Risk factors for bleeding from gastrointestinal angiodysplasia: a case-control study in patients with bleeding and non-bleeding angiodysplasia.

OBJECTIVES: Angiodysplasia (AD) is a common source of gastrointestinal bleeding. Yet, little is known about factors forwarding bleeding in these vascular malformations. The presented study aims to determine risk factors for bleeding that occurs only in patients with symptomatic, but not with asymptomatic, AD. METHODS: Case-control study in patients with AD and either a positive or a negative history of gastrointestinal bleeding in Munich, Germany. Groups were compared by clinical, laboratory, and endoscopic features. RESULTS: 80 patients with (58, f 31, med. age 72) or without bleeding AD (22, f 12, med. age 61) were included. Bleeding from AD was significantly associated with the total number of AD (OR 1.4 (95 % CI 1.1-1.7) p = 0.01) and closure time in PFA/collagen-epinephrine test (OR 1.0 (95 % CI 1.0-1.0) p < 0.01). The total number of AD correlated significantly with age (r = 0.36; p = 0.01). AD were mainly detected in the upper small intestine (> 30 %). Although patients with aortic stenosis suffered not significantly more frequently from bleeding from AD, they demonstrated a loss of high molecular multimers of VWF. CONCLUSIONS: The amount of AD is clearly correlated to the age of the patient. A higher number of ADs and inhibition of primary hemostasis increase the risk of bleeding.

Tailoring of integrin ligands: probing the charge capability of the metal ion-dependent adhesion site.

Intervention in integrin-mediated cell adhesion and integrin signaling pathways is an ongoing area of research in medicinal chemistry and drug development. One key element in integrin-ligand interaction is the coordination of the bivalent cation at the metal ion-dependent adhesion site (MIDAS) by a carboxylic acid function, a consistent feature of all integrin ligands. With the exception of the recently discovered hydroxamic acids, all bioisosteric attempts to replace the carboxylic acid of integrin ligands failed. We report that phosphinates as well as monomethyl phosphonates represent excellent isosters, when introduced into integrin antagonists for the platelet integrin αIIbß3. The novel inhibitors exhibit in vitro and ex vivo activities in the low nanomolar range. Steric and charge requirements of the MIDAS region were unraveled, thus paving the way for an in silico prediction of ligand activity and in turn the rational design of the next generation of integrin antagonists.

Argatroban therapy for heparin-induced thrombocytopenia in ICU patients with multiple organ dysfunction syndrome: a retrospective study.

INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is a serious, prothrombotic, immune-mediated adverse reaction triggered by heparin therapy. When HIT is diagnosed or suspected, heparins should be discontinued, and an alternative, fast-acting, parenteral, nonheparin anticoagulation such as argatroban should be initiated. Limited and inconsistent data exist about dosing of argatroban in intensive care unit (ICU) patients with critical illnesses. METHODS: Retrospective analysis of 12 ICU patients with multiple organ dysfunction syndrome (MODS) treated with argatroban for suspected or diagnosed HIT. RESULTS: The 12 ICU patients with a mean platelet count of 46,000 +/- 30,310 had a mean APACHE II score of 26.7 +/- 7.8 on ICU admission and a mean SAPS II score of 61.5 +/- 16.3 on the first day of argatroban administration. A mean argatroban starting dose of 0.32 +/- 0.25 microg/kg/min (min, 0.04; max, 0.83) was used to achieve activated partial thromboplastin times (aPTTs) >60 sec or aPTTs of 1.5 to 3 times the baseline aPTT. Adjustment to aPTT required dose reduction in six (50%) patients. Patients were treated for a mean of 5.5 +/- 3.3 days. The final mean dose in these critically ill patients was 0.24 +/- 0.16 microg/kg/min, which is about one eighth of the usually recommended dose and even markedly lower than the previously suggested dose for critically ill ICU patients. In all patients, desired levels of anticoagulation were achieved. The mean argatroban dose was significantly lower in patients with hepatic insufficiency compared with patients without hepatic impairment (0.10 +/- 0.06 microg/kg/min versus 0.31 +/- 0.14 microg/kg/min; P = 0.026). The mean argatroban dose was significantly correlated with serum bilirubin (r = -0.739; P = 0.006). CONCLUSIONS: ICU Patients with MODS and HIT can be effectively treated with argatroban. A decrease in the initial dosage is mandatory in this patient population. Further studies are needed to investigate argatroban elimination and dosage adjustments for critically ill patients.