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Suspensions of peripheral blood mononuclear cells (PBMC), monocytes, T or B lymphocytes, platelets or granulocytes, and cell-depleted supernatant fluids of these suspensions inhibited activation of Hageman factor (HF, Factor XII) by ellagic acid, a property not shared by erythrocytes. PBMC also inhibited HF activation by glass or sulfatides. Contaminating platelets may have contributed to inhibition by PBMC. Elaboration of agents inhibiting HF activation required metabolically active cells. The inhibitor(s) in PBMC supernates were not identified with known agents, but had properties of a nonenzymatic protein. PBMC supernates did not contain fibrinogen, nor alter the thrombin, prothrombin, or partial thromboplastin times of normal plasma, amidolysis by activated plasma thromboplastin antecedent (Factor XIa) or activated Stuart factor (Factor Xa) or esterolysis by C1 (C1 esterase); they inhibited plasmin minimally. These experiments suggest that peripheral blood cells may impede intravascular coagulation. Whether this property helps maintain the fluidity of blood is unclear.

beta 2-Glycoprotein I (apolipoprotein H), a constituent of normal human plasma, has been shown to inhibit the generation of amidolytic activity in plasma that has been exposed to negatively charged agents. Studies with purified Hageman factor (factor XII) demonstrate that this inhibitory property is directed against the activation of Hageman factor. In this study beta 2-glycoprotein I inhibited the kaolin-induced generation of clot-promoting properties in solutions of Hageman factor. This effect was localized to an interaction between beta 2-glycoprotein I and kaolin. In contrast, once Hageman factor was activated by kaolin, its clot-promoting properties were not inhibited by beta 2-glycoprotein I. Further, beta 2-glycoprotein inhibited the generation of amidolytic activity against H-D-prolyl-L-phenylalanyl-L-arginine p-nitroanilide dihydrochloride in mixtures of Hageman factor and ellagic acid. The specificity of the action of beta 2-glycoprotein I was confirmed by its neutralization by immunoglobulin fractions of antiserums directed against this protein.

Five patients with classic hemophilia were found to have primary pulmonary hypertension, a disorder not previously recognized in this population. All patients had had their coagulation disorder treated for 10 years or more with self-administered lyophilized concentrates of factor VIII, and all had antibodies to human immunodeficiency virus (HIV). Primary pulmonary hypertension was confirmed by histologic means at autopsy in one patient and by lung biopsy findings in another. In the other three patients, the findings are in agreement with this diagnosis. No patient had underlying cardiac or pulmonary disease, or clinical or pathologic evidence of collagen-vascular disease, vasculitis, parasitic disorders, hemoglobinopathy, or exposure to anorexigenic agents. Whether the primary pulmonary hypertension was related to treatment with lyophilized factor VIII, or to the presence of antibodies to HIV, or both, is unknown.

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.

A modern outline of the physiology of coagulation, a simple approach to the use of laboratory investigation for patients with possible clotting disorders in unexplained hematuria and several illustrative cases are presented. The diagnosis and management of localized fibrinolysis in the genitourinary tract and intravascular coagulation as possible causes of post-prostatectomy hemorrhage are discussed. A minimum of a platelet count, fibrinogen assay and, if possible, measurement of fibrinogen-related antigens should be obtained before administration of epsilon aminocaproic acid.

Incubation of normal human plasma or its euglobulin fraction with chloroform enhances the generation of proteolytic activity attributable to plasmin. The mechanisms involved remain unclear. Earlier, plasmin formation was found to be impaired in the chloroform-treated euglobulin fraction of Hageman trait plasma. We now demonstrate sharply reduced generation of fibrinolytic and caseinolytic activities in prekallikrein-deficient (Fletcher trait) and HMW kininogen-deficient (Fitzgerald trait) plasmas as well. These defects were corrected by addition of the missing factors. In addition, precipitation of the euglobulin fraction of plasma activated small but measurable amounts of HF. With the use of 125I-HF, cleavage of the native molecule into its amino-terminal and carboxy-terminal fragments occurred pari passu with the generation of plasmin. These experiments suggest that one pathway through which HF can bring about formation of plasmin in chloroform-treated euglobulin fractions involves the participation of plasma prekallikrein and HMW kininogen, presumably through mechanisms similar to those evoked by surface activation of HF.

