Search

In five patients with idiopathic osteonecrosis (ON) of the hip, four having hypofibrinolysis mediated by high plasminogen activator inhibitor (PAI-Fx), and one with high Lp(a), our specific aim was to determine whether therapy (Rx) with the anabolic-androgenic steroid, Stanozolol (6 mg/day), would normalize PAI-Fx and Lp(a) and thus potentially ameliorate ON. Prior to Rx, none of the four patients with high PAI-Fx could normally elevate tissue plasminogen activator (tPA-Fx) after 10 min venous occlusion at 100 mm Hg. After 12-18 weeks on Rx, PAI-Fx and stimulated tPA-Fx normalized in all four patients. Prior to Rx, mean (SD) stimulated tPA-Fx was low, 0.4 +/- 0.3 IU/ml (lower limit of normal 2.28 IU/ml). On Rx, stimulated tPA-Fx normalized, rising to 2.83 +/- 1.9 IU/ml, P = .004. Prior to Rx, mean (SD) basal PAI-Fx was high, 99 +/- 68 (upper limit of normal 26.9 U/ml), and fell on Rx to 22.5 +/- 22, P = .004. In two of the five patients normalization of hypofibrinolysis or high Lp(a) was accompanied by major symptomatic improvement. Prior to Rx, and 2 years after onset of unilateral hip pain, one of the four patients with high PAI-Fx and low stimulated tPA-Fx could walk only one block painfully. After 8 weeks on Stanozolol Rx, and continuing through 54 weeks on Rx, he walked 2 miles per day without pain, despite radiographic progression of ON. In three of the four patients with high PAI and with osteonecrosis present 0.3, 2, and 6 years prior to Stanozolol Rx, there was no clinical improvement after 14-156 weeks of Rx despite normalization of stimulated tPA-Fx and PAI-Fx. The fifth patient, 1 month after onset of disabling hip pain, had normal PAI-Fx but high Lp(a) (27 mg/dl), and MRI evidence of bone marrow edema ("transient osteoporosis").(ABSTRACT TRUNCATED AT 250 WORDS)

To assess the hypothesis that beta blocker use and hypertension are associated with high lipoprotein(a) [Lp(a)] or with reduced basal fibrinolytic activity, the authors studied relationships of hypertension and beta blockers to Lp(a), lipids, lipoproteins, apolipoproteins, and basal fibrinolytic activity in 385 patients consecutively referred for diagnosis and therapy of hyperlipidemia. A second aim was to determine possible gender differences in fibrinolytic activity among patients with hypertension. Ninety-nine patients (58 women [88% post-menopausal] and 41 men) had drug-treated hypertension. In women, hypertension was a positive, independent predictor of the major inhibitors of fibrinolysis, plasminogen activator inhibitor antigen (p = 0,017), and plasminogen activator inhibitor activity (p = 0.004). In men and women, major risk factors for atherosclerosis were significant, independent predictors of reduced basal fibrinolysis. Median Lp(a) in the 99 patients with hypertension (16 mg/dL) did not differ from Lp(a) (18 mg/dL) in normotensive patients (p > 0.1). Of the 385 patients, the 39 beta blocker users had higher plasminogen activator inhibitor activity (p = 0.01), higher triglyceride (p = 0.02) levels, and higher Quetelet Indices (p = 0.01) than non-users (n = 346). After covariance adjusting for age, Quetelet Indices, sex, and triglycerides, plasminogen activator inhibitor activity was not higher in beta blocker users than in non-users (p > 0.1). Median Lp(a) did not differ in beta blocker users (16 mg/dL) and in non-users (17 mg/dL), p greater than 0.1. Hypertensive, predominantly post-menopausal women are likely to have high plasminogen activator inhibitor activity and plasminogen activator inhibitor antigen with concurrent reduced fibrinolytic activity, as well as high fibrinogen levels. These independent coronary heart disease risk factors, along with their hypertension, may put hypertensive, post-menopausal women at increased risk for coronary heart disease.

