jo Heeb ◽  
Hans Peter Schwarz ◽  
Mauro Berrettini ◽  
...  

SummaryA method for the quantitative assay of native single chain and kallikrein cleaved two-chain high molecular weight (HMW)-kininogen in plasma is described. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of whole plasma is followed by electrotransfer of the electropherogram to nitrocellulose membranes and detection of the blotted HMW-kininogen with its physiologic ligands, radiolabeled plasma prekallikrein or radiolabeled factor XI. Using unreduced SDS-PAGE cleaved two-chain HMW-kininogen (Mr ∼107,000 and 95,000), is elec-trophoretically separated from uncleaved single chain HMW-kininogen (Mr ∼150,000). Counting the radioactivity of the nitrocellulose pieces corresponding to cleaved HMW-kininogen permits its quantitative measurement by comparison with standards consisting of decreasing amounts of fully dextran sulfate activated normal human plasma. Single chain HMW-kininogen is similarly assayed using reduced SDS-PAGE and unactivated normal human plasma standards.This technique is highly specific and sensitive to about 50 ng of either cleaved or uncleaved HMW-kininogen. Varying amounts of cleaved HMW-kininogen were found in a small series of plasmas from patients suffering from various inflammatory conditions. Higher levels of in vivo cleaved HMW-kininogen were observed during acute attacks of hereditary angioedema due to Cl-inhibitor deficiency. This technique may be useful for the assessment of the degree of in vitro or in vivo activation of the contact system.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2728-2728
Author(s):  
Karen Matevosyan ◽  
Michael Cimo ◽  
Christopher Madden ◽  
Ravindra Sarode

Abstract OBJECTIVE: To investigate hemostatically important clotting factors in patients with mild to moderate prolongation of PT/INR, who generally receive prophylactic FFP transfusions, especially in neurosurgery, because there is scant data in the literature supporting prophylactic plasma therapy. METHODS: 36 plasma samples from 31 neurosurgical patients with PT/INR 12.5–15.0/1.3–1.5 were separated and frozen within 8 hours of collection; these were tested for coagulation factors II, VII and VIII levels, and PT/INR/PTT values were correlated with the factor levels. Retrospective analysis of all neurosurgery patients for whom FFP was ordered with similar PT/INR values was performed both during 5 months of study period and 5 months post-study period, when changes were implemented in FFP administration guidelines. The PT/INR/PTT values were studied 24 hours following the FFP requests in order to evaluate the effect of plasma infusion. Each group was divided in two subgroups: those who received FFP transfusion within 24 hours of the FFP requests, and those who did not. RESULTS: PT/INR/PTT and coagulation factor levels of the 36 samples are seen in Table 1. PT mean 13.78 INR mean 1.38 PTT mean 29.29 PT median 13.5 INR median 1.3 PTT median 29.5 PT range 10.7–18.6 INR range 0.9–1.9 PTT range 19.3–37.9 FII mean 68% FVII mean 53% FVIII mean 156% FII median 66% FVII median 51% FVIII median 126% FII range 34–107% FVII range 28–124% FVIII range 55–547% There was no correlation between PT/INR with FVII levels (p>0.05). All patients had FVII > 15–25%, level recommended as safe for surgery. FII was also hemostatically normal, whereas mean factor VIII level was elevated, that correlated with shortened PTT in many of these patients. Retrospective analysis revealed that during the study period there were a total of 99 FFP requests (69 patients). Of these 68 requests (46 patients) did and 31 (29 patients) did not receive FFP transfusions within the next 24 hours. Mean number of FFP units transfused was 3.03 (median 2, range 1–7). During the post study period a total of 15 requests (for 14 patients) were received; of these 2 did and 13 did not receive FFP transfusions within the next 24 hours. Mean and median number of FFP was 2. PT/INR/PTT at time of request and 24 hours post transfusion are presented in the Table 2 Study Period (99 FFP requests) Post Study Period (15 FFP requests) Transfused (68) Non-Transfused (31) Transfused (2) Non-Transfused (13) At FFP Request At 24 hrs At FFP Request At 24 hrs At FFP Request At 24 hrs At FFP Request At 24 hrs *PT;†INR;♠PTT 13.42* 12.1 11.9 11.29 14.1 12.8 12.22 11.54 1.3† 1.18 1.16 1.1 1.4 1.3 1.18 1.14 28.9♠ 27.98 27.65 27.43 26.6 27.1 27.4 26.99 CONCLUSION: In patients with a mild prolongation of PT/INR, plasma levels of FII and FVII were hemostatically normal, whereas FVIII levels were increased. After FFP transfusions, PT/INR and PTT values did not change suggesting that plasma therapy in these patients was not warranted. After the study there was a drastic reduction (85%) in FFP orders for prophylactic plasma transfusions.


