Activated protein C as disease-modifying therapy in antenatal preeclampsia: An open-label, single arm safety and efficacy trial.

OBJECTIVES: Preeclampsia is characterized by maternal systemic inflammation and coagulation activation, akin to the sepsis syndrome. Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) may modify disease progression to safely prolong pregnancies and improve perinatal outcomes. Both maternal and perinatal risks are highest remote from term. STUDY DESIGN: Open-label, single arm safety and efficacy trial of rhAPC in consenting pregnant women with severe early-onset preeclampsia. Disease severity-matched rhAPC-naïve controls were identified from an existing database. An additional six women were recruited as biomarker controls. MAIN OUTCOME MEASURES: Primary safety outcome: incidence of peripartum bleeding; primary efficacy outcome: duration of pregnancy after enrolment. RESULTS: Twelve (31.6%) of 38 eligible women consented; 3 did not receive the infusion due to staffing. Therefore, 9 women received rhAPC (24 µg/kg/hr for ≤96 h antenatally). No safety issues were identified. There was a marginal prolongation in eligibility-to-delivery intervals for women receiving rhAPC (Mantel-Cox p = 0.052; Gehan-Breslow-Wilcoxon p = 0.049). Compared with both the pre-infusion phase in the rhAPC-treated women themselves and with fullPIERS rhAPC-naïve women, rhAPC was associated with increased urine output during the infusion (6/9 vs 1/9 had urine output >100 mL/h during the infusion, Fisher's exact p = 0.003). CONCLUSIONS: These data support further investigation of APC in women with severe early-onset preeclampsia; recombinant and purified human APC is available. In addition, these data will inform the design and implementation of randomized controlled trials aiming to modify and/or moderate the proinflammatory and proacoagulant state of preeclampsia.

Pathogen inactivation treatment of plasma and platelet concentrates and their predicted functionality in massive transfusion protocols.

BACKGROUND: Trauma transfusion packages for hemorrhage control consist of red blood cells, plasma, and platelets at a set ratio. Although pathogen reduction improves the transfusion safety of platelet and plasma units, there is an associated reduction in quality. This study aimed to investigate the impact of riboflavin/ultraviolet light-treated plasma or platelets in transfusion trauma packages composed of red blood cell, plasma, and platelet units in a ratio of 1:1:1 in vitro by modeling transfusion scenarios for trauma patients and assessing function by rotational thromboelastometry. STUDY DESIGN AND METHODS: Pathogen-reduced or untreated plasma and buffy coat platelet concentrate units produced in plasma were used in different combinations with red blood cells in trauma transfusion packages. After reconstitution of these packages with hemodiluted blood, the hemostatic functionality was analyzed by rotational thromboelastometry. RESULTS: Hemostatic profiles of pathogen-inactivated buffy coat platelet concentrate and plasma indicated decreased activity compared with their respective controls. Reconstitution of hemodiluted blood (hematocrit = 20%) with packages that contained treated or nontreated components resulted in increased alpha and maximum clot firmness and enhanced clot-formation time. Simulating transfusion scenarios based on 30% blood replacement with a transfusion trauma package resulted in a nonsignificant difference in rotational thromboelastometry parameters between packages containing treated and nontreated blood components (p ≥ 0.05). Effects of pathogen inactivation treatment were evident when the trauma package percentage was 50% or greater and contained both pathogen inactivation-treated plasma and buffy coat platelet concentrate. CONCLUSION: Rotational thromboelastometry investigations suggest that there is relatively little impact of pathogen inactivation treatment on whole blood clot formation unless large amounts of treated components are used.

Expanding HIV Testing in African American Communities Through Community-Based Distribution of Home-Test Vouchers.

We investigated the implementation feasibility and effectiveness of community-based HIV home-test voucher distribution in three Indianapolis African American communities. Community-based organizations augmented traditional outreach methods to distribute vouchers for home HIV tests redeemable at three pharmacies during three distribution waves from February to April 30, 2015. Voucher redemption served as a proxy indicator of intent to test for HIV. 315 vouchers were distributed and 47 vouchers were redeemed for a 14.9% redemption rate. Distribution was 46% of plan. Vouchers were redeemed at all three pharmacies, and 21% of visits involved redemption of more than one voucher. The original team of seven distributors in three organizations reduced to a remaining five distributors in two organizations by wave 2. This study suggests that outreach organizations could implement HIV home test voucher distribution, and that people would redeem the vouchers at a pharmacy for an HIV test. Future studies should explore how voucher distribution can expand the current HIV testing system.

Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants.

