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Biomedical subjects

H L Nossel

Publications and source records attributed to H L Nossel.

At least 37 records · Page 2Linked to original sources
PubMed1981

Relative proteolysis of the fibrinogen B beta chain by thrombin and plasmin as a determinant of thrombosis.

Thrombosis results, in part, from localized accumulation of fibrin, implying an imbalance between its rate of formation and dissolution. Astrup postulated that patency of the vascular system depended on a dynamic equilibrium between constantly active coagulation and fibrinolytic systems. Reviews of this hypothesis have concluded that neither thrombin nor plasmin proteolysis makes a major contribution to fibrinogen turnover in normal individuals and that the hypothesis of a dynamic equilibrium between clotting and lysis remains unproven. Thus, the current view is that plasmin simply serves the function of a fibrinolytic enzyme digesting fibrin in the vascular system. Here, I promote the alternative view that the relative rates of proteolysis of the B beta chain of fibrinogen by thrombin and plasmin determine the occurrence of thrombosis. This view is supported by recent data and can be used to make some readily testable predictions.

Fibrinogen↗
PubMed1981

Measurement of desarginine fibrinopeptide B in human blood.

Thrombin converts fibrinogen to fibrin in two steps. First fibrinopeptide A and fibrin I are formed and then fibrinopeptide B (B beta 1-14) and fibrin II. Since it is postulated that fibrin II is important in the genesis of thrombosis, it is of interest to measure fibrinopeptide B in peripheral blood samples. Previous difficulties in interpreting fibrinopeptide B immunoreactivity in plasma resulted from crossreaction of fibrinogen and of plasmin digest peptides B beta 1-42 and B beta 1-21 and from rapid loss of fibrinopeptide B immunoreactivity resulting from cleavage of arginine 14 by blood carboxypeptidase B. We have obviated these difficulties by removing fibrinogen from plasma by precipitation with ethanol and peptides B beta 1-21 and B beta 1-42 by adsorption on bentonite. Fibrinopeptide B is then converted to a desarginine fibrinopeptide B, which is measured in a new specific assay. Studies of the kinetics of fibrinopeptide cleavage showed that when whole blood was allowed to clot in vitro, fibrinopeptide A was cleaved more rapidly than fibrinopeptide B. In 18 patients on an acute care medical ward, desarginine fibrinopeptide B levels were lower than fibrinopeptide A levels and did not correlate with the levels of fibrinopeptide A or B beta 1-42. Desarginine fibrinopeptide B levels were less than 1 pmol/ml in all but two patients. In six patients receiving intraamniotic infusions of hypertonic saline to induce abortion, desarginine fibrinopeptide B levels increased 10-fold from the preinfusion mean level of 0.4 pmol/ml and then decreased. The pattern of changes resembled that of the fibrinopeptide A levels rather than of the B beta 1-42 levels. On the basis of these data it is suggested that plasma desarginine fibrinopeptide B levels reflect fibrin II formation in vivo.

Cross Reactions↗
PubMed1980

Thrombocytopenia in septicemia: the role of disseminated intravascular coagulation.

The mechanism of isolated thrombocytopenia in septicemia is unknown, but compensated disseminated intravascular coagulation (DIC) has been suggested as a possible cause. To investigate this possibility, platelet counts and sensitive assays for in vivo thrombin and plasmin generation, including fibrinogen gel chromatography and fibrinopeptide A (FPA) assays, were obtained on 31 septicemic patients. Fifteen of 17 patients with gram-negative septicemia and 8 of 14 patients with gram-positive septicemia had thrombocytopenia. Platelet survival studied demonstrated a decreased platelet survival. In 11 of 12 patients with severe thrombocytopenia (platelet count less than 50,000mul), there was laboratory evidence of intravascular coagulation. In contrast, there was little evidence of intravascular coagulation in 8 of 11 patients with moderate thrombocytopenia (platelet counts 50,000 to less than 150,000/mul) or in 7 of 8 patients with normal platelet counts. This report indicates that while DIC accompanies thrombocytopenia in many patients with severe thrombocytopenia, there is frequently little evidence for intravascular coagulation in patients with moderate thrombocytopenia. It is apparent that factors other than intravascular thrombin must play a role in producing the thrombocytopenia of septicemia.

Adult↗
PubMed1979

Normal levels of fibrinopeptide A in patients with primary hyperlipidemia.

Fibrinopeptide A (FPA) levels were measured in a group of 130 controls and patients with various types of primary hyperlipidemia to investigate whether an increased steady state level of thrombin activity is present in hyperlipidemic patients. In a subset of 56 subjects, levels of clotting factors II, VII, and X were measured as well. FPA levels in hyperlipidemic patients were not significantly different from those of control subjects. Furthermore, on multiple regression analysis, no significant relationships were found between FPA levels and the concentrations of serum cholesterol or triglyceride, or log triglyceride levels. Statistically significant relationships were found between all three clotting factor levels and triglyceride concentration. The correlation coefficients for these relationships, however, were low, so that the correlations are of questionable pathophysiological significance. A weak relationship also was found between the plasma levels of cholesterol and of factor II. Thus, although small increases in various clotting factors may be found in patients with hyperlipidemia, plasma FPA levels are normal. These data indicate that hyperlipidemia is not associated with a steady state of increased thrombin activity in vivo in humans.

