Search

Summary: Immune thrombocytopenia (ITP) is an autoimmune disease typically associated with severely depleted platelet counts. However, additional symptoms (e.g. increased fatigue and memory/concentration difficulties) can profoundly impact patients' quality of life. The nature and severity of cognitive impairment in ITP, and potential association with patient/disease characteristics were evaluated in 49 adults with relapsed/refractory ITP. The Cogstate Brief Battery quantitatively assessed psychomotor function (DET), attention (IDN), visual learning (OCL) and working memory (ONB) individually, as well as DET/IDN and OCL/ONB composites. Clinically important cognitive impairment (defined as z‐score ≤ −1) for ≥2 individual tests was observed in 29 patients (59%). Impairment was highest for IDN (67% of patients), followed by DET (53%), ONB (39%) and OCL (16%). A higher magnitude of impairment was observed for the DET/IDN composite (mean z‐score −1.54; 95% CI, −1.94 to −1.13) than OCL/ONB (mean z‐score −0.21; 95% CI, −0.49 to 0.07). The severity of cognitive impairment was comparable to mild traumatic brain injury and associated with increasing age and fatigue but unrelated to platelet count or corticosteroid use. Overall, these results warrant a clinical need to further consider the potential of cognitive dysfunction in assessing ITP patients. [ABSTRACT FROM AUTHOR]

Background & Aims: Upregulation of hepatic delta‐aminolevulinic acid synthase 1 with accumulation of potentially toxic heme precursors delta‐aminolevulinic acid and porphobilinogen is fundamental to the pathogenesis of acute hepatic porphyria. Aims: evaluate long‐term efficacy and safety of givosiran in acute hepatic porphyria. Methods: Interim analysis of ongoing ENVISION study (NCT03338816), after all active patients completed their Month 24 visit. Patients with acute hepatic porphyria (≥12 years) with recurrent attacks received givosiran (2.5 mg/kg monthly) (n = 48) or placebo (n = 46) for 6 months (double‐blind period); 93 received givosiran (2.5 mg or 1.25 mg/kg monthly) in the open‐label extension (continuous givosiran, n = 47/48; placebo crossover, n = 46/46). Endpoints included annualized attack rate, urinary delta‐aminolevulinic acid and porphobilinogen levels, hemin use, daily worst pain, quality of life, and adverse events. Results: Patients receiving continuous givosiran had sustained annualized attack rate reduction (median 1.0 in double‐blind period, 0.0 in open‐label extension); in placebo crossover patients, median annualized attack rate decreased from 10.7 to 1.4. Median annualized days of hemin use were 0.0 (double‐blind period) and 0.0 (open‐label extension) for continuous givosiran patients and reduced from 14.98 to 0.71 for placebo crossover patients. Long‐term givosiran led to sustained lowering of delta‐aminolevulinic acid and porphobilinogen and improvements in daily worst pain and quality of life. Safety findings were consistent with the double‐blind period. Conclusions: Long‐term givosiran has an acceptable safety profile and significantly benefits acute hepatic porphyria patients with recurrent attacks by reducing attack frequency, hemin use, and severity of daily worst pain while improving quality of life. [ABSTRACT FROM AUTHOR]

Regulatory agencies are increasingly considering real‐world evidence (RWE) to support label expansions of approved medicines. We conducted a comparative effectiveness study to emulate a proposed randomized trial of romiplostim vs. standard‐of‐care (SOC) therapy among patients with recently diagnosed (≤12 months) immune thrombocytopenia (ITP), that could support expansion of the romiplostim label. We discuss challenges that we encountered and solutions that were developed to address those challenges. Study size was a primary concern, particularly for romiplostim initiators, given the rarity of ITP and the stringent trial eligibility criteria. For this reason, we leveraged multiple data sources (Nordic Country Patient Registry for Romiplostim; chart review study of romiplostim initiators in Europe; Flatiron Health EMR linked with MarketScan claims). Additionally, unlike the strictly controlled clinical trial setting, platelet counts were not measured at regular intervals in the observational data sources, and therefore the end point of durable platelet response often used in trials could not be reliably measured. Instead, the median platelet count was chosen as the primary end point. Ultimately, while we observed a slightly higher median platelet count in the romiplostim group vs. SOC, precision was limited because of small study size (median difference was 11 × 109/L (95% CI: −59, 81)). We underscore the importance of conducting comprehensive feasibility assessments to identify fit‐for‐purpose data sources with sufficient sample size, data elements, and follow‐up. Beyond technical challenges, we also discuss approaches to increase the credibility of RWE, including systematic incorporation of clinical expertise into study design decisions, and separation between decision makers and the data. [ABSTRACT FROM AUTHOR]

