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1.
Haemophilia ; 23(6): 926-933, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28838029

ABSTRACT

INTRODUCTION: Radionuclide synovectomy/synoviorthesis (RS) to manage proliferative synovitis in persons with bleeding disorders has been utilized for decades; however, aggregate US results are limited. AIM: To determine the prevalence of RS utilization, patient and procedure related demographics and functional outcomes in United States haemophilia treatment centres (HTCs). The ATHNdataset includes US patients with bleeding disorders who have authorized the sharing of their demographic and clinical information for research. METHODS: We performed a multi-institutional, observational cohort study utilizing this dataset through 2010. Cases treated with RS procedure were compared to controls within the dataset. Standard template for data collection included patient and procedure related demographics as well as functional outcomes including range of motion (ROM) of the affected joint. Normative age- and sex-matched control ROM was obtained from published data. RESULTS: In the ATHNdataset there were 19 539 control-patients and 196 case-patients treated with RS. Patients with severe haemophilia were more likely to have had RS compared to those with mild/moderate haemophilia, although the proportion of RS performed was similar between severe HA and HB. Inhibitory antibodies, HIV and hepatitis C infection were significantly more common in cases. There were 362 RS procedures captured with 94 cases having >1 RS procedures. CONCLUSIONS: Right-sided joint procedures were more prevalent than left-sided procedures. Overall, case-patients had worse joint ROM compared to control-patients and published normative values. Geographically, there was regional variation in RS utilization, as the Southeast region had the largest percent of case-patients.


Subject(s)
Hemarthrosis/therapy , Hemophilia A/complications , Radioisotopes/therapeutic use , Synovectomy/methods , Synovitis/therapy , Adolescent , Adult , Child , Cohort Studies , Female , Hemarthrosis/etiology , Hemarthrosis/physiopathology , Humans , Male , Range of Motion, Articular , Synovitis/etiology , Synovitis/physiopathology , United States , Young Adult
2.
Haemophilia ; 23(1): 25-32, 2017 Jan.
Article in English | MEDLINE | ID: mdl-27511890

ABSTRACT

INTRODUCTION: A recombinant porcine factor VIII B-domain-deleted product (rpFVIII; OBIZUR, Baxalta Incorporated, Deerfield, IL 60015, USA) was recently approved for treatment of bleeding episodes in adults with acquired haemophilia A (AHA) in the United States. To date, no clinical experience outside the registration study has been reported. AIM: To describe early clinical experience using rpFVIII for AHA. METHODS: A retrospective chart review of seven patients with AHA treated with rpFVIII at four institutions from November 2014 to October 2015. RESULTS: The time to diagnosis of AHA ranged from 5 days to 6 weeks. Six major and one other bleed were treated with rpFVIII following unsatisfactory bypassing agent (BPA) therapy. Good haemostatic efficacy was seen in five of seven cases. rpFVIII loading doses of 100 (n = 6) or 200 U kg-1 (n = 1) increased FVIII activity from <1 to 9% at baseline to 109-650% within 0.25-7 h in six of seven cases. Subsequent median doses ranged from 30 to 100 U kg-1 for 3-26 days. No rpFVIII-related adverse events were reported. Three patients survived with inhibitor eradication, one with persistent inhibitor, two died with inhibitors present and one was discharged and later died from unrelated causes. CONCLUSIONS: rpFVIII showed good haemostatic efficacy with no recurrences in most cases, with consumption substantially less than in the registration study. Treatment decisions were based on FVIII activity levels and clinical assessment. The ability to titrate rpFVIII dose using FVIII activity was considered advantageous compared with BPA therapy. Notable delays in diagnosis were observed.


