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Depression of the vitamin K-dependent modulators of coagulation during the initial phase of oral anticoagulant therapy may lead to a transient hypercoagulable state and skin necrosis. We report a case of skin necrosis associated with inherited protein S deficiency following prolonged coumarin therapy. As a result of a stasis ulceration causing a rise in c4b binding protein and concurrent treatment with topical sulfonamide, we hypothesize that a precipitous decrease in free protein S led to skin necrosis. Progression of the necrosis was halted with unactivated prothrombin complex concentrate. This case confirms the rare association between coumarin induced skin necrosis and protein S deficiency and emphasizes potential drug interactions.

Disseminated intravascular coagulation (DIC) may complicate severe septicemia caused by Staphylococcus aureus. S. aureus can induce spontaneous platelet aggregation in vitro, the rapidity and degree of which correlates with the severity of DIC in patients with sepsis. Purified peptidoglycan from DIC isolates aggregated human platelets in the presence of staphylococcal protein A with significantly shorter aggregation times than did peptidoglycan from non-DIC isolates. Purified teichoic acid from DIC and non-DIC isolates failed to aggregate platelets in vitro, or in vivo in guinea pigs but inhibited the peptidoglycan-induced aggregation in a dose-response manner. These studies suggest that peptidoglycan may mediate S. aureus-induced spontaneous platelet aggregation in vitro and DIC in vivo. The variability among strains of S. aureus to induce DIC and platelet aggregation may depend on the unique composition of their peptidoglycan and perhaps also the extent of exposure or availability of cell wall teichoic acid.

The modern treatment of cardiopulmonary disease is increasingly predicated on the goal of dissolving the offending clot to establish vascular patency as rapidly as possible and then preventing rethrombosis. The availability of thrombolytic agents has made this therapeutic approach possible and the adjunctive use of heparin, coumarin, and aspirin has increased the efficacy of lytic drugs. The administration of any of these medications is associated with inherent risks, which are enhanced when they are used concomitantly. An understanding of coagulation and an appreciation of the pathophysiologic processes of the thrombotic events occurring in cardiopulmonary disease states are critical to the formulation of innovative therapeutic regimens that maximize efficacy and safety. Furthermore, knowledge of the comparative pharmacology of the various thrombolytic agents is useful in explaining the benefits and complications observed in clinical trials.

Plasma cross-linked fibrin-degradation products were analyzed using a D-dimer (DD) immunoassay in patients with deep vein thrombosis (DVT) or acute myocardial infarction (MI) treated with fibrinolytic therapy, and the results were correlated with clot lysis documented angiographically. In 13 patients with DVT, the mean DD concentration increased 10-fold (1,074 +/- 252 to 10,333 +/- 1,004 ng/ml) during therapy, but neither the peak level nor the DD concentration integrated over the course of therapy correlated with clot lysis. Since plasma DD can derive from degradation of soluble plasma fibrin as well as from thrombi, the contribution of the former was estimated by in vitro incubation of the pretreatment plasma with plasminogen activator. Subtraction of this value from the measured posttreatment DD concentration provided a "corrected" level that represented DD originating from lysis of thrombi. This modification resulted in improved correlation of DD levels with clot lysis. The mean corrected peak DD was higher in patients with successful thrombolysis (8,780 +/- 1,352 ng/ml) compared with patients without lysis (3,075 +/- 589 ng/ml, p less than 0.001). There was a moderate correlation between the volume of clot lysed and the corrected peak DD (r = 0.62) and a higher correlation with the corrected DD integrated over the course of treatment (r = 0.97). By contrast, the corrected DD concentrations were near zero in patients treated for MI with or without thrombolytic reperfusion, suggesting that fibrin in small coronary thrombi did not contribute significantly to total plasma DD during therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary embolism is diagnosed over 100,000 times yearly in the United States and is the recognized primary cause of death in at least 10,000 cases. Thrombolytic therapy has been successful in reducing clot burden substantially; however, clinical data are lacking to indicate that thrombolytic therapy improves mortality rates in patients with pulmonary emboli or that the pharmacologic removal of clot will improve future quality of life. The use of thrombolytic agents has been limited by the potential for producing hemorrhagic complications. This paper discusses the pharmacology of numerous thrombolytic agents and their clinical use in research studies intended to determine the safest and most efficacious regimens. Recombinant t-PA infusions appear quite safe and produce very rapid lyses of pulmonary emboli. Innovative administration regimens of urokinase also appear promising. The availability of extremely safe and efficacious treatment regimens should allow for large epidemiologic studies to be conducted to determine whether thrombolytic therapy will improve the morbidity and mortality of pulmonary embolism.

