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Biomedical subjects

O D Ratnoff

Publications and source records attributed to O D Ratnoff.

At least 73 records · Page 4Linked to original sources
PubMed1985

Acquisition of antibody to lymphadenopathy-associated virus in patients with classic hemophilia (factor VIII deficiency).

Antibody to lymphadenopathy-associated virus (LAV) was assayed in 461 serum and plasma samples that had been obtained from 149 patients with classic hemophilia and 64 controls and stored for periods as long as 18 years. No control or patient samples obtained before 1980 contained antibody to this retrovirus. The prevalence of antibody to LAV in the patient samples rose from 15% (2 of 13) in 1980 to 62% (18 of 29) in 1984. During this time, none of 8 untreated hemophiliacs and none of 26 hemophiliacs treated solely with cryoprecipitates had antibody to LAV. In contrast, the prevalence of antibody to LAV among hemophiliacs treated with lyophilized antihemophilic factor rose from 25% (2 of 8) in 1980 to 78% (18 of 23) in 1984. These seropositive hemophiliacs had fewer OKT4 helper cells and lower proliferative responses to mitogen than similarly treated seronegative patients. Treatment with locally prepared cryoprecipitates was not associated with serologic evidence of virus exposure.

Antibodies, Viral↗
PubMed1985

Impaired cell-mediated immunity in hemophilia. II. Persistence of subclinical immunodeficiency and enhancement of natural killer activity by lymphokines.

We performed follow-up studies in 11 patients with asymptomatic classic hemophilia, who on initial study 8 to 12 months previously had demonstrated abnormalities of lymphocyte phenotype and function. Although all subjects remained well, diminished lymphocyte proliferative responses, natural killer activity, and decreased ratios of OKT4 helper/OKT8 suppressor lymphocytes persisted. Moreover, the absolute number of OKT4 helper lymphocytes fell in the patients from a mean of 745 +/- 73/microliter in the first study to 585 +/- 50/microliter in the follow-up study, which was lower than the control value of 857 +/- 87 (P less than 0.02). Despite diminished natural killer activity, patients with hemophilia had at least normal numbers of natural killer cells as determined by the presence of the OKM1 antigens and Giemsa staining to identify large granular lymphocytes. Patients with hemophilia had more Leu 11a-positive cells than controls. Lymphocyte binding to tumor targets was not diminished, and removal of adherent cells did not increase patients' natural killer activity to control levels. Incubation of patients' lymphocytes with alpha-interferon, gamma-interferon, or interleukin-2 resulted in enhancement of natural killer activity but did not reach control levels. Thus the diminished natural killer activity in patients with hemophilia retained responsiveness to lymphokines and was caused either by an intrinsic or acquired defect in the natural killer cell or by modulation by a nonadherent cell. Subclinical immunodeficiency in patients with hemophilia is not transient and is associated with a diminished number of OKT4 helper cells, a finding often associated with clinical immunodeficiency.

Adult↗
PubMed1985

A monoclonal antibody that inhibits activation of human Hageman factor (factor XII).

A monoclonal antibody to human Hageman factor (HF, factor XII) was derived from BALB/c mouse spleen cells fused with NS-1 mouse myeloma cells. This antibody, purified from ascites fluid, reacted with HF to inhibit the activation of HF, purified or in normal pooled plasma, as measured by a coagulation assay. The antibody did not inhibit the coagulant activity of activated HF. The antibody also inhibited the generation of amidolytic activity in HF-ellagic acid mixtures, but failed to inhibit the amidolytic properties of the carboxy-terminal fragment of HF (HFf). Amidolytic activity, absent in an HF-monoclonal antibody mixture, was generated upon treatment with insoluble trypsin. Monoclonal antibody, bound to CNBr Sepharose 4B gel (Pharmacia Fine Chemicals, Piscataway, NJ), reversibly bound HF in plasma or in buffer, without activating it. HF was then eluted with 4 mol/L guanidine HCI. The passage of 125I-labeled HF enzymatically cleaved by trypsin through a column of monoclonal antibody-CNBr Sepharose 4B gel resulted in flow-through of HFf with a molecular weight (mol wt) of 30,000 and HF fragments of mol wt 12,000. Elution with 4 mol/L guanidine HCI yielded several HF fragments (mol wt 80,000, 52,000, and 40,000) but not HFf. These data suggest that the single determinant recognized by the murine monoclonal antibody is not on HFf, but rather on the amino-terminal fragment thought to be involved in the binding activity of HF. The monoclonal anti-HF bound to CNBr-activated Sepharose 4B gel could be used to artificially deplete plasma samples of HF.

Animals↗
PubMed1985

Inhibition of Hageman factor (factor XII) by popcorn inhibitor.

