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Two-year-old purpose-bred beagles (n = 24) infected with Staphylococcus aureus pneumonia were randomized in a blinded fashion for exchange transfusion with either 7- or 42-day-old canine universal donor blood (80 mL/kg in 4 divided doses). Older blood increased mortality (P = .0005), the arterial alveolar oxygen gradient (24-48 hours after infection; P ≤ .01), systemic and pulmonary pressures during transfusion (4-16 hours) and pulmonary pressures for ∼ 10 hours afterward (all P ≤ .02). Further, older blood caused more severe lung damage, evidenced by increased necrosis, hemorrhage, and thrombosis (P = .03) noted at the infection site postmortem. Plasma cell–free hemoglobin and nitric oxide (NO) consumption capability were elevated and haptoglobin levels were decreased with older blood during and for 32 hours after transfusion (all P ≤ .03). The low haptoglobin (r = 0.61; P = .003) and high NO consumption levels at 24 hours (r = −0.76; P < .0001) were associated with poor survival. Plasma nontransferrin-bound and labile iron were significantly elevated only during transfusion (both P = .03) and not associated with survival (P = NS). These data from canines indicate that older blood after transfusion has a propensity to hemolyze in vivo, releases vasoconstrictive cell-free hemoglobin over days, worsens pulmonary hypertension, gas exchange, and ischemic vascular damage in the infected lung, and thereby increases the risk of death from transfusion. more...

Two-year-old purpose-bred beagles (n = 24) infected with Staphylococcus aureuspneumonia were randomized in a blinded fashion for exchange transfusion with either 7- or 42-day-old canine universal donor blood (80 mL/kg in 4 divided doses). Older blood increased mortality (P= .0005), the arterial alveolar oxygen gradient (24-48 hours after infection; P≤ .01), systemic and pulmonary pressures during transfusion (4-16 hours) and pulmonary pressures for ∼ 10 hours afterward (all P≤ .02). Further, older blood caused more severe lung damage, evidenced by increased necrosis, hemorrhage, and thrombosis (P= .03) noted at the infection site postmortem. Plasma cell–free hemoglobin and nitric oxide (NO) consumption capability were elevated and haptoglobin levels were decreased with older blood during and for 32 hours after transfusion (all P≤ .03). The low haptoglobin (r = 0.61; P= .003) and high NO consumption levels at 24 hours (r = −0.76; P< .0001) were associated with poor survival. Plasma nontransferrin-bound and labile iron were significantly elevated only during transfusion (both P= .03) and not associated with survival (P= NS). These data from canines indicate that older blood after transfusion has a propensity to hemolyze in vivo, releases vasoconstrictive cell-free hemoglobin over days, worsens pulmonary hypertension, gas exchange, and ischemic vascular damage in the infected lung, and thereby increases the risk of death from transfusion. more...

Stroke is a devastating complication of sickle cell anemia (SCA) with high recurrence if untreated. Chronic transfusions reduce recurrent strokes but have associated morbidities including iron overload. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) was a multicenter phase 3 randomized trial comparing standard treatment (transfusions/chelation) to alternative treatment (hydroxyurea/phlebotomy) for children with SCA, stroke, and iron overload. SWiTCH was a noninferiority trial with a composite primary end point, allowing an increased stroke risk but requiring superiority for removing iron. Subjects on standard treatment received monthly transfusions plus daily deferasirox iron chelation. Subjects on alternative treatment received hydroxyurea plus overlap transfusions during dose escalation to maximum tolerated dose (MTD), followed by monthly phlebotomy. Subjects on standard treatment (N = 66) maintained 30% sickle hemoglobin (HbS) and tolerated deferasirox at 28.2 ± 6.0 mg/kg/d. Subjects on alternative treatment (N = 67) initiated hydroxyurea and 60 (90%) reached MTD at 26.2 ± 4.9 mg/kg/d with 29.1% ± 6.7% fetal hemoglobin (HbF). Adjudication documented no strokes on transfusions/chelation but 7 (10%) on hydroxyurea/phlebotomy, still within the noninferiority stroke margin. The National Heart, Lung, and Blood Institute closed SWiTCH after interim analysis revealed equivalent liver iron content, indicating futility for the composite primary end point. Transfusions and chelation remain a better way to manage children with SCA, stroke, and iron overload. This clinical trial was registered at ClinicalTrials.gov NCT00122980. more...