In eight patients with Legg-Perthes disease, we assessed the etiologic roles of thrombophilia caused by protein C and protein S deficiency and hypofibrinolysis mediated by low levels of tissue plasminogen activator activity. We speculated that thrombosis or hypofibrinolysis were common causes of Legg-Perthes disease. Three of the eight patients had protein C deficiency; they came from kindreds with previously undiagnosed protein C deficiency. In one of these three kindreds there were six protein C-deficient family members (beyond the proband child), four of whom had thrombotic events as adults. One of the eight patients had protein S deficiency, as did his brother who had sustained mesenteric vein thrombosis at age 43. One of the eight patients who had normal proteins C, S, and antithrombin III had hypofibrinolysis, failing to elevate tissue plasminogen activator activity after 10 min of venous occlusion at 100 mm Hg. Plasminogen activator inhibitor, alpha 2-antiplasmin, and fibrinogen values were normal in all eight patients. Beyond their Legg-Perthes disease, none of the eight patients had evidence for venous thrombosis. Of the eight patients, four had thrombophilia and one had hypofibrinolysis, disorders that we believe contributed to thrombotic venous occlusion of the femur with subsequent venous hypertension and bone death that characterize Legg-Perthes disease.

Our specific aim was to assess within-family relationships of basal fibrinolytic activity and its determinants in hyperlipidemic probands (n = 34) with high lipoprotein (a) [Lp(a)] levels (>35 mg/dL) and their first-degree relatives (n = 74) and in hyperlipidemic probands (n = 19) with Lp(a)

In 191 newly referred hyperlipidemic patients, our specific aim was to assess relationships between levels of lipoprotein(a) [Lp(a)], lipids, apolipoproteins, regulators of basal and stimulated fibrinolytic activity, and D-dimer, a measure of in vivo fibrinolysis. Lp(a) levels correlated with none of the measures of basal fibrinolytic regulators or D-dimer. In 25 patients, levels of stimulated regulators of fibrinolytic activity and D-dimer were measured after 10-minute cuff venous occlusion. Lp(a) levels again correlated with none of the stimulated regulators of fibrinolytic activity or D-dimer. However, both basal and stimulated levels of fibrinolytic regulators and D-dimer were closely related to other major risk factors for coronary heart disease (CHD) including triglyceride, apolipoprotein (apo) A1, apo B, Quetelet index (QI), and sex. By stepwise regression in 191 patients, the following standardized partial regression coefficients were significant (P < or = .05), and model R2 and P values were as follows: basal tissue plasminogen activator (tPA) with apo B-.18, with time .17, with QI -.28, R2 = 17%, P < or = .0001; basal plasminogen activator inhibitor (PAI) with apo B..25, with time -.15, with QI .17, R2 = 14%, P < or = .0001; basal alpha 2-antiplasmin with apo A1.14, with apo B.24, with QI.17, with sex .30, R2 = 25%, P < .0001; basal plasminogen with A1.15, with apo B.21, with QI.17, with sex.17, R2 = 15%, P < or = .0001; basal fibrinogen with Lp(a).17, with QI.21, with sex.26, R2 = 14%, P < or = .0001; D-dimer with sex.15, R2 = 21%, P < or = .048. Given the absence of any relationship between Lp(a) levels and inhibition or stimulation of fibrinolysis regulators or D-dimer either in the basal or stimulated state, we postulate that Lp(a)'s major atherogenic effects are mediated by mechanisms other than reduction of fibrinolysis stimulation or in vivo fibrinolysis.

