Treatment of Congenital Thrombotic Thrombocytopenia Purpura: A New Paradigm.

Congenital thrombotic thrombocytopenia purpura (cTTP) is a very rare disorder worldwide. Standard treatment of recognized cases has been to administer fresh frozen plasma as the source of ADAMTS13, to replenish the absent ADAMTS13 enzyme. An alternative source, a plasma-derived factor VIII concentrate used for hemophilia A, and found to contain this enzyme, was reported to be effective in 1 patient in the United States. We now report details on a US cohort of 8 cTTP patients who have been successfully treated for varying periods with a marketed antihemophilic factor concentrate Koate-DVI. This biological product has been used successfully on demand in varying doses to treat acute exacerbations, as well as prophylactically (3 to 6 U ADAMTS13 every 3 to 21 d). Self-infused at home, in lieu of fresh frozen plasma therapy in the hospital setting, this product has effectively prevented episodes of thrombocytopenia, microangiopathic hemolytic anemia, and the concomitant organ damage in these patients. This specific virus inactivated product can be used to prevent further manifestations of this congenital enzyme deficiency.

The Role of Platelet Activation and Inflammation in Early Brain Injury Following Subarachnoid Hemorrhage.

BACKGROUND: Early brain injury (EBI) following aneurysmal subarachnoid hemorrhage (SAH) is an important predictor of poor functional outcome, yet the underlying mechanism is not well understood. Animal studies suggest that platelet activation and inflammation with subsequent microthrombosis and ischemia may be a mechanism of EBI. METHODS: A prospective, hypothesis-driven study of spontaneous, SAH patients and controls was conducted. Platelet activation [thromboelastography maximum amplitude (MA)] and inflammation [C-reactive protein (CRP)] were measured serially over time during the first 72 h following SAH onset. Platelet activation and inflammatory markers were compared between controls and SAH patients with mild [Hunt-Hess (HH) 1-3] versus severe (HH 4-5) EBI. The association of these biomarkers with 3-month functional outcomes was evaluated. RESULTS: We enrolled 127 patients (106 SAH; 21 controls). Platelet activation and CRP increased incrementally with worse EBI/HH grade, and both increased over 72 h (all P < 0.01). Both were higher in severe versus mild EBI (MA 68.9 vs. 64.8 mm, P = 0.001; CRP 12.5 vs. 1.5 mg/L, P = 0.003) and compared to controls (both P < 0.003). Patients with delayed cerebral ischemia (DCI) had more platelet activation (66.6 vs. 64.9 in those without DCI, P = 0.02) within 72 h of ictus. At 3 months, death or severe disability was more likely with higher levels of platelet activation (mRS4-6 OR 1.18, 95 % CI 1.05-1.32, P = 0.007) and CRP (mRS4-6 OR 1.02, 95 % CI 1.00-1.03, P = 0.041). CONCLUSIONS: Platelet activation and inflammation occur acutely after SAH and are associated with worse EBI, DCI and poor 3-month functional outcomes. These markers may provide insight into the mechanism of EBI following SAH.

A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia.

Stimulation of platelet production by thrombopoietin-receptor agonists (TPO-RAs) is an effective second-line treatment in immune thrombocytopenia (ITP). This 28-day phase 2 study assigned subjects with ITP of ≥3 months to once-daily oral avatrombopag (2.5, 5, 10, or 20 mg), an investigational nonpeptide TPO-RA active in humans, or placebo; subjects completing randomized treatment could enroll in a 24-week extension study. Of 64 randomized subjects, 13% (avatrombopag 2.5 mg), 53% (5 mg), 50% (10 mg), and 80% (20 mg), vs 0% for placebo, achieved a platelet count (PC) response of ≥50 × 10(9)/L with ≥20 × 10(9)/L increase above baseline at day 28. Fifty-three subjects (83%) entered the extension: 52% and 76% had a durable (PC response at ≥75% of their platelet assessments over the last 14 weeks) and overall (stable response or response at any ≥2 consecutive visits) response, respectively. All subjects experienced ≥1 adverse event (AE) (most commonly fatigue, headache, and epistaxis); 19% (n = 12) reported ≥1 serious AE; 10 (16%) withdrew due to an AE (5 due to increased PC). Avatrombopag was active and generally well tolerated, with PC response rates and AE incidence comparable with other TPO-RAs. These studies were registered at www.clinicaltrials.gov as #NCT00441090 and #NCT00625443.

Efficacy and safety of the thrombopoietin receptor agonist romiplostim in patients aged ≥ 65 years with immune thrombocytopenia.

