Fibrinogen Fragments X, Y, D and E Increase Levels of Plasma Fibrinogen and Liver mRNAs Coding for Fibrinogen Polypeptides in Rats

1985 ◽  
Vol 53 (02) ◽  
pp. 212-215 ◽  
Author(s):  
H M G Princen ◽  
H J Moshage ◽  
J J Emeis ◽  
H J W de Haard ◽  
W Nieuwenhuizen ◽  
...  
Keyword(s):  
Regulatory Mechanism ◽  
Degradation Products ◽  
Mrna Level ◽  
Plasma Fibrinogen ◽  
Fibrin Degradation Product ◽  
Fibrinogen Degradation Products ◽  
Fibrin Degradation Products ◽  
First Time ◽  
D Dimer

SummaryPreviously, we demonstrated that in vivo regulation of liver fibrinogen synthesis occurs via the fibrinogen mRNA level. However, the molecular regulatory mechanism of fibrinogen synthesis is still not well understood. Fibrinogen or fibrin degradation products might play an important role in regulating fibrinogen synthesis. In our present study, we have injected rats intraperitoneally with purified homologous fragments and measured the liver content of mRNA specific coding for fibrinogen. Increased levels of fibrinogen mRNA and elevated plasma fibrinogen concentrations were observed in rats after administration of fibrinogen degradation products X, Y, DEGTA Dcate or E. Fragment E or E’ has a less stimulatory effect than X, Y or Dcate, whereas cross-linked fibrin degradation product D dimer does not increase fibrinogen synthesis. This article reports for the first time a stimulatory effect of the high molecular weight fibrinogen degradation products on fibrinogen synthesis.

Identification of D-Dimer-E Complex in Disseminated Intravascular Coagulation (DIC)

1979 ◽  
Author(s):  
A.N. Whitaker ◽  
E.A. Rowe ◽  
P.P. Masci ◽  
P.J. Gaffney
Keyword(s):  
Gel Electrophoresis ◽  
Degradation Products ◽  
Polyacrylamide Gel Electrophoresis ◽  
Stable Complex ◽  
Fibrin Degradation Products ◽  
Pneumococcal Sepsis ◽  
D Antigen ◽  
D Dimer

D-dimer (D2), a product of the plasmin lysis of cross-linked (XL) fibrin, but not of non-XL fibrin or fibrinogen, has been identified in the plasma of patients with DIC due to amniotic fluid embolism. In vitro, D is involved with fragment E as a stable complex (D2-E) but D2 -E has not been identified in vivo before. Fibrin degradation products (FDP) were studied in a patient having fulminant postsplenectomy pneumococcal sepsis and DIC, by immunoprecipitation with anti-fibrinogen (f) and anti-fragment E and characterization by SDS polyacrylamide gel electrophoresis (PAGE). With both antisera soluble HMW fibrin complexes, D2 and E but no X, Y or D were obtained from serum. D2 and E were identified in the supernatant after removing partially XL HMW complexes and fibrinogen from plasma with 2.5 M β-alanine. The presence D antigen in the D2-E complex precipitated by monospecific anti-E was confirmed by crossed Ag-Ab electrophoresis. Crossed Ag-Ab electrophoresis of serum in agarose gave E peaks of slow mobility and no fast-moving free E was found. Thus, D2-E complex exists in vivo and its easy identification, proving the lysis of XL fibrin, would be of value in studying thrombosis. D2-E complex has been identified in other patients with sepsis but at lower concentrations than described above.

scholarly journals Fibrin fragment D-dimer and fibrinogen B beta peptides in plasma as markers of clot lysis during thrombolytic therapy in acute myocardial infarction

Blood ◽  
1990 ◽  
Vol 76 (7) ◽  
pp. 1341-1348 ◽  
Author(s):  
CM Lawler ◽  
EG Bovill ◽  
DC Stump ◽  
DJ Collen ◽  
KG Mann ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Degradation Product ◽  
Degradation Products ◽  
Tissue Type ◽  
Clot Lysis ◽  
Fibrin Degradation Product ◽  
Fibrin Degradation Products ◽  
Group 2 ◽  
D Dimer ◽  
Group 1

