Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 99
Filter
1.
Haemophilia ; 17(5): e949-57, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21362113

ABSTRACT

Recombinant FVIIa is a haemostatic agent administered to patients with severe FVIII or FIX deficiency with inhibitors. Although rFVIIa is effective at stopping bleeding, a reliable assay to monitor its effect is lacking. To characterize the pharmacokinetics and global coagulation effects of rFVIIa for 6 h following a IV dose of 90 µg kg⁻¹. Ten non-bleeding subjects with severe FVIII or FIX deficiency were infused with a single-dose of rFVIIa 90 µg k⁻¹ body weight and blood was collected before and at 0.5, 1, 2, 4 and 6 h postdose. Global haemostasis was characterized throughout the study utilizing whole blood analyses (Hemodyne HAS, TEG, ROTEM). The clearance and half-life of factor FVII:C was estimated as 39.0 ± 8.8 mL h⁻¹ kg⁻¹ and 2.1 ± 0.2 h respectively. There was good inter-assay agreement with respect to clot initiation parameters (R, CT and FOT) and these parameters all fell to a mean of approximately 9 min following rFVIIa dosing. The platelet contractile force (PCF) and clot elastic modulus (CEM) were positively correlated to FVII:C (P < 0.0001), and these parameters were dynamic throughout the 6-h period. The MA and MCF did not correlate to FVII:C nor did they significantly change during the study. Prothrombin F1 + 2 significantly increased following rFVIIa dosing (P < 0.001), but remained steady throughout the study. There was no change in D-dimer concentrations over time. The FOT, R and CT characterized clot initiation following rFVIIa dosing. The PCF and CEM were correlated to FVII:C and characterized the dynamics of platelet function and clot strength over the rFVIIa dosing interval. The clinical significance of these findings needs additional study.


Subject(s)
Factor VIIa/pharmacokinetics , Hemophilia A/blood , Hemophilia B/blood , Adult , Blood Coagulation/drug effects , Blood Platelets/drug effects , Blood Platelets/physiology , Body Weight , Clot Retraction/drug effects , Elasticity/drug effects , Factor VIIa/administration & dosage , Female , Half-Life , Hemophilia A/drug therapy , Hemophilia B/drug therapy , Hemostasis/drug effects , Humans , Male , Metabolic Clearance Rate , Middle Aged , Platelet Function Tests , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacokinetics , Young Adult
3.
Haemophilia ; 13(5): 533-41, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17880440

ABSTRACT

NN1731 is a novel variant of recombinant factor VIIa (rFVIIa) that binds to activated platelets, but has greater enzymatic activity than rFVIIa in generating FXa and thrombin. The effect of NN1731 on clot structure and platelet function was characterized ex vivo in whole blood from healthy volunteers and haemophilic patients. Blood samples from six healthy volunteers, nine haemophilia A patients with and without inhibitors and one acquired haemophilia A patient, were spiked with increasing concentrations (0.32, 0.64 and 1.28 microg mL(-1)) of rFVIIa and NN1731. Platelet contractile force (PCF) or platelet function, clot elastic modulus (CEM) or clot structure, and force onset time (FOT) or the thrombin generation time (TGT) were determined using the Hemodyne Hemostasis Analysis System (HAS). Baseline PCF, CEM and FOT values in patients were abnormal compared to healthy volunteers' baseline values. Overall, haemophilia blood samples with or without inhibitors spiked with NN1731 had significantly greater PCF, CEM and shorter FOT values relative to samples spiked with corresponding doses of rFVIIa. The variability in response to treatment between patients was greater with rFVIIa compared to NN1731. At 1.28 microg mL(-1) (90 microg kg(-1)), NN1731 normalized PCF, CEM and FOT in nine of 10 patients, while rFVIIa normalized these parameters in four of 10 patients. Increasing in vitro concentrations of NN1731 normalized platelet function, clot structure and thrombin generation consistently in haemophilia blood with or without inhibitors. NN1731 may be a promising haemostatic agent for patients with bleeding disorders. These results should be confirmed in an in vivo study.


Subject(s)
Blood Coagulation/drug effects , Factor VII/therapeutic use , Hemophilia A/drug therapy , Platelet Activation/drug effects , Adult , Aged , Blood Platelets/physiology , Clot Retraction/drug effects , Factor VII/pharmacology , Female , Hemophilia A/blood , Humans , Male , Middle Aged , Platelet Count
4.
Haemophilia ; 13(2): 164-71, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17286769

