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.

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.

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.

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.

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.