Stroke is a devastating complication of sickle cell anemia (SCA) with high recurrence if untreated. Chronic transfusions reduce recurrent strokes but have associated morbidities including iron overload. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) was a multicenter phase 3 randomized trial comparing standard treatment (transfusions/chelation) to alternative treatment (hydroxyurea/phlebotomy) for children with SCA, stroke, and iron overload. SWiTCH was a noninferiority trial with a composite primary end point, allowing an increased stroke risk but requiring superiority for removing iron. Subjects on standard treatment received monthly transfusions plus daily deferasirox iron chelation. Subjects on alternative treatment received hydroxyurea plus overlap transfusions during dose escalation to maximum tolerated dose (MTD), followed by monthly phlebotomy. Subjects on standard treatment (N = 66) maintained 30% sickle hemoglobin (HbS) and tolerated deferasirox at 28.2 ± 6.0 mg/kg/d. Subjects on alternative treatment (N = 67) initiated hydroxyurea and 60 (90%) reached MTD at 26.2 ± 4.9 mg/kg/d with 29.1% ± 6.7% fetal hemoglobin (HbF). Adjudication documented no strokes on transfusions/chelation but 7 (10%) on hydroxyurea/phlebotomy, still within the noninferiority stroke margin. The National Heart, Lung, and Blood Institute closed SWiTCH after interim analysis revealed equivalent liver iron content, indicating futility for the composite primary end point. Transfusions and chelation remain a better way to manage children with SCA, stroke, and iron overload. This clinical trial was registered at ClinicalTrials.gov NCT00122980. more...

Stroke is a devastating complication of sickle cell anemia (SCA), affecting 5% to 10% of patients before adulthood. Several candidate genetic polymorphisms have been proposed to affect stroke risk, but few have been validated, mainly because previous studies were hampered by relatively small sample sizes and the absence of additional patient cohorts for validation testing. To verify the accuracy of proposed genetic modifiers influencing stroke risk in SCA, we performed genotyping for 38 published single nucleotide polymorphisms (SNPs), as well as α-thalassemia, G6PD A−variant deficiency, and β-globin haplotype in 2 cohorts of children with well-defined stroke phenotypes (130 stroke, 103 nonstroke). Five polymorphisms had significant influence (P< .05): SNPs in the ANXA2, TGFBR3, and TEKgenes were associated with increased stroke risk, whereas α-thalassemia and a SNP in the ADCY9gene were linked with decreased stroke risk. Further investigation at these genetic regions may help define mutations that confer stroke risk or protection in children with SCA. more...

Stroke is a devastating complication of sickle cell anemia (SCA), affecting 5% to 10% of patients before adulthood. Several candidate genetic polymorphisms have been proposed to affect stroke risk, but few have been validated, mainly because previous studies were hampered by relatively small sample sizes and the absence of additional patient cohorts for validation testing. To verify the accuracy of proposed genetic modifiers influencing stroke risk in SCA, we performed genotyping for 38 published single nucleotide polymorphisms (SNPs), as well as α-thalassemia, G6PD A− variant deficiency, and β-globin haplotype in 2 cohorts of children with well-defined stroke phenotypes (130 stroke, 103 nonstroke). Five polymorphisms had significant influence (P < .05): SNPs in the ANXA2, TGFBR3, and TEK genes were associated with increased stroke risk, whereas α-thalassemia and a SNP in the ADCY9 gene were linked with decreased stroke risk. Further investigation at these genetic regions may help define mutations that confer stroke risk or protection in children with SCA. more...

In the phase I/II pediatric hydroxyurea safety trial (HUG-KIDS), school-aged children with sickle cell anemia receiving hydroxyurea at the maximally tolerated dose (MTD) had variable increases in the percentage of fetal hemoglobin (%HbF). To identify predictors of the HbF response to hydroxyurea therapy, baseline clinical and laboratory values (age, sex, hemoglobin concentration, %HbF, reticulocytes, white blood cell [WBC], platelets, and serum chemistries), as well as treatment variables (number of toxicities, noncompliance, MTD dose, and MTD blood counts) were analyzed in 53 HUG-KIDS children who achieved MTD. Baseline %HbF values (P = .001), baseline hemoglobin concentration (P = .01), MTD dose (P = .02), and compliance (P = .02) were significantly associated with a higher %HbF at MTD; in contrast, age, sex, number of toxicities, and other baseline hematologic parameters were not. After adjusting for variations in baseline %HbF, the baseline reticulocyte count (P = .05) and baseline WBC count (P = .05) were also significantly associated with a higher %HbF at MTD. Hydroxyurea-induced increases in the hemoglobin concentration and mean corpuscular volume (both higher absolute values at MTD and larger positive changes from baseline values), as well as hydroxyurea-induced decreases in reticulocytes and WBC count, were significantly associated with a higher %HbF at MTD. These data suggest that selected baseline laboratory parameters, a higher MTD dose with attention to compliance, and greater therapy-related changes in blood counts may predict the HbF response to hydroxyurea therapy for children with sickle cell anemia. The HbF response to hydroxyurea is variable and complex, however, and even children with low baseline %HbF values can develop substantial increases in %HbF at MTD. more...