ABSTRACT

Both HCV and HIV are common in haemophiliacs previously treated with non-viral-inactivated clotting factor concentrates. Because of increased bleeding risks, little data are available on the safety of percutaneous outpatient liver biopsy (LBx) and impact of HIV coinfection in this population. This study aims at reporting our experience with percutaneous LBx in a cohort of haemophiliacs infected with HCV and describe the spectrum of disease and impact of HIV coinfection. A retrospective review of consecutive patients with haemophilia and HCV who underwent percutaneous LBx was performed. All patients were positive for HCV RNA by commercial assay and received factor concentrate prior to biopsy. A total of 29 male patients (mean age 36, 24 haemophilia A, five haemophilia B, and 44% coinfected with HIV) underwent successful outpatient percutaneous LBx without bleeding complication. Histologic activity index was 6.44 with advanced fibrosis (bridging fibrosis/cirrhosis) in 31%. When patients were stratified by HIV positive (n = 13) vs. HIV negative (n = 16), coinfected patients had higher fibrosis scores and higher proportion advanced fibrosis (54% vs. 12%; P = 0.0167) with no differences in age, demographic or other laboratory parameters. Multivariate logistic regression found that HIV positivity was independently associated with advanced fibrosis (OR = 3.7; 95% CI: 1.17-11.8; P = 0.026). Outpatient percutaneous LBx can be safely performed in patients with haemophilia. Despite similar age, HIV coinfection was an independent predictor of advanced fibrosis. These data support the hypothesis that HIV accelerates fibrosis progression in those coinfected with HCV and highlights the importance of liver histology in this population.


Subject(s)
HIV Infections/complications , Hemophilia A/pathology , Hepatitis C, Chronic/complications , Liver/pathology , Adult , Ambulatory Care , Biopsy/methods , HIV Infections/pathology , Hemophilia A/complications , Hemophilia A/therapy , Hepatitis C, Chronic/pathology , Humans , Male , Retrospective Studies
5.
Opt Express ; 15(21): 13988-96, 2007 Oct 17.
Article in English | MEDLINE | ID: mdl-19550672

ABSTRACT

We use Monte Carlo time-dependent simulations of light pulse propagation through turbulent water laden with particles to investigate the application of Multiple Field Of View (MFOV) lidar to detect and characterize oceanic turbulence. Inhomogeneities in the refractive index induced by temperature fluctuations in turbulent ocean flows scatter light in near-forward angles, thus affecting the near-forward part of oceanic water scattering phase function. Our results show that the oceanic turbulent signal can be detected by analyzing the returns from a MFOV lidar, after re-scaling the particulate back scattering phase function.

6.
J Thromb Haemost ; 4(2): 372-6, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16420568

ABSTRACT

BACKGROUND: Patients with end-stage renal disease (ESRD) who receive enoxaparin are at increased risk for adverse bleeding episodes. This phenomenon appears to occur despite judicious monitoring of antifactor Xa (aFXa) activity. Better monitoring parameters are needed to quantify the anticoagulant effects of enoxaparin in the ESRD population. OBJECTIVES: The objective of this study was to determine the utility of using thrombin generation time (TGT), platelet contractile force (PCF) and clot elastic modulus (CEM) to monitor the degree of anticoagulation in ESRD subjects, and to compare these results to aFXa activity, the current gold-standard monitoring parameter. METHODS: Eight healthy volunteers without renal dysfunction and eight ESRD subjects were enrolled into this study. Subjects received a single dose of enoxaparin 1 mg kg(-1) subcutaneously, and blood samples were obtained for the determination of aFXa activity, TGT, PCF and CEM at baseline, 4, 8, and 12 h postdose. RESULTS: Baseline, 4, 8, and 12-h aFXa activity concentrations were not different between groups. However, the corresponding TGT at 8 and 12 h was significantly prolonged in the ESRD group (P = 0.04, and P = 0.008, respectively). The 4-h peak TGT trended toward significance (P = 0.06). There were no differences in PCF or CEM across time. CONCLUSIONS: These data suggest that the parameter aFXa activity is a poor predictor of the anticoagulant effect of enoxaparin in patients with ESRD. Thrombin generation time appears to be more sensitive to the antithrombotic effects of enoxaparin in this population. Further large-scale trials are needed to corroborate these data.


Subject(s)
Enoxaparin/therapeutic use , Fibrinolytic Agents/therapeutic use , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/drug therapy , Thrombin Time , Adult , Antithrombin III/analysis , Blood Coagulation Tests , Case-Control Studies , Female , Humans , Male , Middle Aged , Prospective Studies
7.
J Thromb Haemost ; 2(8): 1299-304, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15304034

ABSTRACT

Antifactor Xa activity is the gold standard monitoring parameter for low molecular weight heparin (LMWH) derivatives. It is frequently measured in high-risk populations, such as patients with renal dysfunction. Despite antifactor Xa monitoring, however, bleeding in renal dysfunction patients receiving LMWH remains a problem. This study determined the relationship between antifactor Xa activity and three novel coagulation monitoring parameters: thrombin generation time (TGT), platelet contractile force (PCF) and clot elastic modulus (CEM). This study also assessed the effect of renal dysfunction on these relationships. This was an ex vivo pharmacodynamic study of the relationship between antifactor Xa activity and TGT, PCF and CEM in subjects both with and without renal dysfunction. Thirty subjects completed this study (10 controls, 10 chronic kidney disease subjects, and 10 end-stage renal disease subjects receiving hemodialysis). Blood samples obtained from participants were spiked with increasing enoxaparin concentrations (0.25, 0.5, 1.0 and 3.0 IU mL(-1)). Samples were analyzed for TGT, PCF and CEM. The relationship between antifactor Xa activity and TGT, PCF and CEM was determined by Pearson's correlation. The effect of renal dysfunction on the relationship between antifactor Xa activity and TGT, PCF and CEM was determined by analysis of covariance. There is strong correlation between antifactor Xa activity and TGT, CEM and PCF. The presence of renal dysfunction significantly prolongs the TGT, and decreases the CEM relative to controls. These results suggest that patients with renal dysfunction have a greater pharmacodynamic response to LMWH, independent of the pharmacokinetics of LMWH.


