Sara K. Vesely

Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND Neonates and children differ from adults in physiology, pharmacologic responses to drugs, epidemiology, and long-term consequences of thrombosis. This guideline addresses optimal strategies for the management of thrombosis in neonates and children. METHODS The methods of this guideline follow those described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. RESULTS We suggest that where possible, pediatric hematologists with experience in thromboembolism manage pediatric patients with thromboembolism (Grade 2C). When this is not possible, we suggest a combination of a neonatologist/pediatrician and adult hematologist supported by consultation with an experienced pediatric hematologist (Grade 2C). We suggest that therapeutic unfractionated heparin in children is titrated to achieve a target anti-Xa range of 0.35 to 0.7 units/mL or an activated partial thromboplastin time range that correlates to this anti-Xa range or to a protamine titration range of 0.2 to 0.4 units/mL (Grade 2C). For neonates and children receiving either daily or bid therapeutic low-molecular-weight heparin, we suggest that the drug be monitored to a target range of 0.5 to 1.0 units/mL in a sample taken 4 to 6 h after subcutaneous injection or, alternatively, 0.5 to 0.8 units/mL in a sample taken 2 to 6 h after subcutaneous injection (Grade 2C). CONCLUSIONS The evidence supporting most recommendations for antithrombotic therapy in neonates and children remains weak. Studies addressing appropriate drug target ranges and monitoring requirements are urgently required in addition to site- and clinical situation-specific thrombosis management strategies.

Survival and relapse in patients with thrombotic thrombocytopenic purpura.

Survival of patients with thrombotic thrombocytopenic purpura (TTP) improved dramatically with plasma exchange treatment, revealing risk for relapse. The Oklahoma TTP Registry is a population-based inception cohort of all 376 consecutive patients with an initial episode of clinically diagnosed TTP (defined as microangiopathic hemolytic anemia and thrombocytopenia with or without signs and symptoms of ischemic organ dysfunctions) for whom plasma exchange was requested, 1989 to 2008. Survival was not different between the first and second 10-year periods for all patients (68% and 69%, P = .83) and for patients with idiopathic TTP (83% and 77%, P = .33). ADAMTS13 activity was measured in 261 (93%) of 282 patients since 1995. Survival was not different between patients with ADAMTS13 activity < 10% (47 of 60, 78%) and patients with 10% or more (136 of 201, 68%, P = .11). Among patients with ADAMTS13 activity < 10%, an inhibitor titer of 2 or more Bethesda units/mL was associated with lower survival (P = .05). Relapse rate was greater among survivors with ADAMTS13 activity < 10% (16 of 47, 34%; estimated risk for relapse at 7.5 years, 41%) than among survivors with ADAMTS13 activity of 10% or more (5 of 136, 4%; P < .001). In 41 (93%) of 44 survivors, ADAMTS13 deficiency during remission was not clearly related to subsequent relapse.

The incidence of thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS‐13 deficiency

Summary.  Background: Accurate estimates of the incidence of thrombotic thrombocytopenic purpura (TTP) are important to assess the resources required for current treatments as well as to anticipate the need to develop new treatments. Previous estimates have been indirect and have not reported data on patients with ADAMTS‐13 deficiency. Objective: To determine the incidence of patients with TTP‐hemolytic uremic syndrome (HUS) in three categories: all patients with clinically suspected TTP‐HUS, patients with idiopathic TTP‐HUS, and patients with severe ADAMTS‐13 deficiency. Methods: Incidence rates were estimated from the Oklahoma TTP‐HUS Registry, analyzing all 206 consecutive patients from January 1, 1996 to June 30, 2004 who were treated with plasma exchange for their initial episode of clinically suspected TTP‐HUS. ADAMTS‐13 activity was measured in 186 (90%) of the 206 patients. Results: The age–sex–race standardized annual incidence rates were 11.29 × 106 (95% CI: 9.70–12.88) for all patients with clinically suspected TTP‐HUS; 4.46 × 106 (95% CI: 3.43–5.50) for patients with idiopathic TTP‐HUS; and 1.74 × 106 (95% CI: 1.06–2.41) for patients with severe ADAMTS‐13 deficiency (<5% activity). In all three categories, the incidence rates were greater for women and for blacks. For patients with severe ADAMTS‐13 deficiency, the age–sex standardized incidence rate ratio of blacks to non‐blacks was 9.29 (95% CI: 4.33–19.93). Conclusions: Accurate incidence rate estimates for all patients with clinically suspected TTP‐HUS, idiopathic TTP‐HUS, and TTP associated with severe ADAMTS‐13 deficiency have been determined. The greater incidence among women and blacks is comparable with their increased risk for other autoimmune disorders.

