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The degradation of soluble versus insoluble fibrin in vivo
THROXlBOSIS RESE-RCH Printed in the United
LETTER
Vol.
States
TO THE
8, PP. 119-120, Pergamon Press,
1976 Inc.
EDITORS-IN-CHIEF
THE DEGRADATION OF SOLUBLE VERSUS INSOLUBLE FIBRIN IN VIVO.
Boguslaw Lipinski and Victor Gurewich
Vascular Laboratory, Lemuel Shattuck Hospital, Tufts University School of Medicine, Boston, Massachusetts 02130, U.S.A.
(Received
23.10.1975; Accepted by
in revised Editor A.L.
form 10.12.1975. Copley)
In a recent article McKillop, Edgar, Forbes and Prentice (1) suggested that "the digestion of soluble fibrin could represent an important pathway for the production of FDP in viva." This conclusion was based on the following observations in ancrod-treated patients: 1. Lack of intact c(chain in eluate fractions containing soluble fibrin complexes obtained from the plasma of patients by agarose gel filtration. 2. The finding by polyacrylamide gel electrophoresis of a greater loss of a chain in the eluate fractions containing soluble complexes compared to those containing the main (fibrinogen) peak. 3. A rapid fall in plasminogen and fibrinogenydincrease in FDP in the blood of ancrod-treated patients. 4. Reference to a previous study (2) showing preferential degradation of soluble fibrin compared to fibrinogen in streptokinase (SK) treated plasma. As the authors suggest, their findings could be explained by the direct lysis of soluble fibrin. Alternatively, the lysis of ancrod-induced fibrin deposits is also consistent with these observations. The authors' preference for the former explanation may be related to the fact that they have overlooked some publications which indicate that fibrinogen and its soluble derivatives are resistant to degradation by naturally induced fibrinolytic activity. When fibrinolytic activity is induced in vivo by venous occlusion (3), exercise (4), or death (S), there is rapid lysis of clotted or precipitated fibrinogen but no degradation of fibrinogen, soluble fibrin or FDP even after 24 hours incubation of plasma samples. In experimental animals, the clearance of soluble fibrin has been shown to occur by the initial intravascular precipitation of fibrin and subsequent lysis rather than by direct lysis of circulating soluble fibrin (6). The resistance of fibrinogen and its soluble derivatives to degradation by fibrinolytic activity has been attributed to the action of a specific and potent antiactivator found in large excess in human blood (7). We have demonstrated highly preferential binding of this antiactivator to vascular plasminogen activator compared to SK or urokinase (UK). Lysis of fibrin or precipitated fibrinogen requires dissociation of the
119
120
II'JVIVO DEGRADATION
OF FIBRINS
Vol.8,No.l
activator-antiactivator complex which occurs only on a solid phase thus allowing the activator to induce the conversionof plasminogento plasmin. Therefore,experimentalor clinical findings based on the effect of SK or UK must be interpretatedwith considerablecaution. We agree that soluble fibrin is degraded preferentiallyover fibrinogenin SK activatedplasma, but this is not the case when fibrinolyticactivity is induced by natural activators found in blood. In summary, the authors data do not warrant the conclusionthat soluble fibrin is degraded in vivo by plasmin. It is far more likely that ancrodinduced soluble fibrin is first precipitatedand then lysed and that FDP originate entirely from fibrin and not from soluble fibrin complexes. The concept of a preferentialproteolysisof soluble fibrin in vivo remains a speculationunsupportedby fact. REFERENCES 1.
MCKILLOP, D., EDGAR, W., FORBES, C.D. and PRENTICE,C.R.M.: In vivo production of soluble complexes containing fibrinogen-fibrinrelated antigen during ancrod therapy. Thrombos. Res. L, 361, 1975.
2.
KONTTINEN,Y.P., LALLA, M.L.T., and TURUNEN, 0.: Preferentialdegradation of soluble fibrin monomers in streptokinase-activated plasma. Thromb. Diath. haemorr. 2, 403, 1973.
3.
LIPINSKI, B., NOWAK, A. and GIJREWICH, V.: Fibrinolysisversus fibrinogenolysis in man: Resistance of fibrinogen to breakdown by fibrinolytic activity induced by venous occlusion. Experientia30, 84, 1974.
4.
GUREWICH, V., LIPINSKA, I., and LIPINSKI, B.: Exercise-inducedfibrinolytic activity and its effect on the degradationof fibrinogen,fibrin and fibrin-likeprecipitates. Thrombos. Res. S_,647, 1974.
5.
GUREWICH, V., NOWAK, A., LIPINSKA, I. and LIPINSKI, B.: The resistance of.solublederivativesof fibrinogenand the sensitivityof its insoluble forms to fibrinolyticdegradationin blood. Thromb. Diath. haemorr. 32, 582, 1974.
6.
GUREWICH, V., WETMORE, R., NOWAK, A. and LIPINSKI, B.: The fate of soluble fibrin monomer in relation to intravascularfibrin formation and degradation in rabbits. Blood 44, 723, 1974.
7.
GUREWICH, V., HYDE, E. and LIPINSKI, B.: The resistanceof fibrinogen and soluble fibrin monomer in blood to degradationby a potent plasminogen activator derived from cadaver limbs. Blood, 46, 555, 1975.
