Patients with isolated prolonged in vitro bleeding time. Clinical symptoms.

UNLABELLED: In patients with isolated prolonged in vitro bleeding time there is no standardised treatment concept. With this study we characterized the extent of bleeding symptoms. PATIENTS, METHODS: All diagnoses known to cause prolonged in vitro bleeding time (PFA-100) (epinephrine-cartridge >160 s, ADP-cartridge > 120 s) have been excluded, such as platelet function disorders, effects of medications, nutrition or von Willebrand disease. 75 patients (77%, n = 58 women; 23%, n = 17 men, median age 46 (16-81) years were included. All bleeding symptoms have been stored in a databank with help of a comprehensive questionnaire. RESULTS: 78% (n = 54) of all patients reported of having had an operation, 69.8% (n = 37) of them described postoperative bleedings (p = 0.0373). 13.5% (n = 5) of the 54 could remember having been randomly treated by the administration of a transfusion and only 2.7% (n = 1) were treated by substitution of von Willebrand factor. 71% (n = 51) patients indicated haematoma (p = 0.8116). About 33.8% (n = 24) patients had gum bleeding and 40.8% (n = 29, p = 0.7808) patients reported bleeding after the dentist. 41.4% (n = 29) patients suffered under frequent epistaxis (p = 0.0212). There was no correlation between prolonged epinephrine bleeding time to VWF:Ag (rho = 0.16) nor to VWF:RCo (rho = 0.12) nor between prolonged epinephrine and ADP bleeding time (rho = 0.01) nor to ROTEM® analysis. CONCLUSION: Patients with isolated prolonged PFA are mainly women and can be affected by all kinds of bleedings while haematoma is the main symptom. VWD might not be causal.

Use of the platelet function analyzer to minimize bleeding complications after renal biopsy.

BACKGROUND: The bleeding time is frequently used to screen primary haemostasis before surgical procedures, although it poorly predicts the risk of hemorrhage. The platelet function analyzer (PFA), which is also used to screen primary haemostasis, has a higher sensitivity and other advantages, like patient friendliness, higher degree of objectivity and analytical reliability, but needs more extensive clinical validation. METHODS: We compared the predictive values of the PFA-CTs (closure times) and bleeding time for bleeding events after renal biopsy. We prospectively evaluated the complications in patients that underwent a renal biopsy and were screened with PFA in advance (n=170). For comparison we used a historical cohort of patients screened with the bleeding time (n=132). RESULTS: When the PFA-CTs were normal, 26.0% of the patients had a mild bleeding event after the biopsy, which did not differ from the event rate with a normal bleeding time (29.4%). When one or both PFA-CTs were prolonged, 51.3% of the patients had post-biopsy bleeding events independently of the measures to correct the closure time(s), significantly more than with either a prolonged bleeding time (26.7%) or normal PFA-CTs (26.0%). CONCLUSION: For bleeding events, the PFA has a higher positive and similar negative predictive value compared to the bleeding time. Taken into account the additional advantages of the PFA like patient friendliness and better analytical qualities, we prefer the PFA over the bleeding time as a screening tool for primary haemostasis before performing a renal biopsy.

Variability in platelet response to a single daily dose of 150 mg enteric coated aspirin in a high risk population.

PURPOSE: Previous studies have reported inadequate anti-platelet effect in 0.4-35% of patients taking aspirin. Such studies have arbitrarily defined the terms "semi-responders", "non-responders" or "resistant" to variable doses of aspirin on the basis of absolute values derived from different ex-vivo platelet aggregation (PA) methods. Our objective was to define response to 150-mg dose of aspirin in terms of normally distributed values using an ex-vivo measure of PA in a population at high risk for vascular events. METHODS: We prospectively studied high risk patients with either established coronary artery disease (CAD) or stroke or transient ischemic attack (TIA) or peripheral vascular disease or with multiple atherothrombotic risk factors like diabetes plus one of the following-- hypertension, increased total cholesterol, cigarette smoking, micro-albuminuria, low-high density lipoprotein (HDL), family history of CAD and receiving single 150 mg dose of aspirin daily. PA was assessed by chronolog lumi-aggregometer (490-2D) using arachidonic acid (AA) reagent. RESULTS: 130 patients were studied. The response of subjects to aspirin followed a normal, bell shaped distribution curve with a mean and standard deviation (S.D.) of 13.1 +/- 4.4%. 3.1% patients had PA values more than 2 S.D. of the mean, hence termed as hypo-responders to aspirin while another 3.1% patients had PA values less than 2 S.D. of the mean, hence termed as hyper-responders to aspirin. CONCLUSION: There is minimal inter-individual variability in the response to aspirin when tested with AA as the reagent. The response to aspirin follows a normal Gaussian distribution. The prevalence of hypo-responders to aspirin in high risk population is only 3.1%. This is the first study to document "hypo" and "hyper-responders" to single daily dose of 150 mg aspirin. The clinical relevance of these findings remains to be determined.

Pathophysiological classification of chronic rhinosinusitis.