SummaryIn a 29 year old white male with osteonecrosis of both hips and a shoulder, and in his family, we measured basal and stimulated (10 min cuff venous occlusion at 100 mgHg) fibrinolytic activity to determine whether low fibrinolytic activity might be heritable and etiologically associated with osteonecrosis. The proband’s basal tPA-Fx was low, 0.08 IU/ml (normal 0.11-1.94), tPA-Ag was normal (11.6 ng/ml), plasminogen activator inhibitor activity (PAI-Fx) was very high, 119 U/ml (normal 3.5-27), as was his plasminogen activator inhibitor antigen (PAI-Ag), 202 ng/ml (normal 3.2-37.1). The proband’s basal PAI-Fx (119) and PAI-Ag (202) were respectively 6 and 13 standard deviations greater than the mean PAI-Fx (17 ± 15 U/ml) and the mean PAI-Ag (25 ± 13 ng/ml) in 172 concomitantly studied hyperlipidemic men. Alpha-2 antiplasmin, fibrinogen, plasminogen and Lp(a) were normal. Despite lowering TG to 301 mg/dl, basal tPA-Fx remained low, 0.05; PAI-Fx and PAI-Ag remained very high (109 and 191). Following venous occlusion, stimulated tPA-Fx remained very low, 0.1 (normal 2.3-11.3), but tPA-Ag rose normally to 17 (normal 8.4-31.4); stimulated PAI-Fx and PAI-Ag were very high, 134 and 223, (normal PAI-Fx 3.6-24, PAI-Ag 12-96). Stimulated D-dimer was < the 10th percentile, 0.084 μg/ml. With such high PAI-Fx available to bind tPA, occlusionstimulated tPA-Fx could not rise, and fibrinolysis could not be initiated. Neither diseases nor drugs could explain the high PAI-Fx and PAI-Ag, low tPA-Fx, or osteonecrosis. The proband’s father, mother, and sister had very high basal PAI-Ag (240, 69, 66 ng/ml), high basal PAI-Fx (24, 24, 35 U/ml), and normal basal tPA-Fx (0.6, 1.0, and 0.2 IU/ml). Basal PAI-Ag, PAI-Fx, and tPA-Fx were normal in the proband’s son (13, 12, 0.3). The proband’s very high PAI-Fx and PAI-Ag appeared to be inherited, possibly as an autosomal dominant trait, producing hypofibrinolysis. We speculate that his osteonecrosis was caused by familial hypofibrinolysis mediated by high PAI, with subsequent inability to activate fibrinolysis, resulting in inadequate lysis of venous thrombi in bone, impaired bone venous circulation, and venous hypertension of bone characteristic of osteonecrosis.

Skin necrosis associated with protein C deficiency has recently been reported to occur in hemodialysis patients. The clinical presentation and course of this syndrome appears indistinguishable from skin necrosis (purpura fulminans) seen in other settings with inherited or acquired deficiency of the naturally occurring anticoagulant proteins, protein C and S. Patients on maintenance hemodialysis may have low levels of these factors. However, patients on peritoneal dialysis have normal or elevated levels of these proteins despite documented peritoneal losses. We report two patients in whom the occurrence of protein S deficiency and subsequent skin necrosis can be related to demonstrated peritoneal dialysis-associated losses. We suggest that these losses may become critical under appropriate conditions and suggest caution in peritoneal dialysis patients requiring warfarin therapy.

Anticardiolipin antibodies, immunoglobulin G, and M (IgG, IgM) have been associated with recurrent abortion and with maternal death. This study tested whether anticardiolipin titers would be a useful prenatal screening test to determine high-risk pregnancies. Titers were obtained at the first clinic visit in 686 patients, mean gestation, 20 weeks. The outcome variables were taken from a medical records computer data base. IgG anticardiolipin correlated inversely with birthweight (p less than 0.025), but not with gestation. IgM anticardiolipin correlated strongly with the inverse of patient age (p less than 0.0002) and with chronic hypertension (p less than 0.01), but not with preeclampsia. There was a weak correlation with the 1-minute Apgar score (p less than 0.05). Thirty-seven patients had titers of IgG or IgM greater than 3 standard deviations above the mean for nonpregnant patients. Sixteen of these patients were studied for antinuclear antibody and coagulopathy (prothrombin time, partial thromboplastin time, viper venom time) and all were normal. Six of eight patients tested had low range elevated antibody titers to double-stranded DNA. Ten placentas were examined and showed no infarctions. None of the correlations were of practical clinical utility. The biologic basis of the correlations found is of further interest. The value of anticardiolipin titers with lupus erythematosus, or with coagulopathy, was not tested.

Ancrod, which produces in vivo defibrination, has been shown to improve renal function and decrease fibrin deposition and crescents in experimental glomerulonephritis. Ancrod was given for 14 days to 5 patients with glomerulonephritis, moderate to severe renal functional impairment, crescents, and/or fibrin deposition in glomeruli. 4 patients had systemic lupus erythematosus. Ancrod treatment resulted in fibrinogen levels less than 50 mg/dl without bleeding, decrease of previously elevated factor VIII and von Willebrand factor levels, and normalization of in vitro platelet hyperaggregation. Renal function improved in all 5 patients. Serial renal biopsies showed a relatively rapid decrease of glomerular thrombi and necrosis and little increase in glomerular sclerosis. Ancrod administration appears safe, and may have a role in treatment of certain types of glomerulonephritis.