Thrombopoietin receptor agonists increase platelet counts and reduce bleeding risk in patients with immune thrombocytopenia (ITP). Studies have reported that these agents may represent a risk factor for thromboembolic events, especially in the elderly, who are at increased risk for such complications relative to younger patients. In this retrospective analysis, efficacy and safety data for romiplostim in patients with ITP aged ≥65 years versus those aged <65 years are described. Data from 3 studies (N = 159; 24.5% ≥ 65 years of age) were analyzed for efficacy. Data from 13 studies (N = 1037; 28.4% ≥ 65 years of age) were analyzed for adverse events (AEs). Relative risk (RR) ratios with 95% CIs were calculated for duration-adjusted incidences of AEs for romiplostim versus placebo/standard of care (SOC) in patients ≥ 65 and <65 years. Slightly higher platelet response rates were seen among romiplostim-treated patients ≥ 65 versus <65 years. In the safety analyses, 65 (6.3%) received placebo/SOC, 69 (6.7%) received placebo/SOC and then romiplostim, and 903 (87.1%) received romiplostim only. Duration-adjusted AE rates were similar for romiplostim versus placebo/SOC in older and younger patients. The risks for grade ≥ 3 bleeding (RR 1.92; 95% CI, 0.47-7.95) and thromboembolic events (RR 3.85; 95% CI, 0.53-27.96) were numerically but not significantly higher for romiplostim versus placebo/SOC in patients ≥ 65 years. Romiplostim is effective and, with the exception of nonsignificant trends showing increased risks of grade ≥ 3 bleeding and thromboembolic events (a trend observed in other studies), generally well tolerated in older patients with ITP.

Persistence of circulating ADAMTS13-specific immune complexes in patients with acquired thrombotic thrombocytopenic purpura.

Anti-ADAMTS13 autoantibodies are the main cause of acquired thrombotic thrombocytopenic purpura. Binding of these antibodies to ADAMTS13 eventually results in the formation of antigen-antibody immune complexes. Circulating ADAMTS13-specific immune complexes have been described in patients with acquired thrombotic thrombocytopenic purpura, although the prevalence and persistence of these immune complexes over time have hitherto remained elusive. Here, we analyzed a large cohort of patients with acquired thrombotic thrombocytopenic purpura for the presence of free and complexed anti-ADAMTS13 antibodies. In the acute phase (n=68), 100% of patients had free IgG antibodies and 97% had ADAMTS13-specific immune complexes. In remission (n=28), 75% of patients had free antibodies (mainly IgG) and 93% had ADAMTS13-specific immune complexes. Free antibodies were mainly of subclasses IgG1 and IgG4, whereas IgG4 was by far the most prevalent in ADAMTS13-specific immune complexes. Comparison of ADAMTS13 inhibitor and anti-ADAMTS13 IgG (total and subclasses) antibody titers in acute phase and in remission samples showed a statistically significant decrease in all parameters in remission. Although non-significant, a trend towards reduced or undetectable titers in remission was also observed for ADAMTS13-specific immune complexes of subclasses IgG1, IgG2 and IgG3. No such trend was discernible for IgG4; IgG4 immune complexes persisted over years, even in patients who had been treated with rituximab and who showed no features suggesting relapse.

Reversal of coagulopathy using prothrombin complex concentrates is associated with improved outcome compared to fresh frozen plasma in warfarin-associated intracranial hemorrhage.

BACKGROUND: There are no studies demonstrating that prothrombin complex concentrates (PCC) improves outcome compared FFP in patients with warfarin-associated intracranial hemorrhage. METHODS: A prospective, observational study was conducted of patients who received PCC (Bebulin VH), FFP, or PCC + FFP. All groups received vitamin K 10 mg IV. INR reversal (<1.4), adverse events (venous thromboembolism, myocardial infraction, pulmonary edema), major hemorrhage (new or worsened intracranial hemorrhage, anemia requiring transfusion or GI bleed), and 3-month functional outcome were compared between the groups using Chi squared and logistic regression analysis. RESULTS: Of 64 patients, PCC alone was used in 16 (mean dose 48 IU/kg), FFP alone in 25 (mean dose 12.5 ml/kg), and PCC + FFP in 23 (median doses 47.4 IU/kg and 11.4 ml/kg, respectively). INR correction occurred in 88, 84, and 70 %, respectively. There were no differences in time to INR correction or adverse events between the groups, but FFP alone was associated with more major hemorrhage after administration (52 %, OR 5.0, 95 % CI 1.6-15.4, P = 0.006) and PCC with less (6 %, OR 0.1, 95 % CI 0.01-0.8, P = 0.033). After adjusting for age, admission GCS, initial INR, and bleed type, the use of PCC was associated with a lower risk of death or severe disability at 3-months (adjusted OR 0.02, 95 % CI 0.001-0.8, P = 0.039), while FFP alone was associated with a higher risk (adjusted OR 51.6, 95 % CI 1.2-2163.1, P = 0.039). CONCLUSIONS: PCC adequately corrected INR without any increase in adverse events compared to FFP and was associated with less major hemorrhage and improved 3-month outcomes in patients with warfarin-associated intracranial hemorrhage.