The ability of von Willebrand factor protein (vWF) to agglutinate platelets with ristocetin depends upon the presence of its highest molecular weight multimers (HMWM) and its intact carbohydrate structure. Previously we demonstrated that the HMWM are preferentially adsorbed to purified fibrillar type I collagen. The role of the carbohydrate structure of vWF in this function has not been established. In these studies complete desialylation (greater than 95%) of the intact protein by neuraminidase did not interfere with the normal adsorption of vWF activity to type I collagen. In contrast, modification of the penultimate galactose of the desialylated protein with galactose oxidase or beta-galactosidase markedly reduced adsorption of vWF activity by collagen. Subsequent reduction of the oxidized desialylated protein with potassium borohydride completely regenerated the normal adsorption of vWF activity by collagen. Enzymatic modification of the penultimate galactose moiety of vWF resulted in a loss of the HMWM, as observed following SDS-glyoxyl agarose electrophoresis. This was in contrast to desialylated vWF, which appeared intact structurally and which predictably lost its HMWM upon exposure to collagen in a manner similar to native vWF. Therefore, the carbohydrate structure of vWF and, in particular, the penultimate galactose moiety, may be critical for vWF-collagen interactions and for the mediation of primary hemostasis.

Infusions of either fibrinogen fragment D or fibrinogen fragment E into rabbits were followed by increases in fibrinogen synthesis determined by the rate of incorporation of 75Se-selenomethionine into circulating fibrinogen. The degree of stimulation was proportional to the amount of protein infused. When 4.5 mg of each fibrinogen fragment was administered separately to different groups of animals, fibrinogen fragment D was associated with a fourfold increase in fibrinogen synthesis above that in the control animals compared with 1.5-fold increase induced by fragment E. Fragments D and E were assayed for bound sialic acid, the absence of which facilitates binding, transport and catabolism of many circulating glycoproteins by the liver. Fibrinogen fragment D contained 1.3% sialic acid compared to 1.4% in fragment E. These data indicate conservation of sialic acid during plasmic digestion of fibrinogen. The capacity of these glycopolypeptide fragments to stimulate fibrinogen synthesis appears unrelated to the nearly identical quantities of N-acetyl neuraminic acid found in each fragment.

Recombinant human tissue-type plasminogen activator (rt-PA), a relatively clot-specific fibrinolytic agent, represents a novel and promising approach to thrombolytic therapy of pulmonary embolism. Therefore, the efficacy and safety of peripheral intravenous rt-PA therapy were assessed in 47 patients with angiographically documented pulmonary embolism. The drug regimen was 50 mg over 2 hours followed by repeat angiography and, if necessary, an additional 40 mg over 4 hours. By 6 hours, 44 of the 47 patients had angiographic evidence of clot lysis that was slight (n = 5), moderate (n = 12) or marked (n = 27). Among the 34 patients with pulmonary hypertension before treatment (mean pulmonary artery pressure exceeding 17 mm Hg), the pressure decreased from 43/17 (mean 27) to 31/13 (mean 19) mm Hg (p less than 0.0001). Fibrinogen decreased 33% from baseline at 2 hours and 42% from baseline at 6 hours. There were two major complications that required surgical control of bleeding: hemorrhage from a pelvic tumor and mediastinal tamponade in a patient 8 days after coronary artery bypass surgery. The initial results demonstrate that, among selected patients, peripheral intravenous rt-PA can rapidly and, for the most part, safely lyse pulmonary embolism within 6 hours.

