Risk factors of hospitalisation for thrombosis in adults with primary immune thrombocytopenia, including disease-specific treatments: a French nationwide cohort study.

We aimed to assess the risk factors of venous thrombosis (VT) and arterial thrombosis (AT) in adults with primary immune thrombocytopenia (ITP), particularly in relation to treatments. The population comprised all incident primary ITP adults in France between 2009 and 2017 (FAITH cohort; NCT03429660) built in the national health database. Outcomes were the first hospitalisation for VT and AT. Multivariable Cox regression models included baseline risk factors, time-varying exposure to ITP drugs, splenectomy and to cardiovascular drugs. The cohort included 10 039 patients. A higher risk of hospitalisation for VT was observed with older age, history of VT, history of cancer, splenectomy [hazard ratio (HR) 3·23, 95% confidence interval (CI) 2·26-4·61], exposure to corticosteroids (HR 3·55, 95% CI 2·74-4·58), thrombopoietin-receptor agonists (TPO-RAs; HR 2·28, 95% CI 1·59-3·26) and intravenous immunoglobulin (IVIg; HR 2·10, 95% CI 1·43-3·06). A higher risk of hospitalisation for AT was observed with older age, male sex, a history of cardiovascular disease, splenectomy (HR 1·50, 95% CI 1·12-2·03), exposure to IVIg (HR 1·85, 95% CI 1·36-2·52) and TPO-RAs (HR 1·64, 95% CI 1·26-2·13). Rituximab was not associated with an increased risk. These findings help to estimate the risk of thrombosis in adult patients with ITP and to select treatment.

Cancer risk in patients with primary immune thrombocytopenia - A Swedish nationwide register study.

BACKGROUND: Immune thrombocytopenia (ITP) is an autoimmune disease treated with immunosuppressive agents, thrombopoietin receptor agonists, immunomodulation drugs and/or splenectomy. Patients with ITP have been found to have increased risk ofhematological malignancies. Studies investigating stomach/liver cancer are contradictory and the risk of developing other solid tumors is largely unknown. We aimed at estimating risk of overall and organ-specific cancers in patients with primary ITP. METHODS: The study population was Swedish patients with at least one ITP diagnosis recorded in the National Patient Register and a 1:10 matched comparison cohort from the population. The study period covers 1997-2016. The Cancer Register and the Cause of Death Register provided data on malignancies and deaths, respectively. Primary ITP was identified using an established algorithm. We used time-split Cox models to estimate hazard ratios (HRs) with 95 % confidence intervals (CIs), adjusted for age, sex, index-year, county, income, education, Charlson score and number of in- and outpatient contacts. RESULTS: In total 66,134 individuals were included in the study. Patients with ITP had higher risk of gastro-intestinal, skin (all morphologies), lymphoid and hematological cancers. Adjusted HR (95 % CI) for cancer was 1.37 (1.27-1.48), with highest risk during the first year, but with increased risk remaining for up to 20 years for men. For women, the overall risk was increased during the first year, HR (95 % CI) 2.00 (1.55-2.60). A significantly increased liver cancer risk was seen up to 9 years after diagnosis. CONCLUSION: Patients with primary ITP have higher risk of cancer than the population. The observed increased risk does not seem to be solely due to surveillance bias, but might be associated with ITP or its treatments. Treating hematologists need to have high index of suspicion for cancer.

Patient characteristics when starting treatment and patterns of treatment in adults with chronic immune thrombocytopenia.

