Paul M. Aggeler

Plasma Throinboplastin Component (PTC) Deficiency A New Disease Resembling Hemophilia

Summary1. A severe hemorrhagic disease, characterized by a prolonged whole blood coagulation time due to the delayed formation of thrombin, has been described. The patient with this disease was found to have normal plasma concentrations of all the previously described coagulation factors. 2. The corrective factor in normal plasma or serum can be removed by barium sulfate adsorption. A method for the partial purification and concentration of the patients missing factor has been outlined. The defect in the patients blood may be corrected by the addition of plasma free of previously described thromboplastin components (e.g. platelet-free hemophilic plasma), as well as by small amounts of tissue thromboplastin. The name plasma thromboplastin component (PTC) has been assigned to this previously undescribed coagulation factor.Summary 1. A severe hemorrhagic disease, characterized by a prolonged whole blood coagulation time due to the delayed formation of thrombin, has been described. The patient with this disease was found to have normal plasma concentrations of all the previously described coagulation factors. 2. The corrective factor in normal plasma or serum can be removed by barium sulfate adsorption. A method for the partial purification and concentration of the patients missing factor has been outlined. The defect in the patients blood may be corrected by the addition of plasma free of previously described thromboplastin components (e.g. platelet-free hemophilic plasma), as well as by small amounts of tissue thromboplastin. The name plasma thromboplastin component (PTC) has been assigned to this previously undescribed coagulation factor.

HEREDITARY TRANSMISSION OF EXCEPTIONAL RESISTANCE TO COUMARIN ANTICOAGULANT DRUGS. THE FIRST REPORTED KINDRED.

THE variability of response of human beings to many drugs is usually continuous and gives a unimodal frequency-distribution curve for the drug action measured. These unimodal distribution curves ar...

Treatment of Hemophilia B with a New Clotting-Factor Concentrate

Abstract A new concentrate of clotting factors II, VII, IX and X, made from pooled human plasma collected in citrate anticoagulant by a process involving the adsorption of the effluent from Cohn fraction I on DEAE Sephadex and fractional elution of adsorbed material, proved effective for prophylaxis and treatment of acute bleeding episodes. The net return in vivo 15 minutes after injection was approximately 40 per cent of the activity measured in vitro. In 20 kinetic studies various values were: factor IX activity at zero time, 58.7 per cent; half-life of the first component of the disappearance curve, four and six-tenths hours; half-life of the second component, 31.5 hours; equilibration time between first and second components, 22.1 hours; and apparent volume of distribution, 2.7 times plasma volume. The distribution and turnover rates were similar to those found previously with plasma in three of the same patients and to results reported by others with British and French concentrates.

The mild hemophilias: Occult deficiencies of AHF, PTC and PTA frequently responsible for unexpected surgical bleeding

Abstract A detailed clinical and laboratory study was made of forty-six patients with hemophilia A, B or C (AHF, PTC or PTA deficiency) in whom the venous whole blood clotting time was normal. In all patients thromboplastin generation was impaired. The incidence of positive family histories was as great as is usually found in the severe forms of the diseases. The first episode of severe bleeding was often delayed or ignored until adolescence or adult life. Surgical bleeding, particularly after tonsillectomy or tooth extraction, was the most frequent symptom. Episodes of spontaneous bleeding such as hemarthrosis and hematuria were far less frequent than in the severe cases. The concentration of AHF in mild hemophilia A ranged from 8 to 37 per cent, and of PTC in hemophilia B from 9 to 58 per cent. There was only a rough correlation between the specific factor assay values and the severity of symptoms in this group of patients.

Intravascular coagulation in the surgical patient: Its significance and diagnosis

Abstract The role of disseminated intravascular coagulation (DIC) in a series of twelve patients in whom unexplained bleeding developed during or after a surgical procedure was investigated. The patients were operated on for severe, traumatic, life-threatening surgical diseases. The over-all mortality was 83 per cent and the morbidity 100 per cent. Hemorrhagic manifestations ranged from a troublesome ooze at the suture line or venipuncture sites to massive bleeding at the site of operation. It occurred both during and after the operative procedure. The total number of transfusions varied from ten to sixty-three per patient. Hypoxemia was present in 74 per cent and ozotemia in 83 per cent. Sepsis was a frequent and major complication and was responsible for all the late deaths; the organisms were predominantly gram-negative. Hemostatic tests showed thrombocytopenia in 92 per cent, fibrinogenopenia in 58 per cent, and plasminogenopenia in 72 per cent. There was a reduction of one stage prothrombin activity in 91 per cent and of specific clotting factors as follows: factor II 83 per cent, V 82 per cent, VII 92 per cent, VIII 66 per cent, IX 54 per cent, and X 75 per cent. Fibrin degradation products were present in 90 per cent. Postmortem examination in eight patients showed macrothromboemboli, microthromboemboli, or both in four. Bronchopneumonia was common and there was a high incidence of acute tubular necrosis of the kidneys. Five patients received heparin; all died within fortyeight hours of nonhemorrhagic complications. The bleeding disorder was improved in two patients and was not made worse in the other three. One patient received epsilon-aminocaproic acid without improvement. It was concluded that DIC is a common factor responsible for much of the morbidity and mortality in patients requiring surgery for trauma or other life-threatening emergencies in which shock is a factor. It should be suspected on clinical grounds when hemostatic, respiratory, and/or renal failure occur in the immediate postoperative period. Heparin is the therapy of choice but requires courage to administer when the possibility of inadequate surgical hemostasis exists.