New directions to develop therapies for people with hemophilia.

INTRODUCTION: The past few decades have seen a tremendous advancement in the management of hemophilia. Whether it is improved methods to attenuate critical viruses, recombinant bioengineering with decreased immunogenicity, extended half-life replacement therapies to mitigate the burden of repeated infusion treatments, novel nonreplacement products to avoid the drawback of inhibitor development with its attractive subcutaneous administration and then the introduction of gene therapy, the management has trodden a long way. AREAS COVERED: This expert review describes the progress in the treatment of hemophilia over the years. We discuss, in detail, the past and current therapies, their benefits, drawbacks, along with relevant studies leading to approval, efficacy and safety profile, ongoing trials, and future prospects. EXPERT OPINION: The technological advances in the treatment of hemophilia with convenient modes of administration and innovative modalities offer a chance for a normal existence of the patients living with this disease. However, it is imperative for clinicians to be aware of the potential adverse effects and the need for further studies to establish causality or chance association of these events with novel agents. Thus, it is crucial for clinicians to engage patients and their families in informed decision-making and tailor individual concerns and necessities.

FEIBA: a prohemostatic agent.

Factor eight inhibitor bypassing activity (FEIBA), Anti-Inhibitor Coagulation Complex has been used for over 30 years in hemophiliac patients with inhibitors. The history of its use is reviewed here, including issues related to thrombosis, efficacy, and comparison to alternative bypassing agents. The need for surrogate assays to monitor effective hemostasis with the use of FEIBA remains.

A case of factor V inhibitor with complete correction of the PT and aPTT upon mixing.

We read with interest Gartrell's recent report of a woman who developed a factor V inhibitor. Gartrell noted in his report that the inhibitor appeared to exhibit time dependence, as the mixing study showed slightly more prolongation of both the PT and the aPTT after 1 hr than immediately following mixing. We believe Gartrell's article may shed light on a recent intriguing case of a patient with factor V inhibitor at our institution.

Analysis of EQ-5D scores from two phase 3 clinical trials of romiplostim in the treatment of immune thrombocytopenia (ITP).

OBJECTIVE: Utility-based measures of quality of life are recommended by some decision makers in health care. No studies have addressed changes in utility in patients with chronic idiopathic thrombocytopenia (ITP). This study sought to assess the health utilities of patients with chronic ITP and to evaluate the association of change in health utility with changes in other variables, including platelet response status and bleeding events. METHODS: We analyzed EQ-5D data from two international, randomized, placebo-controlled, double-blind, 24-week trials that evaluated the efficacy and safety of romiplostim in adult patients with chronic ITP. RESULTS: A total of 125 subjects participated. Mean change, adjusted for age, gender, splenectomy status, and baseline score using multiple linear regression models was greater for romiplostim versus placebo for the EQ-5D index score (0.05 vs. -0.03, P = 0.015) and the VAS score (6.42 vs. 0.48, P = 0.066); similar for durable platelet responders versus nonresponders; and greater for EQ-5D index scores for subjects who did not have a bleeding event during the study (n = 29) compared to subjects who did have a bleeding event (n = 47) (0.06 vs. 0.005; P = 0.066). CONCLUSIONS: Using romiplostim in cases of chronic ITP was associated with improvement in health-related quality of life as measured by the EQ-5D index score. Health utility scores derived using the EQ-5D in this study may be useful for determining quality-adjusted life years (QALYs) in economic evaluations of romiplostim for treatment of chronic ITP.

Screening coagulation testing using the APTT: which reagent to choose?

APTT testing is integral to hemostasis testing. A prolonged result, however, can be difficult to interpret, depending on the APTT reagent's sensitivity to the lupus anticoagulant. This often generates additional laboratory testing for both factor deficiencies and the presence of a lupus anticoagulant, and in so doing, delays patient management. We have found it useful to provide APTT testing with both a lupus anticoagulant sensitive and insensitive reagent, to facilitate the rapid exclusion of significant factor deficiencies. The following case report illustrates the utility of this approach and provides a backdrop for necessary discussions between laboratories and clinicians regarding which APTT reagent best meets their clinical need for screening hemostasis testing.