PubMed Health⌕ Search

Biomedical subjects

C M Kessler

Publications and source records attributed to C M Kessler.

At least 19 recordsLinked to original sources
PubMed2006

D-dimer, factor VIII coagulant activity, low-intensity warfarin and the risk of recurrent venous thromboembolism.

BACKGROUND: Elevated plasma D-dimer and factor VIII coagulant activity (FVIIIc) may be associated with the risk of recurrent venous thromboembolism (VTE). OBJECTIVES: To evaluate D-dimer and FVIIIc as risk factors for recurrent VTE and assess the efficacy of extended low-intensity warfarin (target International Normalized Ratio 1.5-2.0) in preventing recurrence by biomarker level. PATIENTS AND METHODS: In the Prevention of Recurrent Venous Thromboembolism trial, 508 idiopathic VTE patients treated for > or = 3 months with full-intensity warfarin, and who had stopped warfarin for 7 weeks on average, were randomized to low-intensity warfarin or placebo and followed for 2.1 years for recurrent VTE. Prerandomization blood samples were analysed for D-dimer and FVIIIc. RESULTS: One-third of participants had elevated baseline D-dimer (> or = 500 ng mL(-1)) and one-fourth, elevated FVIIIc (> or = 150 IU dL(-1)). Adjusting for other risk factors, the hazard ratios (HRs) for recurrent VTE with elevated D-dimer or FVIIIc were 2.0 [95% confidence interval (CI) 1.2-3.4] and 1.5 (95% CI 0.8-2.8), respectively. The association of elevated D-dimer with recurrence was larger among patients with one prior VTE (HR 3.2, 95% CI 1.3-8.0) than in patients with more than one event (HR 1.4, 95% CI 0.7-2.2). For patients with one prior VTE on placebo, the annual recurrence incidence was 10.9% with elevated D-dimer and 2.9% with normal values. Low-intensity warfarin was equally effective in recurrence risk reduction in those with normal or elevated biomarkers. CONCLUSIONS: Among patients with idiopathic VTE, measurement of D-dimer, but not FVIIIc, might be useful for risk stratification. The efficacy of extended low-intensity warfarin therapy did not vary by biomarker level.

Adult↗
PubMed2005

B-domain deleted recombinant factor VIII preparations are bioequivalent to a monoclonal antibody purified plasma-derived factor VIII concentrate: a randomized, three-way crossover study.

BACKGROUND: Deletion of the B-domain of recombinant blood coagulation factor VIII (BDDrFVIII) increases the manufacturing yield of the product but does not impair in vitro or in vivo functionality. BDDrFVIII (ReFacto) has been developed with the additional benefit of being formulated without human albumin. OBJECTIVE: The primary objective of this three-way crossover-design study was to compare the pharmacokinetic (PK) parameters of two BDDrFVIII formulations (one reconstituted with 5 mL of sterile water, the other reconstituted with 4 mL sodium chloride 0.9% USP) with those of a plasma-derived, full-length FVIII preparation (Hemofil M) in patients with haemophilia A to determine bioequivalence. METHODS: A series of blood samples were collected over a period of 48 h after i.v. administration of each of the FVIII preparations. Plasma FVIII activity was determined using a validated chromogenic substrate assay. Plasma FVIII activity vs. time curves was characterized for a standard set of PK parameter estimates. Two parameter estimates, the maximum plasma concentration (Cmax) and the area under plasma concentration vs. time curves (AUCs), were used to evaluate bioequivalence. The two preparations were considered bioequivalent if the 90% confidence intervals for the ratio of geometric means for Cmax and AUCs fell within the bioequivalence window of 80% to 125%. RESULTS/CONCLUSION: Results show that each BDDrFVIII formulation is bioequivalent to Hemofil M and the two formulations of BDDrFVIII are bioequivalent to each other.

Adolescent↗
PubMed2005

Dose effect and efficacy of rFVIIa in the treatment of haemophilia patients with inhibitors: analysis from the Hemophilia and Thrombosis Research Society Registry.

