Cocaine use is associated with arterial thrombosis, including myocardial infarction and stroke. Cocaine use results in increased plasma von Willebrand factor (VWF), accelerated atherosclerosis, and ...platelet-rich arterial thrombi, suggesting that cocaine activates the endothelium, promoting platelet-VWF interactions.
Human umbilical vein endothelial cells, brain microvasculature endothelial cells, or coronary artery endothelial cells were treated with cocaine or metabolites benzoylecgonine, cocaethylene, norcocaine, or ecgonine methylester. Supernatant VWF concentration and multimer structure were measured, and platelet-VWF strings formed on the endothelial surface under flow were quantified. Cocaine, benzoylecgonine, and cocaethylene induced endothelial VWF release, with the 2 metabolites being more potent than the parent molecule. Brain microvasculature endothelial cells were more sensitive to cocaine and metabolites than were human umbilical vein endothelial cells or coronary artery endothelial cells. Coronary artery endothelial cells released VWF into the supernatant but did not form VWF-platelet strings. Intracellular cAMP concentration was not increased after treatment with cocaine or its metabolites.
Both cocaine and metabolites benzoylecgonine and cocaethylene induced endothelial VWF secretion, possibly explaining thrombotic risk after cocaine ingestion. VWF secretion is likely to vary between vascular beds, with brain endothelial cells being particularly sensitive. These results suggest that clinical management of cocaine-induced ischemia may benefit from therapies aimed at disrupting the VWF-platelet interaction.
Summary
Utilization of the synthetic vasopressin analogue (1‐deamino‐8‐D‐arginine‐vasopressin, DDAVP) in treatment of mild haemophilia A (MHA, specific clotting factor VIII activity level 0.05–0.4 IU ...mL−1) is convenient and effective for many but not all patients. Genetic testing for patients with MHA is increasingly recognized as providing valuable information for patient care beyond informing reproductive decisions, and as more patients are genotyped, mutation data can be utilized to individualize treatment decisions. To determine if genetic information informs response to DDAVP, a retrospective chart review was performed under Institutional Review Board approval to extract patient data with MHA, genetic mutation results, and response to DDAVP challenge. 62 patients met inclusion criteria. Complete responses (C) presented in mean value IU mL−1 (range), were recorded for 32 of 62(52%) subjects: pre 0.19(0.04–0.45) and post 0.78(0.5–1.95); partial responses (P) were recorded for 15 of 62(24%) subjects: pre 0.1(0.06–0.15) and post 0.4(0.3–0.47); responses that were not clinically significant (N) were recorded for 15 of 62(24%) subjects: pre 0.17(0.02–0.34) and post 0.25(0.03–0.44). Subjects (related and unrelated) with the same mutation showed a trend towards a similar response to DDAVP. Eight genotypes were common to two or more subjects (n = 26). Two genotypes were concordant in all subjects p.Ser2192Ile n = 3(C), p.Ala2220Pro n = 2(P). Of mutations in the C1 or C2 domains, 13 of 15(87%) subjects responded to DDAVP C = 9(60%); P = 4(27%); n = 2(13%). Baseline FVIII:C did not predict magnitude of response to DDAVP. Genetic mutation results can assist with predicting DDAVP responsiveness, but baseline FVIII:C may not.
Background and Objectives
The purpose of our studies was to determine the effects of extended platelet storage on poststorage platelet viability.
Materials and Methods
Normal subjects were recruited ...to donate platelets using two different apheresis systems: either the COBE Spectra (n = 58) or the Haemonetics MCS+ (n = 84). Platelet recovery and survival data from the two systems were compared with each other and with in vitro measurements of the stored platelets.
Results
There were no significant differences in either platelet recoveries or survivals between the two machines between 1 and 8 days of storage. Combining the data from both machines, platelet recoveries decreased by 2·6% and survivals by 0·3 days/storage day. In vitro assays did not predict either platelet recoveries or survivals during storage for 5–8 days. After 9 days of storage, pHs were unacceptable (≤ 6·1), suggesting that 8 days will be the longest possible storage time.