Subject(s)
Hemophilia A/therapy , Recombinant Proteins/therapeutic use , Aged , Aged, 80 and over , Animals , Female , Hemophilia A/drug therapy , Humans , Male , Middle Aged , Retrospective Studies , Swine , Treatment Outcome , Young Adult
3.
J Thromb Haemost ; 13(1): 47-53, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25354263

ABSTRACT

BACKGROUND: The development of neutralizing antibodies, referred to as inhibitors, against factor VIII is a major complication associated with FVIII infusion therapy for the treatment of hemophilia A (HA). Previous studies have shown that a subset of HA patients and a low percentage of healthy individuals harbor non-neutralizing anti-FVIII antibodies that do not elicit the clinical manifestations associated with inhibitor development. OBJECTIVE: To assess HA patients' anti-FVIII antibody profiles as potential predictors of clinical outcomes. METHODS: A fluorescence immunoassay (FLI) was used to detect anti-FVIII antibodies in 491 samples from 371 HA patients. RESULTS: Assessments of antibody profiles showed that the presence of anti-FVIII IgG1 , IgG2 or IgG4 correlated qualitatively and quantitatively with the presence of an FVIII inhibitor as determined with the Nijmegen-Bethesda assay (NBA). Forty-eight patients with a negative inhibitor history contributed serial samples to the study, including seven patients who had negative NBA titers initially and later converted to being NBA-positive. The FLI detected anti-FVIII IgG1 in five of those seven patients prior to their conversion to NBA-positive. Five of 15 serial-sample patients who had a negative inhibitor history and had anti-FVIII IgG1 later developed an inhibitor, as compared with two of 33 patients with a negative inhibitor history without anti-FVIII IgG1 . CONCLUSIONS: These data provide a rationale for future studies designed both to monitor the dynamics of anti-FVIII antibody profiles in HA patients as a potential predictor of future inhibitor development and to assess the value of the anti-FVIII FLI as a supplement to traditional inhibitor testing.


Subject(s)
Autoantibodies/blood , Factor VIII/immunology , Fluorescence Polarization Immunoassay/methods , Hemophilia A/immunology , Immunoglobulin G/blood , Spectrometry, Fluorescence , Adolescent , Biomarkers/blood , Hemophilia A/blood , Hemophilia A/diagnosis , Humans , Male , Predictive Value of Tests , Prognosis , Time Factors , Young Adult
5.
Haemophilia ; 19(1): 51-8, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23004924

ABSTRACT

Little is known about the impact of the recent US economic downturn and health care reform on patient, caregiver and health care provider (HCP) decision-making for haemophilia A. To explore the impact of the recent economic downturn and perceived impact of health care reform on haemophilia A treatment decisions from patient, caregiver and HCP perspectives. Patients/caregivers and HCPs completed a self-administered survey in 2011. Survey participants were asked about demographics, the impact of the recent economic downturn and health care reform provisions on their treatment decisions. Seventy three of the 134 (54%) patients/caregivers and 39 of 48 (81%) HCPs indicated that the economic downturn negatively impacted haemophilia care. Seventy of the 73 negatively impacted patients made financially related treatment modifications, including delaying/cancelling routine health care visit, skipping doses and/or skipping filling prescription. Treatment modifications made by HCPs included delaying elective surgery, switching from higher to lower priced product, switching from recombinant to plasma-derived products and delaying prophylaxis. Health care reform was generally perceived as positive. Due to the elimination of lifetime caps, 30 of 134 patients (22%) and 28 of 48 HCPs (58%) indicated that they will make treatment modifications by initiating prophylaxis or scheduling routine appointment/surgery sooner. Both patients/caregivers and HCPs reported that the economic downturn had a negative impact on haemophilia A treatment. Suboptimal treatment modifications were made due to the economic downturn. Health care reform, especially the elimination of lifetime caps, was perceived as positive for haemophilia A treatment and as a potential avenue for contributing to more optimal treatment behaviours.


Subject(s)
Delivery of Health Care/economics , Economic Recession , Health Care Reform , Hemophilia A/therapy , Adult , Attitude of Health Personnel , Caregivers/psychology , Delivery of Health Care/organization & administration , Female , Health Knowledge, Attitudes, Practice , Hemophilia A/economics , Humans , Male , Patient Satisfaction , Surveys and Questionnaires , United States , Young Adult
6.
Haemophilia ; 18(3): 332-8, 2012 May.
Article in English | MEDLINE | ID: mdl-22044662