Complications of plasma exchange in 71 consecutive patients treated for clinically suspected thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome

BACKGROUND With the increased frequency of diagnosis and improved survival of thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome (TTP-HUS), the morbidity of plasma exchange (PE) treatment has become more important. STUDY DESIGN AND METHODS Data were prospectively collected on 71 consecutive patients referred to the Oklahoma Blood Institute (OBI) for PE treatment for clinically suspected TTP-HUS from mid-1996 to mid-1999. Complications were defined as major or minor, and distinguished between those related to central venous catheter access or to the plasma. RESULTS Twenty-one patients (30%) had 27 major complications, which caused two deaths. The major complications included 2 episodes of hemorrhage after subclavian line insertion (1 death), 1 pneumothorax requiring a chest tube, 12 systemic infections (1 death), 7 episodes of catheter thrombosis requiring removal of the central venous catheter, 2 episodes of venous thrombosis requiring anticoagulant treatment, 2 episodes of hypoxemia and hypotension, and 1 episode of serum sickness. Minor complications occurred in 22 additional patients (31%). Twenty-eight patients (39%) had no complications. CONCLUSIONS The morbidity and mortality of catheter placement and PE are important considerations when PE treatment for clinically suspected TTP-HUS is anticipated.

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: A diagnostic dilemma

BACKGROUND: Thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome (TTP‐HUS) has been described as a specific sequela of allogeneic HPC transplantation (HPCT). Nevertheless, because multiple transplant‐related sequela can cause the characteristic clinical features of TTP‐HUS, the diagnosis is difficult.

The incidence of immune thrombocytopenic purpura in children and adults: A critical review of published reports

Reports of the incidence of ITP are few and their methodology is variable. Accurate estimates of the incidence of immune thrombocytopenic purpura (ITP) are important to understand the medical and public health impact of the disease. To critically review all published reports on the incidence of ITP in children and adults, all articles identified on the Medline database (searched January 1, 1966‐August 7, 2009) that reported data on the incidence of ITP were retrieved. Articles which directly estimated the incidence of ITP were selected for review. Eight articles reported the incidence of acute ITP in children. After review, four were determined to have the strongest estimates, based on the method of patient identification and study design. The lowest incidence estimate in these four studies was 2.2 per 105 children/year (95% confidence interval 1.9, 2.4) and the highest incidence estimate was 5.3 per 105 children/year (95% confidence interval 4.3, 6.4). Three studies reported the incidence of ITP in adults. The estimate from the article with the strongest methodology reported an incidence estimate of 3.3 per 105 adults/year. The current strongest estimate of the incidence of acute ITP in children is between 1.9 and 6.4 per 105 children/year; for adults the current strongest estimate of the incidence of ITP is 3.3 per 105 adults/year. An important limitation of these studies is that they are primarily from Europe and may not be generalizable to all regions. Am. J. Hematol. 2010.

Quinine-Associated Thrombotic Thrombocytopenic Purpura–Hemolytic Uremic Syndrome: Frequency, Clinical Features, and Long-Term Outcomes

