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Biomedical subjects

C M Kessler

Publications and source records attributed to C M Kessler.

At least 73 records · Page 4Linked to original sources
PubMed1992

Coagulation factor IX: successful surgical experience with a purified factor IX concentrate.

The use of plasma-derived coagulation factor concentrates has been marked by the transmission of viral agents. Infusions of factor IX complex concentrates have been additionally complicated by inappropriate thrombosis. Use of these concentrates in the neonate, in those with liver disease, and in surgical patients results in increased risk for this complication. Twenty patients have been infused with a purified coagulation factor IX concentrate for fall-off and recovery studies. A two-compartment model indicated an initial phase half-life of 4.06 +/- 2.86 hr and a beta phase half-life of 20.0 +/- 3.8 hr following the administration of AlphaNine, Coagulation Factor IX (Human). In vivo recovery was 62.7% +/- 13.8%, with an average factor IX coagulant level of 73% +/- 16% at 15 min after the infusion of a mean dose of 45 U/kg. Thirteen previously transfused patients with hemophilia B underwent major orthopedic or general or dental surgery using this purified factor IX. Operative outcomes were excellent in all patients. No excessive bleeding was noted. There was no laboratory or clinical evidence for a disseminated intravascular coagulopathy. The excellent surgical outcomes observed in this multitransfused group with biochemical evidence for active liver disease demonstrates the utility and safety of a purified coagulation factor IX concentrate.

Adult↗
PubMed1992

Recombinant tissue-type plasminogen activator versus a novel dosing regimen of urokinase in acute pulmonary embolism: a randomized controlled multicenter trial.

Thrombolysis of acute pulmonary embolism can be accomplished more rapidly and safely with 100 mg of recombinant human tissue-type plasminogen activator (rt-PA) (Activase) than with a conventional dose of urokinase (Abbokinase) given as a 4,400-U/kg bolus dose, followed by 4,400 U/kg per h for 24 h. To determine the effects of a more concentrated urokinase dose administered over a shorter time course, this trial enrolled 90 patients with baseline perfusion lung scans and angiographically documented pulmonary embolism. They were randomized to receive either 100 mg/2 h of rt-PA or a novel dosing regimen of urokinase: 3 million U/2 h with the initial 1 million U given as a bolus injection over 10 min. Both drugs were delivered through a peripheral vein. To assess efficacy after initiation of therapy, repeat pulmonary angiograms at 2 h were performed in 87 patients and then graded in a blinded manner by a panel of six investigators. Of the 42 patients allocated to rt-PA therapy, 79% showed angiographic improvement at 2 h, compared with 67% of the 45 patients randomized to urokinase therapy (95% confidence interval for the difference in these proportions [rt-PA minus urokinase] is -6.6% to 30.4%; p = 0.11). The mean change in perfusion lung scans between baseline and 24 h was similar for both treatments. Three patients (two treated with rt-PA and one with urokinase) had an intracranial hemorrhage, which was fatal in one. The results indicate that a 2-h regimen of rt-PA and a new dosing regimen of urokinase exhibit similar efficacy and safety for treatment of acute pulmonary embolism.

Acute Disease↗
PubMed1992

Intracerebral platelet accumulation as evidence for embolization of carotid origin.

Arterio-arterial embolism of carotid origin is one major cause of cerebral ischemia. To evaluate the role of blood platelets in this process, In-111 labeled platelet scintigraphy was performed in a series of 250 patients. Of this number, one patient with an 80% carotid stenosis and a normal intracerebral angiogram suffered a transient ischemic attack (TIA) several hours after the injection of radiolabeled platelets. The scintigram showed a pathologic platelet accumulation in the symptomatic carotid area as well as in the ipsilateral brain hemisphere. The authors conclude that this scintigraphic finding of hemispheric platelet aggregates recorded directly after a clinically observed TIA, together with previous observations of retinal emboli after amaurosis fugax attacks, provides strong evidence for the arterio-arterial embolic mechanism of TIA.

Blood Platelets↗
PubMed1992

Platelet-dependent thrombin generation after in vitro fibrinolytic treatment.