Based on a continuing need to provide a more rapid response to requests for thawed fresh frozen plasma, the authors evaluated plasma thawing with the use of a microwave oven and compared it with conventional 37 degrees C waterbath thawing methods. Their results indicate that microwave-thawed plasma contains precipitated denatured protein (mainly albumin and fibrinogen) and that there is a significant reduction of coagulation Factors IX, X, XI, and fibrinogen compared with fresh plasma. They also measured levels of di-ethyl hexyl phthalate after microwave thawing and found its rate of accumulation similar to that of the 37 degrees C waterbath. More importantly, fundamental principles of microwave heating preclude uniform temperatures being maintained throughout the thawing of plasma; hence, the denaturation of plasma proteins is expected to occur under even low heating conditions.

T-cell immunity and serum levels of thymosin alpha 1, beta 2-microglobulin, circulating immune complexes, serum immunoglobulin levels, antibodies to hepatitis surface or core antigen, and to cytomegalovirus, and Epstein-Barr virus were investigated in 51 patients with haemophilia A ranging in age from 2 to 52 years. All patients had received commercial U.S. lyophilized concentrates of antihaemophilic factor (AHF). The mean helper/cytotoxic-suppressor (OKT4/OKT8) ratio of 11 pre-adolescents (1.6 +/- 0.4 SE) was not significantly different from that of age matched normal controls. In contrast, the mean OKT4/OKT8 ratios of 13 adolescent (1.2 +/- 0.2 SE) and 23 adult (0.8 +/- 0.1 SE) haemophiliacs were significantly reduced. Abnormalities of lymphocyte mitogenic responses were found only in adult haemophiliacs. Nine individuals treated with commercial U.S. prothrombin complex concentrates for antibodies directed against AHF or for haemophilia B had normal mean OKT4/OKT8 values. The mean serum thymosin alpha 1 levels for each age category was similar to that of age matched controls; however, regression analysis revealed a significant relationship between elevated thymosin alpha 1 levels and decreased OKT4/OKT8 ratios in adult haemophiliacs (P = 0.012). Although the mean serum level of beta 2-microglobulin was significantly increased in the adult haemophiliac group, there was no correlation between OKT4/OKT8 ratios and any of the other serologic parameters studied.

The effect of intravenous infusions of purified homologous FDP and thrombin on fibrinogen synthesis was evaluated in rabbits. De novo fibrinogen production was measured by the rate of incorporation of 75SeM into circulating fibrinogen. After receiving either 100 or 200 NIH U/kg purified homologous thrombin over 1 hr, rabbits demonstrated threefold and fivefold increases in fibrinogen synthesis, respectively. A correlation between the titers of FDP-fdp and the degree of fibrinogen synthesis was evident. Prior administration of epsilon-ACA prevented the accelerated synthesis of fibrinogen induced by thrombin and inhibited the appearance of FDP-fdp in serum. epsilon-ACA did not interfere with normal fibrinogen production. Fibrinogen synthesis was assessed following infusions of FDP prepared by vitro by digestion of rabbit fibrinogen with plasmin and subsequently identified on SDS-polyacrylamide gels. Preparations which contained predominantly stage 2 intermediate (X, Y, D, and E) or stage 3 final (D and E) fragments accelerated fibrinogen synthesis, whereas those containing predominantly stage 1 fragment X did not. Prior treatment with epsilon-ACA did not alter these results. Infusion of the supernatants derived from immunoprecipitation of the FDP by either anti-rabbit fibrinogen antibody or specific anti-human D and E antibodies significantly diminished the enhanced fibrinogen synthesis induced by the unadsorbed materials. These experiments suggest that the accelerated fibrinogen synthesis induced by thrombin is mediated by FDP, with fragments D and E appearing to be the most potent.