Background: Gaucher disease (GD) manifests heterogeneously and other conditions are often misdiagnosed in its place, leading to diagnostic delays. The Gaucher Earlier Diagnosis Consensus (GED‐C) initiative proposed a point‐scoring system (PSS) based on the signs and covariables that are most indicative of GD to help clinicians identify which individuals to test for GD. Aims: To validate the PSS retrospectively in a test population including patients with GD and other conditions with overlapping manifestations. Methods: Four cohorts of adults with GD, liver disease, haematological malignancy or immune thrombocytopenia were identified from hospital records. Clinical data were audited for GED‐C factors identified as potentially indicative of GD and aggregate scores calculated (sum of scores/number of factors) based on published PSS weightings. Threshold discriminatory PSS scores, sensitivity and specificity were determined by receiver‐operating characteristic analysis. Results: Among 100 patients (GD, n = 25; non‐GD, n = 75), analyses based on 11 possible factors estimated group mean (standard deviation) PSS scores of: GD (n = 14), 1.08 (0.25); non‐GD (n = 38), 0.58 (0.31). Mean between‐group difference (95% confidence interval) was −0.49 (−0.68, −0.31) and area under the receiver‐operating characteristic analysis curve (95% confidence interval) was 0.88 (0.78, 0.97). A threshold PSS score of 0.82 identified all 14 patients with GD in the analysis set (100% sensitivity) and 27 of 38 patients in the non‐GD group (71% specificity). Patients with liver disease and haematological malignancy were most likely to have manifestations overlapping GD. Conclusions: Preliminary validation of the GED‐C PSS discriminated effectively between patients with GD and those with overlapping signs. [ABSTRACT FROM AUTHOR]

Summary: Antibodies to first‐generation recombinant thrombopoietin (TPO) neutralized endogenous TPO and caused thrombocytopenia in some healthy subjects and chemotherapy patients. The second‐generation TPO receptor agonist romiplostim, having no sequence homology to TPO, was developed to avoid immunogenicity. This analysis examined development of binding and neutralising antibodies to romiplostim or TPO among adults with immune thrombocytopenia (ITP) in 13 clinical trials and a global postmarketing registry. 60/961 (6·2%) patients from clinical trials developed anti‐romiplostim‐binding antibodies post‐baseline. The first positive binding antibody was detected 14 weeks (median) after starting romiplostim, at median romiplostim dose of 2 µg/kg and median platelet count of 29.5 × 109/l; most subjects had ≥98·5% of platelet assessments showing response. Neutralising antibodies to romiplostim developed in 0·4% of patients, but were unrelated to romiplostim dose and did not affect platelet count. Thirty‐three patients (3·4%) developed anti‐TPO‐binding antibodies; none developed anti‐TPO‐neutralising antibodies. In the global postmarketing registry, 9/184 (4·9%) patients with spontaneously submitted samples had binding antibodies. One patient with loss of response had anti‐romiplostim‐neutralising antibodies (negative at follow‐up). Collectively, anti‐romiplostim‐binding antibodies developed infrequently. In the few patients who developed neutralising antibodies to romiplostim, there was no cross‐reactivity with TPO and no associated loss of platelet response. [ABSTRACT FROM AUTHOR]

Further confounding the concept of "maintenance-free" is that some treatment effects persist after the treatment ends; B-cell depletion may last for months or years after rituximab and splenectomy creates a lifelong disorder of asplenia. In this quest for clarity, whether "response", "durability" or "remission" is the result of ongoing maintenance treatment is relevant given that many ITP therapies such as the TPO-RA may be ongoing. The last 15 years have shown great progress in the management of immune thrombocytopenia (ITP), ranging from the introduction and licensing of two thrombopoietin receptor agonists (TPO-RA), eltrombopag and romiplostim, to more recently, a Syk tyrosine kinase inhibitor (fostamatinib) and two other TPO-RA (avatrombopag and hetrombopag). [Extracted from the article]

Lactate dehydrogenase (LDH) is present in numerous cell types, including platelets, which have high LDH activity (Hule, [2]). We additionally found a statistically significant inverse correlation between LDH value and concurrently drawn platelet count, suggesting LDH elevation is occurring at least partially due to increased platelet turnover. [Extracted from the article]

