An imaging investigation of in situ uroliths in hospitalized cats in New Zealand and in the United States.

The submission rates of feline uroliths to laboratories and the composition of uroliths have been reported in studies. The prevalence of uroliths reported on imaging findings has not been published. The objective of this retrospective study was to use imaging data to investigate the anatomical location and the prevalence of macroscopic in situ uroliths in cats. Radiographs, sonograms and imaging reports from two cohorts of cats (from New Zealand (n = 497) and the United States (n = 693)) from 2004-2013 were reviewed for the presence of in situ uroliths. Uroliths were categorized by their location in the lower or upper urinary tract. Radiographic studies were performed on 43% (212/497) of the cats from New Zealand and 50% (349/693) of the cats from the USA. Sonographic studies were performed on 57% (285/497) of the cats from New Zealand and 50% (344/693) of the cats from the USA. The total prevalence of uroliths was 3% in the New Zealand cohort and 13% in the USA cohort. Lower tract urolith prevalence in the New Zealand cohort was 2.4% (5/212) in cats ≤ 6y and 1.1% (3/285) in cats >6y. Upper tract urolith prevalence in the New Zealand cohort was 0.5% (1/212) in cats ≤ 6y and 1.8% (5/285) in cats >6y. Lower tract urolith prevalence in the United States cohort was 6.0% (11/183) in cats ≤ 6y and 2.9% (15/510) in cats >6y. Upper tract urolith prevalence in the United States cohort was 2.7% (5/183) in cats ≤ 6y and 10.2% (52/510) in cats >6y. The prevalence of uroliths in the upper tract or lower tract was low in the New Zealand cohort compared to that of cats in the USA cohort, irrespective of age category. Geographical location may be important when evaluating risk factors for feline urolithiasis.

Influence of CYP2C9 and VKORC1 on warfarin dose, anticoagulation attainment and maintenance among European-Americans and African-Americans.

AIMS: The influence of CYP2C9 and VKORC1 on warfarin dose, time to target International Normalized Ratio (INR), time to stabilization, and risk of over-anticoagulation (INR: > 4) was assessed after adjustment for clinical factors, intraindividual variation in environmental factors and unobserved heterogeneity. MATERIALS & METHODS: Common CYP2C9 and VKORC1 polymorphisms were assessed in 302 European-Americans and 273 African-Americans receiving warfarin. Race-stratified multivariable analyses evaluated the influence of CYP2C9 and VKORC1 on warfarin response. RESULTS & CONCLUSION: CYP2C9 and VKORC1 accounted for up to 30% of the variability in warfarin dose among European-Americans and 10% among African-Americans. Neither CYP2C9 nor VKORC1 influenced the time to target INR or stabilization among patients of either race, and neither influenced the risk of over-anticoagulation among African-Americans. The risk of over-anticoagulation was higher among European-Americans with variant VKORC1 1173C/T (p < 0.01) and marginally significant among those with variant CYP2C9 (p = 0.08) genotype. Although CYP2C9 and VKORC1 genotyping can facilitate individualized initiation of warfarin dose in African and European-Americans, the ability to predict the risk of over-anticoagulation is inconsistent across race. Identification of other factors that can predict such risk consistently in a racially diverse group will facilitate individualized maintenance of warfarin therapy.

Three kinships with ALAS2 P520L (c. 1559 C --> T) mutation, two in association with severe iron overload, and one with sideroblastic anemia and severe iron overload.

Mutations in aminolevulinate synthase 2 (ALAS2) are usually associated with sideroblastic anemia and iron overload. The objective of this study was to determine if "mild" mutations in ALAS2 might increase the severity of primary iron overload. Direct sequencing of the ALAS2 gene was performed on 24 subjects with primary hemochromatosis and one subject with sideroblastic anemia with severe iron overload. We identified a novel mutation P520L (c. 1559 C --> T) in ALAS2 in three subjects. Two had severe iron overload and no anemia: one also had HFE C282Y homozygosity, and the other was wildtype for HFE and other iron-related genes. The third subject had sideroblastic anemia with iron overload, and was hemizygous for both P520L and R560H (c. 1679 G --> A) mutations in ALAS2. The P520L mutation was found at a frequency of 0.0013 (741 alleles) in white control subjects, but was not found in 158 alleles from black control subjects. The proline in this position is highly conserved across species from humans to zebrafish. However, genotype/phenotype studies of the families demonstrate that the P520L mutation alone has no iron-associated phenotype, but it may act as a modifier of iron overload in the presence of mutations in HFE or other uncharacterized hemochromatosis genes. Thus, ALAS2 mutations might contribute to more severe iron loading in persons with primary hemochromatosis.

Unusual thromboses associated with protein S deficiency in patients with acquired immunodeficiency syndrome: case reports and review of the literature.

Recent reports indicate that patients infected with HIV are at increased risk for the development of thrombosis. Among other possibilities, an acquired deficiency of protein S (PS), one of the plasma's natural anticoagulants, might explain this tendency. PS deficiency can be classified in three types depending on the levels of total and free protein (antigenic assays) as well as anticoagulant activity (functional assay). Although the prevalence of inherited PS deficiency is not known because of its rarity, several conditions can lead to acquired forms of the disease. We report two AIDS patients with coexistent type III PS deficiency and thrombosis. Our first patient presented with bilateral chronic leg ulcers and a skin biopsy revealed dermal microthromboses. On laboratory evaluation he had PS deficiency and was started on anticoagulation, but was lost to follow-up. The second patient presented with hepatic vein thrombosis (Budd-Chiari syndrome) and was also PS deficient. On long-term anticoagulation, she experienced resolution of the thrombosis. Neither patient had prior personal or family history of venous thrombosis, nor acquired risk factors such as immobility, acute infection, recent surgery, or hormonal therapy. The literature contains a few reports of skin ulcers and Budd-Chiari syndrome associated with PS deficiency, although none in AIDS patients. While a larger number of studies describe an association between PS deficiency and HIV infection, the causal effect of this deficiency on the thrombophilic tendency in AIDS has not been established. We propose that awareness of the increased risk for thrombosis in HIV infection is important to the understanding of disease pathophysiology and management of these patients.

