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The variations of different antiplasmins were studied in a group of patients suffering from thromboembolic conditions and receiving three different regimens of thrombolytic treatment with streptokinase and urokinase. The evaluation of the antiproteases was carried out by chromogenic substrate and radial immunodiffusion. The different administration patterns of the fibrinolytic agents were followed by a clear drop in fast antiplasmin and alpha 2-macroglobulin, while alpha 1-antitrypsin was increased. Antithrombin-III activity was reduced while its protein rose in the intermittent treatment with streptokinase. In the conventional treatment with streptokinase, both the activity and the protein of antithrombin-III increased. With urokinase both the protein and the activity of antithrombin-III were slightly reduced. Plasminogen and fibrinogen decreased in the different regimens of thrombolytic treatment, being more evident in continuous administration of streptokinase.

The incidence of thromboembolic complications is increased in patients with oestrogen-treated prostatic carcinoma. Because reduced antithrombin-III (AT-III) levels are associated with increased risk of thromboembolism we have determined AT-III concentrations during oestrogen therapy and other treatments. Forty-six patients with carcinoma of the prostate were allocated to either treatment with subcapsular orchiectomy, oestrogen administration, or cyproterone acetate, AT-III was determined before treatment, at 2 weeks and 2 months later. During oestrogen therapy there was a significant reduction in AT-III to 77% of the base-line value. No significant changes were found after orchiectomy. During cyproterone-acetate treatment there was a slight but significant increase in AT-III at 2 months. The reduction in AT-III could indicate an increased risk of thromboembolism during oestrogen treatment of patients with carcinoma of the prostate. On the other hand, the unchanged AT-III levels after orchiectomy and the increased levels during cyproterone acetate therapy could mean that the risk of thromboembolism is less with these two forms of treatment.

Plasma levels of prekallikrein and kallikrein were measured in 147 pregnant women by the chromogenic substrate S2302 method. At the same time, individual fibrinolytic inhibitors (alpha 2-plasmin inhibitor, alpha 1-antitrypsin, alpha 2-macroglobulin, antithrombin-III, and Cl-inactivator) were determined by the radial immunodiffusion method. The plasma levels of prekallikrein increased significantly during pregnancy and thereafter decreased during delivery. In patients with severe toxemia of pregnancy and hydatidiform mole, plasma prekallikrein levels were low, below the normal range. On the other hand, plasma kallikrein concentrations were within non-pregnant levels until the end of pregnancy, but the levels increased just before delivery. Although no significant correlation was found between prekallikrein levels and fibrinolytic inhibitory activity in pregnancy, Cl-inactivator concentrations tended to be low only when the prekallikrein level was high. These changes in the prekallikrein-kallikrein system in late pregnancy may be related to activation of the kinin, which results in labor pain.

In summary, this series of 48 patients with acute and chronic DIC demonstrates the reliability of laboratory tests in both aiding a diagnosis of DIC and in offering reasonable predictability of efficacy of therapy, as noted by the correction of abnormalities after delivery of antiprocoagulant therapy for this syndrome. It appears that the diagnostic tests most likely to aid in diagnosis and to reliably inform the clinician when the intravascular clotting process has been stopped are those that determine the antithrombin-III level, the presence of soluble fibrin monomer, and the finding of elevated fibrin(ogen) degradation products, thrombocytopenia and a prolonged thrombin time in the face of the appropriate type of bleeding in the appropriate clinical setting. In addition, it would appear that mini-dose heparin therapy is highly effective in controlling the intravascular clotting process in acute DIC, whereas antiplatelet therapy utilizing two agents is effective in chronic DIC. In addition, in this population, patients with acute disease demonstrated a 74 percent survival rate and those with chronic disease had a 100 percent survival rate from the disseminated intravascular clotting process.

An allogeneic effect factor (AEF) derived from mixed lymphocyte reaction (MLR) cultures of alloactivated A.SW (H-2s) responder T cells and irradiated A/WySn (H-2a) stimulator spleen cells helps an in vitro primary anti-erythrocyte plaque-forming cell PFC response of BALB/c nude spleen cels and also A/WySn but not A.SW T cell-depleted spleen cells. AEF activity is adsorbed by anti-Ik and anti-I-Ak but not by anti-I-Jk, anti-I-ECk, and anti-Is. Gel filtration of ACA 54 resolves AEF into two main components that which appear in the 50,000- to 70,000-mol wt (component I) and 30,000- to 35,000-mol wt (component II) regions, respectively. Component I has a mol wt of 68,000, elutes from DEAE-Sephacel at 0.05-0.1 M NaCl, and has an isoelectric point (pI) of 5.8. It helps A/WySn but not A.SW B cells and, therefore, is H-2 restricted. Component II is not H-2 restricted, because it helps both A.SW and A/WySn B cells. It also stimulates (a) the growth of a long-term cytotoxic cell line in vitro, (b) Con A-induced thymocyte mitogenesis, and (c) the generation of cytotoxic T cells. The latter three properties of component II are not shared by component I. In addition, component II elutes from DEAE-Sephacel at 0.15-0.2 M NaCl and has a pI of 4.3 and 4.9. Ia determinants and Ig VH, CH, L-chain, and idiotypic determinants are not present on either component I or component II. The properties of component II are identical to that of a T cell growth factor produced by Con A-stimulated spleen cells. It is suggested that the H-2-restricted component I of AEF might be an MLR-activated responder T cell-derived Ia alloantigen receptor.