BACKGROUND: Fibrinolytic therapy is associated with frequent rethrombosis. There is evidence of both increased coagulation and platelet activation. METHODS AND RESULTS: Platelet-rich plasma (PRP) or washed platelets were incubated with the fibrinolytic agents urokinase, recombinant tissue-type plasminogen activator (rt-PA), or plasmin at concentrations consistent with those in the plasma of patients treated for myocardial infarction. All of the fibrinolytic agents induced a more rapid generation of thrombin and decreased the clotting times of non-contact-activated PRP than in untreated PRP. This effect was not blocked by the inclusion of thrombin inhibitors during the fibrinolytic treatment. Washed platelets derived from rt-PA-treated PRP induced more rapid thrombin generation when resuspended in untreated plasma or treated plasma. Washed platelets were treated with plasmin, rt-PA, and urokinase and added to platelet-poor plasma. Platelets treated with either plasmin or rt-PA increased the ability of washed platelets to support thrombin generation, but urokinase was without significant effect. CONCLUSIONS: These results indicate not only that plasmin can cause increased platelet support of prothrombin activation but also that rt-PA in the absence of plasminogen can have a direct effect on the platelet, which increases thrombin generation.

Blood Platelets↗
PubMed1992

von Willebrand factor interacts with malignant hematopoietic cell lines: evidence for the presence of specific binding sites and modification of von Willebrand factor structure and function.

von Willebrand factor (vWf) mediates the adherence of platelets to exposed vascular subendothelium. During hematogenous metastasis in certain model systems, platelets are also deposited at endothelial surfaces in heterotypic aggregates with tumor cells. The role of vWf in this metastatic event was investigated by examining the interaction between purified iodine 125-labeled vWf and the human tumor cell lines, U937 and CA46. vWf-tumor cell binding was specific, partially reversible, and saturable at 4 degrees C. At 37 degrees C, however, U937 cell binding sites could not be saturated, suggesting endocytosis as a possible mechanism of interaction. When constant amounts of vWf were added, interactions with tumor cells were complete after 60 minutes, but rapidly dissociated over the next 2 hours. With the addition of specific proteinase inhibitors, vWf remained in stable association with tumor cells throughout a 3-hour time course. Loss of vWf antigen in supernatant samples complemented the 125I-labeled vWf bound directly to tumor cells. However, disproportionately large reductions in vWf functional activity were observed and correlated with alterations in multimeric structure. These data suggest an initial binding of vWf to some tumor cells, followed by a time-dependent loss of structural and functional integrity. VWf may contribute to tumor cell arrest within the microvasculature and may influence other tumor cell-subendothelial interactions as the adhesive function of vWf is subsequently modified.

Amino Acid Sequence↗
PubMed1992

Comparison of dosage schedules of rt-PA in the treatment of proximal deep vein thrombosis.

This study assessed the efficacy and safety of increasing durations of constant-dose intravenous recombinant tissue-type plasminogen activator (rt-PA) in the treatment of deep vein thrombosis. Patients with venogram-documented proximal lower limb (popliteal, iliofemoral) or upper limb (axillary, subclavian) thrombi were given an initial 2-hour rt-PA infusion at 4 micrograms/kg/min, followed by a maintenance infusion of 1 microgram/kg/min for an additional 4, 22, or 33 hours (mean total rt-PA dosages of 54, 127, and 185 mg). A new quantitative venogram scoring system was applied to the study, based on measurements of thrombus volume before and after completion of treatment. Whereas none of the seven patients given treatment for 6 hours and only one of four given treatment for 24 hours showed significant lysis, four of seven who received a prolonged infusion for 35 hours showed lysis of more than 40% of the original thrombus. Overall, the prolonged 35-hour infusion induced 51% lysis of original thrombus, representing a thrombus volume of 16.7 ml dissolved. Hemorrhagic complications were common in all three groups, with four of 18 patients having significant bleeding, including one massive gastrointestinal hemorrhage, two patients with a decrease in hematocrit of more than 10%, and one patient with an intracranial hemorrhage who recovered completely. Pharmacokinetics of the rt-PA showed a steady state antigen concentration of 240 ng/ml and activity of 200 IU/ml during the initial 2-hour infusion and a postinfusion half-life of 5 minutes. Plasma fibrinogen concentrations decreased to approximately 40% to 50% of initial values with all three treatment regimens, but the nadir fibrinogen concentrations did not correlate with either therapeutic efficacy or bleeding complications. One patient with systemic lupus erythematosus had an unusual allergic reaction that manifested primarily as angioedema. This study suggests that rt-PA infusion of 35 hours induces greater thrombolysis of deep vein thrombosis than does a shorter course of 6 or 24 hours, without an increase in hemorrhagic complications.