Recombinant activated factor VII (rFVIIa), licensed in 1999 for treatment of haemophilia patients with inhibitors (HI), represents an important advance in the therapeutic armamentarium. Standard bolus dosing ranges from 90 to 120 mcg kg(-1) every 2-3 h until arrest of bleeding. As licensure, clinical use of rFVIIa has increased and broadened. Clinicians now use a wide dose range, 90-300 mcg kg(-1). High-dose regimens may optimize thrombin generation or burst, and may allow for prolonged dose interval. The Hemophilia and Thrombosis Research Society (HTRS) maintains a registry database to study haemophilia treatment and related disorders, particularly treatment of acute bleeding in HI, acquired haemophilia, FVII deficiency and von Willebrand's disease (VWD). To assess the effect of rFVIIa dose on efficacy and safety in the treatment of acute bleeding in HI, data from the HTRS database from January 2000 through June 2002 were analysed. Bleeding episodes were grouped by bolus rFVIIa dose range: <100, 100-150, 150-200 and >200 mcg kg(-1). Investigator-reported efficacy for the first 72 h of treatment was evaluated. Thirty-eight congenital HI patients were treated for 555 bleeding episodes. Patient age range was 1-55 years (median: 14). Bleeding episodes were spontaneous (45%), caused by trauma (38%), or because of surgery, dental, diagnostic, or medical procedures (17%); bleeding occurred in joint, muscle, and intra/extracranial sites. Treatment location included: 80% at home, 12% at other facilities (treatment centres, ER, inpatient and OR), and 8% at both home/other facilities. Median total dose given over 72 h was 360 mcg kg(-1) (range: 40-4281, mean: 537). Bleeding stopped in 87% of the episodes. Bleeding cessation rate was 84% for the three lower dose groups, and 97% for the highest dose group (P < 0.001). Five patients experienced nine adverse events (AEs). AE rates were <1% for <100, 5% for 100-150, 0% for 150-200, <1% for >200 mcg kg(-1) dose group. Decreased therapeutic response accounted for eight of the nine AEs. These data, which represent the most comprehensive report of rFVIIa use since the USA licensure, demonstrate that bleeding episodes in HI patients can be treated safely and effectively at home and that doses up to 346 mcg kg(-1) appear to be well-tolerated. Additionally, rFVIIa doses >200 mcg kg(-1) appear to significantly increase efficacy (97% in the high-dose group, compared with 84% in the lower dose groups). Optimal dosing remains to be determined; specifically, what the lowest effective dose is and whether a single high-dose bolus eliminates the need for repeated dosing. Recombinant FVIIa appears to have a wide safety margin that may allow dose escalation to address these questions.

Adolescent↗
PubMed2004

Liver biopsy in patients with inherited disorders of coagulation and chronic hepatitis C.

Liver biopsy plays a pivotal role in the management of patients with a variety of liver diseases, including chronic hepatitis C virus. The major risk of the procedure is the potential for significant haemorrhagic complications. Although the data are limited, the procedure does not appear to pose excessive risk to the patient with inherited disorders of coagulation, provided that adequate haemostasis can be achieved prior to the liver biopsy. This requires close coordination of care between the hepatologist and the haematologist. Indications for liver biopsy should be the same in patients with haemophilia as in other populations.

Biopsy↗
PubMed2003

The safety and efficacy of B-domain deleted recombinant factor VIII concentrate in patients with severe haemophilia A.

BACKGROUND: B-domain-deleted recombinant factor VIII (BDDrFVIII) was developed when the B-domain was found to be redundant for maintaining haemostasis. This allows formulation of the final product without albumin added as a stabilizer. METHODS: Three multicentre clinical studies and one pharmacokinetic study were conducted in 218 patients to evaluate the safety and haemostatic efficacy of BDDrFVIII. RESULTS: Previously treated patients (n = 113; median duration, 1711 days; median exposure days, 385; total 98,096,287 IU infused) rated 97-99% of all infusions as good or excellent efficacy. FVIII inhibitor was noted in one patient in the previously treated patient cohort after 113 exposure days. Among 101 previously untreated patients, responses to BDDrFVIII were rated as excellent or good in 92-95% of infusions (median duration, 1413 days; median exposure days, 148; total 12,636,458 IU infused). Thirty-two previously untreated patients developed inhibitors after a median duration of 12 exposure days (range, 3-49). Sixteen of 32 (50%) patients had low levels (< or = 5 Bethesda units) and 16 had high levels of inhibitors. Inhibitors disappeared in six of 14 (43%) of the high-level and six of eight (75%) of the low-level patients who underwent immune tolerance induction therapy. A total of 42 patients underwent surgery and the overall efficacy of BDDrFVIII was rated as excellent or good for 99.6% of infusions. CONCLUSIONS: The results of these clinical studies indicate that BBDrFVIII is safe and effective and has haemostatic activity similar to that of full-length FVIII concentrates.