Subject(s)
Blood Coagulation Tests , Blood Platelets/metabolism , Enoxaparin/pharmacology , Factor Xa Inhibitors , Factor Xa/biosynthesis , Kidney Diseases/blood , Thrombin Time , Thrombin/metabolism , Adult , Anticoagulants/pharmacology , Chronic Disease , Dose-Response Relationship, Drug , Female , Heparin, Low-Molecular-Weight/pharmacology , Humans , Kidney/metabolism , Kidney/pathology , Kidney Failure, Chronic/blood , Male , Middle Aged , Prospective Studies , Risk , Thrombin/biosynthesis , Time Factors
8.
J Thromb Haemost ; 1(9): 1977-83, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12941040

ABSTRACT

Prothrombin activation requires the direct interplay of activated platelets and plasma clotting factors. Once formed, thrombin causes profound, irreversible activation of platelets and reinforces the platelet plug via fibrin formation. Delayed or deficient thrombin production increases bleeding risk. Commonly employed coagulation assays, the prothrombin and partial thromboplastin times, use clot formation as a surrogate marker of thrombin generation. These assays routinely utilize platelet-poor plasma and completely miss the effects of platelets. Other markers of thrombin generation, prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin complex, are typically measured after the fact. We report a simple assay, which employs the onset of platelet contractile force (PCF) as a surrogate marker of thrombin generation. PCF generation occurs concomitant with the burst of F1 + 2 release. The time between assay start and PCF onset is termed the thrombin generation time (TGT). TGT is prolonged in clotting factor deficiencies and in the presence of direct and indirect thrombin inhibitors. TGT shortens to normal with clotting factor replacement and shortens with administration of recombinant factor VIIa. TGT is short in thrombophilic states such as coronary artery disease, diabetes and thromboangiitis obliterans and prolongs toward normal with oral and intravenous anticoagulants.


Subject(s)
Blood Coagulation Tests/methods , Blood Platelets/physiology , Thrombin/biosynthesis , Biomechanical Phenomena , Blood Coagulation/drug effects , Case-Control Studies , Coronary Artery Disease/blood , Hemophilia A/blood , Hemophilia B/blood , Humans
9.
J Thromb Haemost ; 1(2): 243-9, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12871496

ABSTRACT

Thrombin causes platelet activation via multiple pathways, and deficient thrombin generation reduces platelet contractile force (PCF) during clot retraction. We hypothesized that PCF in blood samples from clotting factor-deficient patients would be diminished due to delayed or deficient thrombin generation. Blood samples from patients with fibrinogen, and factor V, VII, VIII, IX, X, XI and XIII deficiencies were compared to samples from normal controls. PCF in patient blood clotted with thrombin (1 NIH UmL(-1)) was compared to PCF in clots formed with batroxobin (0.25 micro g mL(-1)). PCF in the former should be normal, but PCF in the latter is dependent on thrombin generation within the sample and might be deficient. In factor VII-(n = 2, P < 0.05), factor VIII-(n = 6, P < 0.005) and factor XI-(n = 2, P < 0.05) deficient platelet-rich plasmas, PCF in batroxobin-induced clots was significantly lower than in thrombin-induced clots. In factor IX deficiency (n = 2), one patient had a dramatic reduction in PCF while a second patient had increased PCF. PCF was insignificantly (P = 0.346) reduced in two patients with factor X deficiency, and was normal in one patient with factor V deficiency. The factor X result is consistent with work in model systems, which indicates that as little as 1-3% factor X activity is sufficient to restore thrombin generation to normal. The factor V result probably indicates that the deficiency is incomplete. PCF in thrombin-induced clots was normal in all of these patients. Low fibrinogen and factor XIII deficiency reduced PCF in both thrombin- and batroxobin-induced clots. These results indicate that PCF is reduced, probably due to delayed thrombin generation, in some factor-deficient platelet-rich plasma samples.


