Prolonged platelet storage associated with increased frequency of transfusion-related adverse events.

BACKGROUND: Platelets (PLTs) have been associated with the highest rate of transfusion-associated adverse events (AEs) among all blood products. Most of PLT-associated AEs are considered to have an inflammatory mechanism. However, it is still unclear whether prolonged storage of platelets is associated with an increased rate of transfusion-related AEs, especially in the era of universal prestorage leucoreduction. METHODS/MATERIALS: In this retrospective study, 52 649 PLT products consisting of about 80% apheresis PLTs and 20% whole blood-derived (WBD) PLTs were transfused to 9415 patients from July 2011 to March 2017. All the PLTs were leucoreduced prior to storage. All but 69 units of the apheresis PLTs were irradiated and none of WBD PLTs were irradiated. During this period, a total of 284 AEs that were reported to the transfusion service were analysed. RESULTS: Univariate and multivariate logistic analyses showed that apheresis/irradiated PLTs and PLT age were associated with a significantly increased frequency of inflammation type AEs (OR (95% CI): 2·24 (1·32, 4·15) and 1·30 (1·12, 1·52), respectively). There was a significant increase in the frequency of inflammation AEs associated with prolonged storage of apheresis/irradiated PLTs [OR (95% CI): 1·26 (1·03, 1·53)]. In contrast, there was no association between allergic symptoms and PLT age. Moreover, the frequency of transfusion AEs associated with apheresis/irradiated PLTs (57·2/10 000) was significantly higher than that of WBD/nonirradiated PLTs (26·0/10 000) (P < 0·01). CONCLUSION: Prolonged storage of apheresis/irradiated PLTs was associated with a higher frequency of inflammation AEs. Apheresis/irradiated PLTs caused more AEs than WBD/nonirradiated PLTs.

Caplacizumab reduces the frequency of major thromboembolic events, exacerbations and death in patients with acquired thrombotic thrombocytopenic purpura.

Essentials Acquired thrombotic thrombocytopenic purpura (aTTP) is linked with significant morbidity/mortality. Caplacizumab's effect on major thromboembolic (TE) events, exacerbations and death was studied. Fewer caplacizumab-treated patients had a major TE event, an exacerbation, or died versus placebo. Caplacizumab has the potential to reduce the acute morbidity and mortality associated with aTTP. SUMMARY: Background Acquired thrombotic thrombocytopenic purpura (aTTP) is a life-threatening autoimmune thrombotic microangiopathy. In spite of treatment with plasma exchange and immunosuppression, patients remain at risk for thrombotic complications, exacerbations, and death. In the phase II TITAN study, treatment with caplacizumab, an anti-von Willebrand factor Nanobody® was shown to reduce the time to confirmed platelet count normalization and exacerbations during treatment. Objective The clinical benefit of caplacizumab was further investigated in a post hoc analysis of the incidence of major thromboembolic events and exacerbations during the study drug treatment period and thrombotic thrombocytopenic purpura-related death during the study. Methods The Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) for 'embolic and thrombotic events' was run to investigate the occurrence of major thromboembolic events and exacerbations in the safety population of the TITAN study, which consisted of 72 patients, of whom 35 received caplacizumab and 37 received placebo. Results Four events (one pulmonary embolism and three aTTP exacerbations) were reported in four patients in the caplacizumab group, and 20 such events were reported in 14 patients in the placebo group (two acute myocardial infarctions, one ischemic stroke, one hemorrhagic stroke, one pulmonary embolism, one deep vein thrombosis, one venous thrombosis, and 13 aTTP exacerbations). Two of the placebo-treated patients died from aTTP during the study. Conclusion In total, 11.4% of caplacizumab-treated patients and 43.2% of placebo-treated patients experienced one or more major thromboembolic events, experienced an exacerbation, or died. This analysis shows the potential for caplacizumab to reduce the risk of major thromboembolic morbidities and mortality associated with aTTP.

Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies.