ABSTRACT

Advances in therapy have improved life expectancy and quality of life of patients with haemophilia A. Due to the chronic and complex management of this disease, particularly, the development of inhibitors, little is known about their health resource utilization in the real-life setting over time. The aim was to assess the distribution and trend of healthcare resource utilization among US haemophilia A patients with and without inhibitors. The MarketScan® Database, was queried to identify individuals with ≥1 year continuous enrolment, two medical diagnoses of haemophilia A and claims for factor VIII or bypassing agent (to infer inhibitor status) during 2001-2007. Haemophilia-related cost was estimated from inpatient, outpatient and pharmacy claims. Annual cost differences were assessed by age and over a 4-year period for those with continuous enrolment. Among 51 million covered lives, 1044 haemophilia patients were identified, of whom 981 (94%; mean age = 21.2 years) did not have an inhibitor. The median haemophilia-related cost for these patients was $63,935 per patient per year. When normalized by weight, annual cost was stable (no statistically significant differences) among 312 non-inhibitor patients (mean age = 21.8 years) with 4-year continuous data. While there was a wide distribution of haemophilia-related cost among the 63 individuals with an inhibitor (mean age = 15.4 years), only 0.6% of the total haemophilia patients had costs exceeding $1 million per patient per year. This study indicated that most haemophilia A patients were inhibitor-free with relatively stable annual costs over time. There was a wide distribution of haemophilia-related cost for inhibitor patients, while the proportion of patients who incurred extreme high cost was low.


Subject(s)
Coagulants/therapeutic use , Factor VIII/therapeutic use , Health Resources/statistics & numerical data , Hemophilia A/drug therapy , Adolescent , Adult , Blood Coagulation Factor Inhibitors/analysis , Child , Child, Preschool , Coagulants/economics , Databases, Factual/statistics & numerical data , Factor VIII/economics , Health Care Costs , Health Resources/economics , Hemophilia A/blood , Hemophilia A/economics , Humans , Infant , Insurance, Health/statistics & numerical data , United States , Young Adult
7.
J Thromb Haemost ; 8(6): 1372-82, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20230419

ABSTRACT

BACKGROUND: Romiplostim is a peptibody protein that raises platelet counts during long-term treatment of patients with chronic immune thrombocytopenia (ITP). Clinical outcomes related to increased platelet counts include a reduced risk of bleeding and a potential risk of thrombosis. OBJECTIVE: To evaluate bleeding and thrombotic events occurring in chronic ITP patients during two phase 3, randomized, placebo-controlled, 24-week studies of romiplostim and during subsequent treatment in an open-label extension study. PATIENTS/METHODS: In the phase 3 trials, 125 patients were randomized to romiplostim or placebo; romiplostim dose was adjusted to maintain platelet counts of 50-200 x 10(9) L(-1). Patients who completed the phase 3 trials could enroll in the extension study in which all patients received romiplostim. RESULTS: In the phase 3 trials, a significantly greater percentage of patients treated with placebo (34%) had bleeding adverse events of moderate or greater severity than did patients treated with romiplostim (15%, P = 0.018). In the extension study, the incidence of bleeding adverse events of moderate or greater severity decreased from 23% of patients in the first 24 weeks to 12% after 24-48 weeks, remaining < or = 6% thereafter. The exposure-adjusted incidence of thrombotic events was 0.1 per 100 patient-weeks in the phase 3 studies, and 0.08 per 100 patient-weeks in the extension study where patients received romiplostim for up to 144 additional weeks. CONCLUSIONS: The incidence and severity of bleeding was decreased in chronic ITP patients treated with romiplostim compared with placebo, and the incidence of thrombotic events was not different between the two groups.


