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.

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.

Restoring hemostasis: fibrinogen concentrate versus cryoprecipitate.

Fibrinogen plays a key role in the coagulation process, and therefore maintaining adequate quantities of fibrinogen is an essential step in achieving satisfactory hemostasis in patients with acquired hypofibrinogenemia. Potential options for treating acquired hypofibrinogenemia in patients with uncontrolled bleeding include the use of cryoprecipitate or fibrinogen replacement therapy. This review provides a brief overview of the hemostatic process and the methods for assessing coagulopathy and discusses the efficacy and safety of cryoprecipitate and fibrinogen concentrate in restoring fibrinogen levels, achieving hemostasis and reducing transfusion requirements in different patient populations requiring rapid hemostasis. Other issues relevant to the clinical use of these agents in restoring hemostasis, including variations in product composition, preparation time and cost, are also examined.

Changes in von Willebrand factor-cleaving protease (ADAMTS-13) in patients with aortic stenosis undergoing valve replacement or balloon valvuloplasty.

It was the objective of this study to determine whether reduced cleavage of von Willebrand factor (VWF) multimers following aortic valve replacement (AVR) is a consequence of reduced shear stress or postoperative changes in VWF cleavage protease (ADAMTS-13) activity. Aortic stenosis (AS) may be complicated by acquired von Willebrand disease. Aortic valve replacement (AVR) corrects the associated haematologic abnormalities. We enrolled 114 patients with severe AS scheduled for either balloon aortic valvuloplasty (BAV; n=64) or AVR (n=50). Haematologic assessments of VWF levels and activity and ADAMTS-13 were performed before and 24 hours after valve intervention. The VWF:RCo to VWF:Ag ratio, a surrogate for large VWF multimer activity, increased by 37% (p < 0.0001) after AVR and by 10% (p = 0.0002) after BAV. ADAMTS-13 activity significantly decreased after AVR (579 ± 127 to 468 ± 135 ng/ml; p<0.0001), but not after BAV (484 ± 153 to 529 ± 185 ng/ml; p = 0.10). By multivariable analysis, the change in VWF:RCo ratio after AVR was more strongly associated with the fall in ADAMTS-13 than with reduction of valve gradient; whereas the change in gradient better predicted the rise in VWF:RCo after BAV. In conclusion, both BAV and AVR reverse the haematological abnormalities of the acquired von Willebrand syndrome of AS and ADAMTS-13 levels decrease after AVR. These findings suggest that a portion of the haematologic benefit of AVR may be due to a postoperative decline in ADAMTS-13 rather than solely to relief of AS as previously thought.

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.

An algorithmic approach to peripheral artery disease in hemophilia: extrapolation of management principles from noncoagulopathic patients.

The development of peripheral artery disease (PAD), a marker for systemic atherosclerosis and ischemic risk, is an increasingly important concern in the aging hemophilia population. A growing body of data suggests that an absence or deficiency of factor VIII or factor IX may not protect against atherogenesis, implying that the prevalence of PAD in men with hemophilia (MWH) may be higher than previously believed. This article describes special considerations in PAD screening, risk-factor modification, and management in older MWH.

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.

Recurrent orthostatic global amnesia in a patient with postoperative hyperfibrinogenemia.

Transient global amnesia (TGA) is characterized by sudden, temporary dysfunction of antegrade and recent retrograde memory without other neurologic deficits. Although there is sometimes a precipitating event, the origin of TGA remains controversial. We encountered a patient who developed recurrent TGA when upright, in whom the symptom promptly and regularly resolved when supine. Symptoms began about a week after cardiac surgery concurrent with marked hyperfibrinogenemia and acceleration of the erythrocyte sedimentation rate, and abated without recurrence when these laboratory abnormalities were ameliorated by anticoagulant and corticosteroid therapy. Diagnostic studies, including temporal artery biopsy and cerebral angiography, disclosed no anatomic vascular pathology. This is the first report of TGA associated with postoperative inflammation in which amnesia was provoked by orthostatic positioning. In conclusion, these observations implicate ischemia caused by hemodynamic vascular insufficiency as a possible cause of TGA.

Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial.