Essentials An international collaboration provides a consensus for clinical definitions. This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP). The consensus defines diagnosis, disease monitoring and response to treatment. Requirements for ADAMTS-13 are given. SUMMARY: Background Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that leads to microangiopathic hemolytic anemia and thrombocytopenia, and involves capillary and small-vessel platelet aggregates. The most common cause is disseminated intravascular coagulation, which may be differentiated by abnormal coagulation. Clinically, a number of conditions present with microangiopathic hemolytic anemia and thrombocytopenia, including cancer, infection, transplantation, drug use, autoimmune disease, and pre-eclampsia and hemolysis, elevated liver enzymes and low platelet count syndrome in pregnancy. Despite overlapping clinical presentations, TTP and HUS have distinct pathophysiologies and treatment pathways. Objectives To present a consensus document from an International Working Group on TTP and associated thrombotic microangiopathies (TMAs). Methods The International Working Group has proposed definitions and terminology based on published information and consensus-based recommendations. Conclusion The consensus aims to aid clinical decisions, but also future studies and trials, utilizing standardized definitions. It presents a classification of the causes of TMA, and criteria for clinical response, remission and relapse of congenital and immune-mediated TTP.

Acquired thrombotic thrombocytopenic purpura: new therapeutic options and their optimal use.

Advances in our understanding of the pathophysiology of both congenital and acquired thrombotic thrombocytopenic purpura (TTP) have led to both an increased understanding of the disease and novel approaches to therapy. The efficacy of rituximab in acquired TTP has led to consideration of rituximab as a prophylactic therapy to prevent relapse of TTP. Novel therapies that target the A1 domain of von Willebrand factor (VWF) to block the formation of microthrombotic disease have also entered clinical study and have demonstrated promise as potential therapeutic options. Additionally, a recombinant ADAMTS13 protease has been developed which may be an important therapeutic option for both congenital and acquired TTP. The development of these new therapeutic options for patients diagnosed with TTP has increased the importance of conducting prospective, randomized studies with these agents to both confirm their efficacy and more importantly understand their most appropriate role in the treatment of patients with TTP.

A rapid test for the diagnosis of thrombotic thrombocytopenic purpura using surface enhanced laser desorption/ionization time-of-flight (SELDI-TOF)-mass spectrometry.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP), a life-threatening thrombotic microangiopathy, requires immediate diagnosis and plasma exchange therapy. Development of TTP is related to functional deficiency of ADAMTS-13 protease that leads to the accumulation of ultra large von Willebrand factor (VWF) and subsequent platelet thrombosis. Currently no clinical test is available for the rapid detection of ADAMTS-13 activity. OBJECTIVES: The goal is to devise a novel method to rapidly detect functional activity of ADAMTS-13 and improve clinical outcome. METHODS AND RESULTS: A recombinant VWF substrate containing the ADAMTS-13 cleavage site and a 6X Histidine tag was cleaved by ADAMTS-13 in a dose-dependent manner, generating approximately 7739 Da peptide containing a 6X Histidine tag. This cleaved peptide, bound to an IMAC/Nickel ProteinChip, was quantified using Surface Enhanced Laser Desorption/Ionization Time-of-flight Mass Spectrometry (SELDI-TOF-MS). The assay is capable of quantifying ADAMTS-13 activity as low as 2.5% in plasma within 4 h. When the cleaved peptide was quantified as a ratio of an internal control peptide, the test displayed good reproducibility, with an average inter-assay coefficient of variation (CV) of < 33%. Further validation revealed a mean ADAMTS-13 activity of 92.5% +/- 16.6% in 39 healthy donors. Sixteen patients with idiopathic TTP displayed mean ADAMTS-13 activity of 1.73% +/- 3.62%. Further utility of this novel method includes determining the inhibitory titer of ADAMTS-13 antibody in cases of acquired TTP. CONCLUSIONS: We have devised a novel SELDI-TOF-MS assay that offers a rapid, cost-effective, and functionally relevant test for timely diagnosis and management of TTP.

Preliminary experience with a new chemotherapy regimen for adults with acute lymphoblastic leukemia.

We treated 11 consecutive adult patients who presented with acute lymphoblastic leukemia to the University of Chicago with a novel, intensified chemotherapy regimen to evaluate the feasibility and toxicity of this program. Following a 5-drug induction therapy (course A), patients received sequential courses (B and C) of high-dose antimetabolite therapies, in part to replace cranial irradiation for CNS prophylaxis. All patients achieved a complete remission. The regimen was designed with a goal of administering all post-remission therapy in the outpatient setting. With the exception of the initial induction course (A), 3(1/3)8 total patient courses were administered in the outpatient clinic. As expected, the induction and consolidation courses (A and B) of this regimen were associated with grade 4 hematologic toxicity and significant but manageable infectious toxicity. Another novel aspect of the regimen included a combined intravenous and oral dosing schedule designed to sustain methotrexate levels > or = 1.0 microM for 30 hours (course C). There was minimal toxicity with the CNS prophylaxis/high-dose methotrexate course (C). Methotrexate levels at 30 hours ranged from 0.31-4.0 microM, with a median of 1.0 microM (n=37). This study demonstrates that this novel post-remission regimen is feasible in adults and that high concentrations of methotrexate can be sustained in the outpatient setting. The Cancer and Leukemia Group B is presently evaluating the efficacy of this regimen in a large phase II trial (CALGB study 19802).