Subject(s)
Hemorrhage/chemically induced , Receptors, Fc/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Thrombocytopenia/drug therapy , Thrombopoietin/therapeutic use , Thrombosis/chemically induced , Chronic Disease , Double-Blind Method , Humans , Placebos , Prospective Studies , Receptors, Thrombopoietin/agonists , Recombinant Fusion Proteins/adverse effects , Thrombocytopenia/physiopathology , Thrombopoietin/adverse effects
8.
J Thromb Haemost ; 5(8): 1654-9, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17663736

ABSTRACT

BACKGROUND: Thrombosis is not uncommon in children with serious medical conditions. Unfractionated heparin, the most commonly used anticoagulant in the acute management of thrombosis, has significant pharmacologic limitations, especially in infants. Newer anticoagulants have improved properties relative to heparin, and this may enhance the outcome in children. OBJECTIVE: To determine dosing, and to assess the safety and efficacy of bivairudin for infants with thrombosis. METHODS: Infants <6 months old were chosen for this pilot study as they may most benefit from a direct thrombin inhibitor because of their physiologically low antithrombin levels. This was an open label, dose-finding and safety study. Patients received one of three bolus doses and one of two initial infusion doses with subsequent dosing adjusted utilizing the activated partial thromboplastin time. Safety was assessed by specific bleeding endpoints. Efficacy was determined by reassessing the initial imaging study at 48-72 h and by measurement of molecular markers of thrombin generation. RESULTS: Sixteen patients completed the study. All three bolus doses resulted in therapeutic anticoagulation, as did both initial infusion doses. A dose-response effect was noted for the continuous infusion but not the bolus dosing. Two patients met the study criteria for major bleeding, both with gross hematuria, which resolved with a reduction in the bivalirudin infusion rate. In terms of efficacy, 37.5% of patients had complete or partial resolution of their thrombosis by 48-72 h. There was a significant decrease in all three molecular markers of thrombin generation. CONCLUSION: This study demonstrates the potential utility of bivalirudin in the pediatric population.


Subject(s)
Anticoagulants/administration & dosage , Hirudins/administration & dosage , Peptide Fragments/administration & dosage , Thrombosis/drug therapy , Female , Humans , Infant , Infant, Newborn , Male , Partial Thromboplastin Time , Pilot Projects , Prospective Studies , Recombinant Proteins/administration & dosage , Treatment Outcome
9.
Haemophilia ; 13(4): 380-2, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17610551

ABSTRACT

The incidence of intracranial haemorrhage (ICH) in newborns with haemophilia is unknown. Retrospective studies, estimate the incidence to be around 3%. Because of this uncertainty, we analysed the largest inpatient database in the USA, the Nationwide Inpatient Sample (NIS), to better approximate the incidence of ICH in these patients. ICD-9 coding data were used to reference NIS entries of haemophilia (A, B or C) or von Willebrand's disease (VWD), with intraventricular (IVH), subarachnoid (SAH), subdural (SDH) and/or intraparenchymal (IPH) haemorrhage. Of 9.2 x 10(7) hospitalizations from 1988 to 2001, 11% or 1 x 10(7) were newborns. Of these, 0.00527%, or 580 were diagnosed with haemophilia or VWD. Twenty of 580, or 3.4%, experienced an ICH. The ICH rate in non-haemophilic newborns was 0.11% (P value: <0.0001). The rate of ICH among term haemophilic newborns without sepsis, respiratory distress syndrome (RDS) or congenital heart disease (CHD), delivered without vacuum assist was 1.9%. One death occurred on the day of birth in a term neonate with haemophilia C. The mean length of stay for ICH patients with haemophilia was 28 days (median 28, range: 6-143 days). The mean hospital charges for the group were 102,072 dollars (median 67,551 dollars, range: 9624-467,132 dollars). These data add credence to the estimates of ICH in haemophilic newborns and may guide treatment strategies around the time of their birth. Further, uncomplicated delivery of term, otherwise healthy haemophilic newborns may carry a lesser risk of ICH.


