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Biomedical subjects

Guy Young

Publications and source records attributed to Guy Young.

10 recordsLinked to original sources
PubMed2006

Diagnosis and treatment of thrombosis in children: general principles.

Thrombosis is an increasingly recognized complication occurring primarily in children with serious underlying conditions and most often associated with intravenous catheters. There are few clinical trials available to guide the decision-making in the diagnosis and treatment of thrombosis. Although there are published guidelines which suggest how to manage such patients, they are based on data from adult studies and uncontrolled pediatric studies and it is unclear how widely these guidelines are utilized in clinical practice. What is clear is that many additional studies are needed to provide the data required to make evidence-based decisions. Nevertheless, patients today are being diagnosed with thrombosis and must be treated. Diagnosis is based largely on various diagnostic-imaging methods. While Doppler ultrasonography is non-invasive and relatively inexpensive, its sensitivity for the upper venous system is poor. Venography/angiography, the most sensitive method to diagnose venous/arterial thrombosis is underutilized due to the need for peripheral venous access for venography and arterial catheterization for angiography as well as interventional radiology. Newer methods such as computed tomography and magnetic resonance imaging are useful for large vessel disease but are not validated in pediatrics. Treatment is based on the methods that are best at restoring circulation rapidly balanced by the risk for bleeding. Both thrombolysis and anticoagulation can be utilized with the circumstances of each individual patient dictating the choice. The field of pediatric thrombosis continues to advance with numerous new studies currently underway or being planned. In the near future, the results of these studies will allow for better management of pediatric patients with thrombosis.

Child↗
PubMed2006

Safety and pharmacokinetics of recombinant factor XIII-A2 administration in patients with congenital factor XIII deficiency.

Congenital factor XIII (FXIII) deficiency is associated with a tendency for severe bleeding, a risk for spontaneous abortion, and a high rate of spontaneous intracranial hemorrhage. This phase 1 escalating-dose study was developed to evaluate the safety and pharmacokinetics of a single administration of human recombinant FXIII-A2 (rFXIII-A2) homodimer in adults with congenital FXIII deficiency. Pharmacokinetics and activity of rXIII and changes in endogenous B subunit levels were assessed. Recombinant FXIII-A2 homodimer were complexed with endogenous FXIII-B subunits to form an FXIII-A2B2 heterotetramer with a half-life of 8.5 days, similar to that of endogenous FXIII. The median dose response was a 2.4% increase in FXIII activity based on unit per kilogram rFXIII administered. After the administration of rFXIII-A2, clot solubility normalized as measured by clot lysis in urea. Clot strength and resistance to fibrinolysis, as assessed by thromboelastography, also improved. Safety reviews were conducted before each dose escalation; no serious adverse events, including bleeding or thrombosis, were noted during the study. In addition, there was no evidence of the generation of specific antibodies to rFXIII or yeast proteins. Recombinant FXIII appears to be a safe and potentially effective alternative for FXIII replacement in patients with FXIII deficiency.

Adult↗
PubMed2006

Single dose of anti-D immune globulin at 75 microg/kg is as effective as intravenous immune globulin at rapidly raising the platelet count in newly diagnosed immune thrombocytopenic purpura in children.

OBJECTIVE: To conduct a randomized prospective trial of immune globulin treatment for 105 Rh+ children with newly-diagnosed immune thrombocytopenic purpura and a platelet count<20,000/microL, to determine whether anti-D immune globulin (anti-D) is as effective as intravenous immune globulin (IVIg). STUDY DESIGN: Eligible patients received either a single intravenous dose of 50 microg/kg anti-D (anti-D50), 75 microg/kg anti-D, (anti-D75), or 0.8 g/kg IVIg, (IVIg). Patients were monitored for response to treatment and adverse events. RESULTS: By 24 hours after treatment 50%, 72%, and 77% of patients in the anti-D50, anti-D75, and IVIg groups, respectively, had achieved a platelet count>20,000/microL (P=.03). By day 7, hemoglobin concentrations decreased by 1.6 g/dL, 2 g/dL, and 0.3 g/dL in the anti-D50, anti-D75, and IVIg groups, respectively. Headache, fever, or chills occurred least often in the anti-D50 group. CONCLUSIONS: A single 75 microg/kg dose of Anti-D raised the platelet count in children with newly diagnosed immune thrombocytopenic purpura more rapidly than standard-dose anti-D and as effectively as IVIg, with an acceptable safety profile.

Adolescent↗
PubMed2006

New approaches in the management of inhibitor patients.

The most serious current complication of factor replacement therapy for hemophilia patients is the development of neutralizing antibodies to the factor termed inhibitors. Patients with high-titer inhibitors frequently develop serious bleeding complications which do not respond to standard factor replacement therapy. Therefore, they must be treated with the so-called bypassing agents, recombinant factor VIIa and activated prothrombin complex concentrates, neither of which is as effective as standard factor replacement in patients without inhibitors. Immune tolerance therapy aimed at eradicating inhibitors is successful in a majority of patients; however, a sizable minority will have life-long inhibitors and often develop debilitating joint disease. The ultimate goal is to develop strategies aimed at preventing inhibitor development though these have not been realized yet. Until this is achieved, additional novel approaches are needed to improve the treatment of bleeding episodes and to better treat arthropathy once it develops. Finally, there is no laboratory monitoring device which can predict the clinical response of patients to bypassing agents. Thus another goal of current research is to develop such a tool which will enable the individualization of bypassing agent.