Platelet-bacterial interactions were examined in vitro by incubating organisms isolated from patients with septicemia with normal platelet-rich plasma. The potency of various species of gram-positive and gram-negative bacteria to induce irreversible platelet aggregation was then determined in an aggregometer. The aggregation curves produced by the bacteria resembled the normal platelet response to collagen and were impeded by the presence of aspirin. Strains of Staphylococcus aureus and Pseudomonas aeruginosa isolated from 25 different patients produced maximum increases in light transmission and irreversible platelet aggregation with relatively rapid mean aggregation times; six of these patients had clinical and laboratory evidence of disseminated intravascular coagulation. In contrast, isolates of alpha streptococcus and Staphylococcus epidermidis induced irreversible platelet aggregation much less commonly and were associated with considerably longer mean aggregation times. None of the latter group of patients had evidence of disseminated intravascular coagulation. Isolates of bacteria from a small number of patients with subacute bacterial endocarditis uniformly induced irreversible platelet aggregation. Addition of paired bacterial isolates to normal platelet-rich plasma demonstrated a synergistic aggregation response. These data suggest that a relative hierarchy exists in bacterial strain potency to induce irreversible platelet aggregation. The rapidity and degree of aggregation in vitro correlated well with the clinical and laboratory evidence for subacute bacterial endocarditis and disseminated intravascular coagulation in vivo. These observations may provide useful adjunctive laboratory information to help establish the diagnosis of subacute bacterial endocarditis, especially in the clinical setting where the classical findings of endocarditis are not obvious during initial presentation.

Recombinant human tissue-type plasminogen activator (rt-PA) was given via a peripheral vein to 36 patients with angiographically documented pulmonary embolism. The regimen was 50 mg/2 h followed by repeat angiography and, if necessary, an additional 40 mg/4 h. By 6 h, 34 of 36 patients had angiographic evidence of clot lysis, slight in 4, moderate in 6, and marked in 24. The quantitative score improved 21% by 2 h and 49% by 6 h. Fibrinogen decreased 30% from baseline at 2 h and 38% from baseline at 6 h. 2 patients had major complications: in one, bleeding from a pelvic tumour required surgery; in the other, who had had coronary artery bypass surgery eight days earlier, pericardial tamponade developed. These initial results in selected patients make a case for expanded investigational use of peripheral intravenous rt-PA in pulmonary embolism.

A retrospective study was performed to examine the natural course of uncontrolled thrombocytosis associated with chronic myeloproliferative disorders. Thirty-eight patients with polycythaemia rubra vera (PV), myelofibrosis/myeloid metaplasia (MM), chronic myelogenous leukaemia (CML) or essential thrombocythaemia (ET) had platelet counts greater than 1000 X 10(9)/1 and were followed closely for a total of 246 patient years. Eleven of the patients experienced haemorrhagic episodes. Bleeding was twice as frequent in patients over 59 years old as in those younger and no bleeding occurred in those less than 51 years of age. There was no correlation between frequency of bleeding and extent of thrombocytosis. Bleeding events occurred concurrently with use of anti-inflammatory agents in 32% of episodes. The gastrointestinal tract was the most frequent site. Documented thrombotic events occurred in three patients, two of whom had PV with haematocrits greater than 53%. This study suggests that the thrombocytosis of myeloproliferative processes may pose a less serious threat than originally thought and that aggressive lowering of the platelet count may not be indicated in all cases.