Subject(s)
Hemophilia A/complications , Intracranial Hemorrhages/etiology , Pregnancy Complications, Hematologic/etiology , Delivery, Obstetric/methods , Female , Hemophilia A/epidemiology , Humans , Infant, Newborn , Intracranial Hemorrhages/epidemiology , Male , Mortality , Pregnancy , Pregnancy Complications, Hematologic/epidemiology , Retrospective Studies , United States/epidemiology
10.
Haemophilia ; 10(5): 428-37, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15357767

ABSTRACT

The efficacy and safety of an advanced category recombinant antihaemophilic factor produced by a plasma- and albumin-free method (rAHF-PFM) was studied in 111 previously treated subjects with haemophilia A. The study comprised a randomized, double-blinded, crossover pharmacokinetic comparison of rAHF-PFM and RECOMBINATE rAHF (R-FVIII); prophylaxis (three to four times per week with 25-40 IU kg(-1) rAHF-PFM) for at least 75 exposure days; and treatment of episodic haemorrhagic events. Median age was 18 years, 96% of subjects had baseline factor VIII <1%, and 108 received study drug. Bioequivalence, based on area under the plasma concentration vs. time curve and adjusted in vivo recovery, was demonstrated for rAHF-PFM and R-FVIII. Mean (+/-SD) half-life for rAHF-PFM was 12.0 +/- 4.3 h. Among 510 bleeding events, 473 (93%) were managed with one or two infusions of rAHF-PFM and 439 (86%) had efficacy ratings of excellent or good. Subjects who were less adherent to the prophylactic regimen had a higher bleeding rate (9.9 episodes subject(-1) year(-1)) than subjects who were more adherent (4.4 episodes subject(-1) year(-1); P < 0.03). One subject developed a low titre, non-persistent inhibitor (2.0 BU) after 26 exposure days. These data demonstrate that rAHF-PFM is bioequivalent to R-FVIII, and suggest that rAHF-PFM is efficacious and safe, without increased immunogenicity, for the treatment of haemophilia A.


Subject(s)
Factor VIII/therapeutic use , Hemophilia A/drug therapy , Adolescent , Adult , Aged , Child , Double-Blind Method , Factor VIII/adverse effects , Factor VIII/pharmacokinetics , Hemorrhage/prevention & control , Hemostasis/drug effects , Humans , Middle Aged , Recombinant Proteins , Treatment Outcome
11.
Haemophilia ; 10(5): 629-48, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15357790

ABSTRACT

Venous access is essential for delivery of haemophilia factor concentrate. Wherever possible, peripheral veins remain the route of choice, and the use of central venous access devices (CVADs) should be limited to cases of clear need in patients with caregivers able to exercise diligence in CVAD care and should continue no longer than necessary. CVADs are of recognized value for repeated administration of coagulation factors in haemophilia, particularly for prophylaxis and immune tolerance therapy and in young children. Evidence to guide best practices has been fragmentary, and standardized methods for CVAD usage have yet to be established. We have developed management recommendations based upon available published evidence as well as extensive clinical experience. These recommendations address patient and CVAD selection; CVAD placement, care and removal; caregiver/patient guidance; and complications, including infection and thrombosis. In the absence of inhibitors, ports are recommended, primarily because of fewer associated infections than with external catheters. For patients with inhibitors, ports also appear to be associated with fewer infections. Infection is the most frequent complication, and recommendations to prevent and treat infections are supported by extensive clinical data and experience. Strict adherence to handwashing and aseptic technique are essential elements of catheter care. Evidence-based data regarding the detection and treatment of CVAD-related thrombotic complications are limited. Caregiver education is an integral part of CVAD use and the procedural practices of users should be regularly re-assessed. These recommendations provide a basis for sound current CVAD practice and are expected to undergo further refinements as new evidence is compiled and clinical experience is gained.


Subject(s)
Catheterization, Central Venous , Hemophilia A/complications , Catheterization, Central Venous/methods , Catheters, Indwelling , Choice Behavior , Contraindications , Device Removal , Equipment Contamination/prevention & control , Humans , Infection Control , Patient Selection , Postoperative Complications/prevention & control , Risk Assessment , Thrombosis/prevention & control
12.
Semin Hematol ; 41(1 Suppl 2): 1-16; discussion 16-8, 2004 Jan.
Article in English | MEDLINE | ID: mdl-15071785