In 1775 Peter Christian Abildgaard, a Danish veterinarian and physician, conducted experiments on electrical countershock on animals. He succeeded in first rendering fowl lifeless by an electric shock and then reviving them by a countershock applied to the chest. Ventricular fibrillation and defibrillation were not known and could not be documented at that early date, but his report suggests he accomplished these changes long before other physiologists described them. Dr. Abildgaard's long and varied career included many significant contributions to veterinary and human medicine, biology, zoology, botany, physics, chemistry, and mineralogy. He also took an interest and was active in politics, economics, and community affairs. This short biography is intended as a fitting, though belated, tribute to his pioneer work on effects of electric shock.

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.

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.

Blood clotting and fibrinolytic systems were studied in the plasma of a sei whale (Balaenoptera borealis). The sei whale belongs to the suborder baleen whales of the order Cetacea. Whale plasma had a greatly prolonged kaolin-activated partial thromboplastin time and was deficient in Hageman factor (factor XII), Fletcher factor (a plasma prekallikrein), and PTA (factor XI). All other clotting factor activities were present in amounts comparable to that of normal human plasma. Whale plasminogen was activated by human urokinase, but not by streptokinase. Whale plasma contained inhibitory activities against thrombin, activated Stuart factor, activated PTA, activated Fletcher factor, and plasmin.

Spontaneous shortening of the Thrombotest time and an increase in factor VII activity after cold storage of plasma in plastic vials have been described in the plasma of women using OCAs. The phenomenon if CPA is dependent on the presence of HF (factor XII) and is associated with increased plasma kallikrein activity and the disappearance of C1-INH activity. In the present study, spontaneous CPA and shortening of the prothrombin time were observed in 66% of women using OCAs. The prothrombin time was inversely related to factor VII activity and HF coagulant titer, whereas factor VII activity was strongly associated with the titer of HF. The addition of purified HF to normal plasma to a degree observed in OCA users promoted CPA generation and shortening of the prothrombin time. In contrast, reduction of the HF coagulant titer in the plasma of OCA users to a normal level prevented the rise in factor VII activity and shortening of the prothrombin time after cold storage. These data indicate that a high titer of HF, such as that observed in OCA users, is needed for the spontaneous CPA and add support to evidence linking the extrinsic and intrinsic pathways of clotting. The relationship of this in vitro phenomenon to the pathogenesis of thrombosis in women using OCAs is presently unclear. (J Lab Clin Med 99:363, 1982.)

Two siblings with m ild hemorrhagic symptoms had combined functional deficiencies of vitamin K-dependent clotting factors. Prothrombin (0.18-0.20 U/ml) and Stuart factor (Factor X, 0.18-0.20 U/ml) and Stuart factor (Factor X, 0.18-0.20 U/ml) were most severely affected. Antigenic amounts of affected coagulation factors were normal and normal generation of thrombin activity occurred in the patients' plasmas after treatment with nonophysiologic activators that do not require calcium for prothrombin activation. Hepatobilary disease, malabsorptive disorders, and plasma warfarin were not present. Both parents had normal levels of all coagulation factors. The patients' plasmas contained prothrombin that reacted both with antibody directed against des-gamma-carboxyprothrombin and native prothrombin. Crossed immunoelectrophoresis of patients' plasmas and studies of partially purified patient prothrombin suggested the presence of a relatively homogeneous species of dysfunctional prothrombin, distinct from the heterologous species found in the plasma of warfarin-treated persons. These studies are most consistent with a posttranslational defect in hepatic carboxylation of vitamin K-dependent factors. This kindred uniquely possesses an autosomal recessive disorder of vitamin K-dependent factor formation that causes production of an apparently homogeneous species of dysfunctional prothrombin; the functional deficiencies in clotting factors are totally corrected by oral or parenteral administration of vitamin K1.

Hageman factor (factor XII) is a procoagulant upon which the surface-mediated generation of fibrinolytic activity and kinin formation depends. We found that the clotpromoting activity and antigenic properties of Hageman factor were present in lower levels in the plasma of a small group of Oriental subjects than in that of American whites, whereas the levels of plasma prekallikrein (Fletcher factor), high-molecular-weight kininogen (Fitzgerald factor), and plasma thromboplastin antecedent (factor XI) in plasma samples from Oriental subjects did not significantly differ from those from normal white subjects. In one family, there was an excess of plasma Hageman factor antigens with respect to functional activity. These findings stress the importance of defining the racial characteristics of subjects used to establish standards for clotting assays.