Pulmonary embolism is diagnosed 120,000 times yearly in the United States and contributes to 30,000 deaths. This probably represents an underestimate of incidence because massive acute pulmonary embolism may often result in rapid and therefore unexplained death in the absence of autopsy confirmation. The innovative and judicious use of thrombolytic agents by emergency department and paramedical ambulance personnel may lead to a decreased mortality for this disease. Clinical studies are necessary to determine if the cardiopulmonary compromise associated with massive pulmonary embolism can be rapidly reversed through thrombolysis and whether that reversal will lead to increased survival. The use of thrombolytic agents will gain favor only if their risk:benefit and cost:benefit ratios are acceptable. We discuss the results of using first- and second-generation thrombolytic agents in the treatment of pulmonary embolism and review the encouraging data that have emerged from our studies with recombinant tissue-type plasminogen activator (tPA). This agent has relative fibrin specificity and may provide therapeutic advantages over the conventional thrombolytic agents, urokinase and streptokinase, particularly when the latter are administered in the currently recommended dose schedules for treatment of pulmonary embolism.

The phenotypic and ultrastructural characterization of the blast cells from a T-cell acute lymphoblastic leukemia (T-ALL) that was associated with disseminated intravascular coagulation (DIC) is described. The bone marrow blasts were considered to represent neoplastic medullary thymocytes and were acid phosphatase (+), terminal deoxynucleotidyl transferase (-), acid alpha-naphthyl acetate esterase (-), E-rosette (+) at 4 degrees C and 37 degrees C, Fc- and C3-receptor (-), and cALLA-, Ia-, 9.6+, OKT3+, OKT4+, OKT6+/-, OKT8+, OKT10+. On transmission electron microscopic study, the predominant cell was 6 micron in diameter and possessed an irregular nucleus, moderate-sized nucleolus, marginated heterochromatin, abundant Golgi elements and granules, and prominent intermediate filaments. The cells were analyzed with normal and factor-deficient human plasmas and contained significant amounts of tissue factor-like procoagulant activity. This is the first report of a well-characterized medullary thymocyte T-ALL in which DIC was an accompanying feature, and the first demonstration of tissue factor-like procoagulant activity in acute lymphoblastic leukemia. In view of thrombohemorrhagic phenomena observed in association with other medullary thymocyte leukemias, these findings suggest that tissue factor-like procoagulant activity may be a characteristic of medullary thymocyte-derived lymphoid leukemias.

Two patients with surgically implanted right atrial silastic catheters for home hyperalimentation developed central vein septic thrombophlebitis. Initial treatment including removal of the catheter and antibiotic therapy was unsuccessful and both patients had persistent fever and bacteremia. A clinical and microbiologic response occurred when anticoagulation therapy with heparin was added to the treatment regimen. Although a surgical approach has been emphasized in patients with peripheral vein suppurative thrombophlebitis, anticoagulation therapy may be a useful alternative in the treatment of patients with central vein infection.

We evaluated a multicenter cohort of 1219 subjects with hemophilia or related disorders prospectively, focusing on 319 subjects with documented dates of seroconversion to human immunodeficiency virus type 1 (HIV-1). The incidence rate of the acquired immunodeficiency syndrome (AIDS) after seroconversion was 2.67 per 100 person-years and was directly related to age (from 0.83 in persons 1 to 11 years old up to 5.66 in persons 35 to 70 years old; Ptrend = 0.00003). The annual incidence of AIDS ranged from zero during the first year after seroconversion to 7 percent during the eighth year, with eight-year cumulative rates (+/- SE) of 13.3 +/- 5.3 percent for ages 1 to 17, 26.8 +/- 6.4 percent for ages 18 to 34, and 43.7 +/- 16.4 percent for ages 35 to 70. Serial immunologic and virologic markers (total numbers of CD4 lymphocytes, presence of serum interferon or HIV-1 p24 antigen, and low or absent serum levels of anti-p24 or anti-gp120) predicted a high risk for the subsequent development of AIDS. Adults 35 to 70 years old had a higher incidence of low CD4 counts than younger subjects (P less than or equal to 0.005), whereas adolescents had a low rate of anti-p24 loss (P = 0.0007) and subjects 1 to 17 years old had a lower incidence of AIDS after loss of anti-p24 (P = 0.03). These findings not only demonstrate that the risk of AIDS is related directly to age but also suggest that older adults are disproportionately affected during the earlier phases of HIV disease, that adolescents may have a low replication rate of HIV, and that children and adolescents may tolerate severe immunodeficiency better because they have fewer other infections or because of some unmeasured, age-dependent cofactor or immune alteration in the later phase of HIV disease.