Introduction: Patients with Type 1 von Willebrand disease (VWD) have reduced amounts of von Willebrand factor (VWF) in their blood. Desmopressin (DDAVP) has been used to raise the blood levels of VWF in these patients. However, not all patients with Type 1 VWD are known to respond to DDAVP therapy. We sought to compare the levels of Factor VIII, VWF antigen (VWF:Ag), VWF ristocetin cofactor (VWF:RCo), and fibrinogen at different time points after administration of DDAVP. Methods: A retrospective analysis was conducted at a single institution on 89 patients with Type 1 VWD who received a single intravenous dose of 0.3 μg/kg DDAVP. Levels of Factor VIII, VWF:Ag, VWF:RCo, and fibrinogen were measured before and then 30, 60, 90, and 120 minutes after completion of DDAVP administration. Results: Median levels of Factor VIII, VWF:Ag, and VWF:RCo were significantly elevated (P < 0.001) at 30 (175 IU/dL, 111 IU/dL, 127 IU/dL), 60 (218 IU/dL, 138 IU/dL, 139 IU/dL), and 90 (212 IU/dL, 134 IU/dL, 130 IU/dL) minutes time points when compared to their respective baseline values (71 IU/dL, 54 IU/dL, 54 IU/dL). At 60 minutes, 96% of subjects were responders, but three subjects failed to respond at any time point. Conclusion: Measurement of levels of Factor VIII, VWF:Ag, and VWF:RCo, optimally at 60 minutes after the DDAVP infusion, is sufficient to confirm a patient as a responder in a DDAVP challenge test. Curtailing the number of time points of measurement will result in significant savings in cost and time to patients and their providers. [ABSTRACT FROM AUTHOR]

Summary: The thrombopoietin receptor agonist romiplostim is approved for second‐line use in chronic immune thrombocytopenia (ITP), but its effects in patients with ITP for ≤1 year are not well characterized. This analysis of pooled data from 9 studies included patients with ITP for ≤1 year (n = 311) or >1 year (n = 726) who failed first‐line treatments and received romiplostim, placebo or standard of care. In subgroup analysis by ITP duration, patient incidences for platelet response at ≥75% of measurements were higher for romiplostim [ITP ≤1 year: 74% (204/277); ITP >1 year: 71% (450/634)] than for placebo/standard of care [ITP ≤1 year: 18% (6/34); ITP >1 year: 9% (8/92)]. Of patients with ≥9 months on study, 16% with ITP ≤1 year and 6% with ITP >1 year discontinued romiplostim and maintained platelet counts ≥50 × 109/l for ≥6 months without ITP treatment (treatment‐free remission). Independent of ITP duration, rates of serious adverse events and bleeding were lower with romiplostim than placebo/standard of care and thrombotic events occurred at similar rates. In this analysis, romiplostim and placebo/standard of care had similar safety profiles and romiplostim increased platelet counts in patients with either ITP ≤1 year or ITP >1 year, with more treatment‐free remission in those with ITP ≤1 year. [ABSTRACT FROM AUTHOR]

Background: Gaucher disease (GD) presents with a range of signs and symptoms. Physicians can fail to recognise the early stages of GD owing to a lack of disease awareness, which can lead to significant diagnostic delays and sometimes irreversible but avoidable morbidities. Aim: The Gaucher Earlier Diagnosis Consensus (GED‐C) initiative aimed to identify signs and co‐variables considered most indicative of early type 1 and type 3 GD, to help non‐specialists identify 'at‐risk' patients who may benefit from diagnostic testing. Methods: An anonymous, three‐round Delphi consensus process was deployed among a global panel of 22 specialists in GD (median experience 17.5 years, collectively managing almost 3000 patients). The rounds entailed data gathering, then importance ranking and establishment of consensus, using 5‐point Likert scales and scoring thresholds defined a priori. Results: For type 1 disease, seven major signs (splenomegaly, thrombocytopenia, bone‐related manifestations, anaemia, hyperferritinaemia, hepatomegaly and gammopathy) and two major co‐variables (family history of GD and Ashkenazi‐Jewish ancestry) were identified. For type 3 disease, nine major signs (splenomegaly, oculomotor disturbances, thrombocytopenia, epilepsy, anaemia, hepatomegaly, bone pain, motor disturbances and kyphosis) and one major co‐variable (family history of GD) were identified. Lack of disease awareness, overlooking mild early signs and failure to consider GD as a diagnostic differential were considered major barriers to early diagnosis. Conclusion: The signs and co‐variables identified in the GED‐C initiative as potentially indicative of early GD will help to guide non‐specialists and raise their index of suspicion in identifying patients potentially suitable for diagnostic testing for GD. [ABSTRACT FROM AUTHOR]