Abstract The validity of markers in plasma of in vitro thrombolysis was investigated in 12 patients with extensive fibrinogen breakdown (greater than 80%, group 1) and in 12 patients with minimal breakdown (less than 20%, group 2). The patients were treated with 100 mg of recombinant tissue-type plasminogen activator (rt-PA) in the “Thrombolysis in Myocardial Infarction II” (TIMI II) trial. Cross- linked fibrin degradation product levels were measured with two variant enzyme-linked immunosorbent assays (ELISAs), both using a fibrin fragment D-dimer specific capture antibody. In one instance, a tag antibody was used that cross-reacts with fibrinogen (pan-specific tag ELISA); in the other, the tag antibody was specific for fibrin fragment D (fibrin-specific tag ELISA). Apparent concentrations of cross-linked fibrin degradation products at baseline were within normal limits with both assays in most patients. At 8 hours after rt-PA infusion, the measured cross-linked fibrin degradation products were increased about twofold to fourfold in group 2 with both assays. However, in group 1, levels were significantly higher with the pan-specific tag ELISA (5.8 +/- 4.2 micrograms/mL) compared with the fibrin-specific tag ELISA (1.5 +/- 1.3 micrograms/mL). This observation was most likely a result of detection of fibrinogen degradation products in the pan-specific ELISA. Apparent levels of fibrinopeptide B beta 1–42, a marker of fragment X formation, increased during thrombolysis from 4.2 +/- 2.8 pmol/mL to 2,000 +/- 230 pmol/mL in group 1 and from 4.1 +/- 2.1 pmol/mL to 300 +/- 43 pmol/mL in group 2, and were correlated significantly with the extent of fibrinogen breakdown (r = -0.8). Fibrinopeptide beta 15–42 levels increased from 4.3 +/- 3 pmol/mL to 70 +/- 19 pmol/mL in group 1, but did not increase in group 2. The apparent increase in group 1 could be explained by cross-reactivity of fibrinopeptide B beta 1–42 in the fibrinopeptide beta 15–42 assay. We conclude that cross-linked fibrin degradation product levels as measured with a pan-specific tag ELISA and fibrinopeptide beta 15–42 levels as measured with certain monoclonal antibody-based ELISA are influenced by the extent of fibrinogen degradation. Fibrinopeptide B beta 1–42 is a marker specific for fibrinogen breakdown. Cross-linked fibrin degradation product levels, measured with a fibrin-specific tag ELISA, appear to be markers specific for thrombolysis. Consequently, assays similar to the fibrin- specific tag ELISA may provide more accurate information when correlated with clinical endpoints.

The Fibrin Assay Comparison Trial (FACT)

2001 ◽  
Vol 85 (04) ◽  
pp. 671-678 ◽  
Author(s):  
Sybille Zips ◽  
Hanimsah Ergül ◽  
Dieter Heene ◽  
Carl-Erik Dempfle ◽  
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Degradation Products ◽  
Plasma Samples ◽  
Fibrin Degradation Products ◽  
Comparison Trial ◽  
Clinical Conditions ◽  
D Dimer

SummaryAlthough D-dimer has gained widespread clinical use as a parameter for detection of in vivo fibrin formation, the issue of standardization of D-dimer assays remains to be resolved. The FACT study was performed to generate basic data for development of calibrators and standard preparations.A set of 86 samples, including plasma samples from patients with DIC, DVT, and other clinical conditions, serial dilutions of pooled plasma samples, and plasma samples containing fibrinogen- and fibrin derivatives, were distributed to 12 manufacturers of D-dimer assays.D-dimer assays differ concerning specificity for crosslinked fibrin, and preference for either high molecular weight fibrin complexes, or low molecular weight fibrin degradation products. Terminal plasmin digests of fibrin clots for calibration produce aberrant results in some assays, especially those with preference for high molecular weight crosslinked fibrin derivatives. The best conformity is achieved by the use of pooled plasma samples from patients with high levels of D-dimer antigen in plasma. In vitro preparations containing a comparable composition of fibrin derivatives to clinical plasma samples may also serve as reference material.