• The combination of a progestogen and an estrogen (Enovid, Enovid E) has been used successfully in the management of nine patients with hereditary hemorrhagic telangiectasia (HHT) and severe epistaxis: Such therapy was instituted when epistaxis was severe and only after other therapeutic measures had failed. Seven of our patients required the 5-mg tablet (Enovid) to achieve a satisfactory clinical result; two patients received the 2.5-mg preparation (Enovid E). The eight women received cyclic therapy; the man received therapy without interruption. Because of the possibility of serious adverse effects from the drugs, it is required that each patient receive a complete medical evaluation prior to therapy and at frequent intervals while receiving therapy. Enovid therapy for HHT is not recommended for the patient with mild bleeding that can be controlled by conventional therapy. ( Arch Otolaryngol 103:148-151, 1977)

Platelet function was serially followed in a group of 13 children with SCD. Defective platelet aggregation was seen in all 4 patients studied during painful crisis and in 45 percent of patients during “asymptomatic” periods. Stypven times were shorter (perhaps reflecting increased PF-3) in the PRP of patients; however, Stypven times were slightly prolonged following freeze-thawing. Recombination experiments in 8 patients revealed no inhibition of SCD plasma on the function of platelets derived normal controls. These findings are suggestive of partial activation of platelets in SCD and may suggest a role of platelets in the genesis of the vaso-occlusive crisis common in this disorder.

The prostaglandins, especially the PGE series, produce profound effects on platelet function in vitro. It has been reported that PGF2alpha and the PGE series do not affect the clotting mechanism when used to induce midterm abortion, in contrast to that induced with hypertonic saline but the effect of these drugs on the clotting mechanism when used to induce term labor has not been reported. Labor was induced with intravenous PGF2alpha in eight patients, at 32 to 41 weeks' gestation, with premature rupture of the membranes. Three samples were obtained: (1) anteceding the administration of the drug, (2) during the peak drug effect during active labor, and (3) approximately 12 hours post partum. No significant changes were seen in the prothrombin or partial thromboplastin times, platelet numbers or aggregation with ADP, fibrinogen levels, euglobulin lysis times, and circulating fibrin split products. The circulation of thrombin as shown by a specific test for fibrin monomer was not demonstrated.

An acquired bleeding diathesis was first noted in a 51-year-old patient 11 days following an exploratory laparotomy. Laboratory studies indicated the cause of bleeding to be the development of a circulating anticoagulant which inhibited factor V activity. The inhibitor, an immunoglobulin of the IgG class, was separated by use of Sephadex G-200 filtration, disc electrophoresis, and isoelectric focusing. Despite vigorous immunosuppressive, antifibrinolytic, and replacement therapy, including the use of a “prothrombin complex” and plasmaphoresis, the bleeding diathesis could not be reversed and the patient died of hemorrhage. Although inhibitors to factor V are not usually associated with major life-threatening hemorrhage, this case demonstrates that the development of such an inhibitor can be an ominous finding. The use of an aminoglycoside antibiotic in this and other patients so reported may be one of the contributing causes to the development of such an inhibitor.

Eight patients with hereditary hemorrhagic telangiectasia and severe epistaxis were treated with norethynodrel with mestranol (Enovid). Biopsy specimens of typical lesions from two patients were taken for electron microscopy before and after several months of therapy. Characteristic endothelial cell damage and necrosis were noted in the dilated venules of patients before treatment but not after. Unlined channels of blood were found in connective tissue before treatment but not after. These are thought to arise from leaks in the affected venules, and it is suggested that later endothelial ingrowth gives rise to new telangiectasias and may account for the propagation of lesions that are known to develop with age. Reduplicated basal laminae and regenerating endothelial cells were found both before and after treatment.

SummaryAn abnormal fibrinogen was found in a patient associated with disabling recurrent phlebitis and pulmonary emboli, pseudotumor cerebri, gout and endometriosis. The fibrinogen is characterized by (1) abnormal side-to-side and end-to-end polymerization, (2) abnormal fibrinopeptide release, (3) a delayed γ-γ dimerization of the non cross-linked fibrin, (4) a pH optimum of 7-7.8, and (5) a deviation from normal amino acid composition with regard to lysine, aspartic acid, glutamic acid and serine. Since no defect has been found in any of her three children, and since the prothromin and partial thromboplastin times vary from time to time, it is assumed that the defect is acquired. Liver disease, usually associated with acquired abnormal fibrinogen, has been excluded as an etiological cause since liver function tests and biopsy are completely normal.