LETTER
Vol.
States
TO THE
8, PP. 119-120, Pergamon Press,
1976 Inc.
EDITORS-IN-CHIEF
THE DEGRADATION OF SOLUBLE VERSUS INSOLUBLE FIBRIN IN VIVO.
Boguslaw Lipinski and Victor Gurewich
Vascular Laboratory, Lemuel Shattuck Hospital, Tufts University School of Medicine, Boston, Massachusetts 02130, U.S.A.
(Received
23.10.1975; Accepted by
in revised Editor A.L.
form 10.12.1975. Copley)
In a recent article McKillop, Edgar, Forbes and Prentice (1) suggested that "the digestion of soluble fibrin could represent an important pathway for the production of FDP in viva." This conclusion was based on the following observations in ancrod-treated patients: 1. Lack of intact c(chain in eluate fractions containing soluble fibrin complexes obtained from the plasma of patients by agarose gel filtration. 2. The finding by polyacrylamide gel electrophoresis of a greater loss of a chain in the eluate fractions containing soluble complexes compared to those containing the main (fibrinogen) peak. 3. A rapid fall in plasminogen and fibrinogenydincrease in FDP in the blood of ancrod-treated patients. 4. Reference to a previous study (2) showing preferential degradation of soluble fibrin compared to fibrinogen in streptokinase (SK) treated plasma. As the authors suggest, their findings could be explained by the direct lysis of soluble fibrin. Alternatively, the lysis of ancrod-induced fibrin deposits is also consistent with these observations. The authors' preference for the former explanation may be related to the fact that they have overlooked some publications which indicate that fibrinogen and its soluble derivatives are resistant to degradation by naturally induced fibrinolytic activity. When fibrinolytic activity is induced in vivo by venous occlusion (3), exercise (4), or death (S), there is rapid lysis of clotted or precipitated fibrinogen but no degradation of fibrinogen, soluble fibrin or FDP even after 24 hours incubation of plasma samples. In experimental animals, the clearance of soluble fibrin has been shown to occur by the initial intravascular precipitation of fibrin and subsequent lysis rather than by direct lysis of circulating soluble fibrin (6). The resistance of fibrinogen and its soluble derivatives to degradation by fibrinolytic activity has been attributed to the action of a specific and potent antiactivator found in large excess in human blood (7). We have demonstrated highly preferential binding of this antiactivator to vascular plasminogen activator compared to SK or urokinase (UK). Lysis of fibrin or precipitated fibrinogen requires dissociation of the
119
120
II'JVIVO DEGRADATION
OF FIBRINS
Vol.8,No.l
activator-antiactivator complex which occurs only on a solid phase thus allowing the activator to induce the conversionof plasminogento plasmin. Therefore,experimentalor clinical findings based on the effect of SK or UK must be interpretatedwith considerablecaution. We agree that soluble fibrin is degraded preferentiallyover fibrinogenin SK activatedplasma, but this is not the case when fibrinolyticactivity is induced by natural activators found in blood. In summary, the authors data do not warrant the conclusionthat soluble fibrin is degraded in vivo by plasmin. It is far more likely that ancrodinduced soluble fibrin is first precipitatedand then lysed and that FDP originate entirely from fibrin and not from soluble fibrin complexes. The concept of a preferentialproteolysisof soluble fibrin in vivo remains a speculationunsupportedby fact. REFERENCES 1.
MCKILLOP, D., EDGAR, W., FORBES, C.D. and PRENTICE,C.R.M.: In vivo production of soluble complexes containing fibrinogen-fibrinrelated antigen during ancrod therapy. Thrombos. Res. L, 361, 1975.
2.
KONTTINEN,Y.P., LALLA, M.L.T., and TURUNEN, 0.: Preferentialdegradation of soluble fibrin monomers in streptokinase-activated plasma. Thromb. Diath. haemorr. 2, 403, 1973.
3.
LIPINSKI, B., NOWAK, A. and GIJREWICH, V.: Fibrinolysisversus fibrinogenolysis in man: Resistance of fibrinogen to breakdown by fibrinolytic activity induced by venous occlusion. Experientia30, 84, 1974.
4.
GUREWICH, V., LIPINSKA, I., and LIPINSKI, B.: Exercise-inducedfibrinolytic activity and its effect on the degradationof fibrinogen,fibrin and fibrin-likeprecipitates. Thrombos. Res. S_,647, 1974.
5.
GUREWICH, V., NOWAK, A., LIPINSKA, I. and LIPINSKI, B.: The resistance of.solublederivativesof fibrinogenand the sensitivityof its insoluble forms to fibrinolyticdegradationin blood. Thromb. Diath. haemorr. 32, 582, 1974.
6.
GUREWICH, V., WETMORE, R., NOWAK, A. and LIPINSKI, B.: The fate of soluble fibrin monomer in relation to intravascularfibrin formation and degradation in rabbits. Blood 44, 723, 1974.
7.
GUREWICH, V., HYDE, E. and LIPINSKI, B.: The resistanceof fibrinogen and soluble fibrin monomer in blood to degradationby a potent plasminogen activator derived from cadaver limbs. Blood, 46, 555, 1975.