ABSTRACT

Replacement therapy for hemophilia A has evolved from the early use of whole blood, citrated plasma, and cryoprecipitate, to purified factor VIII (FVIII) concentrates, first derived from plasma, then produced by recombinant DNA technology. Recombinant FVIII (rFVIII) concentrates have provided improved safety for patients with hemophilia A since they significantly reduce the risk of transmission of blood-borne infections. Nevertheless, human- or animal-derived plasma proteins are still included at some step in preparation of all previously licensed rFVIII, thereby introducing the potential for transmission of human or animal pathogens. Anti-hemophilic factor (recombinant), plasma/albumin-free method (rAHF-PFM), a novel advanced category rFVIII produced without the addition of human or animal plasma proteins, has been developed with the goal of providing the greatest possible margin of safety to hemophilia patients. This report, based on a symposium of the XIXth International Society on Thrombosis and Haemostasis Congress, provides an overview of the rAHF-PFM development program as well as current findings from the global clinical evaluation of rAHF-PFM in pediatric and adult previously treated patients.


Subject(s)
Factor VIII/therapeutic use , Hemophilia A/drug therapy , Plasma , Recombinant Proteins/therapeutic use , Serum Albumin , Adult , Animals , Child , Clinical Trials as Topic , Evaluation Studies as Topic , Factor VIII/adverse effects , Factor VIII/chemistry , Factor VIII/pharmacokinetics , General Surgery , Humans , Quality Control , Recombinant Proteins/adverse effects , Recombinant Proteins/isolation & purification , Recombinant Proteins/pharmacokinetics
13.
Haemophilia ; 9(5): 588-92, 2003 Sep.
Article in English | MEDLINE | ID: mdl-14511299

ABSTRACT

PURPOSE: To analyse the risk factors for infection associated with central venous access device (CVAD) use in children with haemophilia. METHODS: Risk factors for CVAD infection among patients with congenital haemophilia who had had a CVAD implanted at a single institution were evaluated utilizing the following variables: age at CVAD placement, age at end of study, number of days with a CVAD, percentage of lifetime with a CVAD, and history of inhibitor. RESULTS: Fifty-nine patients had a total of 97,936 (median 1768 days per patient) CVAD days in the study period. The median age at CVAD placement was 2.7 years (range 0-14.0). Twenty-six (44%) patients reported CVAD infections during the study period from January 1993 to October 2000. Twenty-four patients had their CVAD replaced, 17 (71%) of whom reported having infections and seven (29%) of whom had a history of inhibitor. The strongest predictor for having any infections was inhibitor status (P=0.16), although none of the risk factors had statistically significant effects. Among the 26 patients reporting infections, 42% had more than one CVAD-related infection. Seven patients had multiple infections involving the same organism. The mean rate of infection was 0.45 per 1000 catheter days, with a 95% confidence interval of 0.33-0.60. Those with a history of inhibitor had an infection rate of 0.66 compared with 0.38 per 1000 catheter days (P=0.09) for those without a history of inhibitor. Patients who were older (greater than the median age of 2.7) at CVAD placement had a lower rate of infection (0.29 vs. 0.65, P<0.01) compared with those < or =2.7 years. Adjustment for inhibitor status had little impact on these results. For the group as a whole, the median time to first infection was 1977 days from CVAD placement. Patients who were older at CVAD placement or study exit had lower relative hazards of infection (P=0.05 and P=0.09 respectively), while those who had inhibitors had a higher but not statistically significant relative hazard of 1.88 (P=0.13). CONCLUSIONS: These data reveal that while considerable numbers of patients develop CVAD-related infection, the interval between catheter placement and infection can be quite long. In addition, the earlier in life a CVAD is placed, the higher the risk of infectious complications, as evidenced by the tendency towards a higher infection rate. Measures to prevent CVAD-related infection might be focused on very young patients who appear to be at higher risk.