Antibody therapy of acute and chronic leukemias.

The development of antibody-based therapies for the treatment of both acute and chronic leukemias have undoubtedly been one of the most important advances in the treatment of leukemia. The importance of these novel agents lies not only in their unique mechanisms of action, but also their improved side effect profile which allows patients of advanced age or with significant co-morbid medical conditions to receive potentially beneficial therapies. Advances in therapeutic applications of monoclonal antibodies have come from a greater understanding of the biological characteristics of the antibody, as well as the target antigen, both of which impact the potential efficacy of a particular antibody. In the following review we will discuss the clinical development and potential roles of monoclonal antibodies in the treatment of both acute and chronic leukemias.

The Semmes-Weinstein monofilament as a potential predictor of foot ulceration in patients with noninsulin-dependent diabetes.

The objective was to evaluate the Semmes-Weinstein monofilament as a potential predictor of foot ulceration. A case-control study was carried out in a teaching hospital clinic specializing in diabetes and hyperlipidemic disorders. Two groups of patients with noninsulin-dependent diabetes mellitus were studied: 168 with no history of foot lesions (No-Ulcer group, aged 58.1 +/- 9.7 years, duration 11.5 +/- 7.8 years) and 14 who had at least one foot ulceration during the last year (foot ulcer group, aged 60.8 +/- 7.8 years', duration 17.1 +/- 10.5 years). The authors defined and measured a "monofilament index" using a size 5.07 Semmes-Weinstein monofilament on three locations on each foot and then measured peroneal nerve current perception thresholds using the Neurometer at three frequencies: 5 Hz, 250 Hz, and 2,000 Hz. The monofilament index score was lower in patients in the foot ulcer group than in patients in the No-Ulcer group (1.71 +/- 2.36 vs 5.21 +/- 1.81, P < 0.001). A cutoff point at an index of 5 out of 6 yielded a sensitivity rate of 85.71% and a false-positive rate of 16.07%. The peroneal nerve current perception threshold was higher (P < 0.005) in patients in the foot ulcer group than in patients in the No-Ulcer group for all frequencies (605.8 +/- 414.6 vs 181.5 +/- 272.3 for 5 Hz; 743.2 +/- 361.7 vs 251.6 +/- 283.7 for 250 Hz; 859.4 +/- 220.2 vs 423.3 +/- 252.6 for 2,000 Hz). (ABSTRACT TRUNCATED AT 250 WORDS)

Continuous subcutaneous octreotide infusion: dose-response relationships between metabolic effects and octreotide clearance in patients with insulin-dependent (type 1) diabetes.

Octreotide (Sandostatin), a potent and long-acting octapeptide analogue of somatostatin, exhibits variable metabolic effects in type 1 diabetes. We have postulated that interindividual variability in octreotide metabolism could be responsible in part for the differences in metabolic responses reported in previous clinical studies. To this end, we determined plasma levels and MCR of octreotide during 24-hour continuous SC infusion (low dose, 200 micrograms; high dose, 400 micrograms) in nine female, C peptide-negative patients with type 1 diabetes. The metabolic effects of the analogue were assessed by measuring serum glucose, free insulin, glucagon, GH, and PP levels before and at 1- to 2-hour intervals during each dose of the analogue or control (0.9% saline solution) infusion in a single-blind randomized manner. Mean daytime (0800-0000 hours) and bedtime (0000-0800 hours) serum glucose levels decreased significantly (p less than 0.05 to 0.02) during analogue therapy compared with control. Mean serum free insulin levels were significantly (p less than 0.02) greater during octreotide infusion compared with control, despite the similar daily insulin requirements. Both doses of the analogue effectively suppressed 24-hour GH by 50%, glucagon by 50%, and PP by 80%. Steady-state octreotide levels varied considerably among patients (low, mean +/- SEM), 1000 +/- 101, range 638 to 1375 pg/ml; high, mean 1940 +/- 147, range 1032 to 2462 pg/ml). Although mean MCR values were similar with both doses, we observed greater interindividual variability (low, mean 2.45 +/- 0.30, range 1.31 to 3.78 ml/kg/min; high, mean 2.36 +/- 0.19, range 1.68 to 3.48 ml/kg/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic effects of long-acting somatostatin analogue (sandostatin) in type I diabetic patients on conventional therapy.

