Helen I. Glueck

Placental transport of heparin

Abstract Studies on guinea pigs indicated that heparin does not cross the placenta. Subsequently, 7 pregnant women were given heparin before delivery. The anticoagulant effect of heparin was observed in all maternal blood samples obtained at delivery. No anticoagulant effect was noted in samples from their infants. It is concluded that the fetus is safe from the anticoagulant effect of heparin.

Association of Antithrombotic Factor Deficiencies and Hypofibrinolysis with Legg-Perthes Disease*

Thirty-three (75 per cent) of forty-four unselected children who had Legg-Perthes disease were found to have coagulation abnormalities. Twenty-three children had thrombophilia (a deficiency in antithrombotic factor C or S, with an increased tendency toward thrombosis); nineteen of the twenty-three children had protein-C deficiency and four had protein-S deficiency. Seven children had a high level (0.25 gram per liter or more) of lipoprotein(a), a thrombogenic, atherogenic lipoprotein associated with osteonecrosis in adults. Three children had hypofibrinolysis (a reduced ability to lyse clots). The mean age of the children when the Legg-Perthes disease was first diagnosed was 5.8 ± 2.7 years, and the mean age at the time of the present study was 10.1 ± 4.4 years. At least one of the first-degree relatives of eleven of the nineteen probands who had a low protein-C level had a low protein-C level as well; all of these low levels represented previously undiagnosed familial protein-C deficiency. The eleven probands who had familial protein-C deficiency were more likely to have early onset of Legg-Perthes disease (at or before the age of five years) than the eleven children who had normal levels of protein C, protein S, and lipoprotein(a) as well as normal fibrinolytic activity (chi-square = 6.6; p = 0.01). At least one first-degree relative of one of the four probands who had a low protein-S level had a low protein-S level and previously undiagnosed familial protein-S deficiency. At least one first-degree relative of six of the seven probands who had a high level of lipoprotein(a) had a familial high level of lipoprotein(a). Six of the seven children who had a high level of lipoprotein(a) also had a low level of stimulated tissue-plasminogen activator activity, the major initiator of fibrinolysis. At least one first-degree relative of one of the three probands who had normal levels of protein C, protein S, and lipoprotein(a) but low stimulated tissue-plasminogen activator activity also had low stimulated tissue-plasminogen activator activity (familial hypofibrinolysis). Legg-Perthes disease, thrombophlebitis, premature myocardial infarction, and stroke, which are ramifications of the familial thrombophilic-hypofibrinolytic disorders, were common in the first and second-degree relatives of the thirty-three children with Legg-Perthes disease who also had thrombophilic-hypofibrinolytic disorders. CLINICAL RELEVANCE: Protein-C or S deficiency, hypofibrinolysis, or a high level of lipoprotein(a) may result in thrombotic venous occlusion of the femur, which leads to the venous hypertension and osteonecrosis of the femoral head characteristic of Legg-Perthes disease. When Legg-Perthes disease develops in a child, the levels of proteins C and S, lipoprotein(a), and stimulated fibrinolysis should be measured. Early diagnosis of protein-C or S deficiency, hypofibrinolysis, or a high level of lipoprotein(a) in such children may open avenues for pharmacological preventive therapy to reduce thrombophilia, stimulate fibrinolysis, or lower the level of lipoprotein(a), potentially ameliorating the Legg-Perthes disease process.

Relationships between lipoprotein(a), lipids, apolipoproteins, basal and stimulated fibrinolytic regulators, and d-dimer

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.

Acquired type I hyperlipoproteinemia with systemic lupus erythematosus, dysglobulinemia and heparin resistance

Abstract 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.

Platelet thrombopathy in asthmatic patients with elevated immunoglobulin E

Abnormalities of second-wave platelet aggregation were demonstrated in 17 of 33 asthmatic patients in whom drug and diet intake were controlled in the hospital. Mean abnormal responses were significantly greater after epinephrine- (p less than 0.001), adenosine diphosphate-(less than 0.001), collagen- (p = 0.01), and thrombin- (p less than 0.001) induced platelet aggregation in patients with immunologically mediated asthma and serum IgE levels greater than 250 U/ml as compared to patients without immunologic factors and/or normal controls. Mean pollen-specific radioallergosorbent (RAST) binding was also significantly higher in patients with abnormal aggregation as compared to normal platelet responders (p = 0.02). Release of serotonin generally reflected abnormal aggregation patterns in asthmatic patients. Platelet factor 4 release was significantly decreased in the same groups of patients. These results suggest that the allergic state may affect platelet membrane responsiveness to multiple aggregating agents.

Platelet function in sickle cell anemia

Abstract 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.

Cyclic platelet dysfunction in IgE-mediated allergy

Diminished platelet aggregation responses to one or more aggregating agents were found in 25 of 32 patients with nasal allergy studied at the peak of the allergy season. Abnormal in-season platelet aggregation induced by epinephrine and collagen was significantly improved when repeated out-of-season, while incomplete platelet aggregation induced by adenosine diphosphate (ADP) and thrombin was unchanged. Recombination of an in-season serum factor with autologous, out-of-season normally aggregating platelets caused market inhibition of platelet aggregation. Mean bleeding times of 20 symptomatic patients were also prolonged during the height of the pollination season. These data suggest that the allergic diathesis is a model for the study of cyclic, nondrug induction of platelet dysfunction.

Thromboembolic disorders in pregnancy: pathophysiology diagnosis and treatment with emphasis on heparin.

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.

Beta Blockers, Lp(a), Hypertension, andReduced Basal Fibrinolytic Activity

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 tri-glycerides, 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.

Assay of plasma prothrombin with a synthetic substrate.

Summary A method of measuring plasma prothrombin employing a synthetic substrate (TAMe) has been described. The method has been utilized in studying the plasma prothrombin of normal and dicumarolized patients. Assays of dog and rabbit plasma prothrombin are reported. The results are compared with those obtained by a one-stage procedure.