Heparin-based anticoagulant drugs have been widely used for the prevention of blood clotting during surgical procedures and for the treatment of thromboembolic events. However, bleeding risks associated with these anticoagulants demand continuous monitoring and neutralization with suitable antidotes. Protamine, the only clinically approved antidote to heparin, has shown adverse effects and ineffectiveness against low-molecular weight heparins and fondaparinux, a heparin-related medication. Alternative approaches based on cationic molecules and recombinant proteins have several drawbacks including limited efficacy, toxicity, immunogenicity, and high cost. Thus, there is an unmet clinical need for safer, rapid, predictable, and cost-effective anticoagulant-reversal agents for all clinically used heparins. We report a design strategy for a fully synthetic dendritic polymer-based universal heparin reversal agent (UHRA) that makes use of multivalent presentation of branched cationic heparin binding groups (HBGs). Optimization of the UHRA design was aided by isothermal titration calorimetry studies, biocompatibility evaluation, and heparin neutralization analysis. By controlling the scaffold's molecular weight, the nature of the protective shell, and the presentation of HBGs on the polymer scaffold, we arrived at lead UHRA molecules that completely neutralized the activity of all clinically used heparins. The optimized UHRA molecules demonstrated superior efficacy and safety profiles and mitigated heparin-induced bleeding in animal models. This new polymer therapeutic may benefit patients undergoing high-risk surgical procedures and has potential for the treatment of anticoagulant-related bleeding problems.

Buffy-coat platelet variables and metabolism during storage in additive solutions or plasma.

BACKGROUND: Buffy-coat processing allows for the use of platelet additive solutions (PASs). PASs reduce plasma-associated transfusion reactions and conserve plasma for transfusion or fractionation. Platelet (PLT) storage in plasma was compared to storage in three commercially available PASs compared to assess their influence on in vitro laboratory variables. STUDY DESIGN AND METHODS: Platelet concentrates (PCs) were prepared from leukoreduced pools of four buffy coats (BCPs) suspended in autologous plasma or one of PASs (Composol, Fresenius-Kabi; T-Sol, Baxter Corp.; or SSP+, MacoPharma). On Days 1, 2, 3, 5, and 7 of storage, samples were tested for PLT concentration, mean PLT volume (MPV), CD62P, morphology, pO2, pCO2, glucose, lactate and total protein concentration, pH, extent of shape change (ESC), and hypotonic shock response (HSR). Data were analyzed by analysis of variance (ANOVA) with repeated measures and t tests. RESULTS: PLT recoveries from BCPs were higher (p < 0.05) with plasma than any PAS. Storage medium and duration did not affect PLT concentration or MPV over time. CD62P expression and morphology were significantly different among PCs pooled with different media. ANOVA showed (p < 0.05) differences among the rates of change of pCO2, pH, glucose consumption, lactate production, and ESC; PASs such as Composol and SSP+ offered excellent maintenance of pH and low rates of glucose consumption. PAS performed poorly in ESC and HSR compared to plasma. Correlation studies reveal far more significant correlations between variables of PLTs in PAS than in plasma. CONCLUSION: Newer PASs, for example, SSP+ and Composol, can maintain PLT integrity and moderate metabolism similarly to plasma but offer consistently lower PLT recoveries and limited osmotic balance.

Clinical impact of point-of-care vs laboratory measurement of anticoagulation.

Patients using anticoagulation point-of-care (POC) monitors are advised to periodically test these systems against laboratory methods to monitor performance. The international normalized ratio (INR), however, can vary between test systems owing to different instrument-reagent combinations. In a randomized study evaluating warfarin self-management, we compared INR measured by patients on a POC monitor (ProTime, International Technidyne Corporation, Edison, NJ) with those obtained at a hospital laboratory within 1 hour Ninety-one paired INR determinations from 55 patients met inclusion criteria. Clinical agreement in which POC and laboratory INR were within or outside the target INR range occurred in 56 (62%) of 91 cases (kappa = 0.35). The mean (SD) difference between POC and laboratory INR was 0.44 (0.61). Six pairs differed by 1 or more INR units, 3 at study initiation resulting in POC monitor replacement. The accuracy of INR self-testing with ProTime was acceptable. The small failure rate of INR agreement might be clinically important, suggesting the need for external quality control systems.

A randomized trial of patient self-managed versus physician-managed oral anticoagulation.

BACKGROUND: Self-management (SM) of warfarin by patients is an attractive strategy, particularly if it improves anticoagulation control and can be done safely under minimal physician supervision. OBJECTIVE: To compare the effect of SM with physician-management (PM) on the maintenance of therapeutic anticoagulation. METHODS: A randomized, open-label eight-month trial was performed. Patients 18 years of age and older were eligible if they were receiving warfarin for at least one month before enrolment and required anticoagulation for at least one year to a target international normalized ratio (INR) of 2.0 to 3.0 or 2.5 to 3.5. Exclusion criteria were a known hypercoaguable disorder, mental incompetence, a language barrier or an inability to attend training sessions. Patients randomly assigned to SM tested their INR using a point-of-care device (Pro Time Microcogulation System, International Technidyne Corporation, USA) and adjusted their warfarin doses using a nomogram. Patients randomly assigned to PM received usual care from their general practitioner. The primary outcome was to demonstrate 20% improvement in anticoagulation control by SM. RESULTS: One hundred forty patients were randomly assigned (70 per group). Thirteen patients dropped out of SM early due to an inability to self-manage. Based on intention-to-treat analysis, there was no difference in the proportion of INR in range (SM 64.8% versus PM 58.7%, P=0.23) or time in target range (SM 71.8% versus PM 63.2%, P=0.14). Patients managing their own therapy spent less time below the therapeutic range (15.0% versus 27.3%, P=0.04). There were three major complications of thrombosis or bleeding, all occurring in the PM arm. All patients who completed SM preferred to continue with that strategy. CONCLUSIONS: SM was not significantly better than PM in maintaining therapeutic anticoagulation. SM was feasible and appeared safe in the present study population.

