Rachelle Nuss

Lupus anticoagulant and protein S deficiency in children with postvaricella purpura fulminans or thrombosis

OBJECTIVE The objective of this study was to determine the cause of purpura fulminans, disseminated intravascular coagulation, or thrombosis in seven children with varicella. All children were found to have a lupus anticoagulant and acquired protein S deficiency. Thrombosis in five children was associated with presumed or documented infection with streptococcus. STUDY DESIGN Coagulation tests included determinations of the activated partial thromboplastin time, the prothrombin time, the dilute Russell viper venom time, the prothrombin F 1 + 2 fragment, the C4b-binding protein (C4b), total and free protein S antigen, and clotting activities of factors II, V, VII, and X and of protein C and protein S. Autoantibodies to phospholipids, cardiolipin, and protein S were determined in enzyme-linked immunosorbent assays. RESULTS All children had a lupus anticoagulant and acquired protein S deficiency. Thrombosis in five children was associated with presumed or documented infection with streptococcus. All children transiently expressed free protein S deficiency, elevated levels of IgG, IgM, or both binding to protein S, the lupus anticoagulant, and increased concentration of the F 1+2 fragment. Four children also had antiphospholipid or anticardiolipin antibodies. In one child a purified IgG fraction cross-reacted with both protein S and a specific varicella antigen. CONCLUSIONS A subset of children with varicella infection, some of whom are coinfected with streptococcus, are prone to development of a lupus anticoagulant and an autoantibody to protein S, which results in acquired free protein S deficiency. Such children are at risk of having life-threatening thrombotic events.

Nitric Oxide for Inhalation in the Acute Treatment of Sickle Cell Pain Crisis: A Randomized Controlled Trial

CONTEXT Inhaled nitric oxide has shown evidence of efficacy in mouse models of sickle cell disease (SCD), case series of patients with acute chest syndrome, and 2 small placebo-controlled trials for treatment of vaso-occlusive pain crisis (VOC). OBJECTIVE To determine whether inhaled nitric oxide gas reduces the duration of painful crisis in patients with SCD who present to the emergency department or hospital for care. DESIGN, SETTING, AND PARTICIPANTS Prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial for up to 72 hours of inhaled nitric oxide gas vs inhaled nitrogen placebo in 150 participants presenting with VOC of SCD at 11 centers between October 5, 2004, and December 22, 2008. Intervention Inhaled nitric oxide gas vs inhaled nitrogen placebo. MAIN OUTCOME MEASURES The primary end point was the time to resolution of painful crisis, defined by (1) freedom from parenteral opioid use for 5 hours; (2) pain relief as assessed by visual analog pain scale scores of 6 cm or lower (on 0-10 scale); (3) ability to walk; and (4) patients and familys decision, with physician consensus, that the remaining pain could be managed at home. RESULTS There was no significant change in the primary end point between the nitric oxide and placebo groups, with a median time to resolution of crisis of 73.0 hours (95% confidence interval [CI], 46.0-91.0) and 65.5 hours (95% CI, 48.1-84.0), respectively (P = .87). There were no significant differences in secondary outcome measures, including length of hospitalization, visual analog pain scale scores, cumulative opioid usage, and rate of acute chest syndrome. Inhaled nitric oxide was well tolerated, with no increase in serious adverse events. Increases in venous methemoglobin concentration confirmed adherence and randomization but did not exceed 5% in any study participant. Significant increases in plasma nitrate occurred in the treatment group, but there were no observed increases in plasma or whole blood nitrite. CONCLUSION Among patients with SCD hospitalized with VOC, the use of inhaled nitric oxide compared with placebo did not improve time to crisis resolution. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00094887.

Extended red blood cell antigen matching for transfusions in sickle cell disease: a review of a 14‐year experience from a single center (CME)

BACKGROUND: Alloimmunization to red blood cell (RBC) blood group antigens is a major complication for patients with sickle cell disease (SCD), which limits the usefulness of RBC transfusion. Here, we report our experiences with extended RBC antigen matching for SCD patients.