In 1994, Gottschall and coworkers published a report of 9 patients with thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure after ingestion of quinine (1, 2). That report, along with previous reports involving 8 patients, established quinine-associated thrombotic thrombocytopenic purpurahemolytic uremic syndrome (TTPHUS) as a new clinical entity. Five additional patients with quinine-associated TTPHUS have subsequently been described (3). Of these 22 patients, 1 died and 2 developed chronic renal failure. These findings suggested that quinine-associated TTPHUS was rare and that the prognosis for complete recovery was good. We have found that quinine is a common cause of TTPHUS and that death and chronic renal failure are frequent. The frequency of quinine-associated TTPHUS may be related to continued use of quinine for nocturnal leg cramps despite a 1994 ban by the U.S. Food and Drug Administration on over-the-counter marketing (4). The purpose of our report is to describe the frequency, clinical features, and long-term outcomes of quinine-associated TTPHUS. Methods Patients All patients with clinically suspected TTPHUS who are referred to the Oklahoma Blood Institute for plasma exchange treatment are included in the Oklahoma TTPHUS Registry. This allows identification of all patients in our region with clinically suspected TTPHUS. The Oklahoma Blood Institute is the sole provider of plasma exchange in our region, and it is standard practice to treat all adult patients who have TTP or HUS with plasma exchange. The registry has complete clinical and laboratory data on 225 consecutive patients who experienced an initial episode of clinically suspected TTPHUS between 1 January 1989 and 31 December 2000. We excluded patients who developed TTPHUS after bone marrow transplantation (n = 19) and therapy with mitomycin C (n = 9) because their disease course was determined by their primary malignant disease (27 of 28 died). Since 1 January 1995, the third author has been involved in the care of 132 of 142 patients from the registry (93%). Follow-up is complete for 111 of 112 surviving patients (99%). The institutional review boards of the University of Oklahoma and community hospitals have approved the registry. Thrombotic thrombocytopenic purpurahemolytic uremic syndrome was diagnosed by the presence of thrombocytopenia and microangiopathic hemolytic anemia without another apparent cause (5, 6). The syndrome was designated as quinine-associated if the patient ingested quinine regularly, either daily or at least several times each week, at the time of onset and if the syndrome did not recur in the absence of quinine ingestion. Statistical Analysis We used the nonparametric Wilcoxon rank-sum test (intervalratio data) and the chi-square test or the Fisher exact test (categorical data) to compare patients who consumed quinine and those who did not. Patients with quinine-associated TTPHUS were divided into two groups according to the presence or absence of chronic renal failure and were compared by using the Wilcoxon rank-sum test. We used SAS software, version 6.12 (SAS Institute, Inc., Cary, North Carolina), for all analyses. Results Relation of Quinine Ingestion to Onset of Symptoms Seventeen patients had quinine-associated TTPHUS (Table 1). All patients had used quinine tablets for nocturnal leg cramps for many years. In each patient, TTPHUS was apparently provoked by a single tablet. Six patients reported taking quinine tablets regularly. In 11 patients, the mean time since taking the previous quinine tablet was 5 months (range, 2 weeks to 2 years). Four of 17 patients had had abdominal symptoms, headache, or fever and chills after previous quinine ingestions, often multiple times, which suggests quinine hypersensitivity. In patients 2 and 5, quinine was confirmed as the cause of TTPHUS because the syndrome recurred immediately after ingestion of quinine 3 to 6 months after the initial episodes (Table 1). Table 1. Clinical Features and Outcomes of 17 Women with Quinine-Associated TTPHUS Presenting Clinical and Laboratory Features Abdominal pain, nausea, vomiting, and diarrhea were the most common presenting symptoms. Symptoms often began suddenly, within several hours of ingesting quinine. Most patients reported chills and fever; sepsis was a common initial diagnosis (7). Although no patient had a history of renal disease, 16 patients were oliguric or anuric during their initial episode. Patient 2, who had acute renal failure during her first episode, had no renal failure during her two subsequent episodes. Six patients were leukopenic, and 2 patients had hypofibrinogenemia. Eight patients had abnormal results on liver function tests; of these, 2 received an initial diagnosis of hepatitis. These abnormalities have previously been associated with quinine (8-10). Five of 14 patients tested positive for quinine-dependent antiplatelet antibodies (2). Clinical Course and Treatment Fourteen of 16 patients