Case studies in the management of refractory bleeding in patients with haemophilia A and inhibitors.

In haemophilia patients with well-established high-titer inhibitors, even seemingly minor acute bleeding episodes or surgical procedures may become refractory to treatment and transform into limb- or life-threatening situations. In the absence of evidence-based treatment guidelines, this article presents 10 cases of difficult to control acute and surgical bleeding and offers consensus opinions regarding their management from a panel of experienced haemophilia treaters.

Stroke prevention trial in sickle cell anemia.

Stroke occurs in 7-8% of children with Sickle Cell Disease (Hb SS) and is a major cause of morbidity. Rates of recurrence have been reduced from 46-90% to less than 10% through chronic blood transfusions. Prevention of first stroke, however, would be preferable because even one stroke can cause irreversible brain injury. Transcranial Doppler (TCD) ultrasound can detect arterial blood flow rates associated with subsequent stroke risk. By combining TCD screening and a potentially effective treatment, first stroke may be prevented. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) is the first stroke prevention trial in Hb SS and the first randomized, controlled use of transfusion in Hb SS. This multi-center trial is designed to test whether reducing sickle hemoglobin to 30% or less with periodic blood transfusions will reduce first-time stroke by at least 70% compared to standard care. Primary endpoints will be clinically evident symptoms of cerebral infarction with consistent findings on Magnetic Resonance Imaging and Angiography (MRI/MRA) or symptomatic intracranial hemorrhage. Secondary endpoints will be asymptomatic brain lesions detected by MRI in brain areas not involved in primary endpoints. The design calls for a 6-month start-up interval, 18 months of TCD screening and randomization, and observation for stroke from entry through month 54. Key features of the trial are standardized TCD and MRI/MRA protocols interpreted blindly, and blinded adjudication of endpoints. The sample size (60 per treatment group) is based on prospective data relating TCD velocity to risk of stroke. A time-averaged mean velocity of > or = 200 cm/sec is associated with a 46% risk of cerebral infarction over 39 months. The sample size is sufficient to detect 70% reduction in the primary endpoint at 90% power. This trial will determine if transfusion is effective in the primary prevention of stroke. Secondary aims may further the understanding of the effects of transfusion on the brain and guide future research into cerebrovascular disease in Hb SS.

MR marrow signs of iron overload in transfusion-dependent patients with sickle cell disease.

Magnetic resonance (MR) marrow signal in the axial and appendicular skeleton of 13 transfusion-dependent and chelated pediatric patients with sickle cell anemia (SSD) was compared with marrow signal in six non-transfusion-dependent patients with SSD. Hepatic, pancreatic, and renal MR signal were also evaluated. Indication for hypertransfusion therapy was primarily prior history of stroke. Transfusion-dependent patients had evidence of iron deposition throughout the imaged marrow and the liver, despite deferoxamine chelation therapy. Non-transfusion-dependent patients did not demonstrate grossly apparent signs of iron overload. Red marrow restoration was present in the spine, pelvis, and long bones and, in some patients, within the epiphyses. Marrow edema secondary to vaso-occlusive crises was evident in the metaphyses and diaphyses of long bones in areas of both red and fatty marrow and was best seen using fat-saturated T2-weighted imaging techniques.

Middle cerebral artery velocity changes during transfusion in sickle cell anemia.

BACKGROUND AND PURPOSE: Sickle cell disease is associated with cerebral hyperemia, which is therapeutically reduced by transfusion; however, the process of transfusion-induced cerebral perfusion changes has heretofore not been observed. METHODS: We document the acute changes of intracranial arterial velocity in 10 patients (7 with strokes, 3 without) undergoing transfusion therapy using transcranial Doppler ultrasonography. Middle cerebral artery velocities were bilaterally measured every 30 minutes for the duration of transfusion (4 to 5 hours). Regional cerebral blood flow was quantified in 5 of these patients before the transfusion and 24 hours later by the 133Xe technique. RESULTS: Velocities in stroke-associated vessels (64.33 +/- 18.65 cm/s; n = 6) were significantly lower than in uninfarcted territories (99.54 +/- 27.39 cm/s; n = 13), and both types of vessels showed a robust reduction of blood flow velocities during transfusion. The rates of reduction were not significantly different as a function of prior stroke but did correlate with pretransfusion velocities and with the rise in hematocrit (multiple r = .887, P < .001). These reductions occurred rapidly within the first 3 hours of transfusion. Velocities attained at the end of transfusion were maintained in the hour after transfusion and the next day. CONCLUSIONS: We conclude that transfusion induces rapid changes in cerebral hemodynamics that are related to pretransfusion velocities and a rise in hematocrit. Transcranial Doppler provides a safe, simple, and noninvasive technique of monitoring these changes and may provide a means of making therapeutic decisions regarding transfusion therapy in patients with sickle cell anemia.

Prothrombin expression in the adult and fetal rabbit liver.