Subject(s)
Batroxobin/pharmacology , Blood Platelets/drug effects , Blood Platelets/physiology , Coagulation Protein Disorders/blood , Case-Control Studies , Clot Retraction , Coagulation Protein Disorders/genetics , Elasticity , Humans , In Vitro Techniques , Platelet Activation/drug effects , Thrombin/pharmacology , Time Factors
10.
Diabet Med ; 19(10): 862-6, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12358876

ABSTRACT

AIMS: Platelet function and clot structure may be altered in diabetes. We have noted increased platelet contractile force (PCF) and clot elastic modulus (CEM) in patients presenting to the emergency department with chest pain. Twenty-six of the chest pain patients were diabetic. Here, we compare the PCF, CEM and platelet aggregation in diabetic chest pain patients, non-diabetic patients with chest pain and asymptomatic controls. PATIENTS AND METHODS: PCF, CEM and collagen whole blood aggregations were measured in 100 chest pain patients and 25 asymptomatic controls. RESULTS: Platelet concentrations for diabetic patients, non-diabetic patients and controls were identical. PCF was significantly (P < 0.05) elevated in diabetic chest pain patients (9.42 +/- 0.59 kdynes) vs. controls (7.40 +/- 0.32 kdynes). CEM in diabetic patients (29.96 +/- 2.19 kdynes/cm2) was significantly elevated relative to that in non-diabetic chest pain patients (25.22 +/- 0.84 kdynes/cm2) and normal controls (23.18 +/- 0.74 kdynes/cm2). Collagen-induced whole blood aggregation was decreased (P < 0.05) in diabetic chest pain patients vs. controls. PCF values (10.23 +/- 0.76 kdynes) in diabetic patients with haemoglobin A1c > 7% were higher than in any other group. CONCLUSION: PCF and CEM are elevated in diabetic chest pain patients. The significance of these laboratory findings awaits additional clinical studies.


Subject(s)
Blood Platelets/physiology , Chest Pain/blood , Diabetes Mellitus/blood , Adult , Aged , Analysis of Variance , Biomechanical Phenomena , Case-Control Studies , Clot Retraction , Elasticity , Female , Glycated Hemoglobin/analysis , Humans , Male , Middle Aged , Platelet Aggregation , Platelet Function Tests
11.
Blood Coagul Fibrinolysis ; 13(3): 193-7, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11943932

ABSTRACT

Clot retraction is a thrombin-dependent, platelet-mediated contraction of the cellular clot mass. In this study, the effects of delayed, deficient and inhibited thrombin generation on the development of platelet contractile force (PCF) and clot elastic modulus (CEM) were measured. When normal citrated whole blood is clotted by the addition of exogenous thrombin (1 U/ml) and calcium (10 mmol/l), PCF and CEM start to develop within the first minute and begin to level off by 1200 s. If identical samples are clotted with batroxobin (0.21 microg/ml) and calcium (10 mmol/l), both PCF and CEM development are delayed approximately 5 min. After 1200 s of clotting, however, values in the batroxobin system approach those seen with exogenous thrombin. If the added calcium concentration is held constant at 10 mmol/l, increasing the exogenous thrombin concentration from 0 to 0.5 U/ml results in increased PCF and CEM values. Above 0.5 U thrombin, the effect plateaus. At exogenous calcium of 10 mmol/l, increasing batroxobin concentrations (0-0.210 microg/ml) caused a 75% increase in PCF and a 55% increase in CEM. The increase in CEM reached a plateau above 0.05 microg batroxobin/ml. The effects of varying calcium concentrations were evaluated at constant batroxobin (0.21 microg/ml) and thrombin (1 U/ml) concentrations. With thrombin, PCF and CEM increased by > 700% as CaCl2 increased from 0 to 5 mmol/l. Above 5 mmol/l, no additional increases occurred. With batroxobin, PCF did not develop at CaCl2 concentrations < or = 2.5 mmol/l. Above 2.5 mmol/l CaCl2, PCF values increased and at 10 mmol/l CaCl2 were equal to those seen with thrombin. CEM in batroxobin-mediated clots peaked at 10 mmol/l CaCl2 but were 40% less than the values found in thrombin-mediated clots. When the thrombin inhibitor P-PACK was added to the batroxobin system, dose-dependent decreases in PCF and CEM were noted. At 120 micromol/l, P-PACK totally suppressed PCF. PCF in blood from a factor VIII-deficient patient varied significantly when clotted with batroxobin versus thrombin. PCF development in factor VIII-deficient blood was normal with thrombin but is delayed and depressed with batroxobin. PCF values in factor VIII-deficient blood did not reach the thrombin value after 1200 s of clotting, and CEM was significantly less. These results confirm that PCF development is thrombin dependent and that delay or reduction of PCF development results in structurally weaker clots.


Subject(s)
Blood Coagulation/physiology , Blood Platelets/physiology , Clot Retraction , Thrombin/physiology , Adult , Amino Acid Chloromethyl Ketones/pharmacology , Batroxobin/administration & dosage , Batroxobin/pharmacology , Blood Coagulation/drug effects , Calcium/administration & dosage , Calcium/pharmacology , Dose-Response Relationship, Drug , Elasticity , Female , Hemophilia A/blood , Humans , Male , Platelet Activation/drug effects , Thrombin/antagonists & inhibitors , Thrombin/biosynthesis , Thrombin/pharmacology
12.
Ann Rheum Dis ; 61(4): 341-5, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11874838