One hundred random lymphocytes in each of 168 buffy coat preparations from 59 subjects at risk for AIDS (50 homosexuals, 7 hemophiliacs, and 2 combined, all with T4:T8 ratios of less than or equal to 1.2) were screened for the presence of ultrastructural markers, "tubuloreticular structures" (TRS), and "test tube and ring-shaped forms" (TRF). Twenty-six (44%) of the subjects were TRS positive (71 specimens) and 12 (20%) were TRS/TRF positive (34 specimens). TRF were only observed in TRS-positive specimens. There was an inverse relationship between the incidence and abundance of markers and the T4:T8 ratios, i.e., mean T4:T8 +/- SE for TRS-negative, TRS-positive, and TRS/TRF-positive subjects were 0.59 +/- 0.05, 0.42 +/- 0.05, and 0.19 +/- 0.06, respectively. Markers were present for as long as 16 months before AIDS was diagnosed in four subjects and before the appearance of features suggestive of AIDS in two others. The assessment of TEM markers in peripheral blood lymphocytes is a simple method for screening at-risk subjects in whom AIDS is likely to develop.

Studies of the prothrombin time in normals and patients receiving warfarin therapy revealed a marked shortening of the prothrombin time when the blood was collected in any type of collection tube other than a polypropylene tube. This shortening of the prothrombin time in patients receiving coumadin therapy was time and temperature dependent. This in-vitro shortening of the prothrombin time could lead to serious clinical errors involving dosage of warfarin derivatives to be administered to patients.

We assessed the efficacy and safety of peripheral intravenous recombinant human tissue-type plasminogen activator (rt-PA) in 47 patients with angiographically documented pulmonary embolism (PE). We administered 50 mg/2 h and, if necessary, an additional 40 mg/4 h. By 6 hours, 94% of the patients had angiographic evidence of clot lysis that was slight in 5, moderate in 12, and marked in 27 patients. Among the 34 patients with pulmonary hypertension prior to treatment, average pulmonary artery pressure decreased from 43/17 (27) to 31/13 (19) mm Hg (P less than 0.0001). The average lung scan perfusion defect decreased from 37% before therapy to 16% (P less than 0.01) after therapy among the 19 patients who had pre- and post-treatment lung scans. Of 7 patients with pre- and post-treatment imaging and Doppler echocardiograms, hypokinetic right ventricular wall movement (mild in 1, moderate in 2, and severe in 4) normalized in 5 and improved to mild hypokinesis in 2. Right ventricular diameter decreased from 3.9 +/- 1.0 to 2.0 +/- 0.5 cm (P less than 0.005). Fibrinogen decreased 33% from baseline at 2 h and 42% from baseline at 6 h. However, patients with the greatest degree of angiographic clot lysis at 2 h had a preponderance of fibrinogenolysis over fibrinolysis, demonstrated by a lower ratio of cross-linked fibrin degradation products to fibrin(ogen) degradation products (0.14 +/- 0.09 vs. 0.54 +/- 0.82) (P less than 0.04). Among selected patients, peripheral intravenous rt-PA is associated with rapid lysis of PE, improved pulmonary perfusion, and improved right ventricular function.