Joint evaluation instruments for children and adults with haemophilia

With the heightened interest in protocols to prevent or treat complications of haemophilia related to recurrent haemarthroses, there is a need for sensitive joint‐evaluation tools. The World Federation of Haemophilia (WFH) Physical Joint Examination instrument, which was developed for persons with haemophilia worldwide, is not sensitive enough to detect early structural or functional abnormalities. Therefore, we have expanded the WFH instrument to detect more subtle abnormalities of joint structure and function, and in addition, developed a new scale specifically tailored to the dynamic growth and gait development of children. We compared the original and three new instruments in 43 children with haemophilia. The three new scales all showed better correlation with the WFH pain instrument than did the original WFH physical examination instrument (P < 0.01 for each of the new instruments vs. P > 0.05 for the WFH instrument). In addition, results of the new child physical examination instrument best conformed to a normal distribution (P=0.35) and this instrument had better overall statistical performance. This instrument should be studied further in prospective, longitudinal clinical trials of young children.

The Varicella-Autoantibody Syndrome

This cross-sectional study was conducted to determine the incidence of autoantibodies to phospholipids and coagulation proteins in children with acute varicella zoster virus (VZV) infection. Study groups included children with VZV alone or complicated by purpura fulminans and/or thromboembolism. VZV naïve children and children who had VZV >1 y before sample collection formed a control group. Blood was assayed for the following: free protein S (PS), protein C, antithrombin, and prothrombin; antibody binding to these proteins; lupus anticoagulant; anticardiolipin antibody; antiphospholipid antibodies; and prothrombin fragment 1+2. Data regarding coinfections was collected. Forty-three VZV-infected children showed an increased frequency of lupus anticoagulant, anticardiolipin antibody, antiphospholipid antibodies, and autoantibodies to PS, protein C, prothrombin, and antithrombin in comparison to 52 children without acute VZV (p < 0.0001). Seventeen children with VZV and purpura fulminans and/or thromboembolism showed a statistically significant decrease in free PS, significantly increased PS IgG antibody, and significantly increased prothrombin fragment 1+2 (p < 0.0001) compared with the group without acute VZV and the group with uncomplicated VZV. Twenty-six children with uncomplicated VZV showed increased PS IgG antibody (p < 0.001) compared with the children without acute VZV. For all groups combined, elevated PS IgG antibody showed negative correlation with free PS (p < 0.0001) and positive correlation with prothrombin fragment 1+2 (p = 0.0002). Autoantibodies were transient. Transient antiphospholipid and coagulation protein autoantibodies were common with VZV infection, but were not predictive of thrombotic complications.

Combined thrombolytic and anticoagulant therapy for venous thrombosis in children.

OBJECTIVES To evaluate safety, efficacy, and outcome after combination thrombolytic and anticoagulant therapy. STUDY DESIGN An open nonrandomized clinical protocol with prospective standardized monitoring and data collection. Children with a documented first episode of deep vein thrombosis were treated with urokinase 4400 U/kg load and per hour with unfractionated heparin at 10 U/kg/h. At 48 hours heparin infusions were increased to achieve a therapeutic level for 5 days. Children were given therapeutic warfarin for at least 3 months. Outcome was assessed at 48 hours and > or =1 year with history, physical examination, high-resolution imaging, and Doppler ultrasonography +/- impedance and photo plethysmography. RESULTS Thirty-two children were treated. There was 1 thrombotic death, 1 nonfatal thrombus progression, and 1 pulmonary embolism. At 48 hours half of the children showed substantial clot lysis, and on follow-up these children had complete resolution and had no symptoms. Three children with poor early clot lysis had recurrent thromboemboli, pulmonary embolism, or both, 2 had limb pain and swelling, and 2 had asymptomatic swelling. Two children had minor bleeding, whereas systemic reactions were common. CONCLUSIONS Combination therapy in children (urokinase and unfractionated heparin) was safe and efficacious. A prospective, randomized, controlled study in children is needed.