Plasma prothrombin levels in newborn humans are lower than in adults. The same is true of many newborn and fetal mammals, including the rabbit. To determine if the lower levels are due to less expression of the protein, we have compared mRNA for prothrombin in fetal and adult rabbit liver. Northern blots were hybridized with a cDNA for rabbit prothrombin revealing a single mRNA of approximately 2 kb in both adult and fetal animals. mRNA specific for prothrombin was quantitated by slot blotting of RNA prepared from adults and fetuses aged 21 d to term (31 d). Prothrombin-specific mRNA in fetuses was greater than 50% of that in adults even when the fetal plasma prothrombin was only 15% of the adult level. This suggests that low plasma levels in the fetuses are not the result of less transcription. Examination of liver sections revealed that the predominant tissue in the fetus is hematopoietic, not hepatic. In the youngest fetuses, less than 20% of the liver consisted of hepatocytes, yet these fetuses expressed more than 50% of the adult level of prothrombin-specific mRNA. Thus, transcription of prothrombin mRNA may be proceeding at a greater rate in the fetal hepatocyte than in the adult, or hematopoietic cells may be expressing the protein. We conclude that in fetal rabbit liver, prothrombin is expressed at a high level relative to the hepatocyte content and that the cause of the low plasma levels is posttranscriptional.

Double-blind randomized controlled study of phosphatidylserine in senile demented patients.

A double-blind randomized controlled study was conducted in 42 hospitalized demented patients to evaluate the therapeutical effect of phosphatidylserine (BS-PS). Half of the patients received 3 X 100 mg of this product, and the other half a placebo of the same appearance. After a wash-out period, prescription lasted for six weeks. To evaluate the patients, two distinct rating scales were used: the Crichton Scale and an original one (Peri Scale) designed in our geriatric unit (see Appendix). A circle crossing test was added. Out of the 35 patients who completed the trial, 18 had received placebo and 17 BC-PS. The results indicated a trend toward improvement in the BC-PS treated patients and an analysis of covariance showed a significant (p less than 0.05) treatment effect on the Peri Scale. The results at the end of the treatment period were compared with those obtained three weeks later. Here again there was a statistically significant difference in the Peri Scale results, indicating that modifications are drug-related. The behavioral improvement shown in this study is in agreement with experimental studies on aged animals.

[Depot medroxyprogesterone acetate: clinical and metabolic effects (lipids, glucose, hemostasis)]. / Acétate de médroxyprogestérone-dépôt: effets cliniques et métaboliques (lipides, glucose, hémostase).

Medroxyprogesterone acetate (MPA), a potent progestagen, is used as a very efficient contraceptive agent. The method of administration is by a threemonthly or sixmonthly intramuscular injection. The method is particularly convenient when the desired number of children has been reached. Fertility is sometimes reestablished only slowly after stopping the injections. The main side effects are linked to endometrial atrophy (blood loss, amenorrhoea). Other side effects are infrequent and subjective. A controversy has risen over the product, by reference to its effects on beagle dogs. We have reviewed the literature. We also present the characteristics of 313 patients treated during (all together) 8,000 months. These patients belong to a rather poor sample of the population (amongst them many immigrant women), aged about 30, with above average pregnancy and parity rates. We also studied, in 31 patients, serum levels of glucose and lipids, and haemostasis. Side effects and reasons for discontinuing the drug are reported. The Pearl index was 0,75% women-years. There was no average effect on weight, blood tension, glycemia. Triglycerides increased slightly, and there was a discreet activation of coagulation with inhibition of the fibrinolytic activity, but without clinical consequences. We conclude that we can go on prescribing the drug, in view of our study and after reviewing the literature.

Bromocriptine and buccolinguofacial dyskineasias in patients with senile dementia. A quantitative study.

Eight women with senile dementia and buccolinguofacial dyskinesias (BLFD) were given bromcriptine mesylate )from 2.5 to 20.0 mg daily). The frequency of their abnormal movements was quantiated by a method consisting of repeated counts (220 measurements per patient). In six patients, the mean frequency of BLFD was lower during bromocriptine mesylate therapy )even at daily doses of 10 mg or less) as compared with placebo; this result was statistically significant in four of the six. The second day after cessation of bromocriptine therapy, there seemed to be a rebound effect in six patients. These phenomena are discussed in light of the possible existence of presynaptic "autoreceptors" that would explain the paradoxical effects produced by a number of dopamine agonists.

Haemostasis disorders in open heart surgery with extracorporeal circulation. Importance of the platelet function and the heparin neutralization.

The main haemostasis changes observed in a screening study performed in 40 patients who underwent an open heart surgery with extracorporeal circulation (ECC) are: a significant drop in platelet count from the onset of the ECC to the third postoperative day, a decrease of platelet retention and aggregation during ECC with an 8-day persistently increased heparin-neutralizing activity in plasma but not in serum, a moderate decrease of plasma factors I, II, VII-X, X and XIII and a more important drop in factor V which disappears 24 h after ECC, a transitory increase of fibrinolysis during ECC and the lack of FDP elevation in the serum. These disorders require a very good neutralization of the heparin used during ECC. The ratio protamine/heparin can be established by a titration clotting time test. Protamine chloride seems to be more efficacious and to act more quickly than protamine sulfate for the neutralization. An overload in protamine can enhance the hemostatic, biological and clinical disorders. The preventive administration of platelet concentrate immediately after the heparin neutralization contributes to reduce the bleeding disorders related to the quantitative and qualitative platelet defects.