Miguel A. Escobar

Current Concepts of Hemostasis: Implications for Therapy

The revised model of coagulation has implications for therapy of both hemorrhagic and thrombotic disorders. Of particular interest to anesthesiologists is the management of clotting abnormalities before, during, and after surgery. Most hereditary and acquired coagulation factor deficiencies can be managed by specific replacement therapy using clotting factor concentrates. Specific guidelines have also been developed for perioperative management of patients using anticoagulant agents that inhibit platelet or coagulation factor functions. Finally, recombinant factor VIIa has been used off-label as a hemostatic agent in some surgical situations associated with excessive bleeding that is not responsive to conventional therapy.

Standardization of thromboelastography: A report from the TEG-ROTEM working group

Summary.  Laboratory evaluation of bleeding disorders has been performed with the standard clotting assays such as the PT and PTT for several decades. Our improved understanding of the process of blood coagulation has now revealed the important role played by the cellular elements such as platelets, monocytes and red blood cells. The need for a test that can assess clotting in a more ‘global’ manner, beyond the initiation of clot formation, has led to greater interest in assays such as thrombin generation and thromboelastography. Even though there are several publications using thromboelastography it remains a research tool as the methodology is not standardized. In an attempt to show reproducibility and consistency using thromboelastography, a group of investigators from different countries joined hands to form the TEG‐ROTEM Working Group. Two studies were performed using PRP and FVIII deficient plasma and an intrinsic pathway activator. This article summarizes the results of the first international effort at standardization of thromboelastography. Both of the instruments using this technology (TEG® and ROTEM®) were used. Nine laboratories from countries around the globe participated in this effort. The results showed a significant inter‐laboratory variance with CV’s greater than 10%. Although these results were not satisfactory, this has been the first effort to standardize this methodology and significant work remains to be done to improve reliability and reproducibility. These studies were performed on PRP and the results may be more reliable when preformed on whole blood samples. We believe that it is important to continue this work so that we may investigate the usefulness and potential applications of thromboelastography in the evaluation of bleeding and thrombosis.

In non-severe hemophilia A the risk of inhibitor after intensive factor treatment is greater in older patients: A case-control study

Summary.  Background: Twenty‐five percent of new anti‐factor VIII (FVIII) antibodies (inhibitors) that complicate hemophilia A occur in those with mild and moderate disease. Although intensive FVIII treatment has long been considered a risk factor for inhibitor development in those with non‐severe disease, its strength of association and the influence of other factors have remained undefined. Objective: To evaluate risk factors for inhibitor development in patients with non‐severe hemophilia A. Methods: Information on clinical and demographic variables and FVIII genotype was collected on 36 subjects with mild or moderate hemophilia A and an inhibitor and 62 controls also with mild or moderate hemophilia A but without an inhibitor. Results: Treatment with FVIII for six or more consecutive days during the prior year was more strongly associated with inhibitor development in those ≥ 30 years of age compared with those < 30 years of age [adjusted odds ratio (OR) 12.62; 95% confidence interval (CI), 2.76–57.81 vs. OR 2.54; 95% CI, 0.61–10.68]. Having previously received < 50 days of FVIII was also not statistically associated with inhibitor development on univariate or multivariate analysis. Conclusions: These findings suggest that inhibitor development in mild and moderate hemophilia A varies with age, but does not vary significantly with lifetime FVIII exposure days: two features distinct from severe hemophilia A.

Anticoagulation After Cardioembolic Stroke: To Bridge or Not to Bridge?

