Obstetric complications in patients with hereditary thrombophilia identified using the LCx microparticle enzyme immunoassay: a controlled study of 5,000 patients.

Factor V Leiden (FVL) and prothrombin (PT) G20210A mutations are associated with increased risk of deep venous thrombosis, pulmonary embolism, and obstetric complications. The development of inexpensive and reliable screening methods will assist in defining subpopulations of patients at risk who should undergo testing. We used a method, developed by Abbott Laboratories (Abbott Park, IL), to study 5,000 pregnant women and evaluated the association of obstetric complications with the presence of the FVL and PT G20210A mutations. We found a statistically significant association between FVL and stillbirth. There were also trends toward an association between FVL and placental abruption and between PT G20210A and intrauterine growth retardation. In addition, an association may exist between PT G20210A and preterm delivery for white women. All other parameters studied, including miscarriage and preeclampsia, did not show a statistically significant association with FVL or PT G20210A. These results confirm the association between genetic thrombophilia and selected obstetric complications.

The use of recombinant activated factor VII in three patients with central nervous system hemorrhages associated with factor VII deficiency.

BACKGROUND: Recombinant activated factor VII (rFVIIa) is being tested to improve hemostasis in a variety of bleeding disorders. Clinical indications and efficacy are still being evaluated for this product. CASE REPORT: Over a 17-month period, rFVIIa was used to treat central nervous system hemorrhage in three patients who were found to have isolated FVII deficiency (21%, 40%, 27%). Patient A fell 30 feet, Patient B suffered a motor vehicle accident, and Patient C had a spinal cord hematoma. None of the patients had a history of bleeding diathesis. All three patients received rFVIIa after failing initial treatment with fresh-frozen plasma. RESULTS: Patient A was treated with 11 doses (initial dose 95 microg/kg; subsequent doses 8-38 microg/kg) over 10 days; Patient B received 13 doses (45-60 microg/kg) over 13 days; and Patient C received 5 doses (12-24 microg/kg) over 4 days. The prothrombin time corrected from 16.2 +/- 1.8 (mean +/- SD) to 11.2 +/- 1.6 seconds after infusion of rFVIIa, but returned to pretreatment level in 14 +/- 4 hours. At the cessation of therapy, all patients showed neurologic improvement. No complications related to the infusion of rFVIIa occurred. CONCLUSION: The use of rFVIIa may be of value both for its general effect on hemostasis, and specifically in the setting where there is a documented reduction in FVII. Doses lower than those used in patients with FVIII inhibitors appear to be effective in the setting of central nervous system hemorrhage.

Thrombotic microangiopathy associated with unusual viral sequences in HIV-1-positive patients.

BACKGROUND: Thrombotic microangiopathy (TMA) is a rare disorder caused by endothelial cell damage. TMA has been associated with the human immunodeficiency virus 1 (HIV-1) infection, yet only a minority of all HIV-1 patients develops TMA. Since HIV-1 has been shown to interact with endothelial cells, we investigated whether certain mutations in the HIV-1 envelope protein are associated with the development of TMA in HIV-1-infected patients. METHODS: Plasma was obtained from nine HIV-1-positive patients with TMA. Viral loads were determined from the samples and compared with the clinical data. Viral envelope protein sequences from the regions known to be responsible for viral tropism were isolated, sequenced and compared with known HIV-1 isolates. The isolates were expressed as synthetic fusion proteins; binding of these fusion proteins to CD4+ cells as well as to endothelial cell lines was investigated. RESULTS: The viral loads in patients with HIV/TMA were highly variable with no correlation to the clinical status. Most patients carried macrophage-tropic viral envelope protein sequences and an unusual insertion was found in the V2 variable region. The isolates showed increased CD4 binding, but a direct binding to endothelial cells was not observed. CONCLUSIONS: Although TMA is generally diagnosed in patients with advanced HIV-1 infection, viral loads per se were not predictive of TMA in this study. While a direct interaction with endothelial cells was not detectable, specific viral envelope mutations were found in a region known to influence viral tropism. Hence, viral-specific factors might contribute to the pathogenesis of HIV-associated TMA.

Universal red blood cells--enzymatic conversion of blood group A and B antigens.

Accidental transfusion of ABO-incompatible red blood cells (RBCs) is a leading cause of fatal transfusion reactions. To prevent this and to create a universal blood supply, the idea of converting blood group A and B antigens to H using specific exo-glycosidases capable of removing the immunodominant sugar residues was pioneered by Goldstein and colleagues at the New York Blood Center in the early 1980s. Conversion of group B RBCs to O was initially carried out with alpha-galactosidase extracted from coffee beans. These enzyme-converted O (ECO) RBCs appeared to survive normally in all recipients independent of blood group. The clinical trials moved from small infusions to single RBC units and finally multiple and repeated transfusions. A successful phase II trial utilizing recombinant enzyme was reported by Kruskall and colleagues in 2000. Enzymatic conversion of group A RBCs has lagged behind due to lack of appropriate glycosidases and the more complex nature of A antigens. Identification of novel bacterial glycosidases with improved kinetic properties and specificities for the A and B antigens has greatly advanced the field. Conversion of group A RBCs can be achieved with improved glycosidases and the conversion conditions for both A and B antigens optimized to use more cost-efficient quantities of enzymes and gentler conditions including neutral pH and short incubation times at room temperature. Of the different strategies envisioned to create a universal blood supply, the ECO concept is the only one, for which human clinical trials have been performed. This paper discusses some biochemical and clinical aspects of this developing technology.

Cryoprecipitate. Patterns of use.

The type of coagulation factors and proteins in cryoprecipitate determine the appropriate indications for its use. To determine the pattern of use at a tertiary care medical center, we performed a retrospective audit of cryoprecipitate utilization. A total of 51 patients received 88 pools of cryoprecipitate. In 39 patients, cryoprecipitate was transfused for appropriate indications: hypofibrinogenemia (n = 19), tissue plasminogen activator reversal (n = 1), management of massive transfusion (n = 7), correction of uremic bleeding (n = 2), and for making fibrin sealant (n = 10). Overall, these patients used approximately 80% of the cryoprecipitate transfused. In 12 other patients, cryoprecipitate was transfused inappropriately to attempt reversal of the anticoagulant effects of warfarin therapy (n = 6), to treat impaired surgical hemostasis in the absence of hypofibrinogenemia (n = 4), and to treat hepatic coagulopathy with multiple factor deficiencies (n = 2). The patterns of misuse, involving 24% of all cryoprecipitate orders, suggest a widespread misunderstanding and need for focused education about the coagulation factors and proteins present in cryoprecipitate and appropriate indications for its use.