Treating deuterohemin, chloro(deuteroporphyrinato)iron(III), with a non‐coordinating base in DMSO/methanol allows for the isolation of [(deuteroporphyrinato)iron(III)]2, deuterohematin anhydride (DHA), an analogue of malaria pigment, the natural product of heme detoxification by malaria. The structure of DHA obtained from this solvent system has been solved by X‐ray powder diffraction analysis and displays many similarities, yet important structural differences, to malaria pigment. Most notably, a water molecule of solvation occupies a notch created by the propionate side chains and stabilizes a markedly bent propionate ligand coordinated with a long Fe−O bond, and a carboxylate cluster associated with water molecules is generated. Together, these features account for its increased solubility and more open structure, with an increased porphyrin–porphyrin separation. The IR spectroscopic signature associated with this structure also accounts for the strong IR band at 1587 cm−1 seen for many amorphous preparations of synthetic malaria pigment, and it is proposed that stabilizing these structures may be a new objective for antimalarial drugs. The important role of the vinyl substituents in this biochemistry is further demonstrated by the structure of deuterohemin obtained by single‐crystal X‐ray diffraction analysis. Hemozoin‐like structure: A new structural motif for heme dimerization relevant to malarial heme processing and aggregation has been found for the iron(deuteroporphyrin) dimer. [ABSTRACT FROM AUTHOR]

Eltrombopag, an oral thrombopoietin receptor agonist, is dosed daily to treat chronic immune thrombocytopenia (ITP). As it has a half‐life of 26–35 h in ITP patients and requires patents to abide by strict dietary restrictions that may impair quality of life and reduce compliance, we developed an alternative intermittent (AI) eltrombopag dosing protocol for ITP, with dosing less frequent than once daily. Ten patients were treated with AI dosing for a median of 94 (range: 29–156) weeks, with most patients treated with 2–4 weekly doses for extended durations. During AI dosing, 95%, 84% and 71% of all platelet counts were ≥20 × 109 l–1, ≥50 × 109 l–1 and ≥100 × 109 l–1, respectively. Five patients required rescue treatment for thrombocytopenia and World Health Organization grade 1 mucocutaneous bleeding, and there were no thromboembolic events. In summary, intermittently dosed eltrombopag was efficacious in treating chronic ITP in a small cohort, with rates of platelet response and rescue treatment comparable with rates in studies evaluating daily dosing. [ABSTRACT FROM AUTHOR]

Summary: Avatrombopag is an oral thrombopoietin receptor agonist that has been recently approved for treating thrombocytopenia in chronic liver disease patients needing invasive procedures. Clinical trials supporting this new treatment were guided by two double‐blind, dose‐rising, placebo‐controlled Phase 1 studies in healthy adults reported here that assessed safety, tolerability and pharmacokinetic profile of avatrombopag, and its effect on platelet counts. Subjects were randomised (2:1) in the single‐dose study (N = 63) to avatrombopag (1, 3, 10, 20, 50, 75 and 100 mg) or placebo, and in the multiple‐dose study (N = 29) to avatrombopag (3, 10 and 20 mg) or placebo daily for 14 days. There were no serious adverse events (AEs), dose‐limiting toxicities, deaths, AEs causing withdrawal, thromboses or liver function abnormalities. In both studies, avatrombopag peak concentration and exposure increased proportionally relative to dose; half‐life was 18–21 h and independent of dose, supporting once‐daily dosing. Effects on platelet counts depended on dose, concentration and treatment duration. Platelet count increases began 3–5 days post‐administration, with maximum changes of >370 × 109/l over baseline with 20 mg daily after 13–16 days. These data support continued development of avatrombopag for treatment of other thrombocytopenic conditions and provide important guidance for the haematologist in the use of this new thrombopoietin receptor agonist. [ABSTRACT FROM AUTHOR]

