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The seial thrombin time in the diagnosis of consumptive coagulopathy.

Acute consumptive coagulopathy may be initiated by diverse events. It is frequently necessary to establish the diagnosis with urgency. Rational therapy can only be approached with knowledge of the relative impact the primary consumption exerts upon hemostasis as well as the effects of secondary fibrinolysis. A constellation of interlocking tests within the capability of the small laboratory is presented. This includes the prothrombin time, the activated partial thromboplastin time, the serial thrombin time, the heat precipitation fibrinogen level, the platelet count, red cell morphology, the levels of fibrin (fibrinogen) degradation products and selected factor assays. This series can be completed within 45 minutes. Interpretation, with particular emphasis upon the stage in the natural history of the process when evaluation is instituted, and underlying diseases which modify typical patterns are discussed. The discriminant function of the serial thrombin time is stressed.

Adult

Circulating thrombin time anticoagulant in a procainamide-induced syndrome.

Circulating anticoagulants are unusual in drug-induced syndromes. We evaluated the prolonged thrombin time of plasma from a patient with a procainamide-induced syndrome. This defect was shown to be due to a circulating anticoagulant that was not of fibrin or fibrinogen origin and that prolonged thrombin and reptilase clotting times of plasma. Subclinical doses of heparin sodium induced hemorrhagic manifestations in this patient. Following cessation of heparin therapy, the circulating anticoagulant persisted but the bleeding tendency abated. All clinical and laboratory manifestations of this syndrome abated gradually following cessation of procainamide therapy.

Aged

Ontogeny of bovine hemostasis.

Ontogeny of selected hemostatic system components was studied in 120 bovine fetuses which had been divided into eight monthly gestational age groups. Fetal blood was subjected to the following tests: platelet count, partial thromboplastin time, prothrombin time, thrombin time, fibrinogen quantitation, and assays for prothrombin and factors V and VIII. Platelet numbers corresponding to adult numbers were in fetal blood at least as early as gestation day 60, and their numbers varied only slightly thereafter. Bovine blood was incapable of in vitro coagulation at gestation day 90, with all samples coagulating by gestation day 150. Fetal coagulation screening test times (partial thromboplastin time, prothrombin time, and thrombin time) shortened during gestation and were near times of adults at birth. Of the four individual coagulation factors tested, only factor VIII reached adult values in the fetus in utero. Amounts of fibrinogen, prothrombin, and factors V and VIII in the neonate exceeded that of normal adult cattle.

Animals

Hemostatic abnormalities in malignancy, a prospective study of one hundred eight patients. Part I. Coagulation studies.

A prospective study of hemostatic abnormalities in 108 cancer patients was undertken at an oncology clinic in a university teaching hospital. Tests included Quick prothrombin time, activated partial thromboplastin time, thrombin time, platelet count, modified Ivy bleeding time, fibrinogen, fibrin degradation products (FDP), euglobulin lysis time, protamine sulfate test, and factor V, VII, VIII and X assays. Ninety-eight per cent of the patients had one or more abnormal coagulation tests. The commonest abnormalities were elevated fibrin degradation products and prolonged thrombin time. Thrombocytosis occurred in 57% of patients, hyperfibrinogenemia in 46%, thrombocytopenia in 11%, and non had hypofibrinogenmia. It is suggested that platelet count, fibrinogen concentration, and serum FDP assay are the most useful tests in assessing the hemostatic abnormalities in cancer patients, although thrombin time, factor V assay, and bleeding time may also be helpful. The peripheral blood smears of 53 patients were reviewed, and only one showed microangiopathic hemolytic anemia. The data illustrate that subclinical coagulopathy is relatively frequent in patients with malignancy.

Adolescent

Coagulation abnormalities in diabetic coma before and 24 hours after treatment.

A coagulation screen consisting of measurement of the prothrombin time, thrombin time, kaolin caphalin clotting time, platelet count, plasma fibrinogen level, fibrin degradation products and ethanol gelation test was performed on 24 patients with impairment of consciousness due to acute diabetic metabolic decompensation at the start of treatment and 24 hours later. 22 out of 24 patients showed at least one coagulation abnormality on admission of which the commonest were a prolonged prothrombin time, shortened kaolin cephalin clotting.time and raised plasma fibrinogen level. After 24 hours of treatment these values were more normal but 20 out of 22 patients still displayed some abnormality. 15 patients had two or more coagulation abnormalities on admission including 3 patients with haematological abnormalities suggestive of disseminated intravascular coagulation. This group was older and had higher blood ureas than those with fewer abnormalities, but plasma glucose, sodium, potassium and bicarbonate levels were similar in both groups of patients. All 5 patients with hyperosmolar non-ketotic coma and all 3 patients who died without recovering consciousness had two or more coagulation abnormalities on admission.