In the phase I/II pediatric hydroxyurea safety trial (HUG-KIDS), school-aged children with sickle cell anemia receiving hydroxyurea at the maximally tolerated dose (MTD) had variable increases in the percentage of fetal hemoglobin (%HbF). To identify predictors of the HbF response to hydroxyurea therapy, baseline clinical and laboratory values (age, sex, hemoglobin concentration, %HbF, reticulocytes, white blood cell [WBC], platelets, and serum chemistries), as well as treatment variables (number of toxicities, noncompliance, MTD dose, and MTD blood counts) were analyzed in 53 HUG-KIDS children who achieved MTD. Baseline %HbF values (P= .001), baseline hemoglobin concentration (P= .01), MTD dose (P= .02), and compliance (P= .02) were significantly associated with a higher %HbF at MTD; in contrast, age, sex, number of toxicities, and other baseline hematologic parameters were not. After adjusting for variations in baseline %HbF, the baseline reticulocyte count (P= .05) and baseline WBC count (P= .05) were also significantly associated with a higher %HbF at MTD. Hydroxyurea-induced increases in the hemoglobin concentration and mean corpuscular volume (both higher absolute values at MTD and larger positive changes from baseline values), as well as hydroxyurea-induced decreases in reticulocytes and WBC count, were significantly associated with a higher %HbF at MTD. These data suggest that selected baseline laboratory parameters, a higher MTD dose with attention to compliance, and greater therapy-related changes in blood counts may predict the HbF response to hydroxyurea therapy for children with sickle cell anemia. The HbF response to hydroxyurea is variable and complex, however, and even children with low baseline %HbF values can develop substantial increases in %HbF at MTD. more...

Previous studies have determined the short-term toxicity profile, laboratory changes, and clinical efficacy associated with hydroxyurea (HU) therapy in adults with sickle cell anemia. The safety and efficacy of this agent in pediatric patients with sickle cell anemia has not been determined. Children with sickle cell anemia, age 5 to 15 years, were eligible for this multicenter Phase I/II trial. HU was started at 15 mg/kg/d and escalated to 30 mg/kg/d unless the patient experienced laboratory toxicity. Patients were monitored by 2-week visits to assess compliance, toxicity, clinical adverse events, growth parameters, and laboratory efficacy associated with HU treatment. Eighty-four children were enrolled between December 1994 and March 1996. Sixty-eight children reached maximum tolerated dose (MTD) and 52 were treated at MTD for 1 year. Significant hematologic changes included increases in hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, and fetal hemoglobin parameters, and decreases in white blood cell, neutrophil, platelet, and reticulocyte counts. Laboratory toxicities typically were mild, transient, and were reversible upon temporary discontinuation of HU. No life-threatening clinical adverse events occurred and no child experienced growth failure. This Phase I/II trial shows that HU therapy is safe for children with sickle cell anemia when treatment was directed by a pediatric hematologist. HU in children induces similar laboratory changes as in adults. Phase III trials to determine if HU can prevent chronic organ damage in children with sickle cell anemia are warranted. more...

Previous studies have determined the short-term toxicity profile, laboratory changes, and clinical efficacy associated with hydroxyurea (HU) therapy in adults with sickle cell anemia. The safety and efficacy of this agent in pediatric patients with sickle cell anemia has not been determined. Children with sickle cell anemia, age 5 to 15 years, were eligible for this multicenter Phase I/II trial. HU was started at 15 mg/kg/d and escalated to 30 mg/kg/d unless the patient experienced laboratory toxicity. Patients were monitored by 2-week visits to assess compliance, toxicity, clinical adverse events, growth parameters, and laboratory efficacy associated with HU treatment. Eighty-four children were enrolled between December 1994 and March 1996. Sixty-eight children reached maximum tolerated dose (MTD) and 52 were treated at MTD for 1 year. Significant hematologic changes included increases in hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, and fetal hemoglobin parameters, and decreases in white blood cell, neutrophil, platelet, and reticulocyte counts. Laboratory toxicities typically were mild, transient, and were reversible upon temporary discontinuation of HU. No life-threatening clinical adverse events occurred and no child experienced growth failure. This Phase I/II trial shows that HU therapy is safe for children with sickle cell anemia when treatment was directed by a pediatric hematologist. HU in children induces similar laboratory changes as in adults. Phase III trials to determine if HU can prevent chronic organ damage in children with sickle cell anemia are warranted. more...

