The canine erythroid cell system: a new model for study of regulatory mechanism in hemoglobin synthesis.

The total methodology for a new mammalian erythroid cell system which permits direct investigation of the terminal stages of hemoglobin synthesis and assembly is described. The canine system allows quantitative separation of native heme containing alpha and beta chains which recombine to for tetrameric hemoglobin with normal functional properties (n = 2.17). These chains can be utilized for investigation in a cell-free system in which the rates of synthesis of alpha and beta chains are equal (alpha/beta = 0.96 +/- 0.05). Methodology for the quantitative separation of globin allows study of the effects of balanced and unbalanced globin chain synthesis in both the intact cells and the cell-free system.

Local installation of small doses of streptokinase for treatment of thrombotic occlusions of long-term access catheters.

Small doses of streptokinase were infused locally into occluded long-term venous access catheters in seven patients with neoplasia who required such access for the administration of chemotherapy and blood products. This technique resulted in prompt resolution of clot in all patients, was easy to perform, and caused no hemorrhagic side effects or coagulation changes.

Disseminated intravascular coagulation. Approach to treatment.

Disseminated intravascular coagulation (DIC) is a syndrome caused by the systemic generation of thrombin. Most cases are due to pathological activation of the intrinsic coagulation systems (e.g. in sepsis), and/or the extrinsic system (e.g. in malignancy and head trauma). Diagnosis is made by finding abnormalities in at least 3 of 4 laboratory values, namely prothrombin time, platelet count, fibrinogen and fibrinogen/fibrin degradation products. The most common clinical manifestation of DIC is bleeding, with thrombosis in less than 10% of acute cases but more frequently encountered in chronic DIC associated with malignancy. Acute DIC must first be treated by specific therapy of the underlying disease and general support measures. If serial clinical and laboratory monitoring improves, no further treatment is required. If severe or life-threatening haemorrhage occurs or a thrombotic event ensues, heparin anticoagulation followed by aggressive replacement with platelets, fresh plasma and possibly cryoprecipitate is indicated. Heparin doses should be 'therapeutic' (i.e. adequate to overcome the coagulant forces that may have produced a relative heparin-resistant state in the blood). Chronic DIC with haemorrhage, or more usually thrombosis, should also be treated with heparin; warfarin is ineffective. If DIC persists because, for example, a tumour does not regress, long term outpatient subcutaneous heparin therapy may be required.

Fibrinolysis and its current usage.

By activating plasminogen into plasmin, which in turn dissolves fibrin, fibrinolytic agents can dissolve pathologic thrombi. Streptokinase, a fibrinolytic agent derived from group C beta-hemolytic streptococci, is antigenic and can elicit allergic reactions. Urikinase, a fibrinolytic agent obtained by purification from human urine or from human fetal kidney cell culture, is not antigenic, and for this reason can be used repeatedly, if needed, whereas streptokinase cannot be used for retreatment within six months of a course of therapy. Either agent can be introduced into the circulation systemically (intravenously) or locally (via catheter). The indications for systemic therapy include deep-vein thrombosis, pulmonary embolism, and arterial thrombosis and embolism. The indications for local therapy include acute myocardial infarction, arterial thrombosis and embolism, and the clearing of occluded arteriovenous cannulae and access shunts. Contraindications include an actively bleeding lesion, a vascular intracranial disorder, or uncontrolled hypertension; relative contraindications include pregnancy; a recent wound, fracture, surgery, or deep closed biopsy; or a general contraindication to anticoagulation, such as coagulopathy, uremia, or severe liver disease. During thrombolytic therapy, invasive procedures, intramuscular injections, and the use of other anticoagulant or antiplatelet agents should be avoided. Measurement of fibrinogen levels, the titer of fibrin/fibrinogen degradation product, or thrombin time can be used to monitor therapy.

Unique degradation of human fibrinogen by proteases from western diamondback rattlesnake (Crotalus atrox) venom.

Thrombin-coagulability of both human fibrinogen and plasma was rapidly lost upon incubation with western diamondback rattlesnake (Crotalus atrox) venom. The dose- and time-dependent effect was due to direct proteolytic degradation of fibrinogen (Mr 340,000) by venom enzymes. Using purified fibrinogen as the substrate it was demonstrated that the venom degraded the A alpha chain first and then the B beta chain. The degradation pattern of fibrinogen in plasma was different to that of purified fibrinogen, since only the B beta chain was cleaved. A fibrinogen derivative isolated from venom-treated plasma had impaired thrombin-coagulability, Mr 325,000 +/- 10,000, its A alpha and gamma chains appeared intact and only the B beta chain was degraded to a species of Mr 52,000 +/- 1,500. The venom contained three proteolytic enzyme fractions as revealed by gel filtration chromatography. All abolished coagulability of purified fibrinogen, however, only one enzyme fraction rendered plasma incoagulable. The proteolytic enzyme with anticoagulant activity against plasma degraded only the B beta chain of purified fibrinogen, generating a derivative of Mr 325,000, which was identical to that obtained upon incubation of the crude venom with plasma. The polypeptide chain structure of the derivative indicates that the intact B beta chain of fibrinogen plays an important role in the formation of fibrin clots.

