Obesity is associated with poor outcomes of corticosteroid treatment in patients with primary immune thrombocytopenia

Emerging evidence has demonstrated that obesity impacts multiple immune-related diseases. It remains unclear whether and how obesity alters treatment outcomes in patients with primary immune thrombocytopenia (ITP). Thus, we retrospectively investigated 214 treatment-naïve patients who received standard high-dose dexamethasone therapy in Qilu Hospital. Patients with obesity showed significantly lower overall initial response (underweight vs. normal vs. overweight vs. obese: 85.7% vs. 85.2% vs. 72.0% vs. 52.3%, p = 0.001) and initial complete response ([CR], 71.4% vs. 70.4% vs. 53.3% vs. 27.3%, p < 0.001) rates. The same trend was observed in the 6-month sustained response (63.6% vs. 52.3% vs. 35.6% vs. 22.7%, p = 0.03) and sustained CR (36.4% vs. 44.6% vs. 24.4% vs. 9.1%, p = 0.01). The Kaplan–Meier analysis revealed a shortened duration of remission in the obese group (median duration of remission, not reached vs. 16 months vs. 2 months vs. 1 month, p = 0.002). In multivariate regression analysis, obesity was independently associated with poor initial and sustained responses, and an increased risk for relapse. In conclusion, obesity is a negative predictor for outcomes of corticosteroid treatment. A stratified strategy according to body mass index status may facilitate the precision management of ITP.     

A large observational study of patients with primary immune thrombocytopenia receiving romiplostim in European clinical practice

Myelodysplastic Syndromes are oligo‐clonal stem cell disorders that are associated with cytopenias in the peripheral blood. Major causes for morbidity and mortality in myelodysplastic syndromes (MDS) patients are infections mostly due to bacteria or fungi. Beside leucopenia per se in affected patients, function of white blood cells particularly that of neutrophils seems to be impaired. Here we summarize the available data on infections in MDS patients in general and particularly those treated with 5‐azacitidine.     

Prediction of bleeding and prophylactic platelet transfusions in cancer patients with thrombocytopenia

Studies on markers for bleeding risk among thrombocytopenic cancer patients are lacking. This prospective observational cohort study investigated whether platelet parameters and a standardised bleeding questionnaire predicted bleeding or prophylactic platelet transfusions in patients with cancer and thrombocytopenia. Admitted adult patients with cancer and platelet count <80 × 10⁹/L were enrolled, but excluded if they experienced surgery or trauma within 7 days or platelet transfusion within 14 days. Patients were interviewed, blood samples collected and, subsequently, spontaneous bleeding and prophylactic platelet transfusion within 30 days were registered.

Of 197 patients enrolled, 56 (28%) experienced bleeding. In multivariate analyses, predictors of bleeding were infection (adjusted odds ratio (OR) = 2.65 and 95% confidence interval (95% CI) 1.04–6.74); treatment with platelet inhibitors, heparin or warfarin OR = 2.34, 95% CI 1.23–4.48; urea nitrogen OR = 1.15, 95% CI 1.07–1.25; creatinine OR = 1.01, 95% CI 1.01–1.01; and haemoglobin OR = 0.62, 95% CI 0.41–0.93. Specific information regarding previous gastrointestinal bleeding OR = 3.33, 95% CI 1.19–9.34 and haematuria OR = 3.00, 95% CI 1.20–7.52 predicted bleeding whereas the standardised bleeding questionnaire did not.

Prophylactic platelet transfusions were administered to 97 patients. Predictors of prophylactic platelet transfusions were: platelet count OR = 0.96, 95% CI 0.94–0.97; fibrinogen OR = 0.88, 95% CI 0.83–0.95; mean platelet volume OR = 0.69, 95% CI 0.49–0.97; platelet aggregometry with OR = 2.48, 95% CI 1.09–5.64 for collagen-induced platelet aggregation within the lowest quartile; and albumin OR = 1.07, 95% CI 1.01–1.15.

In conclusion, except for immature platelet fraction (IPF), platelet parameters predicted prophylactic platelet transfusion but not bleeding. Bleeding risk factors were previous haematuria or gastrointestinal bleeding, infection, antiplatelet or anticoagulant treatment, high urea nitrogen, low haemoglobin or high creatinine.     