We have identified and characterized a human ß (CC) chemokine, designated HCC-4, that is most closely related to HCC-1 and which demonstrates chemotactic activity for monocytes. Northern analysis of multiple tissue blots and of activated monocytes mRNA shows expression of a 500-bp mRNA. A 1,500-bp mRNA was highly expressed in monocytes activated 12 hours in the presence of interleukin-10 (IL-10) but was absent in monocytes activated for only 1 hour regardless of the presence or absence of IL-10. The upregulation of expression in the presence of IL-10 is in contrast to the downregulatory effects of IL-10 on expression of most other chemokines. Recombinant HCC-4 demonstrated chemotactic activity for human monocytes and THP-1 monocyte cells but not for resting lymphocytes or neutrophils. HCC-4 also induced a Ca2+ flux in THP-1 cells that was desensitized by prior exposure to RANTES. Taken together, these data indicate that HCC-4 is a novel chemokine whose expression is uniquely upregulated by IL-10. more...

We have identified and characterized a human β (CC) chemokine, designated HCC-4, that is most closely related to HCC-1 and which demonstrates chemotactic activity for monocytes. Northern analysis of multiple tissue blots and of activated monocytes mRNA shows expression of a 500-bp mRNA. A 1,500-bp mRNA was highly expressed in monocytes activated 12 hours in the presence of interleukin-10 (IL-10) but was absent in monocytes activated for only 1 hour regardless of the presence or absence of IL-10. The upregulation of expression in the presence of IL-10 is in contrast to the downregulatory effects of IL-10 on expression of most other chemokines. Recombinant HCC-4 demonstrated chemotactic activity for human monocytes and THP-1 monocyte cells but not for resting lymphocytes or neutrophils. HCC-4 also induced a Ca2+flux in THP-1 cells that was desensitized by prior exposure to RANTES. Taken together, these data indicate that HCC-4 is a novel chemokine whose expression is uniquely upregulated by IL-10. more...

Meziani: STAGO: Research Funding.

Septic shock is the most severe form of infection, defined as a subset of sepsis in which circulatory, cellular and metabolic abnormalities are profound and responsible for multiple organ failure and a high mortality-rate. Septic shock is characterized by a broad coagulation activation that can lead to uncontrolled thrombin and fibrin generation, which may evolve to disseminated intravascular coagulation (DIC). DIC increases the risk of death, thus representing a therapeutic target of interest. However, the pathophysiological mechanisms of DIC are not fully understood. Polymorphonuclear neutrophils (PMNs) have recently been identified as potential players of the response to infection by releasing their content, including DNA, histones and granules enzymes. These structures, called neutrophils extracellular traps (NETs), form a large net-like structure in which pathogens get trapped. NETs capture invading pathogens, but also represent a pro-coagulant surface at the interface between immunity and thrombosis. During septic shock-induced DIC, neutrophil activation may result in excessive NET formation. In this study, we originally report the presence of circulating NETs in human blood during septic shock-induced DIC using a simple and robust method. more...

Introduction: Geriatric assessment (GA) is a multidimensional evaluation of patient health and function that may detect impairments not identified as part of routine care, predict treatment-related morbidity and mortality, and inform treatment plans. Given evidence of these benefits, the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend GA for older candidates of hematopoietic stem cell transplantation (HCT). However, both older and younger HCT candidates will often receive multiple rounds of chemotherapy before HCT, leading to functional impairments in all age groups. Furthermore, HCT patients often experience a significant gap between when they are first evaluated and actually proceed to transplant (e.g., while a donor search is conducted), creating an opportunity to identify impairments and optimize function prior to transplant. more...

Wiggins: Incyte, Inc.: Speakers Bureau. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Rizzieri:Millennium: Speakers Bureau; Novartis: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Incyte: Consultancy, Speakers Bureau; TEVA: Consultancy; Spectrum: Consultancy; Kite Pharma: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Horwitz:Abbvie Inc: Membership on an entity's Board of Directors or advisory committees. Sung:Novartis: Research Funding; Merck: Research Funding; Seres: Research Funding. more...

No relevant conflicts of interest to declare.

Thrombocytopenia frequently occurs in septic shock patients and is associated with a worsened outcome. Experimental data indicate that platelets may have a protective role during sepsis. Our aims were to i) assess the potential protective role of platelets during septic shock and ii) evaluate the involvement of platelet P2Y1and P2Y12purinergic receptors. more...

Chao: Genzyme: Research Funding.

No relevant conflicts of interest to declare.