Unreliability of Current Serum Fibrin Degradation Product (FDP) Assays

1985 ◽  
Vol 53 (03) ◽  
pp. 301-302 ◽  
Author(s):  
P J Gaffney ◽  
M J Perry
Keyword(s):  
Monoclonal Antibodies ◽  
Serum Level ◽  
Degradation Product ◽  
Degradation Products ◽  
Polyclonal Antibodies ◽  
Fibrin Degradation Product ◽  
Serum Samples ◽  
Fibrinogen Degradation Products ◽  
A Value

SummaryPreviously, assays of fibrin-fibrinogen degradation products (FDP) had to be performed on serum samples. However, monoclonal antibodies (Mabs) are now available which permit the measurement of FDP directly in plasma. We have employed two Mabs, one monospecific for FDP originating from crosslinked fibrin and another panspecific for the FDP fraction, to determine normal FDP levels in plasma and serum. The monospecific Mab gave a value of 40 ng FDP/ml in plasma and 10 ng/ml in serum, while the serum level of FDP recorded using the panspecific Mab was >1000 ng/ml, at all the concentrations of thrombin employed. Similarly, when a solution of purified fibrinogen was treated with thrombin, the concentration of FDP present in the clot supernatant was >1000 ng/ml when assayed using the panspecific Mab. Thus during serum preparation as much as 75% of the native FDP is incorporated into the clot while in excess of 1000 ng/ml of laboratory generated FDP, probably incompletely polymerized fibrin, is measured using panspecific antisera. These data indicate that current FDP assays using polyclonal antibodies are not a reliable reflection of the FDP level generated in vivo. The use of FDP-specific Mabs which do not react with fibrinogen is recommended for future FDP assays performed directly on plasma.

CLINICAL RELEVANCE OF PLASMA FIBRIN DEGRADATION PRODUCTS DETERMINATION IN PATIENTS WITH DEEP VEIN THROMBOSIS (DVT)

1987 ◽  
Author(s):  
M F Aillaud ◽  
C Roul ◽  
A Elias ◽  
J L Bouvier ◽  
A Serradimigni ◽  
...  
Keyword(s):  
Degradation Products ◽  
Group Versus ◽  
Failure Group ◽  
Vein Thrombosis ◽  
Fibrin Degradation Products ◽  
Successful Group ◽  
The Mean ◽  
Deep Vein ◽  
D Dimer

We have studied fibrin degradation products, D-dimer, in citrated plasma with an ELISA assay using monoclonal antibodies (Asserachrom D-Di Stago).35 patients with DVT< 7 days were studied at day O (DO) that is upon admission before treatment with streptokinase (n=6), heparin (n=5) or LMWH CY222 Choay (n=24). Phlebographies were scored by Marder’s index (MI).At DO, MI = 24.28 ± 10.85 (m ± SD), the mean (± SD) of D-dimer was : 4056 ± 5545 ng/ml (range 950-19000) (normal values < 500 ng/ml). No correlation was found between D-dimer and MI and between D-dimer and clinical delay of DVT.The evolution of D-dimer was studied during 7 days in patients treated with heparin or LMWH (n=29). Blood sampling was undertaken at DO and at 8 h AM, 1 hour before injection at Dl, D3, D5, D7. The evolution of thrombolysis was evaluated by comparing MI at DO and D7. Among patients with MI at DO < 10 (n=25) two groups were compared : - successful group : 8 patients with decrease of MI at D7 < 80% ; - failure group : 11 patients with decrease of MI at D7< 20% : D-dimer at DO were higher in successful group (p< 0.05) ; these results could be explained by better endogenous thrombolysis in this group. The percentages of the decrease of D-dimer at D3 and at D7 compared to DO were higher in the successful group : Successful group versus Failure group (m ± SD) = % decrease at D3 : 46.4 ± 29.2/ 13.4 ± 11 (p< 0.05) ; % decrease at D7 : 52.3 ± 31.5/ 24.2 ± 26.3 (p<0.05) (in agreement with Soria and al, -IX th International Congress of Phlebology, September 1986, Kyoto) ; these results could be explained by a smaller clot mass to be lysed in successful group.In conclusion the level of D-dimer at DO and the intensity of the decrease of D-dimer during 7 days (as from D3) may have a predictive value for in vivo thrombolysis.

scholarly journals Fibrin fragment D-dimer and fibrinogen B beta peptides in plasma as markers of clot lysis during thrombolytic therapy in acute myocardial infarction

Blood ◽  
1990 ◽  
Vol 76 (7) ◽  
pp. 1341-1348 ◽  
Author(s):  
CM Lawler ◽  
EG Bovill ◽  
DC Stump ◽  
DJ Collen ◽  
KG Mann ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Degradation Product ◽  
Degradation Products ◽  
Tissue Type ◽  
Clot Lysis ◽  
Fibrin Degradation Product ◽  
Fibrin Degradation Products ◽  
Group 2 ◽  
D Dimer ◽  
Group 1