A protein derived from sweet corn or popcorn inhibits the enzymatic activity of the carboxy-terminal fragment of Hageman factor (HFf) and of ellagic acid-activated Hageman factor (HF, factor XII). Not clarified is whether the inhibitor is directed at the active site of HF. Filtration of normal plasma or purified HF through columns of popcorn inhibitor bound to agarose gels demonstrated that HF was bound to these gels and could then be eluted by buffers containing 2.0 mol/L sodium chloride. The eluted HF was in the precursor form. Thus, popcorn inhibitor appeared to attach to a point on the carboxy-terminal HFf that was distinct from the enzymatically active site of this clotting factor.

Binding Sites↗
PubMed1985

The influence of estrogen and prolactin on Hageman factor (factor XII) titer in ovariectomized and hypophysectomized rats.

The synthesis of prothrombin in hepatic microsomes is augmented in intact estrogen-treated rats and in hypophysectomized rats treated with purified prolactin. We investigated the influence of these gonadal and pituitary hormones on the titer of Hageman factor (factor XII), reportedly elevated in women using oral contraceptives. Rats were ovariectomized to minimize the influence of endogenous estrogen and progesterone on the Hageman factor titer. The administration of progesterone did not alter the plasma concentration of Hageman factor. In contrast, the infusion of 17 beta-estradiol induced a marked elevation of the plasma Hageman factor titer, as measured functionally and immunologically. The titer of Hageman factor was directly related to both plasma estradiol and prolactin concentrations, indicating that prolactin may play a role in the regulation of plasma Hageman factor titers. In agreement with this, hypophysectomy induced a marked decrease in the Hageman factor level. In hypophysectomized ovariectomized animals, the administration of estradiol restored the Hageman factor titer to normal levels, whereas the infusion of prolactin induced a dramatic rise in the Hageman factor titer to the degree observed in nonhypophysectomized estrogen-treated rats. No further increase in the Hageman factor titer was observed in rats treated with both estradiol and prolactin. These data indicate that estrogens increase the plasma Hageman factor titer both directly and through its release of prolactin and that prolactin may also increase the titer of Hageman factor through estrogen-independent mechanisms.

Animals↗
PubMed1985

Failure to detect variant (CRM+) plasma thromboplastin antecedent (factor XI) molecules in hereditary plasma thromboplastin antecedent deficiency: a study of 125 patients of several ethnic backgrounds.

Plasma samples of 125 patients from 80 kindreds with hereditary plasma thromboplastin antecedent (PTA, factor XI) deficiency were tested by factor XI radioimmunoassay (RIA) and electroimmunoassay (EIA) in an attempt to detect variant molecules. Ninety-six patients (70 kindreds) were Jewish, and 29 (10 kindreds) were of other ethnic backgrounds, namely, Japanese, black American, Korean, Arab, Indian, and English. Seventy-eight patients were homozygotes, and 47 were heterozygotes. Both non-Jewish homozygotes and heterozygotes had lower factor XI activity than respective Jewish subjects. Twenty-eight homozygotes whose factor XI clotting activities (XI:C) were 1.5% to 13% had factor XI-related antigen (XI:RAG) levels less than 10% by EIA. In 72 homozygotes, including 22 patients who were also tested with EIA, XI:C was 2.9% +/- 3.0% (mean +/- SD) and XI:RAG tested by RIA, 2.9% +/- 3.0%. In 47 heterozygotes, XI:C and XI:RAG tested by RIA were 51.9% +/- 16.6% and 51.0% +/- 16.2%, respectively. Similar results were obtained when only unrelated patients (62 homozygotes and 27 heterozygotes) were analyzed. There was a highly significant correlation between XI:C and XI:RAG (RIA) in 38 homozygotes and 47 heterozygotes (r = 0.94, n = 85, P less than 0.001). Thus, we failed to identify functionally abnormal factor XI molecules (CRM+ variant) in these patients with hereditary factor XI deficiency.

Black People↗
PubMed1984

Inherited incomplete deficiency of the fourth component of complement (C4) determined by a gene not linked to human histocompatibility leukocyte antigens.

We have studied a family in which the proband had systemic lupus erythematosus and selective incomplete deficiency of the fourth component of complement (C4) (2-5% of the normal level). An additional six healthy family members also had low C4 levels (2.4-24.1% of normal) but no evidence of lupus. This form of inherited C4 deficiency differs from that in previously reported families in that inheritance was autosomal dominant (rather than recessive), C4 levels were markedly reduced (but not undetectable), and there was no linkage to HLA, BF, or C4 structural loci, all known to be within the major histocompatibility complex.

Adult↗
PubMed1984

Thrombosis and the hypercoagulable state.