ABSTRACT

OBJECTIVES: To examine the role, acceptability, and cost effectiveness of a telephone helpline organised and run by specialist nurses in a district general hospital outpatient rheumatology department. MATERIAL AND METHODS: Patients accessed the telephone helpline by leaving a taped message on an answer phone with a 24 hour response time. Assessment included an audit of the nature and outcome of helpline calls, patient satisfaction with the helpline, and a health economic analysis of the helpline operation. A postal questionnaire was used to assess patient satisfaction; this was sent to the 87 patients who called the helpline during one month, and overall satisfaction with the helpline was assessed. The nature and outcome of all calls was analysed retrospectively using a helpline record book for February and October of one year and February of the following year. From the results of the retrospective analysis and an estimate of the number of general practitioner consultations avoided by provision of the helpline, the cost effectiveness of the helpline was calculated. RESULTS: Of those returning questionnaires, 61/63 (97%) were satisfied with the response time, 63/63 (100%) with the courtesy, and 60/63 (95%) felt that their questions were answered directly and to their satisfaction in 62 (98%) of cases. Had the helpline not been available, 38/63 (60%) patients would have made an appointment with their GP. When these figures were extrapolated to an annual estimation, a basic cost analysis showed that the helpline produced a cost saving to the NHS, largely as a result of GP consultations avoided. CONCLUSION: Clinical advice and support can be provided by a rheumatology helpline set up as an adjunct to a standard outpatient service. The results of a postal questionnaire suggested more than 95% satisfaction with all aspects of the helpline service and that 99% of callers would call the helpline again. The provision of the helpline service contributes to the quality of care provided by an outpatient department and provides benefit to the NHS.


Subject(s)
Ambulatory Care/methods , Arthritis, Rheumatoid/therapy , Hotlines , Hotlines/standards , Adolescent , Adult , Aged , Aged, 80 and over , Ambulatory Care/standards , Arthritis, Rheumatoid/economics , Costs and Cost Analysis , Female , Hotlines/economics , Humans , Male , Middle Aged , Patient Satisfaction , Pilot Projects , Surveys and Questionnaires
13.
Thromb Haemost ; 86(4): 1087-93, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11686328

ABSTRACT

Platelets, a major constituent of thrombus, play a crucial role in the pathogenesis of acute ischemic coronary syndromes. The effect of ultraviolet laser emission on platelets within thrombi is unknown. The effects of increasing levels of laser energy on platelets in whole blood were investigated. Blood samples were obtained by aseptic venipuncture and anticoagulated with 3.8% sodium citrate. Samples were exposed to increased levels (0, 30, 45, 60 mJ/mm2; 25 Hz) of ultraviolet excimer laser fluence (308 nm wave-length) and then tested for ADP and collagen induced platelet aggregation, platelet concentration, and for platelet contractile force (PCF) development. Scanning electron microscopy was used to detect laser induced morphologic changes of platelets and by flow cytometric analysis to detect changes in expression of platelet surface antigens p-selectin (CD 62) and glycoprotein IIb/IIIa (CD 43). Exposure to excimer laser energy produced dose dependent suppression of platelet aggregation and force development ("stunned platelets"). ADP aggregation decreased from 8.0+/-1.1 Ohms (mean+/-SEM) to 3.7+/-0.8 Ohms (p<0.001) to 2.7+/-0.6 Ohms (p <0.001) and to 1.8+/-0.5 Ohms (p <0.001) as the laser energy increased from 0 to 30 to 45 to 60 mJ/mm2, respectively. Collagen induced aggregation decreased from 21.4+/-1.4 Ohms to 15.7+/-1.2 Ohms (p <0.001) to 11.7+/-1.1 Ohms (p <0.001) and to 9.9+/-1.0 Ohms (p <0.001), in response to the same incremental range of laser energy. Platelet contractile forces declined from 34,500+/-3700 to 27.800+/-2700 dynes as laser energy increased from 0 to 60 mJ/mm2 (p <0.03). Platelet concentration did not change with increasing laser energy. The expression of platelet surface antigen p-selectin (CD 62) remained stable through increasing levels of laser energy exposures while the percentage of CD 43 positive platelets significantly increased with exposure to laser energy, yet the level of expression did not exceed 0.5% of cells. Thus, aggregation kinetics are altered in platelets exposed to ultraviolet laser energy as manifested by decreased platelet aggregation and reduction in platelet force development capability. The response is dose dependent and most pronounced at higher energy levels such as 60 mJ/mm2.


Subject(s)
Antigens, CD , Blood Platelets/radiation effects , Lasers , Platelet Aggregation/radiation effects , Ultraviolet Rays , Adenosine Diphosphate/pharmacology , Adult , Blood Platelets/chemistry , Blood Platelets/ultrastructure , Female , Flow Cytometry , Humans , Kinetics , Leukosialin , Male , Microscopy, Electron , Middle Aged , P-Selectin/blood , Platelet Aggregation/drug effects , Reference Values , Sialoglycoproteins/blood , Ultraviolet Rays/adverse effects
14.
Angiology ; 52(10): 711-5, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11666136