Subject(s)
Catheterization, Central Venous/adverse effects , Equipment Contamination , Hemophilia A/complications , Infections/etiology , Adolescent , Age Factors , Catheters, Indwelling/adverse effects , Child , Child, Preschool , Factor VIII/antagonists & inhibitors , Factor VIII/immunology , Hemophilia A/immunology , Humans , Infant , Infant, Newborn , Isoantibodies/blood , Longitudinal Studies , Male , Risk Factors , Time Factors
14.
J Thromb Haemost ; 1(5): 958-62, 2003 May.
Article in English | MEDLINE | ID: mdl-12871361

ABSTRACT

The prothrombin G20210A mutation is a common risk factor for thrombosis which increases the risk of deep vein thrombosis, stroke, and fetal loss. There are few publications of its clinical manifestations in children. Our objective was to determine the clinical manifestations of the prothrombin mutation in children. Via survey of pediatric hematologists, we collected data on children with thrombosis and the prothrombin mutation. Thirty-eight patients with a thrombotic event were identified as having the prothrombin mutation. Children with arterial thrombosis were younger, less than half had additional risk factors present at the time of the event, and had a high frequency of central nervous system thrombosis. Children with venous thrombosis were older, almost always had additional risk factors present, and had thrombosis occur most often in the extremities, although there were also a significant number of events in the central venous and cerebral circulation. There was a striking predilection for central nervous system events as 30% of all the events and 67% of the arterial events occurred there. In all, 14/38 children (37%) had central nervous system thrombosis. Unlike factor V Leiden and deficiencies of proteins C and S which cause venous thromboembolism, the prothrombin mutation in children is often associated with arterial thrombosis and with central nervous system events. In children with the prothrombin mutation and venous thrombosis, other risk factors are usually present. Therefore, children with arterial or venous thrombosis of any location should be evaluated for the presence of the prothrombin mutation.


Subject(s)
Point Mutation , Prothrombin/genetics , Thrombosis/genetics , Adolescent , Age Distribution , Arterial Occlusive Diseases/epidemiology , Arterial Occlusive Diseases/genetics , Child , Child, Preschool , Female , Genetic Predisposition to Disease , Heterozygote , Homozygote , Humans , Incidence , Infant , Infant, Newborn , Male , Retrospective Studies , Surveys and Questionnaires , Thrombosis/epidemiology , Venous Thrombosis/epidemiology , Venous Thrombosis/genetics
15.
Blood Rev ; 16(1): 19-21, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11913988

ABSTRACT

Acute immune (idiopathic) thrombocytopenic purpura (ITP) in childhood is most commonly a self-limiting condition with unexplained onset and resolution. In cases of severe thrombocytopenia, or situations where the condition persists beyond 6 months, treatment may be required to minimize the danger of life-threatening intracranial hemorrhage. Nonsurgical treatment options include corticosteroids, intravenous gammaglobulin (i.v.Ig), or anti-D. Specific indications, benefits, and limitations of these modalities are discussed, with recommendations for future directions in therapy.


Subject(s)
Purpura, Thrombocytopenic, Idiopathic/drug therapy , Acute Disease , Adrenal Cortex Hormones/therapeutic use , Child , Disease Management , Humans , Immunoglobulins, Intravenous/therapeutic use , Isoantibodies/therapeutic use , Rho(D) Immune Globulin
18.
Blood ; 97(6): 1721-6, 2001 Mar 15.
Article in English | MEDLINE | ID: mdl-11238113

ABSTRACT

Genetically controlled variation in alpha2beta1 expression by human blood platelets was previously described. Sixty-two haplotype sequences corresponding to the proximal 5' regulatory region (-1096 to +1) of the alpha2 gene were compared, and a dimorphic sequence -52C>T was identified that is located precisely between 2 tandem Sp1/Sp3 binding elements previously shown to be absolutely required for transcriptional activity of this gene in epithelial cell lines and the erythroleukemic cell line K562. The gene frequency of -52T in a random Caucasian population is approximately 0.35, and the expression of -52T correlates directly with reduced densities of platelet alpha2beta1. In mobility shift analyses, the -52T substitution attenuates complex formation with both Sp1 and Sp3. When transfected into the erythroleukemia cell line Dami, promoter-luciferase constructs bearing the -52T sequence exhibit a 5-fold decrease in activity relative to the -52C construct. In transfected CHRF-288-11 megakaryocytic cells, the corresponding activity decreases by 10-fold. The -52T sequence appears to be in linkage disequilibrium with the previously defined allele A3 (807C; HPA-5b), known to be associated with diminished expression of platelet alpha2beta1. In summary, a natural dimorphism has been identified within the proximal 5' regulatory region of the human integrin alpha2 gene that is responsible for decreased expression levels of the integrin alpha2beta1 on blood platelets through a mechanism that is probably mediated by the nuclear regulatory proteins Sp1 and Sp3.