Adolescent↗
PubMed2002

Viral pharmacovigilance study of haemophiliacs receiving porcine factor VIII.

Porcine factor VIII (FVIII; Hyate:C; Speywood Biopharm Ltd, UK) has been used since 1980 for the treatment both of patients with acquired haemophilia and those with congenital haemophilia and inhibitory antibodies. Each batch is extensively screened using cell-culture techniques to confirm the absence of viruses. The production process does not incorporate specific virucidal treatment steps, such as heat treatment or the addition of a solvent/detergent mixture. Low levels of porcine parvovirus were detected in some batches of the product in late 1996 and supply was suspended. In this retrospective study, sera from 81 recipients of porcine FVIII and 125 other volunteers were screened for evidence of antibodies against a range of porcine viruses: porcine parvovirus (PPV), encephalomyocarditis virus (EMCV), and porcine respiratory and reproductive syndrome virus (PRRSV). The 125 volunteer controls included subjects from six categories: healthy control subjects, pig abattoir personnel, personnel involved in the manufacture of porcine FVIII, recipients of porcine heparin, recipients of porcine insulin, and haemophiliacs treated only with human FVIII. No antibodies to PPV or PRRSV were detected in any subject. Four patients and two volunteers were found to have antibodies to EMCV, but this incidence is similar to that observed in the general population. In conclusion, there was no evidence of transmission of PPR or other marker porcine virus associated with the use of porcine FVIII concentrate (Hyate: C).

Animals↗
PubMed2001

Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates.

Human plasma-derived factor IX (pdFIX) concentrates are routinely used to treat patients with hemophilia B, an X-linked bleeding disorder that affects 1 in 30 000 males, but concerns remain regarding transmission of blood-borne pathogens. Therefore, the safety and efficacy of recombinant human factor IX (rFIX) were evaluated. A 20-center international trial was conducted in previously treated patients with severe or moderate (< 5 IU/dL factor IX activity) hemophilia B. Participants received rFIX for pharmacokinetic studies, treatment of or prophylaxis against hemorrhage, or surgical hemostasis, and were assessed at 3-month intervals for 2 years. Fifty-six subjects were treated. Mean incremental rFIX recovery was 0.75 IU/dL per IU/kg, 30% lower than expected for pdFIX, although the mean half-life was similar. Pharmacokinetic parameters were stable over time. Somewhat lower recoveries were seen in subjects younger than 15 years of age and in those with no detectable factor IX antigen. A total of 7362 infusions of rFIX were administered. All 1796 hemorrhages were controlled, 80.9% of which required only one rFIX infusion. Effective hemostasis was also achieved in prophylactic and surgical settings. One individual developed a low titer (1.2 Bethesda unit) transient inhibitor that spontaneously resolved. rFIX was not associated with serious adverse events, thrombogenicity, or virus transmission. rFIX is safe and effective for the treatment of hemophilia B. Despite a lower recovery compared with pdFIX, rFIX controlled hemorrhage in a wide variety of settings and may provide a safety advantage in terms of risk from blood-borne pathogens.

Adolescent↗
PubMed2001

Management of von Willebrand disease: a survey on current clinical practice from the haemophilia centres of North America.

