Leon Zuckerman

Comparison of thrombelastography with common coagulation tests.

Thrombelastography, although proven as a useful research tool has not been evaluated for its clinical utility against common coagulation laboratory tests. In this study we compare the thrombelastographic measurements with six common tests (the hematocrit, platelet count, fibrinogen, prothrombin time, activated thromboplastin time and fibrin split products). For such comparisons, two samples of subjects were selected, 141 normal volunteers and 121 patients with cancer. The data was subjected to various statistical techniques such as correlation, ANOVA, canonical and discriminant analysis to measure the extent of the correlations between the two sets of variables and their relative strength to detect blood clotting abnormalities. The results indicate that, although there is a strong relationship between the thrombelastographic variables and these common laboratory tests, the thrombelastographic variables contain additional information on the hemostatic process.

Shear-induced activation of platelets

Platelet-rich plasma was subjected to shear in Poiseuille flows through tubes, i.d. = 305, 406 and 508 μm. Bulk-average shear stresses were 300, 750 and 1000 dynes/cm2 and the average residence times were 25–1650 ms. These shears for these residence times did not produce cell lysis but did activate the platelets so that their response to exogenous ADP were reduced and platelet factor 3 was released. Also, thromboelastographic measurements indicated shear-induced hypercoagulability. Allowing samples to stand 30–60 mins after being sheared revealed some of the indicated activation was reversible. Adding the anticoagutant heparin to sheared samples produced an anomalous response. The quantitative results were independent of tube surface-volume ratio, but were dependent on both level of shear stress and on residence time.

The identification of accelerated coagulability

Abstract This report describes a new method for comparing overall clotting characteristics between normal individuals and those with proven malignancy. Native whole blood thrombelastography and celite activated thrombelastography were performed on the same blood collection in 90 normals and 90 patients with new malignancies and the results used to derive a discriminate equation. This equation classified correctly all 90 normals and 80/90 cancer patients. The formulation was verified with an additional 82 patients with only one incorrect classification in the 31 cancer subjects. These results demonstrate a new analysis for accelerated coagulability based on comparative clotting data. Identification of accelerated coagulability in asymptomatic populations may identify occult problems, including cancer.

Diffusion of Oxygen in Plasma and Blood

D in fresh human plasma has been found to decrease almost linearly with total protein content over a wide range of concentration and to vary only +/-4% in normals and +/-13% in abnormals. The average values for D in normal human plasma, at 25 and 37 degrees C, are 1.62 and 2.18 X 10(-5) cm2/sec respectively. For normal human blood at 42% hematocrit, the values of D, at 25 and 37 degrees C, are 1.20 and 1.62 X 10(-5) cm2/sec respectively.

Evaluation of three methods used to identify accelerated coagulability

Abstract This paper summarizes a comparison of three methods of thrombelastographic (TEG) analysis. The study compares parameters suggested by Caprini in Evanston, Pieptea in Bucharest, and Raby in Paris for capturing biological information about accelerated coagulability. Native and celite-activated whole blood TEG tracings used in the Evanston Clinic were applied to measure the three sets of parameters. The analysis involved two defined clinical groups; namely, normals and those with proven new malignancies. The results suggest that a high degree of correlation exists with all of these methods and the clinical groups. The general clinical agreement of all three methods demonstrates one example of the biological significance of thrombelastography, which renders it a valuable analytical tool.

Coagulation changes in the newborn with respiratory failure

Abstract These studies involved clinical and laboratory investigations in 24 infants. Eleven healthy premature and term babies were used to establish a normal laboratory range. Thirteen consecutive infants requiring ventilatory assistance were compared to the normal group according to a broad range of clinical and laboratory measurements. Clinical parameters of the two groups were obviously different. However, the laboratory measurements of clotting appears to be close in each group only within the first 12 hours of extrauterine life. The fibrinolytic system appeared to be the most significantly activated parameter as seen by the initial deviations of the plasminogen and fibrin split products in the ill infants. Related changes in complement C′3 and C′4 were also noted. Two of the study infants survived and their data is shown for prognostic purposes. The earliest results that appeared to discriminate between survivors and fatalities were the plasminogen levels at 12 to 24 hours. We conclude from these data that activation of coagulation, fibrinolytic, and complement systems occurs in all newborns with respiratory failure and is detectable in their laboratory measurements.

