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A family with autosomal dominant macrothrombocytopenia is described. Despite severe thrombocytopenia, only a moderate hemorrhagic tendency was observed. Kinetic studies revealed a normal platelet survival, normal megakaryocytic numbers, and normal bone marrow responsiveness. The rate of platelet production was set low, despite moderately impaired hemostasis and thrombocytopenia; it apparently was set to maintain another platelet parameter at an optimal level. Measurements of total circulating platelet mass and platelet surface suggested that the platelet production was set to maintain the platelet surface rather than the platelet mass at a normal value.

The effect of lipid emulsions on prothrombin time in blood from anticoagulated patients was determined. Blood samples were obtained from 23 patients therapeutically anticoagulated with warfarin (prothrombin time 1.3-2.0 x control). Varying amounts of an intravenous lipid emulsion (Intra-lipid) were added to the blood to simulate concentrations seen in vivo with a constant lipid infusion. The prothrombin time was measured on the plasma from these samples and compared to the prothrombin time of the plasma samples without lipid. The mean decrease in prothrombin times were: 0.29 sec at 50 micrograms/ml, 0.23 sec at 100 micrograms/ml, and 0.29 sec at 200 micrograms/ml. All concentrations showed a statistically significant decrease (p less than 0.05) when compared to the control by the Scheffe test. Lipid emulsions appear to decrease the prothrombin times in anti-coagulated patients. The differences however, were small and not of clinical significance at the concentrations tested.

To further evaluate the role of sialic acid in the dysfibrinogenemia associated with liver disease, we studied the effect of removal of excess sialic acid residues from the fibrinogen of five patients with liver disease on the thrombin time and fibrin monomer aggregation. Patient fibrinogens containing 1.4-3.4 residues of sialic acid per molecule in excess of normal controls, with thrombin times 12-22 sec longer than normal and with abnormal fibrin monomer aggregation, were stripped of their excess sialic acid by incubation with Vibrio cholerae neuraminidase, followed by rapid removal of the enzyme by antineuraminidase antibody affinity chromatography. These partially desialylated patient fibrinogens, with a normal number of sialic acid residues remaining, exhibited normal thrombin times and normal fibrin monomer aggregation. Sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of reduced normal, patient, and partially desialylated patient (sialyl-3H)-fibrinogen exhibited 60% of the radioactivity in the B beta chain and 40% in the gamma chain. There was no radioactivity detectable in the A alpha chain. These studies provide additional evidence that the increased sialic acid content of the acquired dysfibrinogenemia of liver disease is responsible for its functional defect and that the excess sialic acid is distributed on the B beta chain and gamma chains of the fibrinogen.

Intravenous lipids have been shown to have varying effects on coagulation parameters. A patient with short bowel syndrome and recurrent thrombotic episodes who required both intravenous lipids and anticoagulation is described. A constant infusion of a soybean oil emulsion (Intralipid) in his parenteral nutrient solution was demonstrated to interfere with the anticoagulant effect of warfarin. Termination of the infusion and rechallenge with warfarin resulted in prolongation of his prothrombin time to the therapeutic range. Reinstitution of a lipid-free parenteral nutrition regimen has allowed for successful continuation of warfarin therapy.

To test the possibility that a functionally abnormal fibrinogen may exist in some patients with liver disease, we studied the plasma and purified fibrinogens of five patients whose plasma thrombin times were prolonged at least 40% over normal controls. In no patient was there evidence of disseminated intravascular coagulation and/or fibrinolysis. No abnormalities were detected by immunoelectrophoresis of plasmas or purified fibrinogens. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of reduced patient fibrinogens showed normal mobility and amount of Aalpha, Bbeta, and gamma chains. Alkaline polyacrylamide gel electrophoresis and gradient elution, DEAE-cellulose chromatography of admixtures of radio-iodinated patient (125)I-fibrinogen and normal (131)I-fibrinogen showed identical mobility in the gel and simultaneous elution from the column, respectively. Thrombin and Reptilase (Abbott Scientific Products Div., Abbott Laboratories, South Pasadena, Calif.) times of purified patient fibrinogens were prolonged, and calcium ions improved but did not completely correct these defects. Increasing amounts of thrombin progressively shortened the clotting times of patient fibrinogens but not to the level of normal. Addition of equal amounts of patient fibrinogen to normal fibrinogen resulted in a prolongation of the thrombin time of the normal protein. Thrombin-induced fibrinopeptide release was normal. Fibrin monomers prepared from patient plasmas and purified fibrinogens demonstrated impaired aggregation at low (0.12) and high (0.24) ionic strength. These studies demonstrate that some patients with liver disease and prolonged plasma thrombin times have a dysfibrinogenemia functionally characterized by an abnormality of fibrin monomer polymerization.

The therapeutic efficacy of prothrombin-complex concentrates in patients with hemophilia and inhibitors (antibodies) to factor VIII has been increasingly debated. We therefore entered 51 hemophiliacs with factor VIII inhibitors into a double-blind randomized crossover study to compare two commercial prothrombin-complex concentrates (Konyne and Proplex) and an albumin placebo. Acute hemarthrosis of the elbow, knee, or ankle was treated with a single dose of a test preparation and assessed six hours later with objective and subjective criteria. In all measurements the concentrates were significantly more effective than the placebo. The data indicate that although prothrombin-complex concentrates, when used in a single dose, are only partially effective in the treatment of joint hemorrhage in hemophiliacs with inhibitors, their continued use for acute hemarthrosis is justified in the absence of any other effective and readily available therapy for this disorder.

To evaluate the possibility that the carbohydrate composition of fibrinogen may be altered in the dysfibrinogenemia associated with liver disease, we studied the sialic acid content of purified fibrinogen from 12 patients with liver disease and its relationship to the prolongation of the thrombin time. Purified fibrinogen showed that Aalpha-, Bbeta-, and gamma-chains when reduced and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and exhibited prolongation of the thrombin time similar to that of the plasma from which it was derived. Sialic acid content of the purified fibrinogen ranged from 12.7 to 71.4% higher in patient fibrinogens when compared to normal controls. A progressive delay in thrombin time was associated with increasing sialic acid content of the patient fibrinogen. Enzymatic removal of sialic acid from four of the abnormal fibrinogens resulted in a shortening of their thrombin times to the range of the desialylated normal control. Periodic acid-Schiff reagent stained only the Bbeta- and gamma-chains of the reduced patient fibrinogens after sodium dodecyl sulfate-polyacrylamide gel electrophoresis suggesting that the excess sialic acid is located on these two chains. These studies demonstrate a biochemical alteration of the functionally abnormal fibrinogen found in some patients with liver disease, and indicate that the excess sialic acid plays an important role in the functional defect of this protein.