Comparison of thrombopoiesis during ITP and HIV-ITP and response to intravenous gammaglobulin treatment.

Immune thrombocytopenic purpura's diagnosis (ITP) is based on low platelet count and exclusion of clinical conditions rather than a specific diagnostic test. We used the reticulated platelet (RP) assay to study ITP and thrombocytopenia associated with HIV infection (HIV-ITP). Data from 96 ITP and 23 HIV-ITP patients showed low platelet counts (PC) with both high or low %RP suggesting that individuals have different degrees of thrombopoiesis. About 20% of ITP and 46% of HIV-ITP patients had %RP in the 'low' or 'normal' ranges. Grouped by platelet count <30x10(9)/L, 24% ITP and 36% HIV-ITP patients had 'low' to 'normal' %RP. The patient population did not show correlation between PC and %RP, but individuals showed an inverse relationship. Within a week of receiving IVIG, 18 ITP and 9 HIV-ITP patients' PC increased, %RP decreased. Patients with %RP measured within 24 h of IVIG treatment had lower %RP than expected, suggesting dilution by an older platelet population. ITP and HIV-ITP patients' responses to i.v. gammaglobulins were similar. Thrombopoietin levels of ITP patients did not correlate with PC, %RP, or RP count. Estimation of thrombopoiesis by RP assay provides useful information for differentiation among thrombocytopenias.

Patient self-management of oral anticoagulation: a review.

Self-management of warfarin is an evolving strategy that involves self-testing of the international normalized ratio using a point-of-care device and adjustment of warfarin dosage by the patient using a dosage-adjustment nomogram. There is mounting evidence from clinical trials that self-management of warfarin is feasible and is potentially superior to conventional management by physicians in maintaining anticoagulation control. Some advantages of this strategy are convenience, rapid availability of results with timely adjustment of warfarin dosages, increased patient responsibility for their own therapy and enhanced patient satisfaction. Access to point-of-care instruments may prove particularly valuable for patients without ready access to laboratories, frequent travellers who are often away from their home laboratory for extended periods of time and those who experience difficulties with venous blood collection. Self-management may be considered for carefully selected and properly trained individuals. Information from several ongoing clinical trials will aid in determining the value of anticoagulation self-management with respect to complication rates and economic outcomes.

Frequency of heparin-induced thrombocytopenia in critical care patients.

The diagnosis of heparin-induced thrombocytopenia (HIT) in critically ill patients is complicated by lack of information on the frequency of HIT relative to thrombocytopenia from other causes. In addition, results from HIT diagnostic tests have not been clearly evaluated for clinical utility. In this prospective study, we estimated the frequency of HIT and the predictive performance of the heparin-platelet factor 4 enzyme-linked immunosorbent assay (heparin-PF4 ELISA) in 748 consecutive, heparin-treated patients in a combined intensive and coronary care unit. The criteria for diagnosis were as follows: two or more consecutive platelet counts below 150 x 10(3)/mm3 or a 33% or greater decrease in platelet count 5 or more days after beginning heparin, or any time after starting heparin for patients exposed to the agent within the previous 8 weeks; and a positive 14C-serotonin release assay (SRA), the reference standard. Specificity and predictive values for the heparin-PF4 ELISA were estimated in patients who met the clinical criteria for HIT. Of 748 patients, 267 were exposed to heparin for a sufficient length of time to be considered to be at risk for HIT. Forty of these patients (15.0%, 95% confidence interval [CI] 10.7%-19.3%) met the clinical criteria for HIT. Serum samples were available for 32 of these patients, one of whom tested positive by the SRA, yielding a HIT frequency of 0.39% (95% CI 0.01-2.1%). The specificity of the heparin-PF4 ELISA among thrombocytopenic patients with negative SRA results was 71%, and the positive (PPV) and negative (NPV) predictive values of this test were estimated to be 10% and 100%, respectively. The point estimate of the frequency of HIT in critically ill patients was less than 1% in this cohort. The low PPV and high NPV of the heparin-PF4 ELISA suggest that it can be used to exclude HIT as a cause of thrombocytopenia in this patient population.

New developments in acute anticoagulation therapy.

Preview Heparin has been in use for more than 40 years and is still an important agent for inhibiting plasma- and surface-bound thrombin. However, modifications have produced low-molecular-weight heparin, which has better bioavailability and perhaps other advantages over traditional heparin. Another direction of research in anticoagulation therapy has been toward new antithrombin- independent agents. Dr Carter describes the present status of studies on heparin and its derivatives, direct thrombin inhibitors, and ancrod, a component of snake venom.