SummaryEffects of synthetic steroids with progestational and androgenic-anabolic activity (Norethindrone Acetate and Oxandrolone) on coagulation parameters and plasma lipids were studied in 20 patients with familial types III, IV and V hyperlipoproteinemia. Prior to therapy there was a relatively uniform elevation of fibrinogen (284 mg %) and esterase prothrombin (64 U/ml). On therapy mean fibrinogen fell sharply to 223 mg % (short-term) and 195 mg % long-term. There were no increments in other clotting factors, and levels of factor VII and X were decreased on drug in several patients who initially had abnormally high levels. The fall in fibrinogen on therapy did not correlate with concurrent decrements in cholesterol or triglyceride. In hypertriglyceridemic patients predisposed to coronary or peripheral vascular thrombosis, Norethindrone and Oxandrolone appear to ameliorate rather than potentiate any tendency to “hypercoagulability”.

One-stage prothrombin and “TAMe esterase prothrombin” assays were performed on 42 infants and children hospitalized for jaundice. All patients received parenteral vitamin K to exclude hypoprothrombinemia due to vitamin deficiency. Biopsies or surgical specimens were obtained in all. Double-blind techniques were used throughout. The pathologist established the diagnosis, estimated the degree of parenchymal damage, and classified the impairment of function into 4 categories, ranging from none to severe. Fourteen patients showed moderate to severe cellular damage and the diagnosis in 11 of the 14 (78 per cent) was hepatitis. A high degree of correlation was found between the pathologist's estimate of the severity of the hepatic damage and both assays (P=0.001). Since parenchymatous cellular damage was more often associated with hepatitis, abnormal prothrombin values were commoner in this category. Assays were usually normal early with atresia or with infiltrative liver disease. The TAMe assay proved particularly useful when the one-stage method was questionably or moderately abnormal. Since the assays cannot differentiate jaundice due to obstruction from that found with minimal hepatitis or infiltrative liver disease, their use does not preclude biopsy and/or early exploration in the infant.

A combination of norethynodrel-mestranol (Enovid) has been used for the treatment of von Willebrand's disease (V.W.D.), hemophiliacs, and a female carrier of hemophilia with low levels of Factor VIII. This therapy of V.W.D. was successful in 5 females; no response was observed in the single male with V.W.D. The female carrier of hemophilia showed increases in Factor VIII levels with therapy whereas no improvement was noted in two hemophiliacs, one severe (

Autopsy records of 151 patients dying of acute myocardial infarction, in a large private hospital, were reviewed. Half of the patients received anticoagulant therapy. Hemorrhage was not a significant cause of death in Dicumarol-treated patients. Embolic complications, often undiagnosed clinically, were of common occurrence. Adequate anticoagulant therapy effectively reduced, not only the total number of emboli, but also the number of serious or fatal emboli. In this role, anticoagulants serve a useful purpose in the treatment of myocardial infarction.

Newer concepts of blood coagulation and the pathophysiology of phlebitis and pulmonary emboli with particular reference to pregnancy are examined. New as well as established diagnostic procedures are considered. The historical development, pharmacologic effects, and clinical indications for oral anticoagulants and heparin are reviewed. Finally our own data are presented regarding 19 patients with thromboembolic disorders occurring during pregnancy who were tested with heparin as the sole anticoagulant. Because of the favorable outcome, with excellent fetal salvage, we make a plea for the use of heparin as the anticoagulant of choice during pregnancy.

Scintillating hemianopic scotomas are usually caused either by migraine or, more rarely, vertebral-basilar insufficiency. We report two patients in whom this symptom was probably caused by platelet microthrombi or microemboli in pial vessels of the visual cortex. These patients were similar in that they had scintillating scotomas which began after the age of fifty and abnormal platelet aggregability. Since increased platelet aggregability is associated with cerebral vascular accidents and is treatable, older patients who develop teichopsias should have appropriate hematological tests.