ABSTRACT

Treatment of critically ill patients who have heparin-induced thrombocytopenia and thrombosis (HITT) and also renal failure is a challenge. Recombinant hirudin (Refludan, Hoechst Marion Roussel) is a direct thrombin inhibitor indicated for anticoagulation in HITT and approved by the United States Food and Drug Administration. Because this drug is renally cleared, a single dose of hirudin may induce prolonged (up to one week) unpredictable anticoagulation in patients with renal insufficiency. There are a few case reports of patients with renal failure and suspected heparin-induced thrombocytopenia (HIT) in which patients were anticoagulated with Refludan for catheter thrombosis. There is no literature on the therapeutic use of Refludan to treat HITT in patients with diffuse thrombosis and renal failure. The authors report the case of a 44-year-old female dialysis patient with HITT and extensive life-threatening thrombosis. The patient developed common iliac vein occlusion extending to the right atrium with progressive right internal jugular vein thrombus developing while on heparin. Her platelet count dropped to 60,000/microL. She was lethargic and hemodynamically unstable. Refludan was initially given as a bolus of 0.2 mg/kg (total, 12 mg) at a 50% dose reduction based on the patient's ideal body weight. This dose was based on the published pharmacokinetics of Refludan in patients with renal failure. Only 2 additional boluses of 6 mg and 3 mg were needed to extend the duration of therapeutic anticoagulation (measured by PTT) to 140 hours. The patient improved both clinically and radiographically after the treatment with Refludan. There were no additional thromboembolic events or bleeding complications. The platelets returned to normal within a few days. The patient was transitioned to coumadin and discharged from the hospital. She remains stable at 1-year follow-up.


Subject(s)
Anticoagulants/therapeutic use , Heparin/adverse effects , Hirudin Therapy , Hirudins/analogs & derivatives , Kidney Failure, Chronic/complications , Recombinant Proteins/therapeutic use , Thrombocytopenia/chemically induced , Thrombocytopenia/drug therapy , Thrombosis/drug therapy , Adult , Female , Humans , Thrombocytopenia/complications , Thrombosis/complications , Warfarin/therapeutic use
15.
Angiology ; 52(5): 361-6, 2001 May.
Article in English | MEDLINE | ID: mdl-11386389

ABSTRACT

A 35-year-old woman experienced symptomatic calf pain while taking a combination of fenfluramine and phentermine. All symptoms resolved when the medications were stopped, but pain returned when fenfluramine was restarted. Laboratory evaluation revealed mild elevations of aspartate aminotransferase and lactate dehydrogenase and a remarkably shortened prothrombin time (6.3 seconds). Additional studies revealed that the clots were composed of very thin fibrin fibers. All laboratory abnormalities, including the abnormal fibrin structure, completely resolved when fenfluramin was stopped. Direct addition of fenfluramine or phentermine to normal plasma did not alter either coagulation kinetics or fibrin structure, supporting the concept that the induced changes may have originated at the hepatic level. Clots composed of thin fibers are much more resistant to fibrinolysis, and could potentially put such patients at risk for thrombotic complications. This is the first report of clotting abnormalities associated with fenfluramine use. Subsequent to its use in this patient, fenfluramine was removed from clinical use due to reports of acquired valvular heart disease.


Subject(s)
Blood Coagulation Disorders/chemically induced , Fenfluramine/adverse effects , Fibrin/chemistry , Adult , Female , Humans , Prothrombin Time , Time Factors
16.
Am J Cardiol ; 87(7): 849-55, 2001 Apr 01.
Article in English | MEDLINE | ID: mdl-11274939

ABSTRACT

This study was conducted to evaluate the feasibility, safety, and acute results of percutaneous excimer laser coronary angioplasty (ELCA) in acute coronary syndromes. Fifty-nine patients were treated with ELCA (308 nm), including 33 patients with unstable angina pectoris (UAP) (35 vessels with 39 lesions) and 26 patients with acute myocardial infarction (AMI) (26 vessels with 29 lesions). In each patient the target lesion had a complex morphology. Overall, 71% of the patients had contraindications for pharmacologic thrombolytic agents or glycoprotein IIb/IIIa receptor antagonists. All patients received adjunct balloon dilation followed by stent implantation in 88% of patients with AMI versus 76% of patients with UAP (p = NS). Quantitative angiography was performed at an independent core laboratory; 86% laser success and 100% procedural success was achieved in the AMI group versus 87% laser success and 97% procedural success in the UAP group (p = NS). In the AMI group, the minimal luminal diameter increased from 0.77 +/- 0.56 to 1.44 +/- 0.47 mm after lasing to a final 2.65 +/- 0.47 mm versus 0.77 +/- 0.38 to 1.35 +/- 0.4 mm after lasing to 2.66 +/- 0.5 mm final in the UAP group. A prelaser percent stenosis of 76 +/- 17% for the AMI group versus 70 +/- 16% for the UAP group (p = NS) was decreased after lasing to 52 +/- 16% for the AMI group versus 51 +/- 14% for the UAP group (p = NS) and to a final stenosis of 15 +/- 17% for the AMI group versus 12 +/- 15% for the UAP group (p = NS). A 96% laser-induced reduction of thrombus burden area was achieved in the AMI group versus 97% in the UAP group (p = NS). Preprocedure Thrombolysis In Myocardial Infarction flow of 1.3 +/- 0.9 in the AMI group versus 2.3 +/- 1.2 for the UAP group (p = 0.01) increased to a final flow of 3.0 +/- 0 for the AMI group versus 3.0 +/- 0 for the UAP group (p = NS). There were no deaths, cerebrovascular accident, emergency bypass surgery, acute closure, major perforation or major dissection, distal embolization, or bleeding complications in either group. One patient with AMI had localized perforation (caused by guidewire) without sequelae and 1 patient with UAP had an abnormal increase in creatine kinase levels. All 59 patients survived the laser procedure, improved clinically, and were discharged. Thus, early experience in patients with acute coronary syndromes suggest that percutaneous ELCA is feasible and safe.