Fibrinogen synthesis in rabbits was evaluated following intravenous infusions of stage 3 degradation products of homologous fibrinogen or fibrin, prepared in vitro. Fibrinogen production was measured by determining the rate of appearance of 75SeM into circulating fibrinogen. Fibrinogen synthesis increased threefold after the administration of stage 3 FDP (D and E), dialyzed to remove LMW digestion fragments, In contrast, the fdp obtained by plasminolysis of crosslinked thrombin clots or of noncrosslinked ancrod or thrombin clots failed to enhance basal fibrinogen production. Accelerated fibrinogen production was not accompanied by alterations in haptoglobin concentration or by increased incorporation of 75SeM into haptoglobin. Fibrinogen synthesis was not increased after infusions of FPA and FPB.

A 60-year-old Black female presented with a haemorrhagic diathesis and an acquired factor VIII/von Willebrand factor (VIII/vWf) inhibitor. This inhibitor was classified as an IgA immunoglobulin and was active not only against factor VIII coagulant (VIII:C) activity but also against plasma von Willebrand factor (vWf). The purified IgA also interacted with normal platelets to inhibit ristocetin-induced platelet aggregation (RIPA). In contrast, studies with haemophilia A plasma and platelets revealed that the inhibitor did not react significantly with these plasmas or platelets. The significant differences in the inhibition of vWf assay both of the plasma and the platelets of the haemophilia A patients suggests that part of the haemorrhagic diathesis may be related not only to the inhibition of VIII:C but also to interference with platelet function. In addition, these studies suggest that there may be significant differences in the factor VIII-related antigen (VIII R:Ag) on platelets in haemophilia A patients compared to normal.

Treatment of hemophilia, although greatly improved in recent years, continues to be problematic owing to infectious complications of blood product replacement therapy. This report examines the therapeutic options presently available for the treatment of hemophilia, focusing on the potential for repeated viral exposure to influence the progression of infectious disease, decreased risks of viral transmission with blood products produced using newer viral inactivation procedures, higher economic costs of newer blood products, and the current inadequate supply of blood products in the United States.

Patients with protamine allergy present a difficult dilemma when reversal of heparin is required for excessive bleeding. Premedication with steroids and antihistamines has not been shown to effectively prevent anaphylactic reactions in patients with hypersensitivity to protamine. Other heparin antagonists are either not available or are too toxic for human use. This report describes a patient in whom methylene blue was used effectively to neutralize heparin and decrease bleeding due to heparinization. In vitro testing was then done to further define the interaction of heparin and methylene blue. This testing demonstrated that methylene blue neutralized heparin levels of 1 u/ml as well as 10 u/ml. Methylene blue acted as an anticoagulant when present at levels of 3000 micrograms/ml. However, it acted as a coagulant when present in intermediate levels of 800 micrograms/ml and 1600 micrograms/ml. The plasma levels necessary for neutralization of heparin levels of 1 unit/ml (the levels achieved in patient therapeutically anticoagulated) are easily achieved using doses routinely used in treatment of methemoglobinemia. Although the toxicity of methylene blue has been well defined at the lower doses of 2-4 mg/Kg, work still needs to be done to determine safety of the drug at the higher doses necessary to neutralize heparin levels achieved in bypass patients.

Although thrombolytic agents have been available for over 10 years and have demonstrated safety and efficacy in an increasing number of clinical conditions involving thrombotic phenomena, their general acceptance as first-line therapeutic agents in medical management has been slow. Much of the reluctance to use these drugs is based on their associated incidence of hemorrhagic complications, which is several-fold greater than with use of conventional anticoagulants. With the introduction of second-generation thrombolytic agents, made possible through successes in recombinant DNA technology and chemical modifications of previously available compounds, increased fibrin specificity has been achieved and has been translated into increased clinical efficacy and safety. These results will likely improve as innovative regimens using dose modifications or multiple agents with combined synergy are developed. An appreciation of basic coagulation and the pharmacology of anticoagulants and thrombolytic agents is necessary to maximize the benefits of currently available medications, to develop new treatment strategies, and to minimize potential hemorrhagic complications.

