A plasma proteinase inhibitor, alpha 2-plasmin inhibitor (alpha 2PI), is cross-linked with alpha chain of fibrin(ogen) by activated coagulation Factor XIII (plasma transglutaminase). alpha 2PI serves only as a glutamine substrate (amine acceptor) for activated Factor XIII in the cross-linking reaction, and the cross-linking occurs between Gln-2 of the alpha 2PI molecule and a lysine residue (amine donor) of fibrin(ogen) alpha chain, whose position was investigated. alpha 2PI and fibrinogen were reacted by activated Factor XIII. The resulting alpha 2PI fibrinogen A alpha chain complex was separated and subjected to two cycles of Edman degradation using phenyl isothiocyanate for the first cycle and dimethylaminoazobenzene-isothiocyanate for the second cycle. The aqueous phase after the cleavage stage of the second cycle, containing dimethylaminoazobenzene-thiohydantoin-Gln cross-linked with A alpha chain, was subjected to CNBr fragmentation and tryptic digestion. Only one of the peptides was found to have the peak of absorbance at 420 nm, indicating the presence of dimethylaminoazobenzene-thiohydantoin-Gln in that peptide. The peptide was identified as corresponding to residues Asn-290-Arg-348 of A alpha chain by analyses of the NH2-terminal amino acid sequence and amino acid composition. The peptide contains a single lysine at position 303, indicating that Lys-303 of fibrinogen A alpha chain is the lysine residue that forms a cross-link with Gln-2 of alpha 2PI.

Amino Acid Sequence↗

PubMed1986

Conformation-specific monoclonal antibodies to the calcium-induced structure of protein C.

Monoclonal antibodies to various domains of human protein C were characterized, and the cross-reactivity of these antibodies with other vitamin K-dependent proteins was explored. Three antibodies, JTC-1, -2, and -3 reacted with protein C only in the presence of Ca2+ and were shown to bind to the light chain of protein C. It is suggested that these antibodies recognize a gamma-carboxyglutamic acid domain-related conformational change induced by metal ions, evidenced by the fact that half-maximal binding was observed at calcium concentration of 0.5, 0.6, and 0.7 mM, respectively, by the fact that these antibodies, even in the presence of Ca2+, do not react with gamma-carboxyglutamic acid domainless protein C, and by the fact that Zn2+ and Tb3+ support binding in essentially the same way. Each cell line was stabilized by recloning five times. In addition each antibody had a single isoelectric point and was of the IgG1 kappa class. The interaction of antibodies JTC-1, -2; and -3 with protein C-Ca2+ was characterized by a single class of binding sites with Kd of 3.98 X 10(-9) M, 4.01 X 10(-9) M, and 6.76 X 10(-9) M, respectively. However, antibodies JTC-1, -2, and -3 bound to prothrombin-Ca2+ with Kd of 7.81 X 10(-9) M, 2.0 X 10(-7) M, and higher than 1.0 X 10(-5) M, respectively. In addition they had weak affinity for factor X in the presence of Ca2+. The results indicate that the antibodies JTC-1, -2, and -3 are conformation-specific monoclonal antibodies directed against an at least partially common metal ion-induced three-dimensional structure in protein C, prothrombin, and factor X.

Antibodies, Monoclonal↗

PubMed1986

The initiation of fibrinolysis in alpha 2-plasmin inhibitor deficient plasma. Role of fibrin.

Plasmin activity and fibrin degradation products (FDP) are found in alpha 2-plasmin inhibitor (alpha 2-PI) deficient plasma only when clotted, but are not found when the plasma is not clotted. To determine whether fibrin itself could initiate fibrinolysis without activating coagulation enzymes, fibrin monomers were prepared and added to alpha 2-PI deficient plasma. The addition of fibrin monomers resulted in the generation of plasmin activity, a marked increase in FDP concentration, and the release of 125I from 125I-labeled fibrin monomers. Replenishment of the deficient plasma with purified alpha 2-PI abolished the effects of fibrin monomers on the initiation of fibrinolysis. Neither development of plasmin activity, increase of FDP, nor release of 125I was observed. These findings indicate that fibrinolysis can be induced by fibrin itself without activation of coagulation cascade and the induction of fibrinolysis is efficiently blocked by alpha 2-PI.

Blood Coagulation↗

PubMed1986

Excessive fibrinolysis in suspected amyloidosis: demonstration of plasmin-alpha 2-plasmin inhibitor complex and von Willebrand factor fragment in plasma.

We performed a hemostatic evaluation in detail in a patient with suspected amyloidosis who was suffering from several bleeding episodes. He had a shortened euglobulin clot lysis time, decreased alpha 2-plasmin inhibitor (alpha 2-PI), decreased plasminogen, elevated tissue-type plasminogen activator (t-PA), elevated plasmin-alpha 2-PI complex, and decreased ratio of ristocetin cofactor to von Willebrand factor (vWF) antigen. Fibrinogen and fibrin/fibrinogen degradation products levels fluctuated, with abnormal values on several occasions. On crossed immunoelectrophoresis, plasmin-alpha 2-PI complex and vWF fragment were demonstrated in the patient plasma. These abnormal findings and bleeding symptoms improved following the administration of tranexamic acid. Discontinuation of tranexamic acid resulted in deterioration of these parameters. These observations indicate that pathologic fibrinolysis (continuous intravascular plasmin generation) characterized by the consumption of alpha 2-PI and plasminogen, formation of plasmin-alpha 2-PI complex, and fragmentation of vWF contributed to the bleeding in this patient. It is important to recognize excessive fibrinolysis as the underlying cause of bleeding in these patients, since specific treatment with antifibrinolytic agents is effective in controlling the bleeding.

Amyloidosis↗

PubMed1986

Cyst of the septum pellucidum presenting as hemiparesis.

An 11-year-old boy with Down syndrome is presented who suffered progressive hemiparesis on the left side for a period of 5 years. Computed tomography demonstrated a large cyst of the septum pellucidum and a calcified spot in the head of caudate nucleus on the right side. By penetrating the cyst wall to create a communication into the lateral ventricle, shrinkage of the cyst and improvement of the hemiparesis were obtained. The pathogenesis of the hemiparesis was presumed to be attributed to circulatory compromise in the deep cerebral veins, secondary to the cyst.

Brain Diseases↗

PubMed1986

Subdural tapping and irrigation for the treatment of chronic subdural hematoma in adults.

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Chronic Disease↗