Blood Coagulation Factor Inhibitors↗
PubMed2005

Pediatric stroke and methylenetetrahydrofolate reductase polymorphisms: an examination of C677T and A1298C mutations.

Although rare in children, stroke is becoming increasingly recognized as an important cause of morbidity and mortality with an annual incidence of approximately 3 per 100,000 per year. While several studies have documented the underlying mechanisms and pathogenesis related to stroke in adults, including genetic and acquired prothrombotic conditions, the data available on similar conditions in children is limited. Evidence suggests that mutations in methylenetetrahydrofolate reductase (MTHFR) appear to be linked with hyperhomocysteinemia (HHC) and cerebral-thrombotic events in children. While the C677T common missense mutation is the best-characterized MTHFR polymorphism, another common missense mutation, A1298C also exists. A recent study of children demonstrated that the homozygous form of C677T polymorphism occurred two-times as often in those with stroke versus healthy controls. In our retrospective chart review of 33 children seen at Children's Hospital of Orange County from January 1, 2000 to September 30, 2003 with the diagnosis of stroke, we examined both the C677T and A1298C polymorphisms for occurrence and type. In the subset (n=21), which excluded those with a confounding disorder, we observed a significant increase in the frequency of A1298C and C677T homozygosity (0.25 [p=0.01] and 0.20 [p=0.100], respectively); expected rate: (0.06 and 0.08, respectively). Our observed rates of heterozygosity for both MTHFR mutations (0.35 and 0.40, respectively) were consistent with expected rates (0.28 and 0.38, respectively). In all subjects, homocysteine (HC) levels were normal. The results of our study suggest that mutations in MTHFR are associated with pediatric stroke. However, additional studies are required to confirm our findings and to determine if this relationship is causal.

Child↗
PubMed2005

Multifocal Castleman disease in pediatrics: case report.

Multicentric Castleman disease is a rare lymphoproliferative disorder of unknown cause. It is especially rare in children. The authors describe a 4-year-old girl that presented with protracted fever, hypoalbuminemia, thrombocytopenia, anasarca, and disseminated lymphadenopathy. Despite a comprehensive evaluation, her diagnosis remained elusive for several weeks. Eventually, a lymph node biopsy showed the presence of multicentric Castleman disease of mixed type. Due to her relatively poor prognosis and severity of the disease, she was treated with combination chemotherapy consisting of cyclophosphamide, vincristine, doxorubicin, and prednisone. She tolerated her therapy well and is currently free of disease at 36 months of follow-up.

Castleman Disease↗
PubMed2005

Therapy for haemophilia: recent advances and goals for the future.

In the 20th century, haemophilia evolved from a life-threatening, crippling disease to one for which the prognosis is excellent and many patients lead normal, productive lives. Although dramatic achievements in the treatment of haemophilia have occurred, the current therapies have significant drawbacks. Among these is the relatively high incidence of inhibitor development, the requirement for frequent intravenous infusions to prevent bleeding complications, the lack of effective treatment for established joint disease, and the high cost of treatment. The future goal of haemophilia treatment first and foremost is curing this genetic condition via gene therapy. As this goal is likely many years away, improvements in the current factor products in order to reduce the development of inhibitors and to reduce the frequency of therapy are more immediately achievable goals. Finally, improving the treatment of bleeding complications, particularly in inhibitor patients, and developing novel adjunctive therapies for the management of joint disease are also important goals for the near future. This review will discuss in detail the cu-rrent and future goals of haemophilia therapy.

Clinical Trials as Topic↗
PubMed2004

Argatroban as an alternative to heparin in extracorporeal membrane oxygenation circuits.

We investigated the anticoagulant effects of argatroban, a direct thrombin inhibitor, versus heparin in extracorporeal membrane oxygenation (ECMO) circuits. Three sham circuits were prepared according to our hospital's standard practice and run for six hours simultaneously. Two circuits were anticoagulated with argatroban (one with heparin in the wet prime and one without). One circuit had heparin in the initial prime and was then anticoagulated with heparin. We measured thrombin generation (prothrombin fragment 1+2, D-dimer and thrombin-antithrombin complexes), activated clotting times (ACTs) and partial thromboplastin times (aPTTs), and monitored thrombus formation using thromboelastography. ACTs were >1000 s in each circuit throughout assessment. No clot initiation was detected by thromboelastography. Thrombin generation was decreased in circuits anticoagulated with argatroban versus heparin, despite aPTTs being less prolonged. These results suggest that argatroban may be more efficacious than heparin for anticoagulation in ECMO. Additional studies are warranted to further evaluate argatroban in this setting.

Arginine↗
PubMed2004

Current and future antithrombotic agents in children.

Thromboembolic complications are increasing in children, and the use of anticoagulation has seen a dramatic increase despite the lack of randomized clinical trials. The most widely used agents in children are heparin and warfarin, however these agents have limitations that are exaggerated in children. This has led to the use of newer agents with improved pharmacologic properties such as low-molecular-weight heparin, however, the use of novel agents such as direct thrombin inhibitors has been limited to case reports. These agents, however, have potential advantages over heparin, low-molecular-weight heparin and warfarin. Current clinical trials are in progress to define the proper dose of two such agents--argatroban (Argatroban, GlaxoSmithKline) and bivalirudin (Angiomax, The Medicines Company). The selective Factor Xa inhibitor fondaparinux (Arixtra, Sanofi-Synthelabo) has not been used in children; however, there are situations in which this agent may be advantageous. This review will discuss the currently available agents, with an emphasis on those that are novel and their potential uses in children.

Age Factors↗