The validity of markers in plasma of in vitro thrombolysis was investigated in 12 patients with extensive fibrinogen breakdown (greater than 80%, group 1) and in 12 patients with minimal breakdown (less than 20%, group 2). The patients were treated with 100 mg of recombinant tissue-type plasminogen activator (rt-PA) in the “Thrombolysis in Myocardial Infarction II” (TIMI II) trial. Cross- linked fibrin degradation product levels were measured with two variant enzyme-linked immunosorbent assays (ELISAs), both using a fibrin fragment D-dimer specific capture antibody. In one instance, a tag antibody was used that cross-reacts with fibrinogen (pan-specific tag ELISA); in the other, the tag antibody was specific for fibrin fragment D (fibrin-specific tag ELISA). Apparent concentrations of cross-linked fibrin degradation products at baseline were within normal limits with both assays in most patients. At 8 hours after rt-PA infusion, the measured cross-linked fibrin degradation products were increased about twofold to fourfold in group 2 with both assays. However, in group 1, levels were significantly higher with the pan-specific tag ELISA (5.8 +/- 4.2 micrograms/mL) compared with the fibrin-specific tag ELISA (1.5 +/- 1.3 micrograms/mL). This observation was most likely a result of detection of fibrinogen degradation products in the pan-specific ELISA. Apparent levels of fibrinopeptide B beta 1–42, a marker of fragment X formation, increased during thrombolysis from 4.2 +/- 2.8 pmol/mL to 2,000 +/- 230 pmol/mL in group 1 and from 4.1 +/- 2.1 pmol/mL to 300 +/- 43 pmol/mL in group 2, and were correlated significantly with the extent of fibrinogen breakdown (r = -0.8). Fibrinopeptide beta 15–42 levels increased from 4.3 +/- 3 pmol/mL to 70 +/- 19 pmol/mL in group 1, but did not increase in group 2. The apparent increase in group 1 could be explained by cross-reactivity of fibrinopeptide B beta 1–42 in the fibrinopeptide beta 15–42 assay. We conclude that cross-linked fibrin degradation product levels as measured with a pan-specific tag ELISA and fibrinopeptide beta 15–42 levels as measured with certain monoclonal antibody-based ELISA are influenced by the extent of fibrinogen degradation. Fibrinopeptide B beta 1–42 is a marker specific for fibrinogen breakdown. Cross-linked fibrin degradation product levels, measured with a fibrin-specific tag ELISA, appear to be markers specific for thrombolysis. Consequently, assays similar to the fibrin- specific tag ELISA may provide more accurate information when correlated with clinical endpoints.

Influence of Acute Myocardial Infarction and rt-PA Therapy on Circulating Fibrinogen

1993 ◽  
Vol 69 (04) ◽  
pp. 321-327 ◽  
Author(s):  
E Seifried ◽  
M Oethinger ◽  
P Tanswell ◽  
E Hoegee-de Nobel ◽  
W Nieuwenhuizen
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Thrombolytic Agent ◽  
Degradation Products ◽  
Maximum Plasma ◽  
Normal Range ◽  
Fibrinogen Degradation Products ◽  
Fibrin Degradation Products ◽  
Rebound Phenomenon ◽  
The Mean