The effect of HMW kininogen upon the amidolytic properties of two species of activated HF (factor XII), designated HFea and HFf, was studied by using the synthetic substrate S2238. HFea is an agent present in the fluid phase after mixture of HF and Sephadex gels to which ellagic acid has been adsorbed, whereas HFf is the carboxy-terminal fragment separated from HF by limited proteolysis. The specific amidolytic activity of HFea was significantly greater than that of HFf. HMW kininogen enhanced amidolysis by both HFea and HFf. In contrast, kaolin inhibited amidolysis by these enzymes, an effect counteracted by pretreatment of kaolin with HMW kininogen. The mechanisms responsible for these effects of HMW kininogen are uncertain. Its enhancement of amidolysis by fluid-phase HFea ad HFf may be related in part to its capacity to counteract substrate inhibition by S2238. The countervailing effect of HMW kininogen upon the inhibitory properties of kaolin may reflect its capacity to inhibit partially the adsorption of HFea or HFf to kaolin, allowing expression of the amidolytic properties of these enzymes in the fluid phase.

Platelet factor 4 is a polypeptide constituent of platelet alpha granules that is released during platelet aggregation and inhibits heparin-mediated reactions. Hageman factor (factor XII) is a plasma proenzyme that, when activated by certain negatively charged agents, initiates clotting via the intrinsic pathway of thrombin formation. In earlier studies using crude systems, platelet factor 4 inhibited activation of Hageman factor by dextran sulfate or cerebrosides, but not activation of Hageman factor by kaolin or ellagic acid. In the present study we examined the mechanisms of inhibition by platelet factor 4, using purified reagents. Platelet factor 4 inhibited activation of Hageman factor by ellagic acid, as measured by amidolysis of a synthetic substrate of activated Hageman factor, an effect inhibited by heparin or by an anti-platelet factor 4 antiserum. Coating glass tubes with platelet factor 4 before addition of normal plasma significantly lengthened the partial thromboplastin time of normal plasma. In addition, the clot-promoting properties of kaolin were inhibited by its prior exposure to platelet factor 4. Thus, the inhibitory properties of platelet factor 4 directed against the activation of Hageman factor were confirmed in a purified system. In this purified system, in contrast to earlier studies using crude systems, platelet factor 4 inhibited activation of Hageman factor by glass, ellagic acid, or kaolin.

A large number of families have now been described in whom affected individuals have within their plasmas an abnormal species of fibrinogen (factor I). These defects, presumably examples of the phenomenon of allotypy--i.e., the synthesis of variant forms of a normal protein--have been inherited as autosomal dominant characteristics. In the great majority of cases, clotting is abnormally slow when thrombin is added to the abnormal plasma. Sometimes this defect appears to reside in impaired release of fibrinopeptides by thrombin. In other cases, fibrinopeptide release proceeds normally, but aggregation of fibrin monomers is impeded. In the latter instance, aggregation may be abnormally slow or, once it begins, it may proceed at a normal rate. Curiously, a bleeding tendency is more likely to occur in patients in whom fibrinopeptide release is impaired, while dehiscence of operative wounds rarely complicates dysfibrinogenemias associated with impaired aggregation of fibrin monomers; thrombosis has been described in both groups of patients. Most of the reported cases may be distinguished by functional criteria and by the physicochemical behavior and biochemical nature of the abnormal protein. Additonally, one family has been described in which plasma clots abnormally rapidly upon addition of thrombin, and two others in which crosslinking of fibrin by fibrin-stabilizing factor (factor XIII) is defective.

An inhibitor of plasma thromboplastin antecedent (PTA, factor XI), measured in coagulant and radioimmunoassays, was detected in a 60-year-old man with carcinoma of the prostate who had no evidence of a bleeding tendency. Family studies indicated that the patient was either a homozygote or a heterozygote for hereditary factor XI deficiency. In contrast to earlier described patients with factor XI deficiency in whom inhibitors were detected, the patient was unaware of having been transfused with blood or blood products at any time before the discovery of the inhibitor. The inhibitor of factor XI in the patient's plasma appeared to be predominantly in the IgG4 fraction and to be directed at a locus on the factor XI molecule other than the active site; it did not block the amidolytic properties of activated factor XI (XIa). Rather, it appeared to block adsorption of factor XI to negatively charged surfaces. The inhibitor interfered with measurement of other components of the intrinsic pathway of thrombin formation, perhaps explaining the low titres of other coagulation factors of the intrinsic system reported in patients with strong inhibitors directed against factor XI.