: Asymptomatic patients with primary chronic immune thrombocytopenia (ITP) are not recommended treatment if their platelet counts are above 30 × 10/l. Factors such as age and comorbidities may influence clinical manifestations and should be considered for treatment decisions. The aim of this study was to determine the impact of clinical characteristics for initiation of ITP treatment, and the patterns of ITP treatment given. We performed an observational cohort study in Sweden with information from medical records and National Health Registers. Adults diagnosed with incident primary ITP between years 2009 and 2016 were included. Multinomial logistic regression was used to assess the impact of factors predicting treatment start. Out of 858 patients with chronic ITP from 71 hospitals we identified 585 (68%) with a first ITP treatment. For 537 (92%) corticosteroids were the first choice. The median platelet counts at start of treatment was 12 × 10/l (interquartile range 5-27 × 10/l). The variables predicting treatment start were platelet counts below 20 × 10/l and treatment with antihypertensive drugs. Patients with diabetes were less likely to receive corticosteroids. Severe bleeding occurred in 75 (13%) of the patients. Platelet counts below 20 × 10/l, antihypertensive treatment and bleedings were the strongest predictors of treatment start, diabetes yielded lower odds to start corticosteroid treatment. The majority of the patients had corticosteroids as first treatment while second treatment was diverse. Asymptomatic thrombocytopenia is not considered a reason as such for initiating treatment. In the latter years, splenectomy seemed to occur later in the course of treatment.

Impact of risk factors on the occurrence of arterial thrombosis and venous thromboembolism in adults with primary immune thrombocytopenia - Results from two nationwide cohorts.

BACKGROUND: Previous studies have found that patients with Immune thrombocytopenia (ITP) have an increased risk of arterial thrombosis (AT) and venous thromboembolism (VTE). However, risk factors for thrombosis in adults with primary ITP remain unassessed in large cohorts. Aim To assess the occurrence and impact of risk factors for AT and VTE in patients with primary ITP in France and Sweden. METHODS: Both countries have national health databases, including hospital diagnoses and drug dispensing data. Adults with incident primary ITP identified using algorithms between the years 2009-2015 in France, and 2009-2016 in Sweden were included. Cumulative incidence rates (IR) of AT and VTE were calculated by risk factors and multivariable Cox models were used to estimate associations. RESULTS: The study included 7225 patients from France and 2490 from Sweden. The IR of AT were 15.0 (95% CI: 13.4-16.7) and 14.7 (95% CI: 12.4-17.5) per 1000 person-years, respectively. The incidences of VTE were 6.9 (95% CI: 5.9-8.1) and 6.5 (95% CI: 5.1-8.4), respectively. Increasing age, male sex and a previous AT were associated with AT in both countries and so were exposure to antiplatelet drugs in France and a history of VTE and chronic kidney disease in Sweden. Increasing age and a history of VTE were associated with VTE in both countries, in France also cancer. CONCLUSION: The IR of AT and VTE were similar in France. Age and male sex remained the most important risk factors for AT, age for VTE.

Chronic immune thrombocytopenia in Denmark, Sweden and Norway: The Nordic Country Patient Registry for Romiplostim.

BACKGROUND: Population-based cohorts of immune thrombocytopenia (ITP) are useful for understanding occurrence, clinical characteristics and long-term clinical course. This paper describes the content of the Nordic Country Patient Registry for Romiplostim (NCPRR) and provides prevalence and incidence estimates of chronic ITP (cITP). METHODS: The NCPRR, a cohort study established in 2009, includes all adult (≥ 18 years) patients in Denmark, Sweden and Norway with cITP (defined as ITP lasting > 12 months and platelet count < 100 × 109/L), combining data from national health registries and medical records. The NCPRR currently includes prevalent cITP patients diagnosed before 2009 and incident cITP patients diagnosed during 2009-2016. The registry obtains clinical information for cITP patients, including comorbidities, treatments, laboratory values, and complete follow-up for various outcomes. FINDINGS: The NCPRR currently includes 3831 patients with cITP (1258 prevalent; 2573 incident). In 2009, the prevalence of registered cITP was 10 · 0/100,000 (95%CI:9 · 1-11 · 0) adult persons in Denmark and 10 · 7/100,000 (95% CI: 9 · 9-11 · 4) adults in Sweden. During 2009-2016, the incidence rates of cITP per 100,000 person-years were 2 · 8 (95%CI: 2 · 6-3 · 0), 1 · 8 (95%CI: 1 · 7-1 · 9) and 2 · 1 (95%CI: 1 · 9-2 · 2) in Denmark, Sweden and Norway, respectively. Fifty-eight percent of cITP patients were women. At NCPRR inclusion, 30.2% were aged ≥ 70 years, 23% had a platelet count < 50 × 109/L, 17.4% were splenectomized, 41% had prior ITP therapy, and 8.6% had severe comorbidity. INTERPRETATION: The NCPRR provides population-based data on the epidemiology and characteristics of almost 4000 cITP patients and is a valuable resource for research. FUNDING: This study was partly funded by a research grant from Amgen to Aarhus University.