BACKGROUND: Recent consensus statements demonstrate the breadth of the chronic rhinosinusitis (CRS) differential diagnosis. However, the classification and mechanisms of different CRS phenotypes remains problematic. METHOD: Statistical patterns of subjective and objective findings were assessed by retrospective chart review. RESULTS: CRS patients were readily divided into those with (50/99) and without (49/99) polyposis. Aspirin sensitivity was limited to 17/50 polyp subjects. They had peripheral blood eosinophilia and small airways obstruction. Allergy skin tests were positive in 71% of the remaining polyp subjects. IgE was<10 IU/ml in 8/38 polyp and 20/45 nonpolyp subjects (p = 0.015, Fisher's Exact test). CT scans of the CRS without polyp group showed sinus mucosal thickening (probable glandular hypertrophy) in 28/49, and nasal osteomeatal disease in 21/49. Immunoglobulin isotype deficiencies were more prevalent in nonpolyp than polyp subjects (p < 0.05). CONCLUSION: CRS subjects were retrospectively classified in to 4 categories using the algorithm of (1) polyp vs. nonpolyp disease, (2) aspirin sensitivity in polyposis, and (3) sinus mucosal thickening vs. nasal osteomeatal disease (CT scan extent of disease) for nonpolypoid subjects. We propose that the pathogenic mechanisms responsible for polyposis, aspirin sensitivity, humoral immunodeficiency, glandular hypertrophy, eosinophilia and atopy are primary mechanisms underlying these CRS phenotypes. The influence of microbial disease and other factors remain to be examined in this framework. We predict that future clinical studies and treatment decisions will be more logical when these interactive disease mechanisms are used to stratify CRS patients.

Antithrombotic properties of SSR182289A, a new, orally active thrombin inhibitor.

N-[3-[[[(1S)-4-(5-Amino-2-pyridinyl)-1-[[4-difluoromethylene)-1-piperidinyl]carbonyl]butyl]amino]sulfonyl][1,1'-biphenyl]-2-yl]acetamide hydrochloride (SSR182289A) is a novel, potent, and selective thrombin inhibitor. We have examined the antithrombotic properties of SSR182289A administered by i.v. and p.o. routes in several different animal thrombosis models in comparison with reference antithrombotic agents. Oral administration of SSR182289A produced dose-related antithrombotic effects in the following models; rat venous thrombosis (ED(50) 0.9 mg/kg p.o.), rat silk thread arterio-venous (AV) shunt (ED(50) 3.8 mg/kg p.o.), rat thromboplastin-induced AV shunt (ED(50) 3.1 mg/kg p.o.), rat carotid artery thrombosis (ED(200) 5.9 mg/kg p.o.), and rabbit venous thrombosis (ED(50) 7.5 mg/kg p.o.). Administered as an i.v. bolus, SSR182289A showed antithrombotic activity in the above models with ED(50)/ED(200) values in the range of 0.2 to 1.9 mg/kg i.v. SSR182289A increased rat tail transection bleeding time at doses > or =10 mg/kg p.o. In the rat thromboplastin-induced AV shunt model, SSR182289A 10 mg/kg p.o. produced marked antithrombotic effects at 30, 60, 120, and 240 min after administration. Hence, SSR182289A demonstrates potent oral antithrombotic properties in animal venous, AV-shunt, and arterial thrombosis models.

Tratamiento de trombocitopenias inmunes en un modelo experimental / Treatment of immune thrombocytopenias in an experimental model

La púrpura trombocitopénica inmune (PTI) es un desorden hematológico caracterizado por un aumento del consumo de plaquetas. La destrucción plaquetaria es mediada por el sistema retículo-endotelial (SRE), en especial macrófagos hepáticos y esplénicos. Nosotros demostramos que la eliminación específica de estas células utilizando clodronato encapsulado en liposomas (lipclod) induce un aumento del recuento plaquetario. Además, encontramos que la trombocitopenia puede puede ser revertida por el lipclod sin comprometer totalmente la integridad del SRE al cabo de 18h de tratamiento. Los tiempos de sangría de los animales tratados fueron similares a los de los de los animales controles, sugiriendo que la hemostasia está bien controlada en estos animales. Estos datos indican que el uso de lip-clod merece ser considerado como una estrategia de tratamiento para aquellos trombocitopénicos donde se procura elevar rápidamente el recuento plaquetario. (AU)

Pharmacological intervention at disparate sites in the coagulation cascade: comparison of anti-thrombotic efficacy vs bleeding propensity in a rat model of acute arterial thrombosis.

The Tissue Factor/Factor VIIa (TF/FVIIa) complex is an attractive target for pharmacological interruption of thrombin generation and hence blood coagulation, as this complex is the initiation point of the extrinsic pathway of coagulation. TF is a cell membrane-associated protein that interacts with soluble FVIIa to activate factors IX and X resulting in a cascade of events that leads to thrombin generation and eventual fibrin deposition. The goal of this non-randomized study was to evaluate XK1, a specific protein inhibitor of TF/FVIIa, and compare antithrombotic efficacy and bleeding propensity to a previously described Factor Xa (FXa) inhibitor (SC-83157/SN429) and a direct-acting thrombin inhibitor (SC-79407/L-374087) in an acute rat model of arterial thrombosis. All saline-treated animals experienced occlusion of the carotid artery due to acute thrombus formation within 20 minutes. Rats treated with XK1 exhibited a dose-dependent inhibition of thrombus formation with full antithrombotic efficacy and no change in bleeding time or total blood loss at a dose of 4.5 mg/kg, i.v. administered over a 60 minute period. FXa inhibition with SC-83157 resulted in complete inhibition of thrombus formation at a dose of 1.2 mg/kg, i.v.; however, this effect was associated with substantial blood loss. Thrombin inhibition with SC-79407 also afforded complete protection from thrombus formation and occlusion at a dose of 2.58 mg/kg, i.v., and like SC-83157, was associated with substantial blood loss. These data imply that TF/FVIIa inhibition confers protection from acute thrombosis without concomitant changes in bleeding, indicating that this target (TF/FVIIa) may provide improved separation of efficacy vs. bleeding side-effects than interruption of coagulation by directly inhibiting either FXa or thrombin.