Fatigue in adult patients with primary immune thrombocytopenia

Background: Patients with primary immune thrombocytopenia (ITP) commonly describe symptoms of fatigue. However, hematologists rarely consider fatigue a manifestation of ITP. Objectives: To document the prevalence of fatigue among patients with ITP and to determine the patient characteristics that are associated with fatigue. Methods: Using a cross‐sectional design, we surveyed 1871 members of the UK ITP Support Association [585 (31%) responded], and 93 patients enrolled in the Oklahoma (US) ITP Registry [68 (73%) responded] with questions about their ITP and with validated symptom assessment scales for fatigue, daytime sleepiness, and orthostatic symptoms. Results: The prevalence of fatigue among both UK (39%) and US (22%) patients was significantly greater than expected compared with normal subjects (P < 0.0001 and P < 0.0001 respectively). In univariate analysis of the combined cohorts, fatigue was associated with a platelet count <100 000/μL, treatment with steroids, bleeding symptoms, presence of other medical conditions, daytime sleepiness, and orthostatic symptoms. Fatigue was not associated with age, gender, duration of ITP, or splenectomy status. Multivariate analysis of the combined cohorts was stratified for the presence or absence of bleeding symptoms. Among 107 patients with bleeding symptoms, fatigue was independently associated with a platelet count <100 000/μL and female gender. Among 491 patients without bleeding symptoms, fatigue was independently associated with a platelet count <30 000/μL, presence of other medical conditions, daytime sleepiness, and orthostatic symptoms. Conclusions: Fatigue is a common symptom among patients with ITP. These data provide the basis for future studies to define the clinical importance of fatigue in ITP.     

Beyond the platelet count: immature platelet fraction and thromboelastometry correlate with bleeding in patients with immune thrombocytopenia

Platelet counts (PC) estimate bleeding risk in Immune Thrombocytopenia (ITP). We investigated whether measures of thromboelastometry and absolute immature platelet fraction (A‐IPF) would correlate better with acute bleeding score (ABS) than PC or mean platelet volume (MPV). Simultaneous determination of ABS, complete blood count and thromboelastometry was performed in 141 ITP patients; 112 underwent A‐IPF testing. Subgroup analyses were performed for paediatric subjects, PC <60 × 10⁹/l and <30 × 10⁹/l. PC significantly inversely correlated with ABS in all subjects, PC <30 × 10⁹/l and total paediatric cohort. MPV did not correlate with ABS in any subgroup. Thromboelastometry measures of clot firmness, but not PC, significantly correlated with ABS in all subjects with PC <60 × 10⁹/l, and children with PC <60 × 10⁹/l and <30 × 10⁹/l. A‐IPF demonstrated stronger correlation with ABS than did PC among all subjects, those with PC <60 × 10⁹/l, all children and children with PC <30 × 10⁹/l (r = ?0·37; r = ?0·34; r = ?0·44; r = ?0·60) versus ABS with PC (r = ?0·36; ns; r = ?0·32; ns). Stronger correlations of both thromboelastometry measures of clot firmness and A‐IPF than PC with ABS suggest factors beyond PC, i.e. related to platelet function, contribute to ITP bleeding pathophysiology. Thromboelastometry, A‐IPF and ABS can be incorporated into routine or acute visits.     

Effect of thrombopoietin-receptor agonists on circulating cytokine and chemokine levels in patients with primary immune thrombocytopenia (ITP)

Background: Thrombopoietin-receptor-agonists (TPO-RAs) increase platelet production in Immune Thrombocytopenia (ITP) by stimulating Mpl. The effect of TPO-RAs on inflammatory cytokine production in ITP patients has not been well investigated. Methods: Plasma samples from 48 ITP patients treated with TPO-RAs (median age 50 years (inter-quartile range; IQR 20–69), median platelet counts 24 × 10⁹/L (IQR 15–47 × 10⁹/L), 28 females) and 16 healthy controls (nine females, median age 37 years, IQR 22–51 years) were collected before and during treatment, and analyzed for a panel of cytokines and chemokines by enzyme-linked immunosorbent assay and immuno-bead-based multiplex assay. Results: Elevated levels of C-X-C motif chemokine 10 (CXCL10; p < 0.001) and osteoprotegerin (OPG; p < 0.05) were observed in pretreatment samples compared to controls; these levels decreased during 6 months of treatment. Pretreatment levels of transforming growth factor (TGF)-β were lower than in healthy controls and increased after 6 months of treatment (p < 0.05). Levels of sCD40L increased after 6 months of treatment (p < 0.05), but decreased thereafter to pretreatment values. The increase in TGF-β and sCD40L may reflect increased platelet turnover. Levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-10 did not change during treatment. Conclusion: These findings suggest that treatment with TPO-RA creates a more balanced steady-state of immune activation.     