The availability of radioisotopes of iron led to the performance of physiologic studies of the absorption, excretion, and kinetics of iron. The effects of dietary constituents and intestinal secretions upon iron absorption have been thoroughly explored and have permitted the development of tools for nutritional studies in various geographic areas of the world. The basic mechanisms for regulation of iron absorption are not fully understood. However, the isolation and characterization of newer iron-binding proteins, the existence of mucosal receptors in which there is competition for iron-binding sites with other metals, and the identification of a number of animal models with genetic abnormalities of iron absorption provide promise for development in the foreseeable future. The means by which the body informs the intestine to increase or decrease iron absorption is poorly understood, and the abnormality in hemochromatosis and iron overloading disorders remains unexplained. Much has been learned in recent years regarding the structure of iron-containing proteins and the variations that exist in different species. Similar problems remain to be solved with regard to the intermediary metabolism of iron in red blood cell precursors and other cells in the body. It is postulated that the combined usage of physiologic, biochemical, and immunologic investigations will provide the basic information required.

A 34-year-old woman with a family history of pregnancy-associated thrombotic disease developed pre-eclampsia in her 8th month of pregnancy. A severe haemolytic-uraemic syndrome (HUS) developed within 24 h after spontaneous delivery. Because the plasma antithrombin-III (AT-III) was only 15% of the normal concentration, an AT-III concentrate was given intravenously. When the normal level of plasma AT-III was reached, the clinical and biochemical signs of the syndrome disappeared. Renal function and biopsy were normal within 10 days. Because complete recovery is unusual in patients with post partum HUS and no previous reports have described a rapid recovery, the case reported here suggests that infusion of an AT-III concentrate should be tried when plasma AT-III is significantly decreased.

Subcutaneous heparin and plasma infusion were successfully used during an induced abortion in a young woman with familial antithrombin-III deficiency and a history of severe thrombotic episodes.

Plasma antithrombin-III (AT-III) levels in 18 patients on maintenance haemodialysis were studied. AT-III was measured functionally and immunologically before and after dialysis. Simultaneous counts of platelets were made. Prior to dialysis the average AT-III levels and platelet counts were found to be within the lower part of the normal range. On paired analysis the dialysis was seen to induce small, but significant decreases in AT-III levels and platelet counts. A positive linear correlation was found between levels of functionally and immunologically determined AT-III. Replacement of the intravenous application of heparin with an administration of low-dose, subcutaneous heparin is suggested.

Cultured skin fibroblasts from three unrelated patients with idiopathic hemochromatosis and two normal controls were cultured in media containing iron concentrations ranging from 383 to 963 ng/ml. The amount of ferritin accumulating in fibroblasts was related to the iron concentrations, but there was no significant difference in the fibroblasts of patients with hemochromatosis and the normal controls.

Autopsy studies of two infants, one a newborn, the other 4 months old, revealed massive amounts of iron in lysosomes of hepatocytes and pancreatic acinar cells. Iron, which had been transported across the placenta, accumulated in the same cell types as in adults with primary and secondary hemochromatosis. Hemosiderin was found in cardiac muscle cells, gastric and intestinal glands, and endocrine and exocrine organs including pituitary, thyroid, adrenals, islets of Langerhans, and sublingual and sweat glands. The liver was the most affected organ and the normal hepatic architecture was replaced by hepatocytes which were arranged in cluster, pseudoacinar structures, and multinucleated giant cells embedded in a collagen matrix. The islets of Langerhans were hyperplastic and hypertrophic. Ten similar cases, in five families, have been described; no patients liver longer than 4 months. Neonatal iron storage disease is clinically and pathologically distinct from Zellweger's cerebrohepatorenal syndrome and hypermethioninemia (tyrosinemia) neonatal diseases in which large stores of iron are present in hepatocytes. No abnormalities in serum iron, ferritin, or transferrin concentrations were detected in five parents of the affected children.

Gel-filtration (Sephadex G-75) analysis of hepatic cytosol reveals both qualitative and quantitative sex differences in oestrogen-binding proteins. The elution profile of [(3)H]oestradiol-labelled cytosol shows four species of oestrogen-binding proteins (peaks I, II, IV and V) common to both sexes. The amount of [(3)H]oestradiol binding in peak I is equivalent in both males and females and corresponds quantitatively to the specific oestrogen receptor. The amount of binding in the remaining three peaks is greater in males than females. In addition, an oestrogen-binding protein (peak III) is present that is unique to male cytosol. Proteinase-inhibition studies demonstrate that the observed multiplicity of oestrogen-binding proteins is not an artefact of proteolytic breakdown. Sex differences in oestrogen-binding proteins are absent in immature male and female animals; the oestrogen-binding protein profile in immature rats resembles that of an adult female. Gonadectomy of adult animals does not affect the oestrogen-binding-protein profile. In contrast, neonatal (day 1) castration results in partial feminization of the characteristic oestrogen-binding protein profile seen in the adult male; the appearance of Peak III is suppressed and marked decreases in the amount of oestradiol binding occurs in the remaining peaks. Hypophysectomy of adult animals results in near abolishment of the observed sex differences; the male oestrogen-binding protein profile is partially feminized and the female profile is partially masculinized, as characterized by the appearance of [(3)H]oestradiol binding in the region of peak III and increased amounts of binding in peaks IV and V. The present studies demonstrate a multiplicity of oestrogen-binding proteins in liver cytosol and raise the possibility that the presence of some of these proteins may be imprinted at birth through the hypothalamic-pituitary axis, by a mechanism requiring neonatal androgen exposure.