Pathogenesis of the Coagulation Defect Developing During Pathological Plasma Proteolytic (“Fibrinolytic”) States. Ii. The Significance, Mechanism and Consequences of Defective Fibrin Polymerization*

Alkjærsig, Norma; Fletcher, Anthony P.; Sherry, Sol

doi:10.1172/jci104547

Cited by 163 publications

(40 citation statements)

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“…Degradation of native fibrinogen with plasmin produces peptides which strongly inhibit the conversion of fibrinogen to fibrin. Some of the fragments interfere with the polymerization of fibrin rather than with the proteolytic action of thrombin [65]. Plasmic digests of native !fibrinogen have been shown to contain large molecular size fragments [27,28,66], which retain antigenic determinants of the whole molecule.…”

Section: Discussionmentioning

confidence: 99%

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On the Primary Structure of Human Fibrinogen. Isolation and Characterization of N-Terminal Fragments from Plasmic Digests

et al. 1969

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Two N-terminal fragments of a(A)-chain and /l(B)-chain in human fibrinogen have been isolated from a plasmic hydrolyzate. The fragment from the u(A)-chain consisted of 43 amino acid residues including two half-cystine residues. On treatment with thrombin, this fragment produced two other peptides in addition to fibrinopeptideA and its analogues. One was a tripeptide, Gly-Pro-Arg, and the other a peptide containing 24 amino acid residues having N-terminal valine. The partial amino acid sequence of the a(A)-chain has been found to be: Ala-AspSer-Gly-Glu-Gly-Asp-Phe-Leu-Ala-Glu-Gly-Gly-Gly-Val-Arg-Gly-Pro-Arg-Val-Val-Glu-~g-His-G~-Ser-Ala-Cys-Lys-Asp-Ser-Asp-Trp-Pro-Phe-(Cys-Ser-Asp-Glu-Trp-Asn-Tyr)-Lys. I IThe fragment from the /?(B)-chain consisted of 21 amino acid residues. This fragment released fibrinopeptide B on treatment with thrombin. The amino acid sequence of the B(B)-chain fragment is: Pyr-Gly-Val-Asn-Asp-Asn-Glu-Glu-Gly-Phe-Phe-Ser-Ala-Arg-Gly-His-~g-Pro-Leu-Asp-Lys. The linkages between fibrinopeptides and fibrin, which are rapidly hydrolyzed by thrombin, are very resistant towards plasmin.A number of studies on mammalian fibrinogen and fibrin have suggested that both protein molecules are made up of three polypeptide chains, u("A"), /?(B) and y [l--51, respectively. The N-terminal parts of the u("A'))-chain and /?(B)-chain of fibrinogen contain fibrinopeptides "A" and B, which are split off by thrombin during the fibrinogen-fibrin transition Thrombin has a very limited proteolytic action on fibrinogen, resulting in the release of fibrinopeptide "A" and B [6-101. There is strong evidence that arginyl-glycyl peptide bonds in the N-terminal parts of the a("A")-chain and /l(B)-chain in fibrinogen are split by thrombin [S-10,291. Plasmin, which like thrombin also is a proteolytic enzyme with trypsinlike specificity, does not liberate fibrinopeptide A and B from fibrinogen or S-sulfo-fibrinogen [30,31], indicating that the bonds split by thrombin are resistant towards plasmin. One would therefore expect to find polypeptide fragments containing covalently linked fibrino-peptides in plasmic digests of fibrinogen. Isolation and structural studies on such fragments is the subject of this paper. A preliminary note on this work has appeared [31]. MATERIALSHuman fibrinogen waa prepared from pooled citrated plasma according to the method of Blomback and Blombiick [32]. The coagulability of the preparation, as determined spectrophotometrically[33], was 97-100 Ole.

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Section: Discussionmentioning

confidence: 99%

“…S-Sulfo-cysteine was determined as cysteic acid after performic oxidation at 0" [54]. Tryptophan was determined on unhydrolyzed samples by ultraviolet analysk [65].…”

Section: Amino Acid Analysismentioning

confidence: 99%

On the Primary Structure of Human Fibrinogen. Isolation and Characterization of N-Terminal Fragments from Plasmic Digests

et al. 1969

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“…The forces of intermolecular attraction, involved in polymerization, might be diminished as a consequence of net charge differences between fibrin monomer and the proteolysis products. Although the biophysical evidence (2) suggested that the magnitude of the component (fibrin monomer and the 5.27S2ow fibrinogen fragment) differences were small, the possibility that net charge differences at the complex polymer stage might be greater could not be dismissed. Such differences could result in the formation of an inadequate gel, due to both diminished fiber formation and to diminished lateral aggregation of unit fibers.…”

Section: Discussionmentioning

confidence: 99%

“…(Submitted for publication July 13, 1961; accepted December 21,1961) As a result of recent studies, new concepts have arisen concerning the nature and pathogenesis of the coagulation anomaly encountered in spontaneously occurring and iatrogenically induced plasma proteolytic states (1,2). Classically the hemorrhagic diathesis due to abnormal plasma proteolytic activity was attributed to hypo-or afibrinogenemia in combination with proteolytic destruction of a series of coagulation factors.…”

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confidence: 99%

“…clotting time (1,2,4). Further studies have indicated that this large molecular fibrinogen derivative (5.27S2ow, and estimated molecular weight of 83,000) interfered with the later stages of fibrinogen-fibrin conversion-i.e., the polymerization of fibrin monomer to fibrin-whereas the first step, the proteolytic conversion of fibrinogen to fibrin monomer by thrombin was unaffected (2).…”

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