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.

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.

In view of conflicting evidence for a major hepatic role in the synthesis of circulating plasminogen, the precursor of the fibrinolytic enzyme plasmin, we carried out the present study with a sensitive assay in order to measure the accumulation of small quantities of plasminogen in a recycling rat liver perfusion system. We have purified plasminogen from Sprague-Dawley rat plasma and have raised a monospecific antiserum against it in rabbits. Isolated rat liver perfusions were performed with an oxygenated recycling perfusate consisting of a perfluorotributylamine/Pluronic F-68 emulsion (Fluosol 43) free of plasma proteins and blood cells. The system was shown to be capable of synthesizing albumin and transferrin. The cumulative appearance of plasminogen in the perfusate was measured by a sensitive, specific radioimmunoassay. Plasminogen concentration increased progressively during the first 2 hr of perfusion; the observed average net synthesis in five separate experiments was approximately 35 microgram/hr per 100 g of body weight. Exposure of the perfused liver to 18 microM cycloheximide inhibited additional increase in the titer of plasminogen. Evidence for de novo synthesis was provided by the incorporation of 14C-labeled leucine into specific immunoprecipitates of plasminogen and the inhibition of this incorporation by cycloheximide. Analysis of the immunoprecipitates by sodium dodecyl sulfate/polyacrylamide gel electrophoresis revealed a single peak of radioactivity corresponding to Mr of 82,000. These data indicate that the liver is a major site of plasminogen production.

Activation of Hageman factor (Factor XII) upon exposure to negatively charged agents has been attributed to proteolytic cleavage of this molecule. To examine this question, purified Hageman factor was exposed to Sephadex gels to which ellagic acid had been adsorbed. Such Hageman factor, separated from the gels and studied in the fluid phase, was amidolytic. Nonetheless, no cleavage of Hageman factor treated in this way could be demonstrated by sodium dodecyl sulfate/polyacrylamide gel electrophoresis. Thus, activation of Hageman factor by negatively charged agents was not necessarily accompanied by molecular scission.

Hageman factor (HF, Factor XII) is activated by glass, collagen, and ellagic acid, and initiates blood coagulation via the intrinsic pathway. C1q inhibits collagen-induced platelet aggregation and adherence of platelets to glass, effects attributable to the collagen-like region of C1q. We examined the actions of C1q on HF activation. Incubation of C1q with HF before addition of HF-deficient plasma extended the activated partial thromboplastin time. Similarly, when glass tubes were coated with C1q before testing, the partial thromboplastin time of normal plasma was increased. C1q reduced the activation of HF by ellagic acid, as measured by the release of p-nitroaniline from the synthetic substrate H-D-prolyl-L-phenylalanyl-L-arginine-p-nitroanilide dihydrochloride, an effect inhibited by monoclonal anti-human C1q murine IgG and by digestion of C1q by collagenase. Thus, C1q inhibits activation of HF in vitro in clot-promoting and amidolytic assays and suggests a regulatory mechanism for the inhibition of coagulation.

Previous investigators have suggested that the biological activity of plasma prekallikrein is defective in cystic fibrosis. In contrast, no such difference was demonstrable between normal and cystic fibrosis plasma. Esterolytic activity for the synthetic substrate p-toluene sulfonyl-arginine methyl ester (TAMe) evolved normally in cystic fibrosis plasma treated with chloroform and ellagic acid, a measure of generation of plasma kallikrein. Additionally, plasma prekallikrein (Fletcher factor) and high molecular weight kininogen (Fitzgerald factor), a substrate of plasma kallikrein, were normal. Thus, the concept that cystic fibrosis is associated with abnormalities in the plasma kallikrein-kinin system could not be supported.

Bismuth subgallate is an effective agent in preventing hemorrhage after adenotonsillectomy. The experiments described demonstrate that this may occur through the activation of Hageman factor by this agent. Bismuth subgallate shortened the clotting time of whole blood, an action localized to an effect on the early steps of the intrinsic pathway; bismuth subgallate did not accelerate the thrombin time or prothrombin time of normal plasma, but could be substituted for kaolin as an activator of coagulation in assays of the partial thromboplastin time. The action of bismuth subgallate was localized to an effect on Hageman factor. It did not induce coagulation of plasma samples deficient in any of the recognized factors participating in the intrinsic pathway of thrombin formation, but it shortened the clotting time of plasma deficient in factor VII, a component of the extrinsic pathway. Evidence was obtained that Hageman factor exposed to bismuth subgallate corrected the defect of Hageman factor-deficient plasma and acquired amidolytic properties in the absence of other clotting factors. These studies provide a rationale for the hemostatic properties of bismuth subgallate.