Subject(s)
Angina, Unstable/surgery , Angioplasty, Balloon, Coronary , Angioplasty, Balloon, Laser-Assisted , Myocardial Infarction/surgery , Coronary Angiography , Female , Humans , Male , Middle Aged , Treatment Outcome
17.
J Diabetes Complications ; 15(1): 44-54, 2001.
Article in English | MEDLINE | ID: mdl-11259926

ABSTRACT

Eighty percent of patients with diabetes mellitus die a thrombotic death. Seventy-five percent of these deaths is due to cardiovascular complications, and the remainder is due to cerebrovascular events and peripheral vascular complications. Vascular endothelium, the primary defense against thrombosis, is abnormal in diabetes. Endothelial abnormalities undoubtedly play a role in the enhanced activation of platelets and clotting factors seen in diabetes. Coagulation activation markers, such as prothrombin activation fragment 1+2 and thrombin-anti-thrombin complexes, are elevated in diabetes. The plasma levels of many clotting factors including fibrinogen, factor VII, factor VIII, factor XI, factor XII, kallikrein, and von Willebrand factor are elevated in diabetes. Conversely, the level of the anticoagulant protein C (PC) is decreased. The fibrinolytic system, the primary means of removing clots, is relatively inhibited in diabetes due to abnormal clot structures that are more resistant to degradation and an increase in plasminogen activator inhibitor type 1 (PAI-1). Increased circulating platelet aggregates, increased platelet aggregation in response to platelet agonists, increased platelet contractile force (PCF), and the presence of higher plasma levels of platelet release products, such as beta-thromboglobulin, platelet factor 4, and thromboxane B(2), demonstrate platelet hyperactivity in diabetes. This constellation of findings supports the clinical observation that diabetes is a hypercoagulable state. This article briefly reviews the published evidence for this conclusion and the putative roles played by hyperglycemia and hyperinsulinemia in its development.


Subject(s)
Blood Coagulation , Diabetes Mellitus/blood , Diabetic Angiopathies/physiopathology , Thrombophilia/physiopathology , Anticoagulants/blood , Blood Coagulation Factors/metabolism , Diabetes Mellitus/physiopathology , Diabetic Angiopathies/blood , Diabetic Angiopathies/mortality , Humans , Thrombophilia/blood , Thrombophilia/complications , Thrombosis/mortality
18.
J Cardiothorac Vasc Anesth ; 13(1): 58-64, 1999 Feb.
Article in English | MEDLINE | ID: mdl-10069286

ABSTRACT

OBJECTIVE: This investigation examines the hypothesis that the antiplatelet effect of abciximab and its reversal can be monitored using the Hemodyne (Hemodyne, Inc, Midlothian, VA) analyzer and modified Thrombelastograph (Haemoscope, Skokie, IL). DESIGN: In vitro dose-response and reversal study. SETTING: Anesthesia Research (Dallas, TX) and Special Studies Coagulation Laboratories (Washington, DC). PARTICIPANTS: Nine healthy volunteers. INTERVENTIONS: The addition of increasing concentrations of abciximab, 0 to 10 microg/mL, and purified fibrinogen, 50 to 400 mg/dL. The reversal of abciximab, 4 microg/mL, with the addition of fresh platelet-rich plasma (PRP) sufficient to increase the platelet concentration by approximately 10%. MEASUREMENTS AND MAIN RESULTS: Platelet aggregation and platelet contractile force using the Hemodyne analyzer were used as platelet-specific measurements. The Thrombelastograph maximum amplitude (MA) for platelets (MA(PLT)) was calculated by subtracting the MA from a platelet-poor plasma (PPP) sample (MA(ppp)) determined in one thromboelastography well from that of whole-blood MA (MA(WB)) run simultaneously in the second thromboelastography well. The addition of abciximab, 0 to 10 microg/mL, resulted in significant concentration-dependent reductions in platelet aggregation (p < 0.001), platelet contractile force (p < 0.001), and MA(PLT) (p < 0.001). Platelet contractile force (p < 0.03) and MA(PLT) (p < 0.05) were significantly more responsive than MA(WB) to the effect of abciximab, 4 microg/mL, and its reversal with the addition of fresh PRP. Purified fibrinogen concentration directly correlated with thromboelastography MA (r(s) = 0.97; p < 0.001), yet had no effect on platelet contractile force. The addition of abciximab had no measurable influence on the MA(ppp). CONCLUSION: This in vitro study suggests that the Hemodyne analyzer and modified Thrombelastograph might be clinically useful methods to monitor the platelet inhibitory effects of agents such as abciximab.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Drug Monitoring/methods , Immunoglobulin Fab Fragments/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Thrombelastography/methods , Abciximab , Antibodies, Monoclonal/pharmacology , Blood Platelets/drug effects , Blood Platelets/physiology , Dose-Response Relationship, Drug , Drug Monitoring/instrumentation , Fibrinogen/pharmacology , Humans , Immunoglobulin Fab Fragments/pharmacology , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/pharmacology , Thrombelastography/instrumentation
19.
Vox Sang ; 75(4): 270-7, 1998.
Article in English | MEDLINE | ID: mdl-9873262