SU-23397 is a unique new hybrid molecule, the animal profile being characteristic of neuroleptic activity. Although the trial was uncontrolled, there appears to be no doubt that SU-23397 exerts antipsychotic activity between 20 mg and 250 mg daily in severely ill schizophrenic patients. Seven of the ten subjects required at least transient antiparkinson medication. Two patients demonstrated premature ventricular contractions. One patient had infrequent PVCs at baseline which increased in frequency with rising dosage. The other patient developed frequent premature ventricular contractions only after active and medication was initiated and was subsequently withdrawn from the study.

Abnormal coagulation profiles were identified in ten patients with the acquired immunodeficiency syndrome (AIDS) associated with opportunistic infections and malignancies. Activated partial thromboplastin times were elevated in all patients; three of seven had elevated prothrombin times. All patients had lupus-type anticoagulants characterized by rapid prolongations of the partial thromboplastin time in mixing studies, prolonged dilute thromboplastin inhibition assays, and increased Russell viper venom clotting times. Ivy bleeding times were prolonged in three patients with defective platelet aggregation. The lupus anticoagulant was isolated from the sera of healthy heterosexual men and from patients with AIDS with and without the lupus anticoagulant, and in the presence and absence of opportunistic infections. Both polyclonal IgM and IgG lambda from plasma with lupus anticoagulant interfered with clotting studies and platelet aggregation. The inhibitors usually accompanied active opportunistic infections and tended to disappear with successful resolution of infection.

Forty-two male homosexuals and/or hemophiliacs with depressed helper/suppressor T-cell ratios were treated with one of three different doses of thymosin fraction 5 (TF5, 30, 60, and 120 mg), or a single dose of thymosin Alpha One (TA1, 600 micrograms), by daily subcutaneous (SQ) administration for 10 weeks, followed twice weekly for 4 weeks. No major toxicity was noted for any of the preparations tested, although three subjects treated with TF5 had to discontinue therapy because of severe local skin reactions. Of the doses and preparations tested, only 60 mg TF5 was capable of significantly improving (p less than 0.02) mean T-cell lymphoproliferative responses to alloantigens (MLR) for six HTLV-III seropositive subjects who were abnormal prior to therapy. Peripheral blood lymphocytes from subjects treated with 60 mg TF5 also exhibited a transient restoration of mean mitogen-induced interleukin-2 (IL-2) production to normal. No effects were observed with any of the four treatment regimens on absolute helper T-cell numbers, NK activity, antibody titers to HTLV-III, or in the expression of a variety of surrogate markers for acquired immunodeficiency syndrome (AIDS). Four of the six seropositive subjects treated with 60 mg TF5 exhibited a return to depressed baseline MLR, after switching to twice weekly injections. With a median follow-up time of 20 months, six cases of AIDS developed. However, none of the five subjects whose MLR improved following treatment progressed to AIDS. We recommend daily subcutaneous (SQ) administration of 60 mg (40 mg/m2) TF5 for use in combined modality trials, along with drugs capable of suppressing replication of HTLV-III.

The effect of intravenous recombinant human tissue-type plasminogen activator (rt-PA) was compared with that of urokinase in 45 patients with angiographically documented pulmonary embolism (PE) in a randomised controlled trial. The two principal end-points were clot lysis at 2 h, as assessed by angiography, and pulmonary reperfusion at 24 h, as assessed by perfusion lung scanning. All patients received the full dose of rt-PA but urokinase infusions were terminated prematurely (on average after 18 h) in 9 patients because of allergy in 1 and uncontrollable bleeding in 8. By 2 h, 82% of rt-PA-treated patients showed clot lysis, compared with 48% of urokinase-treated patients (p = 0.008; 95% CI for the difference = 10-58%). Improvement in lung scan reperfusion at 24 h was identical in the two treatment groups. The reduction in fibrinogen did not differ significantly between the rt-PA and urokinase groups (45% vs 39% at 2 h and 34% vs 40% at 24 h). The results indicate that in the dose regimens employed, rt-PA acts more rapidly and is safer than urokinase in the treatment of acute PE.