A patient with a factor V inhibitor resistant to all standard methods of therapy was recently reported. Because of this resistance, further investigation of the inhibitor was carried out employing the inhibitory plasma, serum, and isofocused fraction. It has subsequently been shown in vitro by use of the prothrombin time, partial thromboplastin time, and Russell's viper venom time that the activity of the inhibitor is diminished by the addition of calcium chloride or calcium gluconate to the inhibitory plasma, serum, or isofocused fraction before the addition of normal pooled plasma. This inhibitor, an IgG4 (λ) immunoglobulin appears to have a high calcium binding affinity and is markedly potentiated in acid pH. These findings suggest that there may be a role in vivo for calcium infusion as part of the clinical management of such an inhibitor and that the metabolic acidosis associated with hemorrhagic shock may potentiate this type of inhibitor.

THE IMPORTANCE of vitamin K in the prevention of neonatal bleeding is the subject of debate and uncertainty. Doubt has led to vacillating practice: various preparations are used, various doses are administered; indeed, various opinions are expressed with respect to the need for any vitamin K at all. Lying-in services where little hemorrhagic disease is observed and where vitamin K is not given, tend to draw patients from higher socioeconomic groups than services where hemorrhagic disease of the newborn is a significant clinical entity. For example, recent clinical studies demonstrating a high incidence of the disease are reported from Cuba,1Tennessee,2and Texas.3These studies are from services where the patients are predominantly medically indigent and from lower socioeconomic groups. The present studies were undertaken to define the frequency of hemorrhagic disease of the newborn in the medically indigent population of Cincinnati; to redefine an effective prophylactic

The appearance of cold-precipitable fibrinogen (cryofibrinogen, CF) was first reported by Korst and Kratochvil1in migratory thrombophlebitis associated with carcinoma. Campbell and co-workers2studied a patient with purpura and occlusive vascular disease in whose plasma large amounts of the protein were detected. Kalbfleisch and Bird3demonstrated similar findings in the plasma of patients with prostatic carcinoma and with pulmonary fibrosarcoma. In subsequent studies McKee and his associates4detected sizable amounts of the precipitate in the blood of 28 of 650 hospitalized patients. The protein was found to be most frequently associated with metastatic carcinoma, but was also observed in patients with emboli and in collagen disease. Jager5made similar observations in a patient with leukemia, in two patients with pneumonia, and in one with scleroderma. Our interest in this subject was aroused by the finding of a large quantity of cryofibrinogen in the plasma of

Whole blood prothrombin times were determined serially in five groups of randomly selected well newborn "term" infants, none of whom had clinical evidence of bleeding. Prothrombin values in infants given menadione sodium bisulfite (vitamin K) parenterally shortly after birth were stable. The remainder of the infants who were not given vitamin K were divided into subgroups. Twenty-four hours after the first feeding, prothrombin activity of infants fed cow's milk did not differ significantly from that of infants given vitamin K at birth. In contrast, prothrombin times 24 hours after the first feeding of breast fed infants, of infants given bottled human milk, or of infants receiving only sterile water, were all significantly longer than that of infants given vitamin K parenterally. The responses of these newly born infants to the various feeding regimens appear to represent an in vivo assay for dietary vitamin K. The data document hypoprothrombinemia in the majority of infants who do not receive vitamin K parenterally and emphasize the importance of the administration of a small prophylactic dose of the vitamin to all newly born infants.

A case of postheparin lipoprotein lipase deficient hyperchylomicronemia with associated lupus erythematosus is described. As the symptoms of lupus erythematosus progressed, chylomicronemia diminished. Abnormal heparin responsiveness could be demonstrated in vivo and in vitro in the coagulation system and in vivo by decreased postheparin lipolytic activity. It is suggested that in this case lupus erythematosus, possibly because of dysglobulinemia, was associated with abnormal heparin binding that linked the coagulation defects and hyperlipoproteinemia.

SummaryThe clotting mechanism in the human, as measured by conventional methods, appears to be unaffected by intravenous estrogen other than by a slight increase in factor V. Following estrogen, intradermal hyaluronidase wheals persist for a longer period than noted with placebos. These changes are confined to the male. Nonspecific serum hyaluronidase inhibitor increases in both sexes following I.V. estrogen. The peak effect is noted at one to two hours, but the changes persist for approximately 8 hours, usually approaching base line levels at 24 hours. These experiments indicated that I.V. estrogens affect the ground substance. We have not attempted clinical evaluation of the use of intravenous estrogens in control of hemorrhage.

