Acquired hypoprothrombinemia due to non-neutralizing antibodies to prothrombin: mechanism and management.

A patient developed bleeding due to an acute acquired specific prothrombin deficiency. Unlike previously described patients, this patient had no evidence of an associated lupus anticoagulant. Prothrombin activity and antigen were decreased concordantly and the patient's plasma did not neutralize the activity of added prothrombin or interfere with its measurement by electroimmunoassay. Nevertheless, immunoelectrophoresis and experiments using 125I-prothrombin revealed a prothrombin-binding antibody. The residual prothrombin in the patient's plasma was in the form of a prothrombin-antibody complex. Administration of adrenal corticosteroids was associated with a rise in prothrombin activity and cessation of bleeding, but circulating prothrombin was still bound to the antibody. This suggests that non-neutralizing antibodies to prothrombin cause plasma prothrombin deficiency because of a rapid clearance of prothrombin-antibody complexes, which is slowed by adrenal corticosteroids. The antibody had a relatively low affinity for prothrombin (Kd 5 to 8 X 10(-7)) and was transient. It is possible, therefore, that the antibody arose not to prothrombin itself, but to an antigen sharing an epitope with prothrombin.

Radiotherapy plus razoxane for advanced limited extent carcinoma of the lung.

Forty-four patients with limited extent American Joint Committee on Cancer Stage II-III non-small cell carcinoma of the lung were randomly assigned to potentially curative radiation therapy plus one of two schedules of razoxane. The weekly schedule was 1 gram per square meter body surface area (BSA) every 8 hours for two doses per week, and the daily schedule was a fixed dose of 250 mg per day. The 50% Kaplan-Meier survival estimate for both groups combined was 9 months. There was no survival difference between the two dose-schedules. Toxicity was formidable with an 82% incidence of esophagitis, and a 20% incidence of grade III-IV esophagitis. Fifty-nine percent of patients developed hematologic toxicity. This was greater with the weekly dose-schedule (P = 0.01). Forty-one percent of patients developed radiographic or symptomatic pneumonitis. One patient developed a fatal myelitis. This program is no more effective than irradiation alone, and has substantial morbidity.

A mechanism for the hypoprothrombinemia of the acquired hypoprothrombinemia-lupus anticoagulant syndrome.

Antibodies that bind prothrombin without neutralizing its coagulant activity were demonstrated in the plasma of two patients with the acquired hypoprothrombinemia-lupus anticoagulant syndrome. The first patient's plasma contained less than 1% prothrombin activity and no detectable prothrombin antigen. The second patient's plasma contained about 6% of both prothrombin activity and antigen. Neither patient's plasma neutralized the prothrombin coagulant activity of normal plasma or of purified prothrombin added in vitro. Nevertheless, double immunodiffusion studies and binding experiments utilizing 125I-prothrombin demonstrated the presence of prothrombin antibodies in each patient's plasma. A Scatchard analysis of the binding data obtained with different concentrations of 125I-prothrombin and the first patient's plasma indicated the presence of a high affinity antibody, apparent Kd approximately 10(-10)M, and a lower affinity antibody, apparent Kd approximately 10(-9)M. Studies utilizing purified cleavage products of prothrombin suggested that the antibodies were directed against an epitope or epitopes located on the carboxyl-terminal, latent thrombin segment of the prothrombin molecule. We postulate that the acquired hypoprothrombinemia in these two patients and in other reported patients with the acquired hypoprothrombinemia-lupus anticoagulant syndrome stems from rapid clearance from the circulation of prothrombin antigen-antibody complexes.

Anesthesia in septorhinoplasty. Effects of halothane vs nitrous oxide narcotic on bleeding.

The effects of halothane and nitrous oxide narcotic anesthesia on bleeding were studied. Coagulation parameters were examined preoperatively and a half hour after induction. There were no notable changes with either anesthetic technique, and there were no substantial differences between the two anesthesias. A clinical comparison of bleeding, surgical exposure, blood pressure, and duration of surgery also was made. The two anesthetic techniques tested had no notable differences in the previously mentioned parameters on septorhinoplasty.

Syndrome of an acquired inhibitor of factor VIII responsive to cyclophosphamide and prednisone.