Conclusions
These data suggest that, if stored platelet bacterial contamination issues are resolved, significant extension of platelet storage times is possible.
Objectives
Three leucoreduction filters were evaluated – when used alone or combined with centrifuge leucoreduction (C‐LR) – to prevent alloimmune platelet refractoriness in a dog platelet ...transfusion model.
Materials and Methods
Donor platelet‐rich plasma (PRP) or buffy coat (BC) platelets were either filter leucoreduced (F‐LR) or F‐LR/C‐LR, 51Cr radiolabelled and transfused. Weekly transfusions were given for up to 8 weeks or until platelet refractoriness. Recipients who accepted treated transfusions were then given non‐leucoreduced (non‐LR) platelets to determine whether donor‐specific tolerance had been induced.
Results
Acceptance of F‐LR PRP transfusions ranged from 29% to 66%. F‐LR/C‐LR transfusions prepared from PRP were accepted by 92%, from BC by 63% and from pooled PRP by 75% of recipients (p=NS); overall acceptance rate of F‐LR/C‐LR transfusions was 83%. Tolerance to subsequent non‐LR transfusions occurred in 45% of the F‐LR‐/C‐LR‐accepting recipients unrelated to DR‐B compatibility between donors and recipients (P = 0·18).
Conclusion
In a dog platelet transfusion model, acceptance of donor platelets required combining F‐LR with C‐LR as apparently each process removes different immunizing WBCs.
This randomized controlled study was undertaken to determine the effect of recombinant human erythropoietin (rHuEPO) on erythropoiesis, autologous blood collection, and allogeneic transfusion risk in ...elective surgery patients with low baseline hematocrits.
Patients (n = 204) with low baseline hematocrits ( < or = 39%), scheduled for orthopedic surgery within 25 to 35 days, were seen every 3 to 4 days for 21 days. At each visit, 450 mL of blood was collected if the hematocrit was > or = 33 percent, and rHuEPO (600 U/kg) or placebo was administered intravenously.
One hundred seventy-three patients were evaluable. The number of autologous units collected from the rHuEPO and control groups, respectively, was 4.5 +/- 1.0 and 3.0 +/- 1.1 (p < 0.001), and marrow production of red cells increased by 668 +/- 222 and 353 +/- 155 mL over and above baseline production (p < 0.05). Allogeneic blood transfusion was required by 31 percent of control and 20 percent of rHuEPO patients (p = 0.09). Excluding 8 patients who received > 6 units, 29 percent of control and 14 percent of rHuEPO patients required allogeneic blood (p = 0.015). Logistic regression modeling determined that the risk of allogeneic transfusion was reduced by rHuEPO (p = 0.025).
The use of rHuEPO stimulates erythropoiesis, permits the storage of more autologous blood, and reduces allogeneic transfusion risk in patients with low hematocrits who are undergoing elective orthopedic surgery. Additional studies are necessary to determine the optimal schedules of rHuEPO administration and autologous blood collection as well as the cost-effectiveness of this strategy.
In order to assess whether patients with noninsulin-dependent diabetes mellitus (NIDDM) possess normal insulin secretory capacity, maximal B cell responsiveness to the potentiating effects of glucose ...was estimated in eight untreated patients with NIDDM and in eight nondiabetic controls. The acute insulin response to 5 g intravenous arginine was measured at five matched plasma glucose levels that ranged from approximately 100-615 mg/dl. The upper asymptote approached by acute insulin responses (AIRmax) and the plasma glucose concentration at half-maximal responsiveness (PG50) were estimated using nonlinear regression to fit a modification of the Michaelis-Menten equation. In addition, glucagon responses to arginine were measured at these same glucose levels to compare maximal A cell suppression by hyperglycemia in diabetics and controls. Insulin responses to arginine were lower in diabetics than in controls at all matched glucose levels (P less than 0.001 at all levels). In addition, estimated AIRmax was much lower in diabetics than in controls (83 +/- 21 vs. 450 +/- 93 microU/ml, P less than 0.01). In contrast, PG50 was similar in diabetics and controls (234 +/- 28 vs. 197 +/- 20 mg/dl, P equals NS) and insulin responses in both groups approached or attained maxima at a glucose level of approximately 460 mg/dl. Acute glucagon responses to arginine in patients with NIDDM were significantly higher than responses in controls at all glucose levels. In addition, although glucagon responses in control subjects reached a minimum at a glucose level of approximately 460 mg/dl, responses in diabetics declined continuously throughout the glucose range and did not reach a minimum. Thus, A cell sensitivity to changes in glucose level may be diminished in patients with NIDDM. In summary, patients with NIDDM possess markedly decreased maximal insulin responsiveness to the potentiating effects of glucose. Such a defect indicates the presence of a reduced B cell secretory capacity and suggests a marked generalized impairment of B cell function in patients with NIDDM.