Stroke is perhaps the most catastrophic complication of sickle cell anemia (SCA), occurring in 11% of patients with SCA before 20 years of age. There is a definite need for biomarkers that could predict which children with SCA are at greatest risk for developing these irreversible cerebrovascular events. Many candidate genetic polymorphisms have been proposed to affect stroke risk but few have been validated, mainly due to the lack of additional patient cohorts. To validate the accuracy of published genetic modifiers, we genotyped polymorphisms in two large prospective cohorts.Pediatric patients with SCA and documented primary stroke (n=134, average age at stroke = 5.8 ± 2.8 years) were recruited through the Stroke With Transfusions Changing to Hydroxyurea (SWiTCH, NCT00122980) study. As a control non-stroke group, pediatric SCA patients (n=104, average age = 10.2 ± 3.5 years) enrolled in the Hydroxyurea Study of Long-Term Effects (HUSTLE, NCT00305175) were analyzed. All participants in the HUSTLE cohort were over 5 years old and without previous clinical stroke prior to beginning hydroxyurea treatment. We genotyped 38 single nucleotide polymorphisms (SNP's) with published associations for stroke risk, along with α-thalassemia trait, G6PD deficiency and the β-globin haplotype of each patient.Only 5 of the 38 candidate SNPs were associated with stroke risk (Table 1). As previously reported the presence of α-thalassemia trait was also associated with stroke risk (p=0.009). In contrast, G6PD deficiency was not associated with stroke risk. The classical β-globin gene haplotypes were determined for all 238 subjects, resulting in alleles primarily representing the four classical African haplotypes including Benin (57.6%), Central African Republic (21.8%), Senegal (9.2%) and Cameroon (3.2%), as well as atypical haplotypes (8.2%). None of the classical β-globin haplotypes were associated with stroke. However, fine-mapping of the β-globin gene locus identified recombination events within the Aγ-globin gene region, which were significantly over-represented in the stroke versus non-stroke cohorts (n=26.5% vs. n=12.5%, p=0.0001). In particular, one haplotype we term BEN-Memphis has the classical Benin background haplotype but also has recombination between the promoter and intron 2 of the Aγ-globin gene. There were significantly more stroke subjects with this novel BEN-Memphis haplotype (n=9.3% vs. n=0.5%, p<0.001).Our results confirm α-thalassemia trait is significantly protective against stroke in SCA. Fine-mapping of the β-globin gene locus identified novel recombinations within the β-globin gene locus that were associated with stroke risk. These variant haplotypes may be associated with altered γ- or β-globin gene expression. Of the other previously reported polymorphisms, only 5 of 38 SNPs were significantly associated with stroke risk (Table 1). These findings highlight the dangers of accepting non-validated genetic modifiers. The ADCY9 gene is highly expressed in the brain and is critical for neuronal signaling (Hacker BM et al., Genomics 1998). The TEK gene is an endothelial cell expressed tyrosine kinase that is crucial for prevention and recovery from stroke events (Bai Y et al., Neuroscience 2009). The ANXA2 gene has been proposed to affect the hypercoaguable state of SCA (Ling Q et al., J Clin Invest 2004). Finally, mutations in TGFBR3 have been linked with cerebrovascular disease (Santiago-Sim T et al., Stroke 2009). Further investigations at these genetic regions may help define the specific mutations that confer stroke risk or protection in children with SCA.The minor allele frequency (MAF) is given for each SNP. Significance between the control (HUSTLE, n=104) and stroke (SWiTCH, n=134) groups was tested using the Cochran-Armitage test. The HbA2 polymorphism is the Δ3.7kb α-thalassemia single gene deletion.Off Label Use: The off-label drug use of hydroxyurea to treat clinical complications of sickle cell anemia in children will be discussed. more...

No relevant conflicts of interest to declare.

Off Label Use: Hydroxyurea is used to reduce complications of sickle cell anemia.