BACKGROUND: Chronic immune thrombocytopenic purpura (ITP) is characterised by accelerated platelet destruction and decreased platelet production. Short-term administration of the thrombopoiesis-stimulating protein, romiplostim, has been shown to increase platelet counts in most patients with chronic ITP. We assessed the long-term administration of romiplostim in splenectomised and non-splenectomised patients with ITP. METHODS: In two parallel trials, 63 splenectomised and 62 non-splenectomised patients with ITP and a mean of three platelet counts 30x10(9)/L or less were randomly assigned 2:1 to subcutaneous injections of romiplostim (n=42 in splenectomised study and n=41 in non-splenectomised study) or placebo (n=21 in both studies) every week for 24 weeks. Doses of study drug were adjusted to maintain platelet counts of 50x10(9)/L to 200x10(9)/L. The primary objectives were to assess the efficacy of romiplostim as measured by a durable platelet response (platelet count > or =50x10(9)/L during 6 or more of the last 8 weeks of treatment) and treatment safety. Analysis was per protocol. These studies are registered with ClinicalTrials.gov, numbers NCT00102323 and NCT00102336. FINDINGS: A durable platelet response was achieved by 16 of 42 splenectomised patients given romplostim versus none of 21 given placebo (difference in proportion of patients responding 38% [95% CI 23.4-52.8], p=0.0013), and by 25 of 41 non-splenectomised patients given romplostim versus one of 21 given placebo (56% [38.7-73.7], p<0.0001). The overall platelet response rate (either durable or transient platelet response) was noted in 88% (36/41) of non-splenectomised and 79% (33/42) of splenectomised patients given romiplostim compared with 14% (three of 21) of non-splenectomised and no splenectomised patients given placebo (p<0.0001). Patients given romiplostim achieved platelet counts of 50x10(9)/L or more on a mean of 13.8 (SE 0.9) weeks (mean 12.3 [1.2] weeks in splenectomised group vs 15.2 [1.2] weeks in non-splenectomised group) compared with 0.8 (0.4) weeks for those given placebo (0.2 [0.1] weeks vs 1.3 [0.8] weeks). 87% (20/23) of patients given romiplostim (12/12 splenectomised and eight of 11 non-splenectomised patients) reduced or discontinued concurrent therapy compared with 38% (six of 16) of those given placebo (one of six splenectomised and five of ten non-splenectomised patients). Adverse events were much the same in patients given romiplostim and placebo. No antibodies against romiplostim or thrombopoietin were detected. INTERPRETATION: Romiplostim was well tolerated, and increased and maintained platelet counts in splenectomised and non-splenectomised patients with ITP. Many patients were able to reduce or discontinue other ITP medications. Stimulation of platelet production by romiplostim may provide a new therapeutic option for patients with ITP.

The 5, 10 methylenetetrahydrofolate reductase C677T mutation and risk of fetal loss: a case series and review of the literature.

BACKGROUND: The true relationship between methylenetetrahydrofolate reductase C677T homozygosity and risk of recurrent spontaneous abortion is unknown, and it is unclear if women with these mutations should be anticoagulated during pregnancy. OBJECTIVES: We report a series of 8 patients with this issue and review the current literature. METHODS: 8 patients (3 of whom were actively pregnant) were referred with histories of spontaneous fetal loss; hypercoaguability work-ups revealed each were homozygous for the MTHFR C677T mutation without other thrombophilias. RESULTS: In the 3 women who have conceived, treatment with LMW heparin during pregnancy led to two full-term births and one additional pregnancy without complication. For the 5 who have not, we recommended treatment with LMW heparin upon conception. CONCLUSION: We provide evidence to support the relationship between MTHFR C677T mutations and recurrent fetal loss, and to suggest that anticoagulation of these patients during pregnancy can lead to a successful pregnancy outcome.

Reconstruction of the hepatitis C virus epidemic in the US hemophilia population, 1940-1990.

Hepatitis C virus (HCV) is a blood-borne infection readily transmitted by transfusion. Persons with hemophilia were at very high risk of acquiring HCV, but the chronology and correlates of HCV incidence in the US hemophilia population remain unknown. The authors used multiple data sources and new statistical methods to reconstruct HCV incidence in White males with hemophilia A from 1940 through 1990. HCV incidence was approximately 1%/year until 1950 but 2-3%/year by 1955. With mild hemophilia, HCV incidence increased in the 1960s, reaching a plateau of approximately 8%/year from 1969 to 1980. With moderate and severe hemophilia, HCV incidence increased steeply to peaks of 11.7%/year in 1970 and 17.2%/year in 1968, respectively. Overall, HCV incidence declined after 1970, steeply after 1984, to nearly zero by 1990. With improving and increasing use of plasma derivatives, the size of the hemophilia population increased 86% during these 50 years. Study results imply that these life-saving treatments also carried an increasing risk of HCV, particularly before clotting factor concentrates were licensed in the 1970s. They also suggest that multiple synergistic interventions since 1970, particularly donor deferral, screening for hepatitis B and human immunodeficiency virus, and viral inactivation of clotting factor concentrates, were needed to reduce transfusion of HCV prior to its discovery.