Biomedical subjects
Publications and source records attributed to R Nuss.
Skin necrosis and priapism are unusual complications of warfarin therapy. We report a teenager with warfarin-associated skin necrosis and priapism who was subsequently found to be a compound heterozygote for protein C deficiency and a heterozygote for the factor V Leiden mutation.
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To determine the prevalence of activated protein C resistance and the factor V Leiden mutation (position 1691, arginine 506 to glutamine substitution) in children with thrombosis, plasma samples from children with thrombosis were tested for activated protein C resistance. DNA was analyzed for the factor V Leiden mutation. Five of 34 children (15%) had activated protein C resistance; each was heterozygous for the factor V Leiden mutation. All 5 children heterozygous for the factor V Leiden mutation suffered non-CNS venous thromboses comprising 21% of the group of children (5/24) with non-CNS venous thrombotic events. Each of these 5 children had a family history of thrombosis. In conclusion, children with non-CNS venous thrombosis should be evaluated for the factor V Leiden mutation. Children most likely affected are those with a family history of thrombosis.
A child with afibrinogenemia was evaluated for prophylactic cryoprecipitate transfusion due to recurrent episodes of traumatic bleeding. The parents would only consider ongoing transfusion therapy if a limited donor program could be established. Automated plasmapheresis was performed on a regular basis on the patient's parents and a limited number of selected donors. Studies on the initial units collected demonstrated that a single 500 mL plasmapheresis yielded a mean of 606 mg fibrinogen in the cryoprecipitate, which was stored in two bags. A total of 166 U of cryoprecipitate from 84 individual plasmapheresis donations were transfused prophylactically every 2-3 weeks over a 16-month period. Compared to transfusions from random donors, the use of a limited number of apheresis donors resulted in a donor exposure reduction of 87%. Clinically, the patient has had minimal bleeding during this period.
BACKGROUND/OBJECTIVES: Haemophilia is a lifelong bleeding disorder associated with significant morbidity. Because of this for almost 25 years there has been a national network of specialized haemophilia treatment centres (HTCs). Despite this, there is little published information about HTC utilization. We chose to study utilization and satisfaction with care received from the Colorado HTC as compared with that received at other nonspecialized sites. RESEARCH DESIGN: A survey was designed in collaboration between Colorado Department of Public Health and Environment (CDPHE) and the Denver Mountain States Regional Hemophilia Center personnel for telephone administration by CDPHE personnel to all persons with haemophilia (pwh) residing in Colorado in 1994. SUBJECTS: One hundred forty-five persons with haemophilia (77% of those eligible) participated in the survey. RESULTS: The majority of respondents received care from the HTC. Persons less than 21 years of age and those with severe disease were significantly more likely to do so. Satisfaction with care received at the HTC was greater than that received at other sites (P < 0.01). Issues of concern were insurer restricted access to the HTC and the lack of haemophilia knowledge of non-HTC providers. CONCLUSIONS: If HTCs and other specialty centres are to survive in an increasingly managed care environment, in addition to increased patient satisfaction, data documenting improved patient outcome with specialty centre directed care will be necessary to facilitate referral.
OBJECTIVE: To examine the relationship between family communication and HIV risk reduction behaviors among a multisite sample of 125 male youths (ages 12-25) with hemophilia and HIV- infection, as well as their parents. METHODS: Participants completed self-report surveys assessing communication and attitudes regarding HIV risk reduction interventions; adolescents also provided data about their sexual behaviors. RESULTS: Adolescents with parents who discuss sexual issues were more likely to report HIV status disclosure to sexual partners. Most parents were supportive of HIV risk reduction interventions for their adolescents, but the youths themselves tended to endorse only interventions that offered opportunities for recreational activities and socialization with peers. CONCLUSIONS: Findings are discussed in terms of intervention implications and the need for family systems-based programs.
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.
A factor V506 Arg-Gln mutation is the most common inherited cause of thrombophilia in adults. To date, there are no data regarding the detection of this mutation in neonatal blood or the relationship of this dysfunctional factor V to neonatal thrombosis. This study compared a modified activated protein C resistance functional assay with the PCR-based DNA assay for the factor V mutation in 115 prospectively collected umbilical cord blood samples. The incidence of activated protein C resistance in cord blood was 6%. The sensitivity and specificity of the modified assay for the factor V Leiden mutation was 100%.
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.
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.
Nineteen children who presented with thromboses over a 7-year period were found to have a lupus anticoagulant (LA). The initial thrombosis was proximal deep vein thrombosis (DVT) in six children, central nervous system (CNS) in five, primary pulmonary in four, distal DVT in two, central venous in one, and proximal arterial in one. Five children were diagnosed with systemic lupus erythematosus (SLE), including two children for whom thrombosis was the presenting sign of SLE. The remaining 14 children were diagnosed with the antiphospholipid antibody (APA) syndrome. The APA syndrome was manifest by venous or arterial thrombosis in association with a positive LA; positive anticardiolipin antibodies and a fine, speckled antinuclear antibody (ANA) pattern were additionally found in the majority of children. Approximately one-half of the children with SLE or the APA syndrome had a pulmonary embolus, and one-half developed recurrent thrombosis. Oral anticoagulation with coumadin to achieve an INR of > 2.0 prevented thrombosis recurrence. The recognition of a LA in children with thrombosis necessitates evaluation for SLE, APA, and other autoantibodies.