Gaucher disease (GD) is associated with an increased risk for malignancies. Next to hematological malignancies, the development of solid tumors in several organs has been described. The liver is one of the major storage sites involved in GD pathogenesis, and is also affected by liver-specific complications. In this case series, we describe 16 GD type 1 (GD1) patients from eight different referral centers around the world who developed hepatocellular carcinoma (HCC). Potential factors contributing to the increased HCC risk in GD patients are studied. Eleven patients had undergone a splenectomy in the past. Liver cirrhosis, one of the main risk factors for the development of HCC, was present in nine out of 14 patients for whom data was available. Three out of seven examined patients showed a transferrin saturation > 45%. In these three patients the presence of iron overload after histopathological examination of the liver was shown. Chronic hepatitis C infection was present in three of 14 examined cases. We summarized all findings and made a comparison to the literature. We recommend that GD patients, especially those with prior splenectomy or iron overload, be evaluated for signs of liver fibrosis and if found to be monitored for HCC development. [ABSTRACT FROM AUTHOR]

Carbon monoxide (CO) has long been known as the “silent killer” owing to its ability to form carboxyhemoglobin—the main cause of CO poisoning in humans. Its role as an endogenous neurotransmitter, however, was suggested in the early 1990s. Since then, the biological activity of CO has been widely examined via both the direct administration of CO and in the form of so-called “carbon monoxide releasing molecules (CORMs).” This overview will explore the general physiological effects and potential therapeutic applications of CO when delivered in the form of CORMs. [ABSTRACT FROM AUTHOR]

Summary: Thrombocytopenic patients requiring invasive surgery have few options to improve their platelet count preoperatively. This is a single‐centre, retrospective review of thrombocytopenic patients receiving the thrombopoietin receptor agonist romiplostim perioperatively to allow for surgical interventions. Patient characteristics, romiplostim use, and surgical and safety outcomes (bleeding, thrombosis, transfusions) were collected and analysed. Forty‐seven patients underwent 51 surgical procedures (ranging from total hip arthroplasty to open cardiac surgery) with romiplostim support. Thrombocytopenia aetiologies included immune thrombocytopenia, chronic liver disease, haematological malignancy, drug‐related thrombocytopenia, and hereditary thrombocytopenia. Median (range) platelet counts improved, from 47 × 109/l (9–120 × 109/l) at romiplostim initiation to 164 × 109/l (28–603 × 109/l) at the time of surgery (P < 0·0001). A dose of 3 μg/kg per week for 2 doses increased the platelet count to >100 × 109/l in 79% of patients within 14 days. In 96% of cases, surgery proceeded on schedule without delay or cancellation. Four patients had bleeding events unrelated to thrombocytopenia and 1 patient developed deep venous thrombosis. Six patients required red cell transfusion and 3 patients required platelet transfusion perioperatively. In conclusion, romiplostim was effective in increasing platelet counts to allow surgery to proceed safely and on schedule. Bleeding and thromboembolic events were within acceptable limits for this surgical population. [ABSTRACT FROM AUTHOR]

Pure white cell aplasia (PWCA) is a rare hematologic disorder characterized by the absence of neutrophil lineages in the bone marrow with intact megakaryopoiesis and erythropoiesis. PWCA has been associated with autoimmune, drug-induced, and viral exposures. Here, we report a case of a 74-year-old female who presented with severe proximal weakness without pain and was found to have PWCA with nonspecific inflammatory necrotizing myositis and acute liver injury on biopsies. These findings were associated with a recent course of azithromycin and her daily use of a statin. Myositis improved on prednisone but PWCA persisted. With intravenous immunoglobulin and granulocyte-colony stimulating factor therapies, her symptoms and neutrophil counts improved and were sustained for months. [ABSTRACT FROM AUTHOR]