BACKGROUND Most patients with cardioembolic stroke require long-term anticoagulation. Still, uncertainty exists regarding the best mode of starting long-term anticoagulation. Design, Setting, and Patients We conducted a retrospective review of all patients with cardioembolic stroke admitted to our center from April 1, 2004, to June 30, 2006, and not treated with tissue plasminogen activator. Patients were grouped by treatment: no treatment, aspirin only, aspirin followed by warfarin sodium, intravenous heparin sodium in the acute phase followed by warfarin (heparin bridging), and full-dose enoxaparin sodium combined with warfarin (enoxaparin bridging). Outcome measures and adverse events were collected prospectively. Laboratory values were captured from the records. MAIN OUTCOME MEASURES Symptomatic hemorrhagic transformation, stroke progression, and discharge modified Rankin Scale score. RESULTS Two hundred four patients were analyzed. Recurrent stroke occurred in 2 patients (1%). Progressive stroke was the most frequent serious adverse event, seen in 11 patients (5%). Hemorrhagic transformation occurred in a bimodal distribution-an early benign hemorrhagic transformation and a late symptomatic hemorrhagic transformation. All of the symptomatic hemorrhagic transformation cases were in the enoxaparin bridging group (10%) (P = .003). Systemic bleeding occurred in 2 patients (1%) and was associated with heparin bridging (P = .04). CONCLUSIONS Anticoagulation of patients with cardioembolic stroke can be safely started with warfarin shortly after stroke. Heparin bridging and enoxaparin bridging increase the risk for serious bleeding.

Health economics in haemophilia: a review from the clinician’s perspective

Summary.  Health economic evaluations provide valuable information for healthcare providers, facilitating the treatment decision‐making process in a climate where demand for healthcare exceeds the supply. Although an uncommon disease, haemophilia is a life‐long condition that places a considerable burden on patients, healthcare systems and society. This burden is particularly large for patients with haemophilia with inhibitors, who can develop serious bleeding complications unresponsive to standard factor replacement therapies. Hence, bleeding episodes in these patients are treated with bypassing agents such as recombinant activated FVII (rFVIIa) and plasma‐derived activated prothrombin complex concentrates (pd‐APCC). With the efficacy of these agents now well established, a number of health economic studies have been conducted to compare their cost‐effectiveness for the on‐demand treatment of bleeding episodes in haemophiliacs with inhibitors. In a cost‐utility analysis, which assesses the effects of treatment on quality of life (QoL) and quantity of life, the incremental cost per quality‐adjusted life‐year (QALY) gained (US

A study of prospective surveillance for inhibitors among persons with haemophilia in the united states

44 834) indicated that rFVIIa was cost‐effective. Similarly, eight of 11 other economic modelling evaluations found that rFVIIa was more cost‐effective than pd‐APCC in the on‐demand treatment of bleeding episodes. These findings indicate that treating patients with haemophilia promptly and with the most effective therapy available may result in cost savings.

Efficacy and safety of rVIII-Singlechain: Results of a phase 1/3 multicenter clinical trial in severe hemophilia A

Inhibitors are a rare but serious complication of treatment of patients with haemophilia. Phase III clinical trials enrol too few patients to adequately assess new product inhibitor risk. This project explores the feasibility of using a public health surveillance system to conduct national surveillance for inhibitors. Staff at 17 U.S. haemophilia treatment centres (HTC) enrolled patients with haemophilia A and B into this prospective study. HTC staff provided detailed historic data on product use and inhibitors at baseline, and postenrolment patients provided monthly detailed infusion logs. A central laboratory performed inhibitor tests on blood specimens that were collected at baseline, annually, prior to any planned product switch or when clinically indicated. The central laboratory also performed genotyping of all enrolled patients. From January 2006 through June 2012, 1163 patients were enrolled and followed up for 3329 person‐years. A total of 3048 inhibitor tests were performed and 23 new factor VIII inhibitors were identified, 61% of which were not clinically apparent. Infusion logs were submitted for 113 205 exposure days. Genotyping revealed 431 distinct mutations causing haemophilia, 151 of which had not previously been reported elsewhere in the world. This study provided critical information about the practical issues that must be addressed to successfully implement national inhibitor surveillance. Centralized testing with routine monitoring and confirmation of locally identified inhibitors will provide valid and representative data with which to evaluate inhibitor incidence and prevalence, monitor trends in occurrence rates and identify potential inhibitor outbreaks associated with products.

