Hernan Sabio

Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin, sex, and relative high systolic blood pressure

The most common form of neurologic injury in sickle cell anemia (SCA) is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, we sought to identify risk factors associated with SCI. In this cross-sectional study, we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA (HbSS or HbSβ° thalassemia) between the ages of 5 and 15 years with no history of overt stroke or seizures. Neuroradiology and neurology committees adjudicated the presence of SCI. SCIs were diagnosed in 30.8% (251 of 814) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates. The mean age of the participants was 9.1 years, with 413 males (50.7%). In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P < .001), higher baseline systolic blood pressure (P = .018), and male sex (P = .030) were statistically significantly associated with an increased risk of an SCI. Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI. This study is registered at www.clinicaltrials.gov as #NCT00072761.

Evidence for the transmission of parvovirus B19 in patients with bleeding disorders treated with plasma‐derived factor concentrates in the era of nucleic acid test screening

BACKGROUND: Parvovirus B19 (B19V) is a small, nonenveloped virus that typically causes a benign flu‐like illness that occurs most frequently in childhood. The virus is resistant to current viral inactivation steps used in the manufacture of antihemophilic factor concentrates and B19V transmission through these products has been documented. Since 2000, B19V nucleic acid test (NAT) screening of plasma pools has been implemented to further decrease the viral burden in these products, but no study has examined populations using these products to assess the impact of the screening on B19V transmission.

Prevalence of conditions associated with human immunodeficiency and hepatits virus infections among persons with haemophilia, 2001-2003

Summary.  Before the mid‐1980s, haemophilia often was unknowingly treated with contaminated plasma products, resulting in high rates of human immunodeficiency virus (HIV‐1), hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. To estimate the impact of these infections, a new cohort was established. All HCV‐seropositive patients, age 13–88 years, at 52 comprehensive haemophilia treatment centres were eligible. Cross‐sectional data collected during April 2001 to January 2004 (median June 2002) were analysed. Plasma HIV‐1 and HCV RNA were quantified by polymerase chain reaction. Highly active antiretroviral therapy (HAART) was defined as use of at least three recommended medications. Among 2069 participants, 620 (30%) had HIV‐1. Of 1955 with known HBV status, 814 (42%) had resolved HBV and 90 (4.6%) were HBV carriers. Although 80% of the HIV‐1‐positive participants had ≥200 CD4+ cells μL−1, only 59% were on HAART. HIV‐1 RNA was undetectable in 23% of those not taking antiretroviral medications. Most (72%) participants had received no anti‐HCV therapy. HCV RNA was detected less frequently (59%) among participants treated with standard interferon plus ribavirin (P = 0.0001) and more frequently among HIV‐1‐positive than HIV‐1‐negative participants (85% vs. 70%, P < 0.0001). HIV‐1‐positive participants were more likely to have pancytopenia and subclinical hepatic abnormalities, as well as persistent jaundice, hepatomegaly, splenomegaly and ascites. HAART recipients did not differ from HIV‐negative participants in the prevalence of ascites. The clinical abnormalities were more prevalent with older age but were not confounded by HBV status or self‐reported alcohol consumption. Eleven participants presented with or previously had hepatocellular carcinoma or non‐Hodgkin lymphoma. Although prospective analysis is needed, our data reveal the scale of hepatic and haematological disease that is likely to manifest in the adult haemophilic population during the coming years unless most of them are successfully treated for HIV‐1, HCV or both.

Considerations in the evaluation of haemophilia patients for short‐term prophylactic therapy: a paediatric and adult case study

Summary.  The long‐term prophylactic administration of clotting factor concentrate in patients with haemophilia reduces bleeding events, slows joint deterioration, and improves quality of life. Prophylaxis can also be effective when used short‐term to prevent or reduce bleeding associated with trauma, surgery, and athletic activities. While clinical trials are needed to establish the optimal length of prophylaxis following injury, several weeks and possibly months of treatment may be needed. Discontinuing therapy prematurely can result in rebleeding in the injured area.

Effects of a single sickling event on the mechanical fragility of sickle cell trait erythrocytes

Hemolysis contributes to the pathology associated with sickle cell disease. However, the mechanism of hemolysis or relative contribution of sickling due to hemoglobin (Hb) polymerization vs. oxidative damage remains unknown. Earlier studies aimed at deciphering the relative importance of these two mechanisms have been complicated by the fact that sickle red cells (SS) have already been affected by multiple rounds of sickling and oxidative damage before they are collected. In our study, we examine the mechanical fragility of sickle cell trait cells, which do not sickle in vivo, but can be made to do so in vitro. Thus, our novel approach explores the effects of sickle Hb polymerization on cells that have never been sickled before. We find that the mechanical fragility of these cells increases dramatically after a single sickling event, suggesting that a substantial amount of hemolysis in vivo probably occurs in polymer-containing cells.