We evaluated the effectiveness of a more potent and longer-acting somatostatin analogue (SMS 201-995) as an adjunct to insulin therapy, in a double-blind placebo-controlled randomized study of 26 C-peptide-negative type I (insulin-dependent) diabetic patients (20 women, 6 men, aged 22-40 yr) on their conventional drug regimens for 12 wk. Eight patients received a low dose (10 micrograms) of the analogue, 9 received a high dose (50 micrograms) of the analogue, and 9 received placebo subcutaneously before breakfast and dinner. Twenty-four-hour serum glucose, free insulin, plasma growth hormone (GH), and glucagon profiles were obtained before and during treatment at 4-wk intervals. The mean age, duration of diabetes, daily insulin dose, and body weight were not significantly different among the groups. The mean weekly capillary blood glucose values and exogenous insulin requirements were not changed by the SMS 201-995 therapy. Mean glycosylated hemoglobin A1 levels were unchanged in both the analogue- and placebo-treated groups at wk 12. Basal and postprandial glucose, free insulin, GH, and glucagon profiles were not influenced by the SMS 201-995 therapy throughout the study. Nocturnal glucose turnover rates (D-[3-3H]glucose technique) remained unaltered by the analogue therapy. Dose-dependent gastrointestinal (GI) adverse effects (e.g., diarrhea) were documented in the analogue-treated patients. Visual acuity and fundic photomicrographs of our patients were not changed by the analogue therapy. In conclusion, the prominent adverse GI effects our patients experienced preclude the use of larger doses of the analogue that may be necessary to suppress GH and glucagon and improve glucose control in type I diabetic patients.

Comparison of the effects of continuous subcutaneous infusion and split-mixed injection of insulin on nerve function in type I diabetes mellitus.

Comparable groups of type I diabetic patients (n = 19) were matched for age, duration of diabetes, mean HbA1 values, insulin requirements, degree of neuropathy, and the mean of nerve conduction velocities (CV) in median, ulnar, and peroneal motor and median, ulnar, and sural sensory nerves. One group (n = 9) was managed with continuous subcutaneous infusion of (regular) insulin (CSII); the other (n = 10) with split-mixed injections of (intermediate and regular) insulin (SMII). After 12 months, glucose regulation was equally and significantly improved in both groups (P less than 0.005), although it was not sufficiently intense to normalize mean total glycosylated hemoglobin values in either group. Furthermore treatment produced no difference between groups in the values for mean amplitude of glycemic excursions, 12 month average of consecutive M-values or in clinical evaluation. However, in the CSII group, mean CV had increased 6.4% (2.75 + 0.56 m/s; mean +/- SEM) versus 1.3% (0.57 +/- 0.54 m/s) in the SMII group (P less than 0.005). Multivariate analysis on a nerve-by-nerve basis found significantly improved conduction in 2/6 nerves (median motor; ulnar sensory) in the CSII group compared to the SMII group. These results suggest that CSII may provide a more favorable microenvironment for nerve repair.

Absence of hepatic extraction of gastric inhibitory polypeptide in conscious dogs.

Fractional hepatic extraction of gastric inhibitory polypeptide was examined in conscious unrestrained dogs with catheters in the portal vein, hepatic vein, and the carotid artery and Doppler flow probes on the portal vein and hepatic artery. Following a control period, endogenous gastric inhibitory polypeptide was stimulated by oral administration of glucose with and without prior infusion of atropine. In other experiments, gastric inhibitory polypeptide (20 ng/kg/min) was infused into the portal system in association with peripheral infusion of glucose. In none of these experiments was it possible to demonstrate any significant fractional hepatic extraction of gastric inhibitory polypeptide.

Exercise adaptation responses for gastric inhibitory polypeptide (GIP) and insulin in obese children. Possible extra-pancreatic effects.