The optimal treatment of patients with von Willebrand's disease (vWD) remains to be defined. Moreover, it has not been firmly established which, if any, commonly measured parameters of von Willebrand factor (vWF) protein in the plasma are useful in guiding treatment. To better understand what guidelines physicians follow in the management of vWD, we surveyed 194 North American physicians who are members of the Hemophilia Research Society. Ninety-nine per cent of responding physicians depend on factor VIII (FVIII):C, vWF:RCo activity and vWF:AG to diagnose vWD, while only 49% use the bleeding time. The minimal goals of treatment for patients undergoing major surgery/trauma or central nervous system haemorrhage were FVIII:C and vWF:RCo activity greater than 80% while levels of more than 50% for minor surgery and dental extractions were considered adequate. Treatment of vWD was based on the type of vWD with type 1 patients being treated most often with desmopressin acetate (DDAVP) alone, types 2A and 2B patients with a combination of DDAVP and a vWF-containing FVIII product, type 3 patients with vWF-containing concentrate. Viral infections, including human immunodeficiency virus, hepatitis A, B and C viruses, and parvovirus have been seen in vWD and the efficacy of viral attenuation processes is a major criterion for the selection of treatment by physicians. Based on this survey, prospective studies need to be designed to address the clinical efficacy, safety and predictive value of laboratory monitoring of patients with vWD.

Ambulatory Care Facilities↗
PubMed2001

D-dimer testing: the role of the clinical laboratory in the diagnosis of pulmonary embolism.

Pulmonary embolism is a common, yet often unsuspected and unrecognised disease associated with a high mortality. New, objective, "user friendly" and cost effective diagnostic strategies are being explored. D-dimers, the fibrinolytic degradation products of crosslinked fibrin, have emerged as the most useful of the procoagulant activity and ongoing fibrinolysis markers. D-dimer measurements are very sensitive in excluding a diagnosis of pulmonary embolism in the setting of normal values, a low clinical suspicion, and non-diagnostic lung scans. Several assays have been developed and are reviewed.

Biomarkers↗
PubMed2000

New products for managing inhibitors to coagulation factors: a focus on recombinant factor VIIa concentrate.

The treatment of alloantibody and autoantibody inhibitors directed against the factor VIII coagulant protein is one of the most challenging and expensive problems in hematology. Because the currently available plasma replacement products used in this context do not control the bleeding complications in all patients, and because of the usual emergent quality of the bleeding complications, there has been a definite need to have a uniformly reliable product for instant use, which possesses a high degree of hemostatic reliability and safety. The recent introduction of recombinant factor VIIa (rFVIIa) has been a welcome addition to the pharmacologic armamentarium for the treatment of neutralizing antibodies against coagulation factors. The mechanisms of action of rFVIIa have also been interesting and have provided insight into how the coagulation pathway accomplishes adequate hemostasis. This review will discuss this new medication and place into the context of coagulation inhibitor therapy.

Antibodies↗
PubMed1999

Phenotypic expressions of CCR5-delta32/delta32 homozygosity.

OBJECTIVE: As blockade of CC-chemokine receptor 5 (CCR5) has been proposed as therapy for HIV-1, we examined whether the CCR5-delta32/delta32 homozygous genotype has phenotypic expressions other than those related to HIV-1. DESIGN: Study subjects were white homosexual men or men with hemophilia who were not infected with HIV-1. In this study, 15 CCR5-delta32/delta32 homozygotes were compared with 201 CCR5 wild-type (+/+) subjects for a wide range of clinical conditions and laboratory assay results ascertained during prospective cohort studies and routine clinical care. CCR5-delta32 genotype was determined by polymerase chain reaction, followed by single-stranded conformational polymorphism analysis. RESULTS: Hypertension and conditions attributable to hemophilia were the only diagnoses frequently found in clinical records of CCR5-delta32/delta32 study subjects. Based on blood pressure measurement and treatment history, CCR5-delta32/delta32 homozygotes had a 2.8-fold higher prevalence of hypertension than age-matched CCR5-+/+ study subjects (95% confidence interval [CI], 1.2-6.4; p = .01); none of the homozygotes had severe hypertension. Hematologic measures were generally similar across the genotypes, but total lymphocyte counts were approximately 20% higher in CCR5-delta32/delta32 study subjects than in CCR5-+/+ study subjects (p < .05). Among patients with hemophilia who were infected with hepatitis C virus (HCV), mean alanine aminotransferase levels were 117% higher among CCR5-delta32/delta32 homozygotes (p < .05), but serum HCV levels did not differ by CCR5-delta32 genotype. CCR5-delta32/delta32 homozygous study subjects had a lower prevalence of antibodies to measles virus than those with other genotypes, but this association was not confirmed in a group of blood donors. The prevalence of antibodies to nine other common viruses, HBV, and HCV was not related to CCR5 genotype. CONCLUSIONS: CCR5-delta32/delta32 homozygotes are generally similar to wild-type persons. Confirmatory investigations are required to determine whether hypertension, increased lymphocyte counts, and higher hepatic enzyme levels in the presence of HCV infection represent true phenotypic expressions of this genotype. CCR5-delta32/delta32 homozygosity does not provide broad protection against viral infections.