SummaryIn 12 patients treated with 100 mg rt-PA/3 h for acute myocardial infarction (AMI), serial fibrinogen levels were measured with the Clauss clotting rate assay (“functional fibrinogen”) and with a new enzyme immunoassay for immunologically intact fibrinogen (“intact fibrinogen”). Levels of functional and “intact fibrinogen” were strikingly different: functional levels were higher at baseline; showed a more pronounced breakdown during rt-PA therapy; and a rebound phenomenon which was not seen for “intact fibrinogen”. The ratio of functional to “intact fibrinogen” was calculated for each individual patient and each time point. The mean ratio (n = 12) was 1.6 at baseline, 1.0 at 90 min, and increased markedly between 8 and 24 h to a maximum of 2.1 (p <0.01), indicating that functionality of circulating fibrinogen changes during AMI and subsequent thrombolytic therapy. The increased ratio of functional to “intact fibrinogen” seems to reflect a more functional fibrinogen at baseline and following rt-PA infusion. This is in keeping with data that the relative amount of fast clotting “intact HMW fibrinogen” of total fibrinogen is increased in initial phase of AMI. The data suggest that about 20% of HMW fibrinogen are converted to partly degraded fibrinogen during rt-PA infusion. The rebound phenomenon exhibited by functional fibrinogen may result from newly synthesized fibrinogen with a high proportion of HMW fibrinogen with its known higher degree of phosphorylation. Fibrinogen- and fibrin degradation products were within normal range at baseline. Upon infusion of the thrombolytic agent, maximum median levels of 5.88 μg/ml and 5.28 μg/ml, respectively, were measured at 90 min. Maximum plasma fibrinogen degradation products represented only 4% of lost “intact fibrinogen”, but they correlatedstrongly and linearly with the extent of “intact fibrinogen” degradation (r = 0.82, p <0.01). In contrast, no correlation was seen between breakdown of “intact fibrinogen” and corresponding levels of fibrin degradation products. We conclude from our data that the ratio of functional to immunologically “intact fibrinogen” may serve as an important index for functionality of fibrinogen and select patients at high risk for early reocclusion. Only a small proportion of degraded functional and “intact fibrinogen”, respectively, is recovered as fibrinogen degradation products. There seems to be a strong correlation between the degree of elevation of fibrinogen degradation products and the intensity of the systemic lytic state, i.e. fibrinogen degradation.

The Leukocyte Digestion of Fibrinogen Degradation Products (FDP)

1971 ◽  
Vol 26 (03) ◽  
pp. 523-525
Author(s):  
K Gibiński ◽  
B Lipiński ◽  
M Trusz-Gluza
Keyword(s):  
Degradation Products ◽  
Fibrinogen Degradation Products

SummaryWhile the native fibrinogen is not digested by the leucocyte proteases both the early and late FDP are digestible without any denaturating reagent. Thus, this reaction may occur in vivo indicating an unknown role of granulocytes in paracoagulation.

MONOCLONAL ANTIBODIES OF THE IgM AND IgG CLASS SPECIFIC FOR CROSSLINKED FIBRIN DEGRADATION PRODUCTS

1987 ◽  
Author(s):  
P J Gaffney ◽  
L J Creighton ◽  
A Curry ◽  
B MacMahon ◽  
R Thorpe
Keyword(s):  
Monoclonal Antibodies ◽  
Thrombolytic Therapy ◽  
Epitope Mapping ◽  
Degradation Products ◽  
Subcutaneous Route ◽  
Fibrin Degradation Products ◽  
Conformational Epitopes ◽  
Immunoglobulin Class Switching ◽  
Unique Specificity ◽  
D Dimer

Monoclonal antibodies (mabs) to crosslinked fibrin degradation products (XL-FDP) having the general formula D/Y[X]nY/D (known as X-oligomer) and D-D (known as D dimer) have been raised in balb/C mice by both a novel mtrasplenic and a conventional subcutaneous route of immunisation and by combinations of both these procedures. Mabs to X-oligomers (NIBn 52 and NIBn 123) obtained by an intrasplenic procedure have been demonstrated to crossreact only with X-oligomer in a 2-site ELISA procedure and not with D dimer or whole fibrinogen and have been shown to be of value m the examination of clinical material obtained from patients with various types of thrombosis and have also been useful in monitoring the efficacy of thrombolytic therapy. The X-oligomer mabs are immunoglobulins of the M class. It was demonstrated that their unique specificity for conformational epitopes on the large X-oligomer fragments does not reside in the IgM structure since alterative immunisation procedures have been used to generate mabs of the IgG class which have the same specificity. Using immunoglobulin class switching in culture rather than during immunisation was suggested by certain cell lines which produced both IgM and IgG specific for X-oligomer. This latter point needs rigorous validation.Immunoglobulin G type mabs to highly purified D dimer were raised by conventional subcutaneous immunisation of balb/C mice. One of these, NIBn-11, was found to crossreact with PVC-immobilised X-oligomer and D dimer but not with fibrinogen. However NIBn-11 did not bind to D dimer in a 2-site ELISA procedure while crossreactmg quite avidly with X-oligomer. This suggests that the D dimer epitope to which NIBn-11 is directed is expressed in some conformations and not m others and that these conformations are always expressed in the complex X-oligomer group of fragments. These mabs, whilst of value in measuring certain unique fibrin fragments m plasma, are useful in the epitope mapping of fibrinogen/fibrin and their plasmm-mediated

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