Markers of refractory primary immune thrombocytopenia

Refractory immune thrombocytopenia (ITP) is a challenging disease that can be defined by refractoriness to second-line treatments. In this review, we list and comment available evidence about clinical and biological factors associated with refractoriness to splenectomy, thrombopoietin receptor agonists (TPO-RAs), rituximab and fostamatinib, as well as those associated with multirefractory ITP (active disease with failure of rituximab, TPO-RAs and splenectomy).     

Efficacy of combined intravenous immunoglobulins and steroids in children with primary immune thrombocytopenia and persistent bleeding symptoms

Background

The aim of this study was to investigate the effect of the combined administration of intravenous immunoglobulins and steroids as a second-line therapy in 34 children with primary immune thrombocytopenia and persistent, symptomatic bleeding.

Materials and methods

Combined therapy (intravenous immunoglobulins 0.4 g/kg daily on days 1 and 2, and methylprednisolone 20 mg/kg daily on days 1–3) was administered to 12 patients with newly diagnosed ITP who did not respond to the administration of a single therapy (either intravenous immunoglobulins or steroids) and to 22 children with persistent and chronic disease who required frequent administrations (i.e. more frequently than every 30 days) of either immunoglobulins or steroids (at the same standard dosages) in order to control active bleeding.

Results

A response (i.e. platelet count >50×10⁹/L and remission of active bleeding) was observed in 8/12 (67%) patients with newly diagnosed ITP. The clinical presentation of responders and non-responders did not differ apparently. Patients in the chronic/persistent phase of disease had a significantly longer median period of remission from symptoms compared with the previous longest period of remission (p=0.016). The treatment was well tolerated.

Discussion

Our data suggest that the combined approach described is a well-tolerated therapeutic option for children with primary immune thrombocytopenia and persistent bleeding symptoms that can be used in both emergency and/or maintenance settings.     

Intrinsically impaired platelet production in some patients with persistent or chronic immune thrombocytopenia

Persistent or chronic immune thrombocytopenias (P/C‐ITP) are acquired blood disorders lasting more than 3 months or 1 year, respectively. The pathogenesis of these disorders is thought to be immunological. We hypothesized that some patients with P/C‐ITP might have an intrinsic megakaryopoiesis defect. We identified a group of P/C‐ITP patients with acquired isolated mild thrombocytopenia (30–100 × 10⁹/l), undetectable anti‐platelet antibodies, negative autoimmune investigations and no need for treatment. We examined in vitro megakaryocyte differentiation and compared these patients' results with those of acute‐ITP patients and healthy controls. No difference in proliferation, ploidy or expression of surface markers was found. In contrast, P/C‐ITP patients had significantly fewer proplatelet‐forming megakaryocytes. This novel observation demonstrated that some patients diagnosed with P/C‐ITP have an intrinsic megakaryopoiesis defect independent of the bone‐marrow environment. Further investigations are needed to dissect mechanisms underlying this impaired proplatelet formation in these patients.     

Combination of recombinant factor VIIa and fibrinogen corrects clot formation in primary immune thrombocytopenia at very low platelet counts

Haemostatic treatment modalities alternative to platelet transfusion are desirable to control serious acute bleeds in primary immune thrombocytopenia (ITP). This study challenged the hypothesis that recombinant activated factor VII (rFVIIa) combined with fibrinogen concentrate may correct whole blood (WB) clot formation in ITP. Blood from ITP patients (n = 12) was drawn into tubes containing 3·2% citrate and corn trypsin inhibitor 18·3 μg/ml. WB [mean platelet count 22 × 10⁹/l (range 0–42)] was spiked in vitro with buffer, donor platelets (+40 × 10⁹/l), rFVIIa (1 or 4 μg/ml), fibrinogen (1 or 3 mg/ml), or combinations of rFVIIa and fibrinogen. Coagulation profiles were recorded by tissue factor (0·03 pmol/l) activated thromboelastometry. Coagulation in ITP was characterized by a prolonged clotting time (CT, 1490 s (mean)) and a low maximum velocity (MaxVel, 3·4 mm × 100/s) and maximum clot firmness (MCF , 38·2 mm). Fibrinogen showed no haemostatic effect, whereas rFVIIa reduced the CT and increased the MaxVel. The combination of fibrinogen and rFVIIa revealed a significant synergistic effect, improving all parameters (CT 794 s, MaxVel 7·9 mm × 100/s, MCF 50·7 mm) even at very low platelet counts. These data suggest that rFVIIa combined with fibrinogen corrects the coagulopathy of ITP even at very low platelet counts, and may represent an alternative to platelet transfusion.     