Adolescent

Progestational agents and blood coagulation. VIII. Effect of low-dose, alternate-day, estrogen-progestin combinations on blood coagulation factors in man, with a special note on the effect of freezing of blood samples.

Changes in the blood coagulation system were studied in three groups of 20 patients each. The first group received 0.5 mg. of norethindrone daily, plus 0.06 mg. of ethinyl estradiol on alternate days from cycle Day 5 through 25. The second group, all of whom had been fitted with an intrauterine contraceptive device (IUD), received no hormonal treatment and served as a control group. The third group received 0.5 mg. of norethindrone daily, combined with 0.045 mg. of ethinyl estradiol given on alternate days from cycle Day 5 through 25. Blood samples were drawn prior to the initiation of the study and after three months of treatment. Tests of the following parameters of the blood coagulation system were performed: direct platelet count; platelet adhesiveness; prothrombin time; thrombin time; fibrinogen; factor II assay; activity of factors V, VII, VIII, IX, and X; antithrombin III; and fibrin/fibrinogen degradation products. For a number of these factors, both fresh and frozen blood samples were examined. It was concluded that the two treatment regimens, with the use of alternate-day estrogen administration over a three-month period, had no clinically significant effect on the blood coagulation system.

Adolescent

Early increase of a new platelet coagulant activity in rats fed a thrombogenic diet.

A recently described platelet coagulant activity (factor X activating activity), whose pathophysiological significance is as yet unknown, was studied in rats fed a fat-rich (thrombogenic) diet for 1, 2 and 7 weeks and compared to rats fed normal laboratory chow. Whatever the duration of the special feeding period, a highly significant shortening of the clotting time, used for measuring this activity, was observed. When the platelet coagulant activity of individual "fat-fed"rats was quantitated by reference to that of individual control animals, we found a mean increase of 350% (n = 9) after one week and 267% (n = 3) after two weeks of dietary treatment. Partial thromboplastin time, thrombin time and soluble fibrin monomer complexes did not differ in control and treated animals. It seems that platelet coagulant activity, as measured in our test system, is one of the first laboratory parameters to be modified by fat-rich diets. These findings may be relevant to an understanding of the role of platelet coagulant activities other than platelet factor 3 in thrombotic phenomena.

Animals

The Passovoy defect: further characterization of a hereditary hemorrhagic diathesis.

We studied a coagulation abnormality present in 12 members of five kindreds who bruised easily and bled excessively after minor trauma. Their activated partial thromboplastin times were between 32 and 39 seconds (normal, 22.8 to 28.8 seconds). Prothrombin times, thrombin times, platelet-function tests and the levels of factors XII, XI, IX, VIII, prekallikrein and high-molecular-weight kininogen were normal. Within these kindreds inheritance of prolonged partial thromboplastin times followed an autosomal and probably dominant pattern. The prolonged thromboplastin times were corrected by normal plasma and by normal plasma adsorbed with celite, but there was no mutual correction between plasmas of the patients. These subjects shared a common defect in the intrinsic pathway of coagulation that we designate by the proband's surname, Passovoy.

Adolescent

Gelfoam and autologous clot embolization: effect on coagulation.

An episode of disseminated intravascular coagulation following therapeutic gelfoam embolization to control bleeding from esophageal varices in a patient with liver disease is presented. We have since followed 13 patients prospectively (six control and seven gelfoam/autologous clot) to determine the effect of this procedure on clotting. We were unable to show significant differences between the two groups as measured by the prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen and platelet count. However, fibrin (ogen) degradation products were significantly elevated (p less than .01) in the gelfoam/autologous clot group. We suspect this occurred secondary to clot lysis at the site of embolization. No subsequent bleeding diathesis attributable to this abnormality occurred in any of the patients.

Disseminated Intravascular Coagulation

Blood coagulations studies in pregnant patients with infective hepatitis.