Background: Thrombopoietin receptor agonists increase platelet (PLT) counts and are approved for the treatment of chronic immune thrombocytopenia (ITP). These agents may also be useful for the management of thrombocytopenia in patients requiring surgical procedures.Study Design and Methods: We conducted a retrospective review of patients with thrombocytopenia (baseline PLT count, <150 × 10(9) /L) who received romiplostim before planned operative procedures. We characterized patient demographics, dosing and duration of romiplostim use, success in achieving PLT counts high enough for surgery, and clinical outcomes.Results: Eighteen patients underwent a total of 22 operative procedures, including three Jehovah's Witnesses who underwent five procedures. Etiologies of thrombocytopenia included mild ITP (not on romiplostim at baseline), liver disease, hematologic malignancy, and drug-related thrombocytopenia. Median PLT count at romiplostim initiation was 47 × 10(9) /L (range, 11 × 10(9) -120 × 10(9) /L). All patients experienced a PLT count increase over a median of 4 weeks; median PLT count at surgery was 144 × 10(9) /L (range, 28 × 10(9) -370 × 10(9) /L). PLT counts increase to more than 150 × 10(9) /L in four of five Jehovah's Witness patients by the time of surgery. There were no surgical delays or cancellations due to thrombocytopenia. Four bleeding events occurred; none were fatal and none occurred at a PLT count of fewer than 80 × 10(9) /L. No definitive thromboembolic events occurred.Conclusion: Romiplostim successfully increased preoperative PLT counts allowing operative interventions, was well tolerated, did not lead to any significant thromboembolic events, and avoided the need for transfusion. Romiplostim may be of clinical utility in the preoperative management of thrombocytopenic patients, especially those unable to receive or unresponsive to PLT transfusion. [ABSTRACT FROM AUTHOR]

The discovery of thrombopoietin ( TPO, also termed THPO) in 1994 was a major achievement in understanding the regulation of platelet production. In prior decades, physiological studies had demonstrated that platelets were produced from bone marrow megakaryocytes and that the megakaryocytes responded to thrombocytopenia by increasing their number, size and DNA ploidy. In 1958, it was proposed that a 'thrombopoietin' must exist that regulated this interaction between the circulating platelet mass and the bone marrow megakaryocytes. After over three decades of effort, TPO was finally purified by five independent laboratories. TPO stimulated megakaryocyte colony-forming cell growth and increased the number, size and ploidy of megakaryocytes. When the genes for TPO or TPO receptor were eliminated in mice, megakaryocytes grew and platelets were made, but at 15% of their normal number. A first generation of recombinant human (rh) TPO molecules [rh TPO and pegylated recombinant human megakaryocyte growth and development factor ( PEG-rh MGDF)] rapidly entered clinical trials in 1995 and increased platelet counts in humans undergoing non-myeloablative chemotherapy but not in those undergoing stem cell transplantation. Antibodies developed against PEG-rh MGDF and development of these recombinant thrombopoietins ended. A second generation of TPO receptor agonists (romiplostim and eltrombopag) was then developed. Neither of these TPO receptor agonists demonstrated any significant untoward effects and both are now licensed in many countries for the treatment of immune thrombocytopenia. This review describes the significant experiments that have surrounded the discovery of TPO and its clinical development. [ABSTRACT FROM AUTHOR]

Romiplostim was effective, safe, and well-tolerated over 6-12 months of continuous treatment in Phase 3 trials in patients with immune thrombocytopenia ( ITP). This report describes up to 5 years of weekly treatment with romiplostim in 292 adult ITP patients in a long-term, single-arm, open-label study. Outcome measures included adverse events (including bleeding, thrombosis, malignancy, and reticulin/fibrosis), platelet response (platelet count >50 × 109 per litre), and the proportion of patients requiring rescue treatments. Treatment-related serious adverse events were infrequent and did not increase with longer treatment. No new classes of adverse events emerged. Thrombotic events occurred in 6·5% of patients and were not associated with platelet count. Median platelet counts of 50-200 × 109 per litre were maintained with stable doses of romiplostim (mean 5-8 μg/kg; generally self-administered at home) throughout the study. A platelet response was achieved at least once by 95% of patients, with a platelet response maintained by all patients on a median 92% of study visits. There was a low rate of bleeding and infrequent need for rescue treatments. In conclusion, this study demonstrated that romiplostim was safe and well-tolerated over 614 patient-years of exposure in ITP patients, and that efficacy was maintained with stable dosing for up to 5 years of continuous treatment. [ABSTRACT FROM AUTHOR]