Platelet Dysfunction — Differentiation of a Newly Recognized Primary Type from That Produced by Aspirin

Abstract A recently described hemorrhagic disorder characterized by defective platelet aggregation induced by collagen and epinephrine appears to be caused, in part, by the same abnormality induced by aspirin ingestion — that is, inhibition of release of intrinsic platelet adenosine diphosphate (ADP). In contrast to the aspirin-induced defect, bleeding time was greatly prolonged, platelet adhesiveness was markedly impaired, adhesion of platelets to collagen fibrils was deficient, and aggregation of platelets by serotonin and glass beads was impaired. Both phases of epinephrine-induced platelet aggregation were blocked, whereas with aspirin only the second phase was absent. There was rapid disaggregation after low-molar ADP whereas with aspirin the rate was only slightly increased. As with the aspirin-induced platelet abnormality aggregation of platelets by trypsin, collagen and centrifugation was blocked, but aggregation by high-molar ADP and thrombin was normal. Platelet transfusions temporarily correcte...

Covert anticoagulant ingestion: study of 25 patients and review of world literature.

Twenty-five patients with covert ingestion of oral anticoagulant drugs were studied. Most of the patients were women who were either connected with the medical profession or were previously treated with antigoagulants. The most common findings were ecchymoses, hematuria, and a markedly prolonged prothrombin time. The anticoagulant drug was identified in the plasma of all 25 patients. Most patients responded promptly to administration of vitamin K1. The most common motives were malingering and suicide. The world literature was reviewed for covert ingestion of oral anticoagulant drugs and 48 other cases were found. The correct diagnosis is important to focus the physicians attention on the psychiatric rather than the somatic aspects of the disorder.

Hemophilia in a woman

Abstract A case of hemophilia (factor VIII deficiency) in a woman belonging to a large family of hemophilic subjects is presented. The clinical and laboratory findings in the proposita and in other carrier women and affected men in the kindred are discussed. Analysis of the family pedigree indicated no reason for believing that the proposita had a genetic constitution other than heterozygous for the hemophilia loci. A chromosomal abnormality such as trisomy, monosomy, XY constitution or gross abnormality of an autosome was ruled out by karyotype analysis. Other causes of factor VIII deficiency in women, such as von Willebrands disease or a circulating anticoagulant, were excluded by appropriate methods. Assuming a normal distribution of plasma factor VIII in the female carrier population, the 4 per cent concentration found in the proposita could be expected to occur by chance alone only once in several hundred billion times. The possibility that the proposita might be a homozygous hemophilic woman because of inheritance of one defective X chromosome and mutation of the other appears more likely, since if the assumption of distribution normality is correct, this might occur once in one hundred thousand times. The frequency of cases such as this suggests that other unknown mechanisms may be responsible for low factor VIII concentrations in the plasma of female heterozygotes.

Surreptitious Ingestion of Coumarin Anticoagulant Drugs

Excerpt Coumarin and indanedione anticoagulant drugs are commonly used in the treatment of thromboembolic disorders. In addition, they have been used occasionally to accomplish murder (1), to commi...

Effect of Synthetic Vitamin K Compounds on Prothrombin Concentration in Man

Summary Three synthetic vitamin K compounds were administered to 26 patients with hypoprothrombinemia. Following treatment the prothrombin concentration: (1) was markedly elevated in 11 patients with obstructive jaundice, (2) was not elevated in 8 and only slightly elevated in 3 patients with chronic diseases of the liver; (3) was not elevated in 1 patient, and after an initial delay was elevated in 1 patient with acute diseases of the liver; (4) was moderately elevated in 2 patients, one with non-tropical sprue, and the other with gastro-colic fistula. When considered in terms of the dosages employed, there were no significant qualitative differences in the relative effectiveness of the three compounds. No untoward reactions were observed except that the patients receiving large doses of 4-amino-2-methyl-naphthol-hydrochloride complained of slight burning pain at the site of injection.