Subject(s)
Alleles , Antigens, CD/genetics , Gene Expression Regulation/genetics , 5' Untranslated Regions , Blood Platelets/metabolism , DNA-Binding Proteins/metabolism , Down-Regulation , Genes, Regulator , Humans , Integrin alpha2 , Integrins/metabolism , Leukocytes, Mononuclear/metabolism , Linkage Disequilibrium , Pregnancy Proteins/metabolism , Protein Binding , Receptors, Collagen , Sp1 Transcription Factor/metabolism , Transcription, Genetic/genetics
19.
Semin Hematol ; 37(1 Suppl 1): 35-41, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10676923

ABSTRACT

Immune (idiopathic) thrombocytopenic purpura (ITP) in children is usually acute and self-limiting, but may become chronic in 10% to 30% of patients. Salient issues in the treatment of childhood chronic ITP (cITP) include the following: the choice of immunomodulatory agent; the child's desire for unrestricted physical activity; interventions to avoid or defer splenectomy; and, finally, choosing when (and how) to perform splenectomy. Treatment for children with cITP during childhood usually is extrapolated from that for acute ITP. Treatment with pooled intravenous immunoglobulin (IVIg) and anti-D immunoglobulin often gives an acute response followed by a predictable decay of platelet count. Corticosteroids usually lead to a platelet increase; however, the associated adverse effects of chronic usage are generally unsatisfactory for most children and adolescents. With pulsed, high-dose corticosteroids, a durable platelet response is the exception, not the rule. More aggressive immunosuppression is usually reserved for patients who are symptomatic and refractory to the above treatments, Including splenectomy. Although the estimated success rate ranges from 70% to 90%, the long-term outcome of splenectomy in children with cITP in not well described. In addition, the risk of fatal postsplenectomy infections is significant. A familiar initial strategy among pediatric hematologists thus involves deferral of splenectomy with the reasonable possibility of spontaneous recovery. Corticosteroids, anti-D, and IVIg are effective, temporizing medical alternatives to splenectomy in treating cITP in children. Quality-of-life measurements in children with cITP may help to stimulate the development of new approaches.


Subject(s)
Adjuvants, Immunologic/therapeutic use , Adrenal Cortex Hormones/therapeutic use , Purpura, Thrombocytopenic, Idiopathic , Splenectomy , Child , Child, Preschool , Humans , Infant , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Purpura, Thrombocytopenic, Idiopathic/surgery
20.
Am J Hematol ; 60(2): 126-9, 1999 Feb.
Article in English | MEDLINE | ID: mdl-9929104

ABSTRACT

We describe a novel, de novo point mutation in one antithrombin (AT) allele resulting in type I AT deficiency and thrombophilia. Low plasma AT activity as well as low plasma AT antigen were documented in the propositus, but not in the parents, or in a male sibling. AT gene analysis by sequencing polymerase chain reaction-amplified genomic DNA from exon 5 of the propositus revealed a novel point mutation, GAG-->TAG at codon 271, resulting in a stop codon (Glu271STOP). This mutation was not demonstrable in the other members of his immediate family. DNA marker polymorphism analysis indicated the expected parentage. Based on allele frequency data for Caucasians in the United States the cumulative paternity index, or CPI, for the propositus and his father is 219,077. This corresponds to a probability of paternity of 99.9995% based on a prior probability of 50%. Included in this analysis is a linkage analysis of a trinucleotide repeat in intron 5 of the AT gene of the various family members, which also confirmed maternity and paternity. These studies provide documentation of the first spontaneous mutation of an AT gene in a thrombophilic individual, resulting in a type I AT deficiency.


Subject(s)
Antithrombins/deficiency , Antithrombins/genetics , Glutamine/genetics , Point Mutation , Thrombophilia/genetics , Adolescent , Base Sequence , Codon , DNA Mutational Analysis , Humans , Male , Paternity , Polymerase Chain Reaction
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