ABSTRACT

BACKGROUND AND OBJECTIVES: The changes that occur in platelets as they undergo storage have been documented by aggregometry as well as by flow cytometry. However, one of the most essential platelet functions, the induction of clot retraction, has not been quantitatively assessed in stored platelets. We describe two potentially useful methods, platelet-induced clot retraction and clot strength, to assess effect of storage of platelets in blood banks or of platelet preparations subjected to freezing or freeze-drying. These methods have previously been developed for bedside monitoring of patients receiving c7E3 (Reopro(R)). MATERIALS AND METHODS: Platelet-induced clot retraction (PICR) and clot strength were measured with the Hemodyne and Thromboelastograph, respectively. Paired Study: Fresh platelet concentrates (n = 3) were obtained from leukapheresis donors and divided into two equal units; one unit was tested within 4 h of collection and the other stored for 5 days at 22 degrees C in a platelet incubator and tested. Unpaired Study: Fresh platelet concentrates (n = 15) were obtained from leukapheresis donors and tested within 4 h of collection and compared to outdated platelets (n = 30; random or single donor) that had been stored for 5 days at 22 degrees C in a platelet incubator. Alternative Preservation Methods: Lyophilized platelets, platelets chilled to 4 degrees C, platelets frozen at -70 degrees C in 5% dimethyl sulfoxide (DMSO) or in the absence of a cryoprotectant. RESULTS: Paired Study: Stored platelets demonstrated an increase in PICR; the difference was not significant (p = 0.55). There was no difference in clot strength between fresh and outdated platelets (p = 0.90). Unpaired Study: When compared to fresh platelets, stored platelets demonstrated a 2-fold higher PICR (p = 0.0011). On the other hand, there was no difference in the time to onset of PICR (p = 0.08) and there was no difference in clot strength between fresh and outdated platelets (p = 0.14). Alternate Preservation Methods: In contrast, PICR and clot strength were reduced in platelets frozen at -70 degrees C in 5% DMSO and absent in lyophilized platelets, in platelets frozen at -70 degrees C in the absence of cryoprotectants or stored at 4 degrees C. CONCLUSION: The data indicate that the ability of platelets to induce clot retraction and to enhance clot strength is not altered by storage, despite functional abnormalities in aggregation and agglutination. These data suggest that quantitative measurements of PICR and clot strength may be simple, useful tools for assessing the function of stored platelet concentrates, platelets that have undergone freezing or exposure to alternative buffers and for evaluating platelet functions relevant to PICR.


Subject(s)
Blood Banks , Blood Platelets/pathology , Clot Retraction , Cryopreservation , Evaluation Studies as Topic , Freeze Drying , Humans , Platelet Aggregation , Sensitivity and Specificity
20.
Transfus Med Rev ; 11(2): 106-15, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9140170

ABSTRACT

With the realization that the skin bleeding time is often an unreliable measure of platelet function, efforts have been made to identify ways to assess qualitative platelet dysfunction. Currently available techniques measure platelet adhesion, platelet aggregation, the ability of platelets to retard or stop flow through fibers, and the contribution of platelets to in vitro clot formation. Glass bead adhesion, which continues to be performed in some laboratories, is gradually being replaced by measures of platelet adhesion to filters composed of glass fibers, Dacron fibers, or collagen. In each instance, anticoagulated platelet-rich plasma or whole blood flows through the filter under a regulated pressure gradient. The amount of blood flowing through the filter versus time and/or the time to filter occlusion are measured. Recent developments in platelet aggregation have focused on whole blood and stagnation point flow aggregation techniques. Whole blood aggregation does not require blood sample processing and accommodates blood obtained from citrated vacutainer tubes. Stagnation point flow measures both platelet adhesion and aggregation and may be able to detect pathologically-enhanced platelet function. Global measures of hemostasis attempt to simultaneously evaluate the adequacy of fluid phase coagulation and platelet function. Currently available techniques include Thromboelastography, SonoClot Analyzer, Hemodyne Hemostasis Analyzer, PITT, and Hemostatometry. Although each of these technologies have been shown to provide interesting data in the research setting, the ability of any of these techniques to detect abnormal or clinical inadequate platelet function remains to be established.


Subject(s)
Blood Platelets/physiology , Bleeding Time , Hemostasis , Humans , In Vitro Techniques , Platelet Adhesiveness , Platelet Aggregation
SELECTION OF CITATIONS
SEARCH DETAIL
...