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Children with sickle cell anemia have a 5–10% incidence of primary stroke, after which they have a 50–90% risk of stroke recurrence. Monthly transfusions with a goal of maintaining sickle hemoglobin (HbS) <30% can lower the risk of secondary stroke to 10–20%. In practice, however, this 30% goal can be difficult to achieve, due to both physiological and practical considerations. The NHLBI-sponsored Phase III Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial will compare standard therapy (transfusions and chelation) to alternative therapy (hydroxyurea and phlebotomy) for the prevention of recurrent stroke and management of iron overload in children with sickle cell anemia and previous stroke. In SWiTCH, transfusions in the standard treatment arm will be given according to the current academic standard, rather than an arbitrary %HbS level. To determine the current academic community standards for secondary stroke prophylaxis in children with sickle cell anemia, 23 SWiTCH clinical sites reported data from children receiving monthly transfusions to prevent recurrent stroke. Transfusion-related data were collected for all SWiTCH-eligible patients over the 12-month period from 9-1-04 until 8-31-05, including age, weight, transfusion type and volume, and pre-transfusion hemoglobin concentration and %HbS. Data were analyzed both "per transfusion" and "per patient". A total of 3543 transfusions were administered to 295 pediatric patients over this 12-month period, with a median of 12 transfusions per patient. The average age (mean ± 1 SD) was 12.0 ± 3.8 years and the average weight was 39.7 ± 16.2 kg. The average volume of blood administered per transfusion was 14.2 ± 7.1 mL/kg with an annualized transfusion volume of 160 ± 78 mL/kg/year. Most children (56%) received primarily simple transfusions, 37% primarily exchange transfusions (20% manual partial, 17% automated), and 7% multiple transfusion types. Most children had good adherence to the transfusion program, with late transfusions (defined as >7 days after the scheduled date) occurring once in 22% and twice or more in 12% of children. The average pre-transfusion Hb was 9.0 ± 0.7 gm/dL. The average pre-transfusion %HbS was 35 ± 11 %, with a median %HbS value of 34%. Potential "cutoff " %HbS values for SWiTCH included 34% (50th percentile of reported values), 43% (75th percentile), and 52% HbS (90th percentile). These data indicate that transfusions to prevent recurrent stroke vary among academic pediatric institutions and 30% HbS may not be a realistic goal for this study. Although the goal for transfusions in the SWiTCH standard treatment arm will remain 30% HbS, maintaining an average pre-transfusion HbS value of ≤ 45% will be required to reflect the academic community standard. more...

Acquired von Willebrand’s syndrome (AVWS) is a rare but probably underdiagnosed hemorrhagic disorder often associated with hematological or cardiovalvular disorders. Diagnostic workup remains challenging, particularly in patients with normal or increased von Willebrand factor antigen (Ag) and ristocetin cofactor (RCo). Here, we present a retrospective single-center study of 35 patients diagnosed with AVWS based on (i) a history of recent onset of bleeding, (ii) a negative family history of von Willebrand’s disease, and (iii) abnormal plasma VWF multimers. AVWS was associated with monoclonal gammopathy (n=11), cardiovalvular disorders (n=16), or other conditions (n=8) including myeloproliferative and autoimmune disorders. The PFA-100® screening test was inconclusive due to anemia (hematocrit <30 %) or thrombocytopenia (<100/nl) in 10 patients (29 %); prolonged closure times were observed using collagen/epinephrine and collagen/adrenalin in 20 of 25 (80 %) and 18 of 25 (72 %) patients, respectively. Factor VIII:C was reduced below 50 IU/dl in 7 of 35 patients (20 %). VWF Ag and RCo were reduced below 50 IU/dl in 8 patients (23 %). VWF Ag and RCo were normal or increased in all patients with cardiovalvular disease and in four of eleven patients with gammopathy. Median VWF Ag was higher in cardiovalvular disease (median 202 IU/dl, range 90 to 608) compared to gammopathy (median 31 IU/dl, range 8 to 468, p<0.02 by Mann Whitney U test). Of 27 patients with normal or increased VWF Ag and RCo, 12 (44 %) had a reduced collagen binding activity (CBA) or CBA to Ag ratio <0.7; 10 (37 %) had a borderline CBA ratio between 0.7 and 0.8; 5 (19 %) had a normal CBA >0.8. A normal or increased VWF Ag together with a CBA ratio >0.7 was observed both in patients with cardiovalvular disease (n=9), gammopathy (n=2) and other disorders (n=4). However, in all patients the largest VWF multimers were decreased (n=14) or absent (n=21). In conclusion, no single test was sufficient to detect all cases of AVWS. The PFA-100® test is of limited use in this population because of its limitation in anemia or thrombocytopenia and because of its low sensitivity. A significant number of patients present with a normal or increased VWF Ag and RCo as well as a CBA ratio >0.7 emphasizing the importance of multimer analysis in all patients with suspected AVWS. more...