Stromal‐derived factor‐1 gene variations in pediatric patients with primary immune thrombocytopenia

Primary immune thrombocytopenia (ITP) of childhood is an autoimmune disease characterized by abnormally increased destruction of platelets and decreased megakaryopoiesis. Stromal‐derived factor‐1 (SDF‐1) plays a role in megakaryopoiesis and may be involved in the pathogenesis of ITP. Five single nucleotide polymorphisms (SNPs) of the SDF‐1 gene, including rs1801157, rs2839693, rs2297630, rs1065297, and rs266085, were assessed in 100 children with ITP and 126 healthy controls. The genotypes were analyzed by tetra ARMS polymerase chain reaction and confirmed by direct sequencing. Compared with controls, the rs2839693 A/A and rs266085 C/T genotypes were decreased in ITP patients (P = 0.004 and 0.007, respectively). The odds ratios of the latter genotypes were 0.48, 95% CI 0.28–0.82. Further analysis of the relationship between SDF‐1 polymorphisms and clinical features showed that rs2297630 A/G was associated with protection from chronicity (P = 0.002; OR, 0.07; 95% CI, 0.01–0.61) and steroid dependence (P = 0.007; OR, 0.10; 95% CI, 0.01–0.84) in ITP patients. However, rs266085 genotype C/C was associated with risk of steroid dependence (P = 0.012, OR 3.87, 95% CI 1.27–11.77). The findings of this study suggest that SDF‐1 gene variations may be associated with the occurrence and prognosis of childhood ITP.     

A diagnostic approach that may help to discriminate inherited thrombocytopenia from chronic immune thrombocytopenia in adult patients

Inherited thrombocytopenia (IT) is a heterogeneous group of rare diseases that are often confused with immune thrombocytopenia (ITP). The objective of this study was to supply clinicobiological elements that allow a distinction to be drawn between IT and chronic ITP. We then compared 23 adult patients with IT and 9 patients with chronic ITP. Our study revealed six discriminating criteria: (i) an age of discovery <34 years: positive predictive value (PPV) = 88.2% [63.6; 98.5], (ii) a family history of thrombocytopenia: PPV = 100.0% [82.4; 100.0], (iii) a personal history of bleeding: PPV = 100% [76.8; 100.0], (iv) a mean platelet volume >11 fL: PPV = 93.3% [68.1; 99.8], (v) an excess of giant platelets on blood smear: 100.0% [76.8; 100.0], and (vi) a percentage >44% of platelets with a surface area >4 µm² in electron microscopy: PPV = 83.3% [58.6; 96.4]. If at least three of these criteria were combined, it was possible to distinguish IT from chronic ITP with 91.3% [72.0; 98.9] sensitivity and PPV = 100.0% [66.4; 100.0] specificity. The secondary objective of this study was to assess the prevalence of potential IT diagnosis in patients with chronic thrombocytopenia of uncertain origin. Applying our diagnostic approach to a series of 20 cases allowed us to estimate that 40% of them could be suffering from IT. Finally, our diagnostic approach may help to correctly distinguish IT from chronic ITP, particularly in the context of macrothrombocytopenia.     

Thromboembolic events among adult patients with primary immune thrombocytopenia in the United Kingdom General Practice Research Database

Background

The risk of thromboembolic events in adults with primary immune thrombocytopenia has been little investigated despite findings of increased susceptibility in other thrombocytopenic autoimmune conditions. The objective of this study was to evaluate the risk of thromboembolic events among adult patients with and without primary immune thrombocytopenia in the UK General Practice Research Database.

Design and Methods

Using the General Practice Research Database, 1,070 adults (≥18 years) with coded records for primary immune thrombocytopenia first referenced between January 1^st 1992 and November 30^th 2007, and having at least one year pre-diagnosis and three months post-diagnosis medical history were matched (1:4 ratio) with 4,280 primary immune thrombocytopenia disease free patients by age, gender, primary care practice, and pre-diagnosis observation time. The baseline prevalence and incidence rate of thromboembolic events were quantified, with comparative risk modelled by Cox’s proportional hazards regression.

Results

Over a median 47.6 months of follow-up (range: 3.0–192.5 months), adjusted hazard ratios of 1.58 (95% CI, 1.01–2.48), 1.37 (95% CI, 0.94–2.00), and 1.41 (95% CI, 1.04–1.91) were found for venous, arterial, and combined (arterial and venous) thromboembolic events, respectively, when comparing the primary immune thrombocytopenia cohort with the primary immune thrombocytopenia disease free cohort. Further event categorization revealed an elevated incidence rate for each occurring venous thromboembolic subtype among the adult patients with primary immune thrombocytopenia.