Profile of Insulin Release Due to Intrapancreatic Glyburide Infusion

Intrapancreatic glyburide infusion in dogs (0.02 mg. per kg. of body weight) for five minutes provoked immediate, marked insulin release into the portal venous blood. Compared to control animals, the normal intrinsic insulin levels were exaggerated at intervals of approximately eighty minutes. Lack of immediate hypoglycemia suggests that the insulin release is merely secondary in contributing to the anti-diabetic property of this agent. An amount of tolbutamide fifty times as great caused a weak, delayed insulin response. The delayed blood glucose response is probably caused by the combined action of glyburide and circulating insulin.

Regulation of Insulin Release by Pancreatic Glucagon

In order to localize the site of its insulinogenic stimulus, glucagon was infused individually into the pancreas, liver, and peripheral circulation of normal dogs. Blood levels of insulin, glucose and nonesterified fatty acids were monitored in the femoral artery, portal and hepatic veins. The pancreatic artery infusions provoked a more rapid and marked insulin release initially than the same amount of glucagon given into the portal or femoral vein. The degree of hyperglycemia was comparable in the three groups, although the pancreatic group had more suppression of fatty acids probably related to the enhanced insulin secretion. Intrapancreatic infusion of glucagon in amounts sufficient to release insulin always produced concomitant hyperglycemia. In comparison, small amounts of glucose administered by the same route released insulin without elevating the blood glucose level. Larger quantities of glucose, calculated to produce insulin levels similar to those attained with glucagon, provoked hyperglycemia of lesser magnitude and shorter in duration. The effect of epinephrine on glucagon-stimulated insulin infusion. A quantity of intrapancreatic epinephrine which normally inhibits the glucose stimulus had no effect on delaying the insulin response until the amount of epinephrine was tripled. Simultaneous measurements of insulin and glucose in the hepatic venous blood during the intrapancreatic infusion resulted in response curves similar to those found in the portal vein. Even though the hepatic venous glucose values were almost identical during the infusions at the three different sites, insulin values were two to three times lower with portal or femoral than with pancreatic infusions. We conclude from the data that glucagon does play an independent role in the release of insulin from the pancreas, but that its effectiveness is less than glucose under normal circumstances. The glucagon stimulus is effective despite the presence of ordinary amounts of epinephrine. Since the magnitude of the insulin released from intra-portal glucagon is limited and delayed, the importance of its action as a gut factor in response to an oral glucose load is challenged.

Hematologic changes following burns.

Abstract These studies demonstrate statistically significant changes between the platelet counts, FDP and plasminogen levels, and C3 and 5-min kinin activity of three groups separated according to their prognostic indices. Subsequent analysis of survivors confirms these trends and reveals additional supporting test data. We postulate that intravascular contamination occurs following major burns due to tissue trauma, and continues as burn wound sepsis develops. Standard heparin therapy does not significantly inhibit Hageman factor, plasmin, complement, or kinin activation products. It is not surprising that this anticoagulant does not change FDP levels or modify the course of most burns; however, further studies are needed to clarify this situation.

Contact activation of heparinized plasma

Abstract We investigated the celite activation of coagulation in heparinized plasma. Celite is shown, using the thrombelastograph, to produce clotting in plasma samples containing pharmacologic levels of heparin (e.g. 1.45 U/ml). We demonstrate that the celite-induced clotting involves Hageman factor, requires calcium, and is not due to celite absorption of heparin. Incubation at 37°C of celite activated plasma samples prior to recalcification, causes a progressive loss in coagulation potential. Unheparinized samples do not exhibit a similar loss. We found that the minimum concentration of heparin required to prevent celite-activated coagulation also reduces celite-activated esterase activity. Massive contact activation is suggested as the most likely explanation for the observed clotting of heparinized samples. Qualitative effects of cellular elements in the plasma are also reported. Finally, the results suggest that using celite activated samples in the thrombelastograph is an improved method for clinical monitoring of heparin effectiveness.