The factor V Leiden mutation in children with cancer and thrombosis

Thromboembolic phenomena, frequently observed in children with cancer who are undergoing chemotherapy, can cause significant morbidity and, less frequently, mortality. Many contributory factors have been identified. Whether the recently identified and most common coagulation defect predisposing to thrombosis, factor V Leiden, is associated with thrombosis in this setting, has not been explored. The current study was undertaken to determine the prevalence of the factor V Leiden mutation in children with cancer who developed thromboembolic phenomena as compared to those with cancer who did not. Genomic DNA was amplified using the polymerase chain reaction (PCR), followed by digestion of the amplification product with the restriction enzyme MnlI. The digested PCR products were then size‐fractionated to classify samples as heterozygous, homozygous or normal for the factor V Leiden mutation. 67 children with cancer were evaluated for the factor V Leiden mutation. One of 32 children with cancer and thrombosis, and none of 35 who had not experienced thrombotic problems, was found heterozygous for this mutation. We conclude that the factor V Leiden mutation does not play a significant role in the overall incidence of thromboses that occur in children with cancer.

Utility of magnetic resonance imaging for management of hemophilic arthropathy in children

We hypothesized that magnetic resonance imaging (MRI) would improve clinical and plain-radiograph assessments of children with hemophilic arthropathy. Thirteen children, aged 7 to 16 years, with severe factor VIII deficiency and one or more target joints were identified. A target joint was defined as a joint into which hemorrhage had occurred at least twice a month for at least the previous 6 months. After review of history, examination, and plain radiography, a recommendation regarding synovectomy or prophylaxis with factor VIII concentrate was made for each target joint. The MRI of each target joint was then reviewed. Fourteen target joints (three elbows, three knees, eight ankles) were evaluated. On the basis of clinical and plain-radiograph data, synovectomy was recommended for five and prophylaxis for seven joints. Discontinuation of prophylaxis was recommended for two ankles in one child. The MRI examination confirmed that four of five potential synovectomy candidates had markedly hypertrophied synovium and could benefit from surgery; one of five was excluded from synovectomy because synovial hypertrophy was minimal. Two of seven children recommended for prophylaxis were given substantially altered plans after MRI. In all, approximately 40% of joint assessments were modified as a result of the MRI findings. We conclude that MRI should be included in the evaluation of some children with hemophilic arthropathy.

Thrombosis in otherwise well children with the factor V Leiden mutation

OBJECTIVE To determine whether resistance to activated protein C caused by the factor V Leiden mutation (Arg506 to Gln) is associated with thrombosis occurring during childhood. STUDY DESIGN Children with thrombosis were screened for activated protein C resistance. Children found resistant to activated protein C had DNA analysis for the factor V Leiden mutation. Family members of the children with activated protein C resistance were similarly studied. RESULTS Three of fourteen children examined had abnormal normalized activated protein C sensitivity ratios. One child had protein S deficiency. The children had hyperlipidemia. Molecular confirmation of the factor V Leiden mutation was obtained for all three children. Family members of each of the three children were affected. CONCLUSIONS Children have thromboses in association with the factor V Leiden mutation, as do adults. This mutation may be identified as an isolated risk factor or in association with other risk factors for thrombosis.

Management of chronic middle ear effusion with prednisone combined with trimethoprim-sulfamethoxazole.

Fifty-three patients were enrolled and evaluable in a randomized, double-blinded controlled clinical trial comparing prednisone for 7 days plus trimethoprim-sulfamethoxazole (TMP/SMZ) for 30 days vs. TMP/SMZ alone in treating chronic middle ear effusion (MEE). Clearing of the effusion in both ears or in one when only one was involved was called complete resolution; clearing in one of two effected ears was called partial resolution. The outcomes 2 weeks after initiation of therapy of 26 patients initially treated with prednisone plus TMP/SMZ were complete resolution in 20, partial resolution in three, and unchanged in three. The outcomes in 27 patients initially treated with TMP/SMZ alone were complete resolution in eight, partial resolution in three, unchanged in 13 and development of acute otitis media in three (P<0.01 for complete resolution). Two weeks after initiation of therapy, patients with a MEE that failed to clear were crossed over to the alternative regimen. Overall 29 of 41 patients (71%) who received oral prednisone plus TMP/SMZ initially or after the crossover had complete resolution of their middle ear effusion at 2 weeks after starting prednisone and TMP/SMZ. Five of 35 (14%) patients treated with prednisone plus TMP/SMZ and one of six (17%) patients treated with TMP/SMZ alone who had complete resolution at 4 weeks required subsequent referrals for tympanostomy tubes. A course of prednisone for 7 days plus TMP/SMZ for 30 days with monthly follow-up should be considered in children with MEE persisting beyond 6–8 weeks before referral for tympanostomy tube placement.