Adult↗
PubMed1991

An introduction to factor VIII inhibitors: the detection and quantitation.

Spontaneous development of autoantibodies against factor VIII:C (FVIII:C) protein in a nonhemophiliac is a rare but significant clinical occurrence that frequently is associated with life-threatening hemorrhagic complications. These autoantibodies often arise as an epiphenomenon of various disease states that are autoimmune or manifest a component of immune dysfunction. The present symposium reviews the immunochemistry of FVIII:C auto-antibodies and describes ways in which this knowledge has been applied to gain insight into the structure-function relationship of the FVIII:C protein. Also discussed are the etiology and natural history of acquired FVIII:C inhibition as well as evolving approaches to its treatment. Therapeutic options for this condition continue to expand, and choice of the optimal regimen for each patient is based on many considerations, including the level of the inhibitor, the underlying disease state, clinical responses to previous treatment, and degree of antibody interaction with heterologous purified FVIII:C protein. Acquired FVIII:C autoantibodies isolated from nonhemophiliacs are characterized as heterogeneous, noncomplement-fixing, nonprecipitating immunoglobulins directed against functional epitopes (antigenic sites) of FVIII:C in a time- and temperature-dependent manner. The clinical significance of these inhibitors is determined qualitatively by studying in vivo survival of FVIII:C activity with infused replacement materials or quantitatively by laboratory mixing tests that measure the capacity of the inhibitor to neutralize FVIII:C activity. In the United States inhibitor potency is expressed most commonly in Bethesda Units (BU), where 1.0 BU is the reciprocal dilution of patient test plasma, permitting detection of 50% residual FVIII:C activity in a mixture with normal pooled plasma. In Europe, FVIII inhibitors are now often quantitated in New Oxford Units, which are derived from neutralizing-mixing studies of patient test plasma with diluted FVIII concentrate. One Oxford unit is equivalent to approximately 0.83 BU. Although analyses that measure functional inhibition of FVIII:C activity by the autoantibody provide a useful tool to assess clinical efficacy of therapeutic regimens, these assays may not recognize nonactivating antibodies. These immunoglobulins may bind to alternative epitopes and significantly influence plasma clearance, survival times, and circulating levels of infused FVIII:C protein. Finally, this symposium will speculate on the potential application of innovative approaches to inhibitor therapy, based on results from numerous provocative studies on the nature of the human immune response.

Autoantibodies↗
PubMed1991

Skin necrosis following prolonged administration of coumarin in a patient with inherited protein S deficiency.

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.

Adult↗
PubMed1991

Disseminated intravascular coagulation associated with Staphylococcus aureus septicemia is mediated by peptidoglycan-induced platelet aggregation.

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.

Animals↗
PubMed1991

The pharmacology of aspirin, heparin, coumarin, and thrombolytic agents. Implications for therapeutic use in cardiopulmonary disease.

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.

Aspirin↗
PubMed1990

Critical role of the carbohydrate moiety in human von Willebrand factor protein for interactions with type I collagen.

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.

Blood Platelets↗
PubMed1990

Modern treatment of pulmonary embolism.

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.

Fibrinolytic Agents↗
PubMed1990

Quantitation of venous clot lysis with the D-dimer immunoassay during fibrinolytic therapy requires correction for soluble fibrin degradation.

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)

Adult↗
PubMed1989

A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia.

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.

Acquired Immunodeficiency Syndrome↗
PubMed1989

The use of purified clotting factor concentrates in hemophilia. Influence of viral safety, cost, and supply on therapy.

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.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Methylene blue for neutralization of heparin.

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.

Adult↗
PubMed1989

Anticoagulation and thrombolytic therapy. Practical considerations.

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.

Anticoagulants↗