Our understanding of thrombosis remains anchored to Virchow's view that the evolution of a thrombus is fostered by vascular damage, by retarded blood flow, and by alterations in the blood itself that increases its likelihood to clot. The last of these forces, the so-called hypercoagulable state, has been defined in many ways. For example, some evidence exists that increased titers of clotting factors or increased numbers of circulating platelets may be correlated with a thrombotic tendency. A more exciting way that clotting factors might contribute to thrombosis is that under certain conditions the titer of their activated forms might reach critical levels in the circulation. Another possibility is that a thrombotic tendency may be caused by qualitative alterations in clotting factors or platelets. The firmest evidence that alterations in blood clotting may be related to thrombosis is the undoubted high incidence of recurrent thromboembolism in patients with familial deficiencies of antithrombin III or protein C, an inhibitor of antihemophilic factor (factor VIII) and proaccelerin (factor V). Impaired fibrinolytic mechanisms may also predispose to thrombosis. Not yet explained is the fact that patients with lifelong hemostatic alterations in peripheral blood sustain only a handful of thrombotic episodes.

Blood Coagulation↗
PubMed1983

Thrombosis or myocardial infarction in congenital clotting factor abnormalities and chronic thrombocytopenias: a report of 21 patients and a review of 50 previously reported cases.

Nine patients are described with hereditary clotting factor abnormalities and thrombosis and 35 others previously reported in the literature. An additional 11 patients with myocardial infarction observed by the authors and 12 more reported by others are also included. A patient with non-immune thrombocytopenia and myocardial infarction is presented, as well as three additional patients recorded in the literature. This study underscores the little-recognized phenomenon of uncontrolled thrombosis in these patients with "experiments of nature," in whom clotting studies reflect an impairment of coagulation comparable in degree to that achieved by oral anticoagulant therapy.

Adult↗
PubMed1983

Influence of augmented Hageman factor (Factor XII) titers on the cryoactivation of plasma prorenin in women using oral contraceptive agents.

Prolonged cold storage of plasma may induce the conversion of plasma prorenin (inactive renin) to renin. This phenomenon is exaggerated in oral contraceptive (OC) users; the titer of Hageman factor (HF, Factor XII) in OC users is higher than in nonusers. The present study relates these observations. The increment in plasma renin activity (PRA) during cold storage, as measured by generation of angiotensin I, correlated strongly with the initial plasma titer of HF. Increasing the HF titer of nonusers to that observed in OC users by addition of purified HF increased cold-induced PRA at least twofold, while reducing the plasma HF titer of OC users correspondingly decreased cold-induced PRA. Thus, in OC users, the enhanced conversion of plasma prorenin to renin during cold storage reflects the elevated plasma titer of HF.

Angiotensin I↗
PubMed1983

Wasp sting anaphylaxis.

Profuse hemostatic defects were demonstrable 14 hr after wasp sting anaphylaxis. The patient's plasma contained an agent or agents that interfered with the action of thrombin, impeding the release of fibrinopeptide A from fibrinogen and the hydrolysis of the synthetic amide H-D-prolyl-L-phenylalanyl-L-arginine p-nitroanilide. This inhibitor could not be equated with known plasma inhibitors of thrombin nor with heparin. Additionally, the titers of nearly all other known clotting factors were reduced as compared to levels obtained after the patient's recovery. Of particular interest were profound reductions in the titers of proaccelerin (factor V) and high molecular weight kininogen. A normal titer of Hageman factor (factor XII) argued against participation of contact-activated mechanisms in the induction of the multiple abnormalities observed. Attempts to demonstrate the release of procoagulant or anticoagulant substances from the patient's convalescent blood, plasma, serum, or leukocytes upon challenge with wasp venom were unsuccessful. The observations reported confirm and extend information concerning hemostatic abnormalities in anaphylaxis, and point out the need to examine further this puzzling association.

Adult↗
PubMed1983

Activation of Hageman factor (factor XII) by sulfatides and other agents in the absence of plasma proteases.

Incubation of purified human HF (factor XII) with sulfatides, EA, kaolin, or glass resulted in the generation of amidolytic activity in the apparent absence of other enzymes. Sulfatides or EA rapidly and efficiently initiated intrinsic coagulation in normal plasma but, under the conditions tested, only trivially corrected the prolonged partial thromboplastin clotting times of plasma deficient in prekallikrein or HMWK. Preliminary incubation of HF with crude IgG directed against plasma kallikrein or SBTI did not influence the results. The presence of albumin greatly enhanced activation of the amidolytic properties of purified HF by EA, even when albumin had been lipid-extracted or treated with DFP or SBTI; albumin also increased activation of HF by sulfatides. Internal cleavage and minimal scission of the HF molecule accompanied the generation of amidolytic properties in mixtures of HF and sulfatides; cleavage was not blocked by SBTI. These experiments demonstrate that negatively charged substances can activate HF in absence of other enzymes and that this activation is accompanied by formation of a two-chain species of HF.

Aniline Compounds↗