Earlier studies of the coagulation mechanism in patients undergoing hypertonic saline-induced abortion yielded data ranging from a normal clotting mechanism to evidence of frank disseminated intravascular coagulation. Because of this wide variability, patients were monitored to determine the moment of fetal death and the relationship of this episode to the appearance of circulating soluble fibrin and fibrin split products. Circulating soluble fibrin measured by a new technique was detected in seven of eight patients at the time of fetal death. Elevation of the level of fibrin split products, as well as modest depressions of factor VIII and fibrinogen were detected somewhat later. Values for factor VIII and fibrinogen did not fall to levels usually associated with hemorrhage. Thus, disseminated intravascular coagulation can occur without the classically described changes in the clotting mechanism.

Study of the bleeding tendency in uremia in 26 subjects, 10 of whom were bleeding, showed platelet counts and plasma coagulation factors to be normal. There was a significant inverse correlation between the level of serum urea nitrogen and creatinine, and the adhesiveness of the platelets. Platelet adhesiveness was significantly lower in bleeding subjects than in those without bleeding. A prolonged bleeding time was more frequent in the group with bleeding. Abnormal prothrombin consumption was found only in bleeding subjects despite normal numbers of platelets and plasma coagulation factors. The ingestion of urea in 10 normal volunteers prolonged the bleeding time in five and decreased the platelet adhesiveness, which fell to pathologic levels, in eight. These observations suggest a direct effect of urea or one of its metabolites on platelet function and help define the bleeding defect of uremia.

• In an earlier report on the kidney in systemic lupus erythematosus (SLE), we described a subset of patients with circulating anticoagulants; many had glomerular and arteriolar thrombosis in the absence of necrosis and subendothelial deposits. The present study extends these observations to a larger group of patients with SLE and a circulating anticoagulant, and compares its findings with those in patients with SLE without evidence of an anticoagulant. It demonstrates (1) a higher prevalence of clinically recognizable thrombotic events in the venous and arterial circulations in patients with SLE and a detectable anticoagulant; (2) a probable shortening in life span; (3) a higher prevalence of glomerular thrombi; (4) elevated levels of factor VIII antigen and von Willebrand factor; and (5) significantly lower platelet counts and decreased in vitro platelet aggregration in response to adenosine diphosphate, epinephrine, and collagen. Since prednisone treatment often results in improvement or disappearance of a prolonged partial thromboplastin time, the test most commonly used for screening of a circulating anticoagulant, we suggest that the prevalence of this abnormality may be underestimated in patients with SLE. ( Arch Intern Med 1985;145:1389-1395)

Repeated measurements of coagulation factor activities were done on blood from 16 patients with Sickle Cell Disease over a one year period. Sixty-two coagulation profiles were available for analysis during well periods and 12 profiles on 6 patients were obtained during painful crisis. The profiles included measurements of the prothrombin time, partial thromboplastin time, thrombin time, platelet count, quantitation of Factors I, II, V, VII, VIII, IX, X, XI, XII, measurement of fibrin split products, fibrin monomer, and platelet aggregation with collagen ADP and epinephrine. Factor II was significantly lower than normal, platelet counts were significantly increased, and platelet aggregation with collagen epinephrine and ADP were impaired in approximately one-third of patients in. the absence of known injestion of platelet active drugs. Fibrin monomer as measured by radioactive amine incorporation (JCI 50:2235, 1971) was increased once in each of 4 patients but there were no increased levels of fibrin split products in the serum and no significant differences in results during well and painful crisis periods. Therefore, no evidence of chronic intravascular coagulation was found. The decreased concentration of prothrombin may be a result of liver impairment. The increased platelets and abnormal aggregation are unexplained.