To examine the role of antihemophilic factor (factor VIII) preparations in the pathogenesis of subclinical immunodeficiency in hemophilia, we tested the in vitro effects of these products on immune function. Both lyophilized antihemophilic factor (LAHF) and cryoprecipitates inhibited lymphocyte proliferation in a dose-dependent fashion. Further studies indicated that LAHF interfered with an early event in proliferation and also that prolonged incubation of human lymphocytes with LAHF resulted in an irreversible inhibition of lymphocyte proliferation without detectable cytotoxic effects. LAHF also inhibited the production of interleukin-2 (IL-2) by human lymphocytes and by Jurkat tumor cells, suggesting that inhibition of IL-2 production was not mediated through effects on interleukin-1. Gel filtration of LAHF revealed two peaks of inhibitory activity; one with mol wt greater than 2 X 10(6) comigrated with factor VIII coagulant activity and antigen, whereas another with mol wt approximately 6 X 10(5) was devoid of factor VIII activity and antigen. Further study will ascertain whether administration of factor VIII-containing preparations contributes to the subclinical immunodeficiency seen in patients with hemophilia or serves as a cofactor in the development of clinical immunodeficiency after exposure to the retrovirus human T-lymphotropic virus type III.

The prolonged partial thromboplastin time observed in the plasma of a 71-yr-old asymptomatic man was related to the deficiency of a hitherto unrecognized agent. The patient's plasma also exhibited impaired surface-mediated fibrinolysis and esterolytic activity and impaired generation of kinins and of the property enhancing vascular permeability designated PF/Dil. The patient's plasma contained normal amounts of all known clotting factors except Fletcher factor (a plasma prekallikrein) which was present at a concentration of 10-15% of pooled normal plasma. Fletcher trait plasma, however, contained normal amounts of the agent missing from the patient's plasma and corrected the defects in clotting, fibrinolysis, and vascular permeability. Fletcher trait plasma was less effective in correcting generation of kinins and esterolytic activity, presumably because of the patient's partial deficiency of prekallikrein. The site of action of the factor deficient in the patient's plasma appeared to be subsequent to the activation of Hageman factor and plasma prekallikrein. A fraction of normal plasma, devoid of other clotting factors, corrected the defect in clotting in the patient's plasma; a similar fraction of the patient's plasma did not correct this abnormality. No evidence yet exists pointing to the familial nature of the patient's defect. Tentatively, the patient's disorder may be referred to by his surname as Fitzgerald trait, and the agent apparently deficient in his plasma as Fitzgerald factor.

Hemostatic changes and hyperestrogenemia have been reported in men during myocardial ischemia and acute myocardial infarction. Because marked augmentation of Hageman factor (factor XII) titer is induced by estrogen intake in humans, we studied the factors participating in the surface-mediated reactions of clotting in patients with documented acute myocardial infarction. We report lower coagulant titers of Hageman factor, prekallikrein, high molecular weight kininogen, and plasma thromboplastin antecedent (factor XI) in the plasma samples of patients with acute myocardial infarction than in control samples. Further, the plasma estradiol titers of patients with acute myocardial infarction were not significantly different from those of controls. In contrast, the prolactin concentration of patients with acute myocardial infarction was elevated. These data suggest that other nonhormonal factors such as excessive consumption may influence the observed reduction in the titers of surface-mediated clotting factors in acute myocardial infarction.

Estimation of the titer of procoagulant antihemophilic factor (AHF) and the concentration of AHF-like antigens, as detected by heterologous antiserum, provides a method for diagnosis of the carrier state of classic hemophilia. Among 87 obligate carriers, 82, or 94%, could be identified as carriers by logarithmic discriminant analysis because the titer of procoagulant AHF was disproportionately lower than the concentration of AHF-like antigens relative to normal women. Women who were the mothers of individuals with isolated cases of hemophilia appeared to be carriers in at least 85% of cases, suggesting that the frequency of cases due to fresh mutations is low. The validity of the techniques used is supported by the frequency with which the carrier state was recognized in daughters of hemophiliacs who themselves had no sons. Corrected for the known error of the method, 48% of 75 such daughters appeared to be carriers, not significantly different from their anticipated chance of 50%.