Pharmacokinetic properties of IB1001, an investigational recombinant factor IX, in patients with haemophilia B: repeat pharmacokinetic evaluation and sialylation analysis

Recombinant VIII (rVIII)-SingleChain is a novel B-domain-truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). The participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N = 146) or on-demand (N = 27). The total cumulative exposure was 14 306 exposure days (EDs), with 120 participants reaching ≥50 EDs and 52 participants having ≥100 EDs. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate (ABR) was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated as excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low ABR in patients on prophylaxis, and a favorable safety profile in this large clinical study. This trial was registered at www.clinicaltrials.gov as #NCT01486927.

Neutralization of genetically diverse Hiv-1 strains by Iga antibodies to the gp120–cd4-binding site from long-term survivors of Hiv infection

IB1001 trenacog alfa is an investigational recombinant factor IX (FIX) for the treatment and prevention of bleeding in individuals with haemophilia B. To compare the pharmacokinetics (PK) of IB1001 with nonacog alfa in individuals with haemophilia B and to assess the relationship between sialylation and PK of IB1001 (NCT00768287). A randomized, double‐blind, non‐inferiority, cross‐over study conducted in participants aged ≥12 years weighing ≥40 kg, with severe or moderately severe haemophilia B (FIX activity ≤2 IU dL −1). PK parameters were derived using observed FIX concentration levels and actual PK sampling times, and repeated in a subset of participants who had received IB1001 prophylaxis for 4–18 months. A retrospective analysis was conducted in subgroups according to the sialylation levels of IB1001 (50.8, 57.8–59.0%, or 71.7%). In the 32 adolescent and adult males evaluated, there were no clinically meaningful differences in PK parameters between those receiving IB1001 75 IU kg−1 or nonacog alfa. The lower limit of the one‐sided 95% confidence interval for the ratio of AUC0‐t and AUC0‐∞ (IB1001/nonacog alfa) was 0.90, establishing non‐inferiority. Terminal phase half‐lives were similar (29.7 ± 18.2 h for IB1001 and 33.4 ± 21.2 h for nonacog alfa). The PK results were stable for up to 18 months of IB1001 exposure; the impact of sialylation levels was not clinically meaningful. There were no clinically meaningful PK differences between IB1001 and nonacog alfa. IB1001 was well tolerated and without safety concerns. The non‐inferiority of IB1001 to nonacog alfa supports IB1001 becoming a useful alternative recombinant agent for the management of haemophilia B.

Thrombelastography-Guided Factor VIIa Therapy in a Surgical Patient with Severe Hemophilia and Factor VIII Inhibitor

Objective:To identify an HIV epitope suitable for vaccine development. Design:Diverse HIV-1 strains express few structurally constant regions on their surface vulnerable to neutralizing antibodies. The mostly conserved CD4-binding site (CD4BS) of gp120 is essential for host cell binding and infection by the virus. Antibodies that recognize the CD4BS are rare, and one component of the CD4BS, the 421–433 peptide region, expresses B-cell superantigenic character, a property predicted to impair the anti-CD4BS adaptive immune response. Methods:IgA samples purified from the plasma of patients with HIV infection were analyzed for the ability to bind synthetic mimetics containing the 416–433 gp120 region and full-length gp120. Infection of peripheral blood mononuclear cells by clinical HIV isolates was measured by p24 ELISA. Results:IgA preparations from three patients with subtype B infection for 19–21 years neutralized heterologous, coreceptor CCR5-dependent subtype A, B, C, D, and AE strains with exceptional potency. The IgAs displayed specific binding of a synthetic 416–433 peptide mimetic dependent on recognition of the CD4-binding residues located in this region. Immunoadsorption, affinity chromatography, and mutation procedures indicated that HIV neutralization occurred by IgA recognition of the CD4BS. Conclusion:These observations identify the 421–433 peptide region as a vulnerable HIV site to which survivors of infection can produce powerful neutralizing antibodies. This indicates that the human immune system can bypass restrictions on the adaptive B cell response to the CD4BS, opening the route to targeting the 421–433 region for attaining control of HIV infection.