Ketosis-prone diabetes is heterogeneous. Its causes could include novel β-cell functional defects. To characterize such defects, 103 patients with diabetic ketoacidosis were evaluated for β-cell ...autoimmunity and human leukocyte antigen (HLA) class II alleles, with longitudinal measurements of β-cell function and biochemical and clinical parameters. They were classified into four Aβ groups, based on the presence of glutamic acid decarboxylase (GAD)65, GAD67, or IA-2 autoantibodies (A+ or A−) and β-cell functional reserve (β+ or β−). The group distribution was: 18 A+β−, 23 A−β−, 11 A+β+, and 51 A−β+. Collectively, the two β− groups differed from the two β+ groups in earlier onset and longer duration of diabetes, lower body mass index, less glycemic improvement, and persistent insulin requirement. HLA class II genotyping showed that the A−β− group differed from the A+β− group in having lower frequencies of two alleles strongly associated with autoimmune type 1 diabetes susceptibility: DQA*03 and DQB1*02. Similarly, the A−β+ group differed from the A+β+ group in having a lower frequency of DQB1*02. Ketosis-prone diabetes comprises at least four etiologically distinct syndromes separable by autoantibody status, HLA genotype, and β-cell functional reserve. Novel, nonautoimmune causes of β-cell dysfunction are likely to underlie the A−β+ and A−β− syndromes.
To determine the feasibility of collecting 2 units (450 mL) of red cells per donation by apheresis technology, apheresis red cell collections were compared to whole-blood donations. Forty blood ...donors were equally divided between the two study arms on the basis of gender and iron supplementation (650 mg ferrous gluconate/day vs. no supplementation). During the 1-year study period, the apheresis participants donated 450 mL of red cells three times, and the whole-blood donors gave 225 mL of red cells (1 unit of blood) on six occasions. There were no reported side effects during the 102 whole-blood donations, whereas symptoms were noted in 83 percent of the 59 apheresis procedures. The most common symptoms were numbness and tingling, which were relieved by a decrease in the plasma-return rate or by the administration of oral calcium supplements. Seven donors dropped out or were deferred during the study. Two whole-blood donors left with medical problems unrelated to the study, one apheresis donor and one whole-blood donor dropped out of the study because of excessive fatigue, and three non-iron-supplemented whole-blood donors had unacceptably low hematocrit levels. By the end of the study, 70 percent of the apheresis donors considered the procedure acceptable, 15 percent were undecided, and 15 percent thought it was not acceptable. As measures of iron balance, the serum ferritin and the red cell zinc protoporphyrin:heme ratios were significantly more abnormal in the non-iron-supplemented donors than in the iron-supplemented donors. However, there were no differences in iron balance according to the donation method.
Many lawyers, military legalists, scholars, and policymakers continue to march the United States down the road to full membership in the International Criminal Court (ICC). This article explores the ...darker side of such a trek, from both legal and strategy perspectives, by examining three important fracture points that make joining the ICC irreconcilable with our Constitutionally-based republican form of government: Constitutionally protected individual rights; the American legal notion of the individual right of self-defense, and the influence of Sharia law.
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