required hemodialysis. (Patient 17 died before beginning treatment.) Two patients required permanent dialysis, while the remaining 12 required a median of 6 hemodialysis sessions (range, 2 to 31 sessions). Eleven of these 12 patients survived, and their urine output normalized in a median of 13 days (range, 6 to 25 days). In 6 patients, the serum creatinine concentration normalized in a median of 38 days (range, 19 to 380 days). Four patients died: Three died during the initial episode, and 1 died of heart failure while receiving continual hemodialysis 5 years after her second episode. Eight of 14 patients who survived the initial episode (57%) developed chronic renal failure; they were older than the other 6 patients (68 years vs. 55 years; P = 0.04). Five of the 8 patients with chronic renal failure had a history of hypertension or diabetes, compared with 1 of the 6 patients without renal failure (P = 0.14). Comparison of Patients with Quinine-Induced TTPHUS and Other Patients in Whom TTPHUS Was Clinically Suspected Beginning on 1 July 1995, all patients presenting with first episodes of clinically suspected TTPHUS (n = 132), as well as their families, were explicitly asked about quinine tablets and quinine-containing remedies and beverages (11). Fourteen patients (11%) had taken quinine tablets, and 118 had not. Seven had taken other drugs reported to cause TTPHUS (12): cyclosporine (n = 3), ticlopidine (n = 2), gemcitabine (n = 1), and pentostatin (n = 1). Patients with quinine-associated TTPHUS were all women and were older than patients who had not taken quinine (Table 2). Neurologic abnormalities, thrombocytopenia and anemia, death, and rate of relapse did not differ significantly between the two groups. Renal failure was more severe and elevated levels of serum lactate dehydrogenase were higher in patients with quinine-associated TTPHUS. Table 2. Comparison of Patients with Quinine-Associated TTPHUS and Patients with TTPHUS Not Associated with Quinine Discussion In our case series, quinine hypersensitivity was a common cause of TTPHUS and the most common cause of drug-associated TTPHUS. The older age of patients with quinine-associated TTPHUS was consistent with the more common occurrence of leg cramps in older persons (13). However, it is not known why all of our patients were women, since leg cramps, and therefore presumed quinine use, are equally common in men (13). Of note, 17 of the 22 previously reported patients (77%) were women (2, 3). In our patients, quinine-associated TTPHUS was a serious illness. Three of 17 patients (18%) died during the initial hospitalization, and 8 of 14 patients who survived the initial episode developed chronic renal failure. One patient died of complications of chronic renal failure 5 years after a second episode. Even in the 6 patients whose serum creatinine concentrations returned to normal, complete recovery was initially uncertain because the high initial serum creatinine concentrations (mean, 716 mol/L [8.1 mg/dL]) (Table 1) and brief duration of symptoms (8 hours to 4 days) suggested preexisting renal disease. However, serum creatinine concentrations can increase very rapidly in patients with TTPHUS (14), probably because of severe tissue ischemia indicated by the extreme elevation of serum lactate dehydrogenase levels (15). The mean initial value of lactate dehydrogenase in these 6 patients was 53 kat/L [3200 U/L]). Quinine-associated TTPHUS is probably caused by drug-dependent antibodies, since it can be triggered by a single quinine tablet taken many months after a previous exposure or even by quinine-containing beverages, such as tonic water (1, 16). This is distinct from TTPHUS caused by mitomycin C and cyclosporine, which is dose-dependent (12). The broad spectrum of clinical abnormalities suggests a broad spectrum of quinine-dependent antibody specificity. Previous case reports have documented quinine-dependent antibodies to platelets, granulocytes, lymphocytes, and endothelial cells (1, 2, 8). Measurements of von Willebrand factorcleaving protease activity have not been reported in patients with quinine-associated TTPHUS. A designation of TTPHUS is supported by the severity of neurologic complications, thrombocytopenia, hemolysis, and the occasional absence of renal failure. Since all previously reported patients were described as having HUS, not TTP, quinine was omitted from some discussions of drug-associated TTP (17, 18). Therefore, clinicians could fail to consider quinine as a possible cause if a patient with severe neurologic abnormalities, thrombocytopenia, and hemolysis is thought to have TTP rather than HUS. Our data are limited by our case definition, which is based on referral for plasma exchange treatment and excludes patients in whom quinine hypersensitivity is manifested principally by abnormalities that are uncommon in TTPHUS (7-10). However, our case definition also allowed prospective, consecutive identification of all patie

Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: a randomized trial.

Context Vitamin K decreases the international normalized ratio (INR) in overanticoagulated patients who receive warfarin therapy, but its effect on clinical outcomes is less clear. Contribution Trial investigators detected no differences in the frequency of bleeding, thromboembolism, or death among overanticoagulated patients who received warfarin therapy and were randomly assigned to receive low-dose vitamin K or placebo. Caution The study was underpowered to detect differences in major bleeding. Implication Low-dose vitamin K corrects the INR in overanticoagulated patients who received warfarin therapy, but it has little effect on clinical outcomes. Withdrawal of warfarin may be all that is necessary to manage elevated INRs. The Editors Warfarin is a remarkably effective drug for primary and secondary prevention of arterial and venous thromboembolism. Among commonly used medications, warfarin is unique because its doseresponse characteristics are highly unpredictable, varying both among and within individuals over time. As a result, warfarin therapy requires ongoing monitoring using the international normalized ratio (INR), a value that reflects the degree to which warfarin has reduced coagulation factor levels and the coagulant potential of blood (1). For most indications, an INR range of 2.0 to 3.0 is targeted; INR values less than 2.0 are associated with an increased risk for thromboembolism, and INR values greater than 4.0 are associated with an increase in bleeding complications. The risk for bleeding, particularly intracranial bleeding, increases markedly as the INR exceeds 4.5 (13). Even in clinics dedicated to warfarin management, INRs are outside the therapeutic range one third to one half the time (4). When managing a patient with an INR greater than 4.5 who is not bleeding, clinicians generally either withhold warfarin treatment and allow the INR to decrease to the desired value or administer vitamin K (orally or intravenously) to more rapidly reduce the INR (1, 510). Small randomized trials have shown that a single dose of low-dose oral vitamin K (for example, 1 to 2.5 mg) effectively reduces the INR in otherwise-stable overanticoagulated patients within 24 hours of its administration; however, these studies were not large enough to determine whether low-dose vitamin K reduces bleeding without increasing the risk for thromboembolism (1115). A recent systematic review (16) supported this observation. To determine whether oral vitamin K is indicated in overanticoagulated patients who are not bleeding, we did a randomized trial in which we allocated oral vitamin K or placebo, 1.25 mg, to patients who presented with an INR of 4.5 to 10.0. The primary outcome measure was the frequency of all forms of bleeding events during the first 90 days. Our hypothesis that bleeding events would be reduced was based on our previously published, smaller studies of low-dose oral vitamin K administered to various patient groups. In these studies, we found a consistent and rapid decrease in the INR after low-dose vitamin K was administered (13, 15, 1722). Methods Study Patients We identified patients with INRs of 4.5 to 10.0 in participating outpatient anticoagulant therapy clinics. We screened patients as they presented for routine INR assessment and considered them for eligibility if they were receiving warfarin therapy with a target INR of 2.0 to 3.5, their most recent INR was between 4.5 and 10.0 in the past 24 hours, and they were not bleeding. We excluded patients if discontinuation of warfarin therapy was scheduled and if they were younger than 18 years, had a life expectancy less than 10 days, had an indication for acute normalization of their INR (such as imminent surgery), had a known severe liver disease, had a history of a major bleeding event within 1 month, had a known bleeding disorder, had received thrombolytic therapy within 48 hours, had a platelet count less than 50109 cells/L, could not take oral medications, had a known allergy to vitamin K, or could not return for laboratory or clinical monitoring. Study staff at each participating anticoagulant therapy clinic approached patients who met inclusion criteria for consent to participate. This study ran in parallel with a cohort study in which patients with INRs greater than 10.0 received oral vitamin K, 2.5 mg. Patients were otherwise identical to those enrolled in this study, and we followed them for similar outcome events. The results of the concurrent cohort study will be presented in a subsequent paper. Randomization and Treatment We instructed all eligible, consenting patients to withhold warfarin for 1 day and randomly assigned them to receive a capsule containing either vitamin K, 1.25 mg, or placebo. Randomization was done by using a computer-generated random-number table at the coordinating and methods center and was stratified by clinical center. Vitamin K capsules were compounded from 5-mg vitamin K tablets (Merck & Co., Whitehouse Station, New Jersey) by a commercial pharmacy with Health Canada approval (Clinical Trials Application control number 092635). Placebo capsules contained inert filler and were indistinguishable from the capsules that contained vitamin K. Random allocation of patients was accomplished when site-specific study personnel dispensed the next numbered study drug container at each clinical center; thus, patients, treating clinicians, and research coordinators were unaware of treatment allocation. In 2 centers, we monitored the INR of outpatients in clinics or laboratories outside the clinical center. In such centers, we obtained consent for the study by telephone, and the study drug was shipped within hours to the patients home by using a courier service. In all cases, we confirmed receipt and consumption of the study drug on the day of randomization by telephone. In the remaining centers, in which patients were seen in person, consent and study drug administration occurred at the same time that the elevated INR was detected. Follow-up and Outcome Measures At enrollment, we advised patients to promptly seek medical evaluation if they developed signs or symptoms of bleeding or thromboembolism. At minimum, we assessed patients by telephone or in person on days 1, 3, 7, 14, 28, and 90 after randomization. Additional contact and INR sampling necessary to manage the patients anticoagulant therapy were done at the discretion of the patients physician. At each follow-up, we sought signs and symptoms of bleeding and thromboembolism and collected details about all such events. We asked patients a focused series of questions to help them recall these events. We reviewed and abstracted medical records of all suspected bleeding episodes, thromboembolism, and deaths. Our primary outcome measure was the frequency of bleeding events during the 90 days after randomization. We defined major bleeding as fatal bleeding, bleeding requiring transfusion of 2 or more units of packed red blood cells, bleeding resulting in a therapeutic intervention (such as endoscopy), or objectively confirmed bleeding into an enclosed space. We defined minor bleeding as bleeding resulting in a medical assessment that did not meet criteria as a major bleeding event. We defined trivial bleeding as all patient-reported bleeding events that did not result in a medical assessment. We combined all reported bleeding events (major, minor, and trivial) for this analysis. We chose to combine these events because our clinical experience suggested that reducing medically unimportant but bothersome bleeding, such as epistaxis, bruising, and menorrhagia, was a clinically important goal for our patients; patients with a minor or trivial bleeding event may be at greater risk for subsequent major bleeding; and the frequency of major bleeding was likely to be very low, calling into question the feasibility of a study powered to detect differences in major bleeding events. Secondary outcome measures included the frequency of major bleeding events, objectively confirmed venous or arterial thromboembolism, and death during the 90 days after randomization. We chose the 90-day period on the basis of our previous studies wherein we found a significant reduction in bleeding events (90 days) after the administration of similar doses of oral vitamin K (13). We hypothesized that low-dose oral vitamin K might influence a bleeding event during this extended period, because even small doses of this highly lipophilic drug might have an extended influence on INR control (and thus the risk for bleeding and thrombosis). In post hoc analyses, we examined the frequency of all bleeding and major bleeding events in the first 7 days and the number of clinical events in patients who were older than 70 years at enrollment. An independent adjudication committee, blinded to treatment allocation and not otherwise involved in the study, reviewed all bleeding events, thromboembolism, and deaths. Confirmation of venous thromboembolism required a nononcompressible venous segment on ultrasonography, an intraluminal filling defect on venography or computed tomographic pulmonary angiography, or a segmental (or larger) mismatch defect on ventilationperfusion lung scan. Arterial thromboembolism required either direct surgical visualization of thrombus; an intraluminal filling defect on angiography; or clear evidence of a new ischemic event on an objective test, such as electrocardiography, computed tomography, or magnetic resonance imaging. We advised clinics to reinstitute warfarin therapy once the INR was within the therapeutic reference interval after administration of the study drug. The clinicians who cared for the patients determined the warfarin dose when the drug was readministered. Target INR ranges for individual patients did not change as a result of the elevated INR that led to enrollment. Statistical Analysis Our primary analysis was an intention-to-treat comparison of the proportions of patien