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OBJECTIVE: The objective of our study was to evaluate the age, sex, clinical conditions, family history, site, catheter association, means of radiologic evaluation, development of pulmonary involvement, prevalence of antithrombin III, protein C and protein S deficiencies, and lupus anticoagulants in children who suffered a thrombotic event. METHODS: Data were collected on children over 1 month of age who had or developed a thrombotic event from 1987 through 1993 at two pediatric centers. RESULTS: Sixty-one children (mean age, 10 years) suffered a thrombotic event. Males and females were equally affected. A variety of clinical prothrombotic conditions similar to those described in adults could be identified for two thirds of the children. Family history was positive in seven children. The primary thrombotic site for two thirds of the children was the central nervous system and other centrally located blood vessels. Diagnosis of the primary thrombotic site was primarily by ultrasound. A central vascular access device was associated with 25% of thromboses. Lung involvement occurred in 20%. Two thirds of the children were evaluated for a lupus anticoagulant and a deficiency of protein C and protein S; two thirds had one of these diagnosed. For further analyses, children without an underlying prothrombotic systemic illness or precipitant at the time of thrombosis (n = 20) were compared to those with these conditions (n = 41). Central nervous system thromboses were significantly increased in the children without prothrombotic conditions. The prevalence of a deficiency of protein C or protein S or the presence of a lupus anticoagulant approached 90% in the group without prothrombotic conditions as compared with 50% in the other group. CONCLUSION: We conclude that prospective multicenter pediatric thrombosis studies are warranted to confirm our preliminary findings of a high incidence of lupus anticoagulants and protein C and protein S deficiency in children with thromboses.
In this study, 13 children with severe hemophilia were given routine replacement infusions of factor VIII or IX to treat arthropathy. The children who had a mean age of 6.9 years (range 2.0-12.5) at initiation of prophylaxis had experienced an average of 43 acute hemorrhages (range 8-127) in the year prior to prophylaxis, of which a mean of 24 (range 5-46) were into joints. Therapy was begun in five children, using factor VIII concentrate at 20 U/kg three times a week, and one boy received factor IX concentrate 40 U/kg twice a week. This dose schedule was inadequate for three factor VIII-deficient boys and for the one factor IX-deficient boy. Two of three factor VIII-deficient boys responded to an increase to 30 U/kg prior to the 3-day interval. The dose frequency was increased to three times a week for the factor IX-deficient boy, but he continued to bleed and was taken to synovectomy. One of the original five factor VIII-deficient boys plus seven other factor VIII-deficient boys were begun on factor VIII 20 U/kg every other day; 3 boys ceased bleeding. Trough factor VIII levels were measured 24 hr after an infusion in the five boys who continued to bleed. Factor VIII dosage was adjusted to achieve a trough level of > 1%; 4 responded to an increase in the dose of factor VIII; 1 had an adequate trough but, due to compliance issues, was taken to synovectomy. Serial clinical and radiographic assessments determined stabilization of joint disease in more than one-half of the boys. No child showed reversal of abnormal radiographic findings. Institution of aggressive factor VIII and IX concentrate in children with established hemophilic arthropathy does not reverse joint disease but may alter the clinical course of hemophilia. Future studies to compare this intervention with primary prophylaxis instituted prior to the onset of recurrent joint hemorrhage are warranted.
PURPOSE: We report on the safety and efficacy of heparin anticoagulation for the treatment of neonatal renal vein thrombosis. PATIENTS AND METHODS: Six consecutive, prospectively identified, critically ill neonates with renal vein thrombosis were studied. Diagnosis of renal vein thrombosis was based on history and examination and confirmed with renal ultrasound. All neonates were treated with continuous i.v. heparin titrated to achieve a therapeutic whole blood clotting time and/or APTT. RESULTS: Renal vein thrombosis was bilateral for three of six neonates. Heparin infusion rates varied from 8 to 40 U/kg/h and were administered for 7-14 days. Two neonates developed hemorrhagic complications; one had disseminated intravascular coagulation but did not hemorrhage until heparin toxicity ensued, and another was well until an umbilical catheter was removed while he was therapeutically heparinized. Renal outcome at 3 months to 6 years showed hypertension in one neonate, atrophic kidneys in two, and both hypertension and an atrophic kidney in one. CONCLUSIONS: Bleeding was a significant complication of heparin therapy for neonatal renal vein thrombosis. Renal dysfunction was not prevented in four of six neonates treated with heparin. Alternative approaches to titrate heparin, alternative anticoagulants, or fibrinolytic therapy should be considered as therapy for neonatal renal vein thrombosis.
PURPOSE: Magnetic resonance imaging (MRI) was used for evaluation of refractory joint swelling in a 7-year-old boy with hemophilia. PATIENT AND METHODS: This patient with no evidence of an inhibitory had refractory left knee swelling despite receiving appropriate factor VIII concentrate infusions. RESULTS: A plain radiograph showed soft tissue swelling and a calcification in the left suprapatellar region. On MRI a discrete suprapatellar pouch could be detected and was subsequently surgically resected. CONCLUSION: We believe that MRI should be considered when evaluating children with hemophilia who have refractory joint swelling and no evidence of an inhibitor.
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.