SYSTEMIC sporotrichosis is a rare but well-recognized opportunistic fungal infection, usually occurring in patients with hematological or lymphoreticular malignant neoplasms, alcohol abuse, long-term high-dose steroid treatment, or diabetes mellitus.1-3We describe a woman who became infected with human immunodeficiency virus ([HIV], formerly denoted human T-lymphotropic virus type III/lymphadenopathy-associated virus) following transfusion therapy for an acquired factor VIII inhibitor and who developed disseminated cutaneous sporotrichosis three years later. Report of a Case A 71-year-old woman was initially seen in March 1986 with a four-month history of progressive fatigue, weight loss, fever, and multiple enlarging cutaneous ulcers. More recently she had also noted night sweats, nonproductive cough, left shoulder pain, and painless right ankle swelling. Three years before admission to the hospital, in December 1982, gross cutaneous hemorrhage developed, and she was found to have an acquired factor VIII inhibitor of high titer (25 Bethesda units) with a residual plasma factor

Acute arterial obstruction must be relieved immediately to prevent gangrene. Obstruction in major vessels can be relieved surgically; however, distal thrombus propagation obstructs circulation. Small arterial thrombosis is resistant to current therapy, namely, anticoagulants to limit thrombosis and more recently enzymatic lysis of the clot. 37,49 Streptokinase, 3,22,32,48,49 plasmin ( fibrinolysin), 6,13,14,49,61 and chymotrypsin 34,48,49 have been used to lyse intravascular thrombi. Objective evidence that thrombi are lysed and that clinical improvement follows is frequently lacking. The thrombolytic ability of enzymes decreases after three days as the aging clot is covered with endothelium and organizes. 3,6,49 In very fresh thrombi lysis has been reported in 5 to 20 minutes. 3,14,67 Clinically this is rare and fortuitous. The maximum safe systemic dose must be defined for each enzyme. The range between effective therapy and toxicity may be nil. Immunological phenomenon, fever, chills, hypotension, nausea, vomiting, and abnormalities of the hemopoietic and coagulation

THE USE of sodium heparin in adults is a wellknown aspect of modern therapy. The recent availability of highly concentrated aqueous heparin preparations has made subcutaneous administration both effective and reliable. This route of administration often has replaced the more cumbersome intravenous method. Heparin has restricted use in infancy, in contrast to the adult patient. It has been used as an anticoagulant in laboratory blood specimens, in the syringe rinse during exchange transfusions,1and occasionally in transfusion blood itself.1Because of the infrequent use of heparin in the nursery and because of the increasing use of the highly concentrated solutions elsewhere in the hospital, an awareness of these potent solutions is in order. An infant with a coagulation disorder resulting from inadvertently administered concentrated heparin is described. Report of a Case The mother was a 19-year-old, married, white primiparous woman. Her blood group was 0, Rh positive. Following

HYPOFIBRINOGENEMIA and associated coagulation defects complicating giant cavernous hemangioma in an infant have been reported rarely.1,2It is the purpose of this paper to describe such a case. Following radiation therapy the hemangioma regressed and the deficiencies in fibrinogen and other coagulation factors returned to normal. Materials and Methods The bleeding time was performed by the method of Ivy3and the clotting time by the single tube method of Lewis and Glueck.4Platelet counts were performed by the method of Dameshek.5The prothrombin time (ProT) was measured by the method of Quick.6In one instance the ProT was performed after 0.1 ml of a 1% solution of bovine fibrinogen (Armour) was added to both test and normal plasma. Blood-clotting factor V was measured by the method of Stefanini and Dameshek7; factors VII-X complex were measured by methods previously described.8Factor VIII was assayed

Excerpt This paper reports the occurrence of a myocardial infarction in a patient with an absolute deficiency of the Hageman factor (XII). Myocardial infarction has been described in two patients w...

Excerpt It is a well known clinical observation that a low concentration of plasma prothrombin which does not respond to the administration of vitamin K indicates serious liver disease.1-10The usef...

The determination of the prothrombin time, particularly the prothrombin content of plasma, is a useful but often neglected liver function test in the adult. 1-4 It occurred to us that similar studies might be of value in infancy during the period of life when most liver function tests are of equivocal value. 5-7 Since preliminary studies were encouraging, it became important to determine values for prothrombin and the prothrombin complex in the normal full-term infant. These values are the subject of this report. Materials and Methods A total of 28 normal full-term infants were followed during the first 12 to 18 months of life. The group included 22 Negro (12 male, ten female) and six white (two male, four female) infants. Each child was regularly examined by one of us (J. S.) in a well-baby clinic. The infants' weights were recorded on each visit. All initial determinations, with two exceptions