Unfractionated heparin and other antithrombin mediated anticoagulants.

Clinical practice over the past decade has evolved to include new agents, LMWH and synthetic polysaccharides, that bind to and enhance the activity of antithrombin similar to UFH. These drugs differ from UFH since their anticoagulant effect consists predominantly, or entirely, of anti-Xa activity. More important, the new drugs have greater predictability with regard to dosing. In clinical studies the new agents have proven as good as or better than UFH with regard to efficacy and toxicity. The synthetic polysaccharide may possess the greatest efficacy, but possibly with increased bleeding risk. However, UFH still has one advantage over these agents, the ability of its anticoagulant effect to undergo essentially complete reversal with an available drug, protamine sulfate. Thus, clinical situations favoring UFH over these newer parenteral agents still exist.

Clinical pathology consultation improves coagulation factor utilization in hospitalized adults.

Coagulation factor replacement can effectively treat or prevent most hemophilia complications, but it is expensive. Although published data describe how to achieve therapeutic goals through cost-effective selection and dosing of replacement products, criteria are not universally known or followed. A review of our institution's experience revealed overdosing of coagulation factors in the majority of patients treated during a 12-month period, at a cost that approached $700,000. Consequently, we established mandatory clinical pathology consultation before releasing such factors. In the subsequent 30 months, 32 adults received 64 courses of treatment. For patients with hemophilia A, the mean cost per admission was reduced by approximately 27% (total savings, $61,536). For patients with factor VIII inhibitor, there was an approximate 6% cost reduction (total savings, $47,292). The combined savings was $108,828. The mean plasma factor level achieved during the intervention period was 84% +/- 55% compared with 117% +/- 58% for the preintervention period (P = .008). Neither the number of treatment (factor transfusion) days nor the number of RBC transfusions changed significantly. Our data support that pathology consultation yields consistent and appropriate therapy and improves resource utilization.

Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment.

CONTEXT: Hydroxyurea increases levels of fetal hemoglobin (HbF) and decreases morbidity from vaso-occlusive complications in patients with sickle cell anemia (SCA). High HbF levels reduce morbidity and mortality. OBJECTIVE: To determine whether hydroxyurea attenuates mortality in patients with SCA. DESIGN: Long-term observational follow-up study of mortality in patients with SCA who originally participated in the randomized, double-blind, placebo-controlled Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), conducted in 1992-1995, to determine if hydroxyurea reduces vaso-occlusive events. In the MSH Patients' Follow-up, conducted in 1996-2001, patients could continue, stop, or start hydroxyurea. Data were collected during the trial and in the follow-up period. SETTING: Inpatients and outpatients in 21 sickle cell referral centers in the United States and Canada. PATIENTS: Two-hundred ninety-nine adult patients with frequent painful episodes enrolled in the follow-up. Follow-up data through May 2001 were complete for 233 patients. INTERVENTION: In the MSH, patients were randomly assigned to receive hydroxyurea (n = 152) or placebo (n = 147). MAIN OUTCOME MEASURE: Mortality, HbF levels, painful episodes, acute chest syndrome, and blood cell counts. The randomized trial was not designed to detect specified differences in mortality. RESULTS: Seventy-five of the original 299 patients died, 28% from pulmonary disease. Patients with reticulocyte counts less than 250 000/mm3 and hemoglobin levels lower than 9 g/dL had increased mortality (P =.002). Cumulative mortality at 9 years was 28% when HbF levels were lower than 0.5 g/dL after the trial was completed compared with 15% when HbF levels were 0.5 g/dL or higher (P =.03 ). Individuals who had acute chest syndrome during the trial had 32% mortality compared with 18% of individuals without acute chest syndrome (P =.02). Patients with 3 or more painful episodes per year during the trial had 27% mortality compared with 17% of patients with less frequent episodes (P =.06). Taking hydroxyurea was associated with a 40% reduction in mortality (P =.04) in this observational follow-up with self-selected treatment. There were 3 cases of cancer, 1 fatal. CONCLUSIONS: Adult patients taking hydroxyurea for frequent painful sickle cell episodes appear to have reduced mortality after 9 of years follow-up. Survival was related to HbF levels and frequency of vaso-occlusive events. Whether indications for hydroxyurea treatment should be expanded is unknown.

The effect of lupus anticoagulant in the second-generation assay for activated protein C resistance.

The activated protein C resistance (APCR) assay is the test of choice to screen for factor V Leiden. We evaluated the effect of lupus anticoagulant on the baseline clotting time of the second-generation APCR assay with plasma samples from 54 patients to determine whether a falsely low APCR ratio could be predicted. We also assessed whether a modification of the assay could make it more reliable in the presence of strong lupus anticoagulants. Of 54 plasma samples, 5 yielded a false-positive APCR ratio, and all 5 had a prolonged baseline clotting time. Further dilution (1:40) of the plasma samples in factor V-deficient plasma led to correction of the APCR ratio and did not affect the sensitivity of the test for factor V Leiden. Our data support that the baseline clotting time is a good predictor of a false-positive APCR test result and should be checked before calculating the ratio. The modified APCR assay reliably identified the false-positive ratios and could be used to screen for factor V Leiden in samples with strong lupus anticoagulant.