Feasibility and pharmacokinetics of carbamazepine oral loading doses.

The pharmacokinetics and adverse effects of an oral loading dose of carbamazepine administered in tablet or suspension form were studied. Patients on a hospital epilepsy unit who were to receive carbamazepine as a discharge medication were randomly assigned to receive either an oral 8-mg/kg loading dose of the tablet formulation or the same dose of the suspension on an empty stomach. Blood samples were drawn before and at intervals up to 12 hours after the loading dose. Adverse effects were evaluated subjectively and objectively. Total and free serum carbamazepine and carbamazepine-10, 11-epoxide (CBZE) concentrations were determined by high-performance liquid chromatography. Six adult patients were enrolled in and completed the study. All the patients achieved therapeutic total carbamazepine levels; the suspension group did so within two hours and the tablet group within five hours. Maximum serum carbamazepine concentrations ranged from 7.10 to 9.92 mg/L, area under the concentration-versus-time curve from 54.85 to 82.23 micrograms.hr/L, and terminal elimination half-life from 14.05 to 15.71 hours. Adverse effects were mild, few, and short-lived; none of the patients developed gastrointestinal toxicity. Adverse effects were not associated with total or free carbamazepine and CBZE concentrations or with total or free CBZE:carbamazepine ratios. An oral loading dose of carbamazepine 8 mg/kg achieved therapeutic levels within two hours when given as a suspension and within five hours when given as tablets and was well tolerated in all patients.

Reform of the Medicare program.

Financing of the Medicare program is under stress because of national economic and demographic trends. A comprehensive overview of the required changes is imperative. The American Medical Association has proposed to place Medicare funding out of the political arena and to place it under the administration of an independent commission such as the Federal Reserve Board. Further, the plan would initiate a voucher system financed by a tax on adjusted gross income during the working years invested through a new public trust fund.

Physician reimbursement: the environment for change.

Escalation of costs for physician care services in the Medicare program has elicited measures to rein in these expenditures. These include freeze and control of physician fees, limits on reimbursement for certain procedures, and mandated assignment of clinical laboratory service charges. An important step in rationalizing physician fees lies in the resource cost-based relative value study undertaken by the American Medical Association together with Harvard University economists. The results should redress inequities inherent in the current reimbursement system and allow a more suitable distribution of funds within the profession.

Techniques for evaluating the cause of bleeding in the ICU. Diagnostic clues and keys to interpreting hemostatic tests.

Begin by obtaining both a bleeding and a family history to help ascertain whether the disorder is acquired or inherited. On physical examination, look for multiple bleeding sites or profuse bleeding; these can indicate a systemic bleeding diathesis. Order hemostatic tests. Prolonged aPTT points to a defect in the intrinsic or common coagulation pathway; prolonged PT, to a defect in the extrinsic or common pathway. Thrombin time is abnormal when hypofibrinogenemia, afibrinogenemia, or thrombin inhibitors are present. Bleeding time is prolonged in thrombocytopenia, platelet dysfunction, severe hypofibrinogenemia, and von Willebrand's disease. Factor assays also may be needed to further define the defect.

Bone marrow necrosis.

Extensive bone marrow necrosis is an unusual histologic finding most commonly identified after autopsy. We describe a patient with poorly differentiated lymphocytic lymphoma who manifested pancytopenia and marrow necrosis. Bone marrow scanning with 99mTc-sulfur-minicolloid provided a noninvasive means to assess the extent of marrow damage. Our patient's condition improved clinically following cytotoxic chemotherapy demonstrating that marrow necrosis may be associated with a treatable disease.

Selective intra-arterial streptokinase therapy in the immediate postoperative period.

We report successful lysis of acute arterial calf thrombosis by intra-arterial streptokinase infusion seven hours after retroperitoneal dissection and repair of an ipsilateral common femoral artery laceration. No systemic effects or complications developed. Local intra-arterial thrombolytic therapy is more effective and safer than intravenous systemic therapy and may now be considered in the immediate postoperative period, providing the drug is delivered downstream from the operative site.

Hemostatic function in cancer patients.

We performed coagulation profiles including a complete blood count (CBC), prothrombin time (PT), activated partial thromboplastin time (aPTT), and quantitation of fibrinogen, antithrombin III (AT III), plasminogen, and fibrin/fibrinogen degradation products (FDP) on 73 cancer patients. All had solid tumors with clinically documented metastases. Eleven patients had strong clinical and laboratory evidence of disseminated intravascular coagulation (DIC). Fifty-five of the remaining 62 patients had no clinical evidence of serious hemorrhage or thrombosis at the time of testing. Thirty-one (50%) non-DIC patients had no abnormal clotting tests. Our data indicate that a majority of cancer patients, with or without hepatic involvement, are able to maintain normal or near normal hemostatic function in vitro until advanced stage of disease. Deviation from normal for PT, aPTT, or TT, depressed AT III activity, or increased FDP signal the presence of complicating pathophysiologic events such as DIC or cirrhosis. Diminution of fibrinogen level or AT III activity and elevation of FDP are more sensitive indicators of DIC than prolongation of PT, aPTT, or TT.