Thirteen obese children and matched controls were fed a mixed meal, and responses were evaluated at fixed intervals for glucose, insulin, and gastric inhibitory polypeptide (GIP). The obese children were evaluated before and within 48 h after completion of a 5-mo exercise training program (ETP). The ETP included three aerobic exercise sessions per week and modest diet restrictions. Caloric expenditure was increased by approximately 300 kcal/exercise session. Weight gain was minimal over the 5 mo. An unexpected increase in GIP response and improved insulin tolerance were recorded for the obese children post-ETP. GIP values were higher (P less than 0.05) at 30 and 60 min and led to a highly significant elevation (P less than 0.01) of the integrated GIP response for post-ETP obese versus both pre-ETP and normal-weight controls. Insulin values were lower (P less than 0.05) at 30 and 60 min and led to a lower integrated insulin response (P less than 0.0585) for post-ETP obese children. However, the obese children continued to secrete more insulin (P less than 0.05) than normal-weight controls. Glucose tolerance, similar for pre-ETP obese subjects and controls, did not change in post-ETP children. Exercise-induced improvement in glucose utilization in these obese children was associated with an increase in GIP secretion. This contrasts with reports that calorie restriction will improve glucose utilization with decreased insulin and GIP secretion. The study demonstrates a previously unreported uncoupling of GIP and insulin secretion and suggests shifts in peripheral tissue sensitivity to insulin-induced glucose uptake. These shifts may, in part, be influenced by GIP.

Identification of tissue insulin receptors: use of a unique in vivo radioreceptor assay.

An in vivo radioreceptor assay for polypeptide hormones has been developed and applied to the identification of tissue insulin receptors. The theoretical basis for this assay is presented elsewhere in this issue. 125I-insulin and 131I-albumin were infused into male rats with increasing amounts of unlabeled insulin. Plasma samples were taken at 1-min intervals until the animals were killed at 5 min. Tissue samples were excised and weighed and the activity due to each isotope counted. By comparing the differential distribution of the labeled tracers and applying the results to a compartment model, the specific, displaceable binding of insulin to tissue receptors could be demonstrated. Binding was detected in the liver, muscle, fat, adrenal glands, pancreas, small intestines, and spleen.

Theoretical basis for a new in vivo radioreceptor assay for polypeptide hormones.

To date the in vivo identification and quantitation of specific hormone receptors has been difficult, time consuming, and lacking in sensitivity. We present the theory underlying a new in vivo radioreceptor assay for polypeptide hormones based on receptor theory derived from in vitro investigations and in vivo kinetic and autoradiographic studies. The assay was developed from a tissue model and a theory of hormone distribution. Measuring the labeled hormone distributed between the plasma and interstitial space in the presence or absence of excess unlabeled hormone permits the accurate determination of hormone specifically bound to receptors. This approach eliminates the problem of nonspecific binding due to free tracer, hormone degradation products, or labeled non-hormone molecules. A receptor compartment and specific binding of hormone are calculated from only four measured parameters: total tissue labeled hormone, tissue albumin, plasma labeled hormone, and plasma albumin. The method is applicable to most tissues and hormones under a variety of conditions and permits simultaneous comparison of multiple tissues in the same animal under identical conditions.

Production of 12-hydroxyeicosatetraenoic acid and vitamin E status in platelets from type I human diabetic subjects.

Vitamin E content and biosynthesis of 12-hydroxyeicosatetraenoic acid (12-HETE) have been measured in platelets from type I diabetic subjects and age- and sex-matched, nondiabetic control subjects. Platelets from diabetic subjects synthesized significantly greater quantities of 12-HETE than did platelets from control subjects when 12-HETE synthesis was induced by thrombin or collagen, either in the presence or absence of indomethacin. Platelet conversion of exogenously added arachidonic acid (AA) to 12-HETE was not significantly different between the diabetic and control groups in the absence of indomethacin, although a small but significant increase in the conversion of AA to 12-HETE was present in the diabetic group platelets when indomethacin was added to the reaction. Vitamin E content was significantly reduced in platelets from the diabetic subjects, when compared with platelets from the control subjects, although plasma vitamin E levels were not significantly different between the two groups. Thrombin- and collagen-induced platelet 12-HETE synthesis demonstrated a significant negative linear correlation with platelet vitamin E content when measurements from both diabetic and control groups were combined. The above data suggest a relationship between low vitamin E content and increased 12-HETE synthesis in platelets from type I diabetic subjects.