The C-Data Project of the NIH-NHLBI funded Comprehensive Sickle Cell Centers Program was designed to establish a large and geographically diverse patient registry of persons with sickle cell disease regularly followed in the 10 comprehensive sickle cell centers. Opened to enrollment in March 2005 the database now contains current demographic, clinical, and health related quality of life information on 1,673 participants. Retrospective patient data are abstracted from the medical record at enrollment and updated from both patient interviews and medical record review at semi-annual contacts. Common sickle cell clinical events are defined in the context of modern diagnostic criteria so that as prospective data collection continues an unparalleled database of the burden of disease sickle cell syndromes may cause will emerge. While data are preliminary, interesting descriptive statistics have been derived. As of June 2006, 69% of participants are ≤17 yrs of age [peds], 63% have HbSS, 50% are female, and over half have been followed for 5 or more years in the same center. At least one episode of acute chest syndrome was reported by 56% of all subjects (51% peds, 76% adults) and of painful crisis by 69% (62% peds, 94% adults). CNS events occurred in 18% including ischemic stroke in 6% of peds and 11% of adults. Cholecystectomy was the most common surgical procedure reported in 19% (10% peds, 53% adults). Splenectomy was reported in 11% (10% peds, 16% adults), tonsillectomy in 12% (10% peds, 18% adults), and permanent central lines had been placed in 7% (5% peds, 15% adults). Adults reported acute and chronic renal failure in 6% and 3% respectively, and proteinuria in 11%. Transfusion during the past year was reported by 32%, and 54% of patients have received at least one transfusion during their lifetime. Iron overload was reported by 7% (5% peds, 14% adults). One or more hospitalizations within the last two years were reported by 62% (60% peds, 71% adults). Admissions were primarily for management of painful crisis in 39%, fever in 16%, and acute chest syndrome in 10%. Within the last year an MRI of the brain was performed in 16% and transcranial doppler (TCD) in 23% of pediatric patients. A cardiac echo was performed within the last year on 33% of adults. Hydroxyurea, the chemotherapy agent recommended for use by severely involved patients, was prescribed for 23% (18% peds, 41% adults). Twice daily prophylactic penicillin use in the last year was reported by 67% peds and 25% adults. At least 19% of patients had participated in at least one other research study. This database will be an invaluable tool for assessment of adherence to recommendations for care, heath services planning, and outcomes assessment. Year 1 data have demonstrated that CDATA will be able to facilitate the planning of multi-center research studies, provide a mechanism for identifying specific individuals within a center who are potentially eligible for participation in intervention studies, and provide the clinical data to support DNA based genotype-phenotype assessments. more...

Children with sickle cell anemia have a 5–10% incidence of primary stroke, after which they have a 50–90% risk of stroke recurrence. Monthly transfusions with a goal of maintaining sickle hemoglobin (HbS) <30% can lower the risk of secondary stroke to 10–20%. In practice, however, this 30% goal can be difficult to achieve, due to both physiological and practical considerations. The NHLBI-sponsored Phase III Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial will compare standard therapy (transfusions and chelation) to alternative therapy (hydroxyurea and phlebotomy) for the prevention of recurrent stroke and management of iron overload in children with sickle cell anemia and previous stroke. In SWiTCH, transfusions in the standard treatment arm will be given according to the current academic standard, rather than an arbitrary %HbS level. To determine the current academic community standards for secondary stroke prophylaxis in children with sickle cell anemia, 23 SWiTCH clinical sites reported data from children receiving monthly transfusions to prevent recurrent stroke. Transfusion-related data were collected for all SWiTCH-eligible patients over the 12-month period from 9-1-04 until 8-31-05, including age, weight, transfusion type and volume, and pre-transfusion hemoglobin concentration and %HbS. Data were analyzed both "per transfusion" and "per patient". A total of 3543 transfusions were administered to 295 pediatric patients over this 12-month period, with a median of 12 transfusions per patient. The average age (mean ± 1 SD) was 12.0 ± 3.8 years and the average weight was 39.7 ± 16.2 kg. The average volume of blood administered per transfusion was 14.2 ± 7.1 mL/kg with an annualized transfusion volume of 160 ± 78 mL/kg/year. Most children (56%) received primarily simple transfusions, 37% primarily exchange transfusions (20% manual partial, 17% automated), and 7% multiple transfusion types. Most children had good adherence to the transfusion program, with late transfusions (defined as >7 days after the scheduled date) occurring once in 22% and twice or more in 12% of children. The average pre-transfusion Hb was 9.0 ± 0.7 gm/dL. The average pre-transfusion %HbS was 35 ± 11 %, with a median %HbS value of 34%. Potential "cutoff " %HbS values for SWiTCH included 34% (50thpercentile of reported values), 43% (75thpercentile), and 52% HbS (90thpercentile). These data indicate that transfusions to prevent recurrent stroke vary among academic pediatric institutions and 30% HbS may not be a realistic goal for this study. Although the goal for transfusions in the SWiTCH standard treatment arm will remain 30% HbS, maintaining an average pre-transfusion HbS value of ≤ 45% will be required to reflect the academic community standard. more...