1987 ◽  
Author(s):  
B Lämmle ◽  
B L Zuraw ◽  
M J Heeb ◽  
H P Schwarz ◽  
J G Curd ◽  
...  

A method for the quantitative assay of native single chain and kallikrein cleaved two-chain high molecular weight kininogen (HMWK) in plasma has been developed. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of whole plasma is followed by electroblotting of the electropherogram to nitrocellulose membranes and detection of the inmobilized HMWK with its physiologic ligands, plasma prekallikrein or factor XI. Using 1251-prekallikrein or 125I-F.XI overlay nitrocellulose bound HMWK can be visualized by autoradiography.Using unreduced SDS-PAGE cleaved two-chain HMWK (Mr 107,000 and 95,000) is electrophoretically separated from uncleaved single chain HMWK (Mr 150,000). Counting the radioactivity of the nitrocellulose pieces corresponding to cleaved HMWK permits its quantitative measurement by comparison with standards consisting of decreasing amounts of fully dextran sulfate activated normal human plasma. Single chain HMWK is similarly assayed using reduced SDS-PAGE and unactivated normal human plasma standards.This technique is highly specific and sensitive to ˜ 50 ng of either cleaved or uncleaved HMWK. Varying concentrations of cleaved HMWK were found in plasmas from patients suffering from various systemic inflanmatory conditions. Higher levels of in vivo cleaved HMWK were observed during acute attacks of hereditary angioedema due to Cl-inhibitor deficiency.This technique may be useful for the assessment of the degree of in vitro or in vivo activation of the contact system of plasma.


Blood ◽  
1977 ◽  
Vol 49 (2) ◽  
pp. 219-231 ◽  
Author(s):  
R Egbring ◽  
W Schmidt ◽  
G Fuchs ◽  
K Havemann

Abstract To show whether direct proteolysis of coagulation factors may play a role in patients with so-called consumption coagulopathy, granulocytic neutral proteases in the plasma of patients with acute myelocytic leukemia and septicemia were assayed by one- and two-dimensional Laurell electrophoresis. Complexes between serum alpha1-antitrypsin and elastase-like granulocytic protease could be demonstrated in those patients with acute myelocytic leukemia and septicemia who also had moderate or severe coagulation defects. Despite the presence of a high antiprotease potential, addition of the elastase-like enzyme to normal plasma resulted in coagulation defects in vitro comparable to those seen in the patients. These results and the ability of the elastase- like protease to destroy isolated clotting factors suggested that in certain types of coagulation factor deficiencies direct proteolysis rather than consumption of clotting factors due to disseminated intravascular coagulation may be operational.


1981 ◽  
Author(s):  
Hyman Engelberg ◽  
Stephen Lee

The scientific literature is contradictory as to the normal presence of heparin activity in human blood. The question has physiologic and clinical significance. The purpose of this study was to investigate whether biologic heparin activity was demonstrable in extracts of normal human plasma. The method involved initial precipitation of the plasma proteins by methanol-acetone, proteolysis of the precipitated proteins by papase or trypsin, dialysis of the supernatant, lyophilization, and then assay. The final extract showed heparin activity using the Kabi chromogenic substrate, the activated partial thromboplastin time test, and the anti factor Xa procedure. The level of heparin activity was 10-25 units % (app. 1-2 mg/L of plasma). We conclude that endogenous heparin activity is present in normal human plasma at physiologically significant levels, and that it is protein bound.


1975 ◽  
Author(s):  
W. Schmidt ◽  
R. Egbring ◽  
K. Havemann ◽  
H. Beeser

To examine whether direct proteolysis of coagulation factors may play a role in patients with so called consumption coagulopathy, an elastase-like and a chymotrypsin-like neutral protease isolated from human granulocytes were investigated for their influence on several purified clotting factors. The elastaselike protease induced a rapid destruction of fibrinogen, factors II, VIII, XII and XIII activity, whereas a moderate effect on factor V and VII activity was observed. The chymotrypsin-like enzyme showed a rapid inactivation of factor VIII, moderate effect on factor VII and XIII and only a weak activity against fibrinogen, factor II and XIII. Incubation of factor V with both enzymes leads to a transitory activation. In spite of the presence of a high antiprotease potential in plasma, addition of the elastase-like enzyme to normal plasma resulted in an activation of several coagulation factors. As it has been shown that the proteases are activity released from granulocytes in presence of antigen-antibody complexes, endotoxin and polynucleotides, the results given above together with the appearence of granulocytic proteases in the plasma of patients with acute leucemia and septicemia suggest that in certain types of coagulation factor deficiencies direct proteolysis rather than consumption of clotting factors due to dissiminated intravascular coagulation may be operational.


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