Evidence for the continued transmission of parvovirus B19 in patients with bleeding disorders treated with plasma‐derived factor concentrates

Gajardo and colleagues contend that our finding of continued increased prevalence of parvovirus B19 (B19V) antibodies among users of plasma-derived factor concentrates relative to people with bleeding disorders unexposed to any blood or factor product may have been influenced by exposure to product not subjected to B19V nucleic acid test (NAT) screening or to exposure to lowpurity products during the study period. The authors also disagree with our characterization of B19V as resistant to viral inactivation steps used in the manufacture of antihemophilic factor concentrates. We understand and discuss in our article that B19V NAT screening was not initiated at the same time for all products. Nonetheless, we provided evidence, based on our finding of higher B19V prevalence in later years of the study period, that our findings were not likely due to transmissions that occurred solely in earlier years. For example, among 2to 4-year-old children exposed to plasma-derived products, 77% of the specimens tested were drawn between 2006 and 2009—well after studies showed relatively complete adoption of screening. Others have reported the detection of B19V in products purchased in 2008. The authors suggest that our study findings may also have been influenced by users of less highly purified products such as activated prothrombin complex concentrates. However, only 7% of subjects in our study were exposed to these products. We fail to understand the disagreement with our statement that B19V is resistant to viral inactivation by the methods used during the manufacture of these products, especially when the authors base their argument on reports that demonstrate “some steps” are able to inactivate B19V “with higher efficacy” than for porcine parvovirus. In our opinion, higher efficacy of inactivation does not equate to inactivation and implies resistance by B19V to these processes. B19V and other Parvoviridae have diameters of approximately 20 to 25 nm. While nanofiltration with pore size of not more than 20 nm (effective in reducing viral loads) has been applied to some Factor (F) IX concentrates, a majority of currently available plasmaderived and recombinant FVIII products either are not routinely subjected to nanofiltration or are filtered using a pore size of 35 nm. The currently available prothrombin complex concentrates also use a pore size of 35 nm. A recent comprehensive review concluded that currently available data provide evidence that B19V and other similar viruses are able to circumvent the current fractionation and purification steps. Our purpose was to evaluate whether B19V transmission was continuing to occur after a voluntary screening process was introduced as an additional component of product safety programs designed to prevent B19V transmission to users of these products. Manufacturers (and the authors of this letter) make claims that this and other steps in the manufacturing process result in a product that is safe. However, the authors point out that there were significant differences in the ways in which this voluntary screening process was implemented, which according to an FDA study resulted in continued B19V presence in end product and according to our study resulted in viral transmission to patients. While we applaud the manufacturers in pursuing viral safety of clotting factor concentrates, we feel that continued surveillance of recipients for viral transmission is important. The ultimate test of transmission is the detection of B19V as a surrogate for other viruses that may escape viral inactivation in the recipient plasma. We agree with Gajardo and colleagues that manufacturers need to be diligent in efforts to further improve the safety margin of these products. Left unsaid by Gajardo and colleagues is that no such screening program can protect against unknown viruses in the blood supply. We continue to believe along with others that while screening is an important adjunct to a product safety scheme, improved removal and/or viral inactivation methods for B19V and similar viruses are needed.

Thalassemia-like phenotype in a novel complex hemoglobinopathy with α, β, δ globin chain abnormalities.

The occurrence of multiple abnormalities of &agr;, &bgr;, &dgr;, and &ggr; globin genes may lead to unusual and complex phenotypes when they arise simultaneously in the same individual. Here, we report the findings of an African American boy who coinherited 3 heterozygous globin gene abnormalities: the unstable &bgr;-globin chain variant; hemoglobin (Hb) Showa-Yakushiji [&bgr;110(G12) Leu→Pro], the &dgr;-globin chain variant; HbB2 [&dgr;16(A13) Gly→Arg] and &agr;+-thalassemia (&agr;+-thal); (&agr;-3.7/&agr;&agr;). Hb Showa-Yakushiji had been previously described in Japanese, Indian, and European populations. We report its first occurrence in a child of African ancestry who presented with anemia not responsive to iron and an incomplete &bgr;-thalassemia minor phenotype. Although the clinical and laboratory features of Hb Showa-Yakushiji mimic those of a &bgr;-thalassemia, the coinheritance of the &dgr;-globin chain variant Hb B2 suppressed the relative increase in Hb A2 usually observed in heterozygotes for the Hb Showa-Yakushiji mutation. Protein-based methods detected only a trace amount of HbB2 and failed to reveal presence of Hb Showa-Yakushiji and &agr;+-thal. The latter were only identified through DNA analyses. The diagnostic difficulties, molecular characteristics, and genotype/phenotype correlations of this novel complex hemoglobinopathy syndrome are reviewed.