Cholesterol↗
PubMed1979

Sequence of fibrinogen proteolysis and platelet release after intrauterine infusion of hypertonic saline.

Plasma fibrinopeptide B (Bbeta1-14 or FPB) immunoreactivity was studied by radioimmunoassay in patients who received intrauterine infusion of hypertonic saline to terminate pregnancy. FPB immunoreactivity increased with thrombin treatment (TIFPB) suggesting the presence of a larger FPB-containing peptide, since purified FPB is not altered by thrombin, whereas thrombin increases the immunoreactivity of Bbeta1-42 (which includes FPB) 10-fold. TIFPB immunoreactivity in plasma, drawn 4 h after hypertonic saline infusion eluted from Sephadex G-50 similarly to isolated Bbeta1-42. Streptokinase, incubated with normal plasma progressively generated TIFPB immunoreactivity, which showed a major component which eluted from Sephadex G-50 similarly to Bbeta1-42. Streptokinase generated TIFPB much more rapidly in reptilase-treated plasma that contains fibrin I, (which still includes FPB), indicating that fibrin I is preferred over fibrinogen as a substrate for plasmin cleavage of arginine (Bbeta42)-alanine (Bbeta43). Serial studies were then made in 10 patients receiving intrauterine hypertonic saline. Fibrinopeptide A (FPA) levels rose immediately, reached a peak between 1 and 2 h, were declining at 4 h, and were normal at 24 and 48 h. TIFPB levels rose slightly in the 1st h, reached a peak at 4 h, and had returned to base-line values at 24 h. Serum fibrinogen degradation product levels were unchanged at 1 h, reached their highest level at 4 h, and were still markedly elevated at 24 and 48 h. Fibrinogen levels dropped slightly being lowest at 4 and 24 h. Platelet counts declined in parallel with the fibrinogen levels over the first 4 h, but continued to decrease through 48 h. Beta thromboglobulin (betaTG) levels generally paralleled FPA levels whereas platelet factor 4 (PF4) levels showed only slight changes. The data indicate that immediately after intrauterine hypertonic saline infusion thrombin is formed that cleaves FPA from fibrinogen to produce fibrin I and releases betaTG and PF4 from platelets. Later plasmin cleaves Bbeta1-42 from fibrin I to produce fragment X, which is further degraded to form serum fibrinogen degradation products. This sequence of proteolysis indicates that plasmin action on fibrin I serves as a mechanism that regulates fibrin II formation by removing the Bbeta chain cleavage site, which is required for thrombin action in converting fibrin I to fibrin II.

Abortion, Induced↗
PubMed1978

Radioimmunoassay of platelet factor 4 and beta-thromboglobulin: development and application to studies of platelet release in relation to fibrinopeptide A generation.

Platelet and fibrinogen survival and turnover studies have shown that platelet activation and fibrin formation may occur to different degrees in different thrombotic disorders. More direct evidence of differential involvement of platelet activation and fibrin formation should be provided by specifically measuring the products of these reactions, i.e. released platelet proteins and fibrinopeptide A. Two platelet proteins, platelet factor 4 (PF4) and beta-thromboglobulin (betaTG), were isolated and characterized, and sensitive and specific radioimmunoassays were developed to measure them. These assays were employed, along with the radioimmunoassay for fibrinopeptide A (FPA), to study the release of PF4 and betaTG in relation to FPA cleavage. PF4 and betaTG were released by ADP and collagen with time course and concentration dependence similar to that of [14C]serotonin release. FPA was not cleaved from fibrinogen during ADP or collagen-induced platelet release. Thrombin caused release of PF4 and betaTG as well as cleavage of FPA. Cleavage of FPA occurred with concentrations of thrombin about 100 times less than did release of PF4 and betaTG, and release of [14C]serotinin required still higher thrombin concentrations. Release of [14C]serotonin and platelet proteins was similar as a function of time. Sodium citrate was found to inhibit platelet release induced by thrombin.

Beta-Globulins↗
PubMed1978

The effects of ancrod, the coagulating enzyme from the venom of Malayan pit viper (A. rhodostoma) on prothrombin and fibrinogen metabolism and fibrinopeptide A release in man.

The action of ancrod on fibrinogen and prothrombin metabolism was studied in six healthy individuals by the use of 131I-fibrinogen and 125I-prothrombin and by measurement of blood levels of fibrinopeptide A. Two untreated healthy controls were studied at the same time. Rapid defibrinogenation occurred during the initial 3 hr ancrod infusion, and fibrinogen levels were maintained near zero throughout the study. Large quantities of non-thrombin-clottable TCA-precipitable 131I material could be demonstrated in the circulation, reaching a maximum 3 to 6 hr after ancrod infusion and clearing with a half-life of 6 hr. Gel filtration of 6 hr plasmas demonstrated the presence of complexes larger than fibrinogen, as well as degradation products of fibrinogen-fibrin. Prothrombin concentration and metabolism were unchanged by ancrod treatment. Fibrinopeptide A levels in the ancrod group were greather than 4,000 ng/ml during the initial defibrinogenation, declined to greater than 80 ng/ml, and then increased to high levels after 3 days. These studies provide explanations of previous observations concerning the specificity of ancrod and demonstrate that rapid clotting of fibrinogen and dissolution of fibrin can occur in vivo without recruitment of the classic coagulation mechanism.

Adult↗