The C-Data Project of the NIH-NHLBI funded Comprehensive Sickle Cell Centers Program was designed to establish a large and geographically diverse patient registry of persons with sickle cell disease regularly followed in the 10 comprehensive sickle cell centers. Opened to enrollment in March 2005 the database now contains current demographic, clinical, and health related quality of life information on 1,673 participants. Retrospective patient data are abstracted from the medical record at enrollment and updated from both patient interviews and medical record review at semi-annual contacts. Common sickle cell clinical events are defined in the context of modern diagnostic criteria so that as prospective data collection continues an unparalleled database of the burden of disease sickle cell syndromes may cause will emerge. While data are preliminary, interesting descriptive statistics have been derived. As of June 2006, 69% of participants are ≤17 yrs of age [peds], 63% have HbSS, 50% are female, and over half have been followed for 5 or more years in the same center. At least one episode of acute chest syndrome was reported by 56% of all subjects (51% peds, 76% adults) and of painful crisis by 69% (62% peds, 94% adults). CNS events occurred in 18% including ischemic stroke in 6% of peds and 11% of adults. Cholecystectomy was the most common surgical procedure reported in 19% (10% peds, 53% adults). Splenectomy was reported in 11% (10% peds, 16% adults), tonsillectomy in 12% (10% peds, 18% adults), and permanent central lines had been placed in 7% (5% peds, 15% adults). Adults reported acute and chronic renal failure in 6% and 3% respectively, and proteinuria in 11%. Transfusion during the past year was reported by 32%, and 54% of patients have received at least one transfusion during their lifetime. Iron overload was reported by 7% (5% peds, 14% adults). One or more hospitalizations within the last two years were reported by 62% (60% peds, 71% adults). Admissions were primarily for management of painful crisis in 39%, fever in 16%, and acute chest syndrome in 10%. Within the last year an MRI of the brain was performed in 16% and transcranial doppler (TCD) in 23% of pediatric patients. A cardiac echo was performed within the last year on 33% of adults. Hydroxyurea, the chemotherapy agent recommended for use by severely involved patients, was prescribed for 23% (18% peds, 41% adults). Twice daily prophylactic penicillin use in the last year was reported by 67% peds and 25% adults. At least 19% of patients had participated in at least one other research study. This database will be an invaluable tool for assessment of adherence to recommendations for care, heath services planning, and outcomes assessment. Year 1 data have demonstrated that CDATA will be able to facilitate the planning of multi-center research studies, provide a mechanism for identifying specific individuals within a center who are potentially eligible for participation in intervention studies, and provide the clinical data to support DNA based genotype-phenotype assessments. more...

Acquired von Willebrand's syndrome (AVWS) is a rare but probably underdiagnosed hemorrhagic disorder often associated with hematological or cardiovalvular disorders. Diagnostic workup remains challenging, particularly in patients with normal or increased von Willebrand factor antigen (Ag) and ristocetin cofactor (RCo). Here, we present a retrospective single-center study of 35 patients diagnosed with AVWS based on (i) a history of recent onset of bleeding, (ii) a negative family history of von Willebrand's disease, and (iii) abnormal plasma VWF multimers. AVWS was associated with monoclonal gammopathy (n=11), cardiovalvular disorders (n=16), or other conditions (n=8) including myeloproliferative and autoimmune disorders. The PFA-100® screening test was inconclusive due to anemia (hematocrit <30 %) or thrombocytopenia (<100/nl) in 10 patients (29 %); prolonged closure times were observed using collagen/epinephrine and collagen/adrenalin in 20 of 25 (80 %) and 18 of 25 (72 %) patients, respectively. Factor VIII:C was reduced below 50 IU/dl in 7 of 35 patients (20 %). VWF Ag and RCo were reduced below 50 IU/dl in 8 patients (23 %). VWF Ag and RCo were normal or increased in all patients with cardiovalvular disease and in four of eleven patients with gammopathy. Median VWF Ag was higher in cardiovalvular disease (median 202 IU/dl, range 90 to 608) compared to gammopathy (median 31 IU/dl, range 8 to 468, p<0.02 by Mann Whitney U test). Of 27 patients with normal or increased VWF Ag and RCo, 12 (44 %) had a reduced collagen binding activity (CBA) or CBA to Ag ratio <0.7; 10 (37 %) had a borderline CBA ratio between 0.7 and 0.8; 5 (19 %) had a normal CBA >0.8. A normal or increased VWF Ag together with a CBA ratio >0.7 was observed both in patients with cardiovalvular disease (n=9), gammopathy (n=2) and other disorders (n=4). However, in all patients the largest VWF multimers were decreased (n=14) or absent (n=21). In conclusion, no single test was sufficient to detect all cases of AVWS. The PFA-100® test is of limited use in this population because of its limitation in anemia or thrombocytopenia and because of its low sensitivity. A significant number of patients present with a normal or increased VWF Ag and RCo as well as a CBA ratio >0.7 emphasizing the importance of multimer analysis in all patients with suspected AVWS. more...