Severe hemorrhage in children with newly diagnosed immune thrombocytopenic purpura

Controversy exists regarding management of children newly diagnosed with immune thrombocytopenic purpura (ITP). Drug treatment is usually administered to prevent severe hemorrhage, although the definition and frequency of severe bleeding are poorly characterized. Accordingly, the Intercontinental Childhood ITP Study Group (ICIS) conducted a prospective registry defining severe hemorrhage at diagnosis and during the following 28 days in children with ITP. Of 1106 ITP patients enrolled, 863 were eligible and evaluable for bleeding severity assessment at diagnosis and during the subsequent 4 weeks. Twenty-five children (2.9%) had severe bleeding at diagnosis. Among 505 patients with a platelet count less than or equal to 20 000/mm(3) and no or mild bleeding at diagnosis, 3 (0.6%), had new severe hemorrhagic events during the ensuing 28 days. Subsequent development of severe hemorrhage was unrelated to initial management (P = .82). These results show that severe bleeding is uncommon at diagnosis in children with ITP and rare during the next 4 weeks irrespective of treatment given. We conclude that it would be difficult to design an adequately powered therapeutic trial aimed at demonstrating prevention of severe bleeding during the first 4 weeks after diagnosis. This finding suggests that future studies of ITP management should emphasize other outcomes.

The Potential Protective Effect of Youth Assets on Adolescent Alcohol and Drug Use

OBJECTIVES We examined the association between adolescent alcohol and drug use and 9 youth assets in a low-income, inner-city population. METHODS An in-person survey of 1350 adolescents and parents assessed youth assets and risk behaviors. We analyzed data with chi(2) tests and logistic regression analyses. RESULTS When we controlled for appropriate variables, there were significant positive relationships between several youth assets and nonuse of alcohol and drugs. Furthermore, youths who possessed all of the statistically significant youth assets were 4.44 times more likely to report nonuse of alcohol and 5.41 times more likely to report nonuse of drugs compared with youths who possessed fewer youth assets. CONCLUSIONS Our study supports the view that specific youth assets may protect youths from alcohol and drug use.