Coagulation studies were made on 22 pregnant women with acute infective hepatitis and on 15 normal control pregnant women in third trimester. Fourteen hapatitis patients had clinical evidence of liver failure and all of them had a haemorrhagic diathesis; none of the patients without liver failure showed clinical evidence of haemostatic defects. Coagulopathy was present in most patients, its severity being greater in those with hepatic failure. Significant alterations were observed in bleeding time, whole blood clotting time, prothrombin time, thrombin time, plasma fibrinogen and serum levels of fibrinogen degradation products. The last three disturbances were most frequent in patients with liver failure. Increased fibrinolysis and disseminated intravascular coagulation also appeared to play a contributory role, particularly in patients with hepatic failure.

Adolescent

Congenital deficiency of alpha 2-plasmin inhibitor associated with severe hemorrhagic tendency.

alpha(2)-Plasmin inhibitor (alpha(2)PI) is a recently characterized, fast-reacting plasmin inhibitor in human plasma that appears to play an important role in regulation of in vivo fibrinolysis. We report here a case of complete deficiency of alpha(2)PI in man. The patient, a 25-yr-old Japanese man, had a life-long severe bleeding tendency (hemarthrosis and excessive bleeding after trauma). The following tests were within normal limits: platelet count, bleeding time, thrombin time, prothrombin time, partial thromboplastin time, titers of known clotting factors, platelet glass bead retention, Factor VIII-related antigen, platelet aggregation by ADP, collagen and ristocetin, and clot retraction. Routine liver function tests were also normal. The only abnormal finding was that whole blood clot lysis was extemely rapid and was complete in 4-8 h. The concentration of plasma protease inhibitors, including alpha(2)-macro-globulin, antithrombin III, alpha(1)-antitrypsin, and C1INH, were all normal. The concentration of alpha(2)-PI in the patient's plasma, assayed by immunological methods, was <0.1 mg/100 ml (normal concentration, 6.1+/-0.88 mg/100 ml [mean+/-SE]) and functional assays showed a complete deficiency of alpha(2)PI. Addition of purified alpha(2)PI to the patient's whole blood completely corrected the accelerated fibrinolysis. The patient's parents, four siblings, and four other members of this family were asymptomatic, but the titers of alpha(2)PI in their plasmas were congruent with50% of normal pooled plasma. There were three consanguineous marriages in this family, and the alpha(2)PI deficiency appears to have been inherited as an autosomal recessive trait. We speculate that alpha(2)PI deficiency in this patient has led to uninhibited in vivo fibrinolysis that probably causes the severe hemorrhagic tendency. Thus, this study indicates the important role of alpha(2)PI in hemostasis.

Adult

Thrombus weight as a measure of hypercoagulability induced by drugs.

Thrombus weight was used as a measure of the thrombus enhancing effect of drugs in 135 rats. The weight of thrombus formed in one hour, on a 20 x 0.5 mm platinum wire, inserted in the vena cava was taken as a measure of thrombosis. The change in thrombus weight which followed the injection of ellagic acid to activate the coagulation system, adenosine diphosphate to activate the platelets, and epsilon-aminocaproic acid to inhibit the fibrinolytic system, was measured. Pilot studies showed that the drug doses used brought about the appropriate changes in the factors named. The mean thrombus weight in 45 control animals was 1.93 mg. Ellagic acid increased it about five-fold, and epsilon-aminocaproic acid almost two-fold, while adenosine diphosphate reduced it by almost a half. Concurrent controls were used in each case. Clotting tests (whole blood clotting time, kaolin-activated whole blood clotting time, thrombin time, and partial thromboplastin time), performed at the end of the hour, showed no significant correlation with thrombus weight.

Adenosine Diphosphate

Soluble fibrin complexes in early fibrin digests.

Early fibrin digests were analyzed in the ultracentrifuge and were found to contain compounds with molecular weights up to 3 X 10(6); these compounds are considered to be soluble fibrin complexes. Their similarity with intermediate polymers in inhibited clotting systems has been stressed. Their viscosity at low shear rates is extremely high; therefore, a rapid method to establish their presence in plasma would be the measurement of plasma and serum viscosity at low shear rates, moreover, they shorten the clotting time (thrombin time) of fibrinogen considerably.

Animals