Miglustat (Zavesca®) is approved for the oral treatment of adult patients with mild to moderate type 1 Gaucher disease (GD1) for whom enzyme replacement therapy is unsuitable, and for the treatment of progressive neurological manifestations in adult and paediatric patients with Niemann-Pick disease type C (NP-C). Gastrointestinal disturbances such as diarrhoea, flatulence and abdominal pain/discomfort have consistently been reported as the most frequent adverse events associated with miglustat during clinical trials and in real-world clinical practice settings. These adverse events are generally mild or moderate in severity, occurring mostly during the initial weeks of therapy. The mechanism underlying these gastrointestinal disturbances is the inhibition by miglustat of intestinal disaccharidase enzymes (mainly sucrase and maltase), leading to sub-optimal hydrolysis of carbohydrates and subsequent osmotic diarrhoea and altered colonic fermentation. Transient decreases in body weight, which are often observed during initial miglustat therapy, are considered likely due to gastrointestinal carbohydrate malabsorption and associated negative caloric balance. While most cases of diarrhoea resolve spontaneously during continued miglustat therapy, diarrhoea also responds well to anti-propulsive medications such as loperamide. Dietary modifications such as reduced consumption of dietary sucrose, maltose and lactose have been shown to improve the gastrointestinal tolerability of miglustat and reduce the magnitude of any changes in body weight, particularly if initiated at or before the start of therapy. Miglustat dose escalation at treatment initiation may also reduce gastrointestinal disturbances. This article discusses these aspects in detail, and provides practical recommendations on how to optimize the gastrointestinal tolerability of miglustat. [ABSTRACT FROM AUTHOR]

BACKGROUND: ADAMTS13 cleaves ultralarge von Willebrand factor (VWF) and plays a significant role in vascular biology and thrombotic thrombocytopenic purpura. CD36, a transmembrane protein present on endothelial cells and platelets (PLTs), binds to thrombospondin via three thrombospondin type 1 repeats. ADAMTS13 contains eight thrombospondin type 1 repeats. STUDY DESIGN AND METHODS: An enzyme-linked immunoassay was used to explore the binding of recombinant human CD36 (rHuCD36) to recombinant human ADAMTS13 (rHuADAMTS13). A competition assay between rHuADAMTS13 and recombinant human (rHu)-thrombospondin-2 for binding to CD36 was then performed. Subsequently, binding of rHuADAMTS13 to PLT membrane fragments expressing CD36 (PLT glycoprotein IV) and glycoprotein Ib/IX was assessed. To examine the functional significance of an ADAMTS13-CD36 interaction, ADAMTS13 activity measured by a fluorescence resonance energy transfer assay was investigated in the presence of either rHuCD36 or concentrated PLTs. RESULTS: rHuCD36 bound to rHuADAMTS13 in a dose-dependent fashion. rHu-thrombospondin-2 competed with ADAMTS13 for CD36 occupancy, but even high concentrations of rHu-thrombospondin-2 failed to completely block binding of rHuADAMTS13 to rHuCD36. rHuADAMTS13 bound to PLT membrane fragments expressing CD36 (PLT glycoprotein IV) in preference to PLT membrane fragments expressing glycoprotein Ib/IX. ADAMTS13 activity was not inhibited by the presence of either rHuCD36 or concentrated PLTs. CONCLUSION: rHuADAMTS13 binds to both rHuCD36 and PLT membrane CD36 in vitro. The binding of CD36 to rHuADAMTS13 with retention of its enzymatic activity is consistent with a proposed role for CD36 in localizing ADAMTS13 on the endothelial cell surface where it regulates the cleavage of VWF. [ABSTRACT FROM AUTHOR]

Information about several papers discussed at a conference about clinical and ethical issues on hematopoietic growth factors use in normal blood and stem cell donors is presented. Topics include basic science, clinical effects and uses, side effects, and theoretical complications of hematopoietic growth factors. The conference featured several speakers including John Adamson, Paolo Anderlini, and Richard Benjamin.

Various agents to treat immune thrombocytopenic purpura (ITP) have been developed on the principle that stimulating the thrombopoietin (TPO) receptor would increase platelet production. First-generation agents—recombinant human thrombopoietin (rHuTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG rHuMGDF)—showed promise, but observations of antibody formation to PEG rHuMGDF led to the discontinuation of development of both agents. Second-generation agents—the TPO peptide mimetics, TPO non-peptide mimetics, and TPO agonist antibodies—have been developed to reduce or eliminate the problem of antigenicity. Clinical studies for some of these agents, such as AMG 531 (romiplosim, Nplate) and eltrombopag (Promacta), are demonstrating their relative safety and efficacy in increasing platelet counts in patients with ITP; AMG 531 and eltrombopag are in late-stage clinical development and are able to stimulate platelet production in patients with ITP. Some differences in safety profiles have been described and are undergoing further study. There are currently seven second-generation TPO receptor agonists that have been reported in the literature, representing the potential advantages—and continuing challenges—with this novel class of platelet-stimulating therapies for ITP and possibly thrombocytopenia in other disease states as well. [ABSTRACT FROM AUTHOR]