Six patients with an acquired inhibitor of factor VIII had the following clinical characteristics: older age group; absence of definable, underlying disease; a low titer of the factor VIII inhibitor; notable residual plasma factor VIII activity despite the inhibitor; serious bleeding not controlled by infusion of factor VIII; and disappearance of the inhibitor after treatment with cyclophosphamide and prednisone. These findings delineate a syndrome characteristic of a subset of patients with an acquired factor VIII inhibitor. It is important to emphasize that such patients may bleed uncontrollably despite the misleading presence of residual plasma factor VIII activity in vitro, and that the inhibitor disappears after immunosuppressive therapy. Thus, we believe that patients with this syndrome should be treated with cyclophosphamide and prednisone as soon as the inhibitor is identified.

Thrombosis in patients with the lupus anticoagulant.

A retrospective study was carried out to determine the frequency of thrombosis in patients with the lupus anticoagulant. Thirty-five patients fulfilled laboratory criteria for the diagnosis of the lupus anticoagulant. Eight of these patients had evidence of clinically significant thrombosis while their plasma showed a prolonged partial thromboplastin time due to the anticoagulant. Four of the patients wity thrombosis had concurrent autoimmune disease and three other patients were receiving phenothiazine medication. Moderate thrombocytopenia was noted in four patients with thrombosis. None of the patients with the lupus anticoagulant bled abnormally. This study suggests that patients with the lupus anticoagulant may be at increased risk of thrombosis.

Hepatic scan defects following radiotherapy for lymphoma.

Twenty-one patients with lymphoma were evaluated for the presence of hepatic scan defects following radiotherapy to fields which included the left lobe of the liver. Two distinct patterns of hepatic scan defects were noted: (a) a radiation port defect (Type I), and (b) attenuation of the left lobe (Type II). Five of seven patients evaluated within six weeks after radiotherapy demonstrated Type I defects but all seven subsequently developed Type II defects. Seventeen of the 21 patients developed Type II defects which have persisted (follow-up, up to 66 months). These characteristic defects should not be confused with other causes of hepatic scan defects in evaluating patients with lymphoma. The defects occur in a high percentage of patients and may persist for long periods.

Metastatic cloacogenic carcinoma of the anus: sequential responses to adriamycin and cis-dichlorodiammineplatinum(II).

A case of cloacogenic carcinoma of the anus with pulmonary metastases successfully treated with adriamycin and subsequently with cis-dichlorodiammineplatinum(II) (CDP) is reviewed. Cloacogenic carcinoma of the anus is a very uncommon tumor, and this is the first report of a major response to chemotherapy alone. Adriamycin and/or CDP should be considered in the therapy of this tumor.

Leucovorin in combination chemotherapy of breast cancer.

Cyclophosphamide, 5-fluorouracil, methotrexate, and prednisone were administered for 165, 28-day cycles to 33 patients with metastatic breast cancer. Because of serious infections (fever larger than or equal to 101 degrees F. granulocytes less than 1,000/mm, 3 and hospitalization) and 1 drug death in the first 4 patients, oral calcium leucovorin, 20 to 30 mg/m2 orally, was given 2 days after methotrexate in subsequent treatment cycles. There were 26 cycles without calcium leucovorin and 6 serious infections; 139 cycles with calcium leucovorin and 5 serious infections (p = 0.002). Objective response was seen in 13 of 18 evaluable patients with no previous treatment and in only 2 of 11 patients with previous treatment (p = 0.0065). Equivalent doses were given to all subsets of patients. It is concluded that leucovorin added to the above combination of drugs can preserve antitumor activity while decreasing serious infections and that prior therapy significantly decreases the response rate to this combination.

Successful therapy with methotrexate of a multicentric mixed lymphoma of the central nervous system.

Primary lymphoma of the central nervous system (CNS) is extremely rare. A case of mixed histiocytic lymphocytic lymphoma of the CNS that initially occurred in the spinal cord is reported. Multicentric recurrence following radiotherapy was successfully treated with intrathecal methotrexate and the patient remains free of disease after 4 years. The role of intrathecal methotrexate as alternative therapy following irradiation failure is discussed.