Epidemic meningococcemia and purpura fulminans with induced protein C deficiency.

Patients with epidemic infections caused by Neisseria meningitidis serogroup C were studied to assess the relationship of abnormal coagulation parameters to prognosis. Patients were categorized into stages within the first hour of observation according to severity of illness. During the epidemic years 1986 through 1991, 113 patients with bacteriologically proven N. meningitidis infection were observed, 15 of whom died. Purpura fulminans was seen in 28 patients, of whom 14 (50%) died. Among the 14 surviving patients who had purpura fulminans, 10 suffered gangrene with deforming autoamputation secondary to the dermal microvascular thrombosis and hemorrhagic necrosis. Evaluation of the induced diffuse intravascular coagulation in 59 patients included studies of the naturally occurring anticoagulants, focusing on protein C and protein S. The magnitude of the declining levels of protein C, the degree of thrombocytopenia, and the presence of fibrin split products are directly related to the clinical severity of the illness (P = .0053). Thus, in individuals with severe disease expression, the risk of purpura fulminans with death or deformity was significantly increased when the platelet count was < 50,000 cells/mm3 (P = .0001) and protein C levels were low (P = .0158). The immaturity of the protein C system in children who are < 4 years of age may contribute to the rapid and more frequent pathogenesis of purpura fulminans. Therapy directed at replacement of the naturally occurring anticoagulants, such as protein C, may ultimately improve the prognosis for individuals with purpura fulminans.

A functional assay for protein C in human plasma.

We describe a functional assay for protein C in human plasma samples based on the ability of activated protein C to prolong the kaolin-cephalin activated partial thromboplastin time of normal plasma. Protein C is separated from its inhibitor by elution of a barium citrate precipitate, and activated by incubation with human alpha-thrombin for one hour. Thrombin is then inhibited by antithrombin III and heparin, heparin neutralized by protamine sulfate, and protein C activity measured in the partial thromboplastin time. 24 normal subjects had a mean protein C level of 94 +/- 12% (SD) of the activity in pooled normal plasma. Seven patients with severe liver disease had a mean protein C of 28%. Eleven patients with disseminated intravascular coagulation had a mean protein C of 29%. Eight patients receiving warfarin therapy had a mean protein C of 17%. The assay is relatively simple and should be suitable for general laboratory use.

Severe depression of antithrombin III associated with disseminated intravascular coagulation in women with fatty liver of pregnancy.

Serial coagulation studies were done in four women with acute fatty liver of pregnancy. All had coagulopathy, laboratory evidence of diffuse intravascular coagulation, and marked depletion of plasma antithrombin III. Two of these women had persistent intravascular coagulation for 4 days after delivery. The others had prompt control of intravascular coagulation coincident with elevation of the antithrombin III concentration by plasma transfusion. Severe antithrombin III depression may be a major cause of the persistent intravascular clotting and can be corrected by plasma transfusion.

Antithrombin III and anti-activated factor X activity in patients with acute promyelocytic leukemia and disseminated intravascular coagulation treated with heparin.

Two patients diagnosed as having acute promyelocytic leukemia (APL) and disseminated intravascular coagulation (DIC) were closely followed from the day of admission until completion of the first course of chemotherapy with serial coagulation studies including plasma levels of functional antithrombin III activity (AT III) by fluorometric analysis and anti-activated Factor X activity (anti-Xa) by coagulation assay. Both patients were treated with intravenous heparin and the presence of heparin in plasma was followed by the thrombin time. Consistently normal levels of AT III (greater than 80%) were found despite evidence of intravascular coagulation. However, plasma levels of anti-Xa were often low (less than 70%) and increased only in the presence of heparin. The significance of these results in relationship to heparin therapy for disseminated intravascular coagulation of APL is discussed.

Antithrombin III and anti-activated factor X activity in patients with acute promyelocytic leukemia and disseminated intravascular coagulation treated with heparin.

Two patients diagnosed as having acute promyelocytic leukemia (APL) and disseminated intravascular coagulation (DIC) were closely followed from the day of admission until completion of the first course of chemotherapy with serial coagulation studies including plasma levels of functional antithrombin III activity (AT III) by fluorometric analysis and anti-activated Factor X activity (anti-Xa) by coagulation assay. Both patients were treated with intravenous heparin and the presence of heparin in plasma was followed by the thrombin time. Consistently normal levels of AT III (greater than 80%) were found despite evidence of intravascular coagulation. However, plasma levels of anti-Xa were often low (less than 70%) and increased only in the presence of heparin. The significance of these results in relationship to heparin therapy for disseminated intravascular coagulation of APL is discussed.

Depression of functional and antigenic plasma antithrombin III (AT-III) due to therapy with L-asparaginase.

Eleven patients with leukemia and lymphoma were treated with 14 courses of E. coli L-asparaginase. Abnormalities of the coagulation screening tests and decreased fibrinogen levels were observed in all patients during treatment. Significant depressions of functional (mean 32%) and antigenic (mean 48%) antithrombin III were observed by day 14 of therapy. There was no laboratory evidence of intravascular coagulation during 11/14 courses of L-asparaginase. Crossed immunoelectrophoresis of plasma obtained at the antithrombin nadir did not demonstrate an abnormal pattern which can be associated with an abnormal antithrombin III or an increase in antithrombin III-coagulation factor complexes. The major underlying mechanism of this depression is believed to be decreased hepatic synthesis, and the low levels of antithrombin III may be associated with an increased risk of thrombosis.

Factor V anticoagulants: clinical, biochemical, and immunological observations.

A patient who had received multiple transfusions for complications of acute hemorrhagic pancreatitis developed a potent factor V anticoagulant with bleeding due to defective hemostasis. Despite its potency, the anticoagulant disappeared within 15 days of its first manifestation. A second patient with adenocarcinoma of the colon developed an anticoagulant to factor V postoperatively after a single blood transfusion. The anticoagulants appeared to react stoichiometrically with factor V in normal plasma in vitro. They had the physicochemical properties of immunoglobulins, and their activity was neutralized by antihuman immunoglobulin antiserum. One anticoagulant appeared to be slightly more active against homologous than against autologous factor V, but it also inhibited heterologous factor V. Both anticoagulants progressively inactivated intrinsic prothrombin activator formed from normal reagents in the incubation mixture of the thromboplastin generation test, thus confirming that factor V is required for the effective action of the intrinsic prothrombin activator. Since the anticoagulants were immunoglobulins whose activity was consumed in their reaction with factor V, consumption of anticoagulant activity was used to detect factor V antigenic material in test materials. Human serum without factor V clotting activity was found to consume anticoagulant activity, i.e., to contain inactive factor V antigenic material. Plasma from two patients with hereditary factor V deficiency (parahemophilia) failed to consume significant anticoagulant activity. Thus, the lack of factor V activity in these patients represents a deficiency of factor V molecules rather than the synthesis of a defective molecule with impaired clotting activity.