In bone marrow biopsies, stromal structural fibres are detected by reticulin and trichrome stains, routine stains performed on bone marrow biopsy specimens in diagnostic laboratories. Increased reticulin staining ( reticulin fibrosis) is associated with many benign and malignant conditions while increased trichrome staining ( collagen fibrosis) is particularly prominent in late stages of severe myeloproliferative diseases or following tumour metastasis to the bone marrow. Recent evidence has shown that the amount of bone marrow reticulin staining often exhibits no correlation to disease severity, while the presence of type 1 collagen, as detected by trichrome staining, is often associated with more severe disease and a poorer prognosis. It was originally thought that increases in bone marrow stromal fibres themselves contributed to the haematopoietic abnormalities seen in certain diseases, but recent studies suggest that these increases are a result of underlying cellular abnormalities rather than a cause. A growing body of evidence suggests that increased deposition of bone marrow stromal fibres is mediated by transforming growth factor- β and other factors elaborated by megakaryocytes, but it is likely that other cells, cytokines and growth factors are also involved. This suggests new avenues for investigation into the pathogenesis of various disorders associated with increased bone marrow stromal fibres. [ABSTRACT FROM AUTHOR]

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) and granulocyte colony-stimulating factor (G-CSF) promote haematopoietic progenitor cell maturation. We reviewed the findings for healthy volunteers/donors who developed haematological malignancies following PEG-rHuMGDF or G-CSF administration. Information was reviewed for three of 538 volunteers who received PEG-rHuMGDF in clinical trials and two of 200 donors who underwent G-CSF mobilised stem cell harvesting procedures for sibling stem cell transplants. Mantle cell, diffuse large B-cell lymphoma and chronic lymphocytic leukaemia were diagnosed 1–5 years after PEG-rHuMGDF exposure among three volunteers. For one patient, thrombocytopenia due to autoantibodies to PEG-rHuMGDF developed shortly after PEG-rHuMGDF administration and persisted until chemotherapy was administered. All three achieved complete remission, although one patient relapsed. Acute myeloid leukaemia was diagnosed 4 and 5 years after G-CSF mobilisation in two donors who underwent peripheral blood stem cell donation for sibling allogeneic haematopoietic stem cell transplantation. Following intensive chemotherapy, one died from acute leukaemia and the second is in complete remission. Controversy exists over the appropriateness of administering haematopoietic growth factors to healthy individuals. While a causal relationship with haematological malignancies cannot be demonstrated, long-term follow-up among healthy individuals who receive haematopoietic growth factors is needed. [ABSTRACT FROM AUTHOR]

PLTs stored at 22°C have the potential for bacterial contamination, a problem that could be reduced by 4°C storage. Nevertheless, PLTs stored at 4°C exhibit a significantly reduced life span. This study was performed to determine whether treatment of PLTs with thrombopoietin or cytochalasin B plus ethylene glycol bis(β-aminoethyl ether) N,N′-tetraacetic acid (EGTA)-AM could prevent exponential loss of PLTs stored at 4°C. Autologous baboon PLTs were stored at 22 or 4°C. The 4°C stored PLTs were treated with 1.5 ng per mL thrombopoietin, with 1 µmol per L cytochalasin B, and 80 µmol per L EGTA-AM (cyto-EGTA) or not treated and labeled with 111In-oxine to study their in vivo recovery and life span. PLT function was assessed by correction of an aspirin-induced prolonged bleeding time. Aggregation responses and morphology were also assessed. PLTs stored at 22°C had normal in vivo recovery and linear survival. PLTs stored at 4°C, whether or not they were treated with thrombopoietin, had normal recovery and exponential survival. Aggregation of cyto-EGTA-treated PLTs was similar for PLTs stored at 4°C and fresh PLTs, but decreased in PLTs stored at 22°C for 5 days. The addition of cyto-EGTA to PLTs before 4°C storage inhibited morphologic changes that occurred in PLTs stored at 22°C and cold-induced PLT clumping, but did not prevent exponential disappearance of the PLTs. Addition of thrombopoietin or cyto-chalasin B and EGTA-AM to PLTs before 4°C storage did not prevent exponential loss of PLTs. [ABSTRACT FROM AUTHOR]

Editorial. Introduces a series of articles on immunohematology. Discussion of the peculiar aspects of the clinical biology of thrombopoietin (TPO); Study of the recombinant forms of TPO; Investigation of TPO in nonchemotherapy trials.