Conclusions

Patients with primary immune thrombocytopenia are at increased risk for venous thromboembolic events compared with patients without primary immune thrombocytopenia.     

Elevated levels of T-cell immune response cDNA 7 in patients with immune thrombocytopenia

Objectives

This study aimed to investigate the expression levels of T-cell immune response cDNA 7 (TIRC7) in immune thrombocytopenia (ITP) patients before and after high-dose dexamethasone (HD-DXM) treatment.

Methods

Forty-four patients with ITP were enrolled and received dexamethasone (40 mg/day) for 4 consecutive days. Patients who had platelet counts more than 50 × 10⁹/l or less were defined as responders or non-responders, respectively. Quantitative polymerase chain reaction and enzyme-linked immunosorbent assay were used to measure RNA level and plasma level of TIRC7, respectively.

Results

TIRC7 levels (RNA and plasma level) were significantly higher in ITP than that in control (P < 0.0001). However, after treatment, TIRC7 levels were significantly decreased in responders (P < 0.0001) but not in non-responders (P > 0.05).

Discussions

TIRC7 might be associated with the pathogenesis of ITP, and TIRC7 levels could be used as an indicator to evaluate patients’ response to HD-DXM treatment.     

Stromal cell-derived factor-1 rs2297630 polymorphism associated with platelet production and treatment response in Chinese patients with chronic immune thrombocytopenia

Stromal cell-derived factor-1 (SDF-1), signaling through CXCR4, is implicated in megakaryopoiesis and platelet production. SDF-1 rs2297630 is a functional polymorphism in linkage disequilibrium with other functional variants in SDF-1. This study aimed to investigate the role of SDF-1 rs2297630 in chronic ITP. The genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism and confirmed by direct sequencing. Immature platelet fraction (IPF) was performed using Sysmex XE-2100. Anti-platelet autoantibodies were assayed by enzyme-linked immunosorbent assay. The main characteristics at diagnosis and the outcome of chronic ITP in 201 Chinese patients were retrospectively reviewed. There was no significant difference in either genotype or allelic distribution between ITP patients and the controls (p = 0.114; p = 0.787). However, both heterozygote (GA) and homozygote minor allele (AA) patients had significantly increased megakaryocyte quantity compared to homozygote genotype (GG) patients at diagnosis (p = 0.011). The mean IPF values of GA and AA genotype patients were higher than those observed in the GG genotype patients when platelet counts ≤50 × 10⁹/L at diagnosis (p = 0.007). Patients with GA and AA genotype showed a higher response rate to standard treatments than patients with GG genotype (p < 0.001). In particular, GA and AA genotype patients had a significantly increased chance of responding to steroids, intravenous immunoglobulin (IVIG), and thrombopoietin analogs (p = 0.007; p = 0.029; p = 0.034, respectively). No significant difference was found between anti-platelet antibodies and genotypes (p = 0.296). In summary, the SDF-1 rs2297630 was associated with platelet production and treatment response in Chinese patients with chronic ITP.     

Low‐dose rituximab in adult patients with primary immune thrombocytopenia

Backgrounds: Rituximab 375 mg/m² weekly for 4 wks has significant activity in adults with primary immune thrombocytopenia (ITP). In this setting, several evidences support the possible use of lower doses of rituximab. Objectives: To investigate the activity of low‐dose rituximab as salvage therapy in previously treated symptomatic ITP. Methods: Forty‐eight adult patients were treated prospectively with rituximab 100 mg weekly for 4 wks. Results: Overall and complete responses (CR) (platelet level ≥ 50 and 100 × 10⁹/L) were 60.5% and 39.5%, respectively. In responders, the median time to response was 35 d (range: 7–112 d). The median time of observation was 18 months (range 3–49 months). Sixteen of 29 responding patients (55%) relapsed and 14 needed further treatments. The 12‐ and 24‐month cumulative relapse‐free survival was 61% and 45%, respectively. In univariate analysis, CR rate was in inverse relation with weight OR = 0.95, CI_95% [0.91; 0.99] (P = 0.019) and age OR=0.96, CI_95% [0.93; 0.99] (P = 0.047). Cox regression model showed that relapse probability increases as weight (HR = 1.06, CI_95% [1.0031; 1.111]) and period between diagnosis and rituximab therapy (HR = 1.01, CI_95% [1.002; 1.017]) increase. One patient developed an interstitial pneumonia 1 month after the end of rituximab treatment. No other infectious, hematologic or extra‐hematologic complications were documented during follow‐up. Conclusions: Low‐dose rituximab is active in ITP but has moderate long‐term effect. A comparative study with standard dose is warranted.