Adult↗
PubMed1999

Hemostatic responses to maximal exercise in oral contraceptive users.

OBJECTIVE: This study examined the effect of exercise on markers of fibrinolysis and coagulation in users and nonusers of oral contraceptives. STUDY DESIGN: Fourteen oral contraceptive users and 14 nonusers performed a maximal exercise test on a cycle ergometer. Blood samples were collected before and immediately after the completion of the test. A repeated-measures analysis of variance was used for statistical analysis with values considered significant at P =.05. RESULTS: Acute maximal exercise resulted in significant increases in tissue plasminogen activator activity in both groups. There was a trend toward a smaller increase in tissue plasminogen activator activity in oral contraceptive users, but the difference between groups was not statistically significant. Plasminogen activator inhibitor 1 activity was reduced with exercise in both groups but with a significantly greater decrease observed in the nonusers (P <.0001). Prothrombin fragment 1+2 was significantly higher (P <.0001) in the oral contraceptive group but did not change with exercise. Epinephrine levels before and after exercise were similar between the 2 groups, but postexercise norepinephrine concentrations were significantly lower (P =.026) in the oral contraceptive users. CONCLUSION: These data suggest that oral contraceptive use blunts the fibrinolytic response to exercise. This, together with increased coagulation activation in oral contraceptive users, may alter the hemostatic balance during exercise.

Adult↗
PubMed1999

Oral contraceptives and smoking, current considerations: recommendations of a consensus panel.

In a closed meeting, members of the consensus panel evaluated the presentations of the scientific panel and developed a series of recommendations. They outlined clinical imperatives related to the identification and education of patients who smoke, the physician's role in smoking cessation, and the prescription of oral contraceptives for patients who smoke. They also outlined research objectives for the future. The most important suggestions include the following: All patients should be asked about their smoking status at every visit, and all smokers should be encouraged and helped to quit. The decision to prescribe an oral contraceptive requires a detailed personal and family history of thrombotic disease. Measurement of lipid profile should be considered, along with exercise and dietary intervention, for smokers >35 years old who use or request oral contraceptives. Patients >35 years old who smoke heavily (>15 cigarettes/d) should be denied the use of oral contraceptives. Preliminary data suggest that an oral contraceptive with the very low dose of 20 micrograms ethinyl estradiol may be safer for oral contraceptive users who smoke, even for those >35 years old who have an occasional cigarette, but these laboratory findings require clinical corroboration.

Cardiovascular Diseases↗
PubMed1999

Essential role of LAT in T cell development.

The linker molecule LAT is a substrate of the tyrosine kinases activated following TCR engagement. Phosphorylated LAT binds many critical signaling molecules. The central role of this molecule in TCR-mediated signaling has been demonstrated by experiments in a LAT-deficient cell line. To probe the role of LAT in T cell development, the LAT gene was disrupted by targeting. LAT-deficient mice appeared healthy. Flow cytometric analysis revealed normal B cell populations but the absence of any mature peripheral T cells. Intrathymic development was blocked within the CD4- CD8- stage. No gross abnormality of NK or platelet function was observed. LAT is thus critical to both T cell activation and development.

Adaptor Proteins, Signal Transducing↗