Cardiovascular and bleeding outcomes in a population-based cohort of patients with chronic immune thrombocytopenia.

Essentials Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count. We conducted a cohort study of 3 584 chronic ITP patients from the Nordic countries. Cardiovascular events occurred across all platelet count levels. Cardiovascular or bleeding events were strong prognostic factors for all-cause mortality. Background Among patients with chronic immune thrombocytopenia (cITP), little is known regarding risk factors for cardiovascular and bleeding outcomes and how these events influence mortality. Objectives We examined the rate of cardiovascular events and bleeding requiring a hospital contact according to platelet count levels, as well as the prognostic impact of these events on all-cause mortality in adult patients with cITP. Methods We identified all cITP patients registered in the Nordic Country Patient Registry for Romiplostim during 1996 to 2015. Absolute risks and hazard ratios across platelet count levels based on Cox regression analysis were computed, adjusting for age, sex, prevalent/incident cITP, smoking, and comorbidities. We also compared all-cause mortality rates in cITP patients with and without cardiovascular and bleeding events. Results Among 3 584 cITP patients, 1-year risks were 1.9% for arterial cardiovascular events, 1.2% for venous thromboembolism, and 7.5% for bleeding. Rates of cardiovascular events were similar across platelet counts. Patients with platelet counts <50 × 109 /L had >2-fold higher rates of bleeding than patients with normal platelet counts. These associations were unchanged in time-varying analyses that considered changes in platelet counts during follow-up. Occurrences of cardiovascular and bleeding events were associated with 4-fold to 5-fold increases in 1-year mortality. Conclusions Among patients with cITP, the 1-year risks of cardiovascular events were 1% to 2%, while nearly 8% experienced a bleeding event within 1 year. Cardiovascular events occurred across all platelet levels, while low platelet counts were associated with increased hazards of bleeding. Cardiovascular and bleeding events were strong prognostic factors for mortality.

Pharmacological agents preceding a diagnosis of immune thrombocytopenia in adult patients developing the chronic form: A Swedish national register study.

Patients with primary chronic immune thrombocytopenia (cITP) have been reported to use more anti-infective medications, even before diagnosis of immune thrombocytopenia (ITP). The more common use of anti-infective medications may be due to general health problems, requiring medication in the early stages of cITP and before the diagnosis is set, rather than infections preceding the disease. Accordingly, cITP may not only be associated with use of anti-infective medications but also with medications for more general symptoms. OBJECTIVE: To investigate use of medications for general symptoms, such as analgesics and vitamin supplements in patients with ITP developing the chronic form, the year preceding their first primary diagnosis in comparison with such use in the general population. METHOD: Swedish Health Registers were used to identify adult patients (n=1087) with primary cITP during 2006-2012 and data on medications. Standardized Incidence Ratios (SIRs) and 95% confidence intervals (CI), were estimated as a measure of relative risk. RESULTS: The association for overall studied medications was SIR=1.36 (95% CI 1.32-1.41). A majority of the point estimates were above unity. CONCLUSION: In patients with cITP, prescription fills for medications used to treat pain conditions and vitamin deficiencies are more common in the year preceding their first diagnosis as compared with prescription fills in the general population. Our results suggest that patients later diagnosed with cITP receive treatment due to symptoms that could be signs of an early ITP. Accordingly, in investigations for unspecific pain symptoms and vitamin deficiencies, cITP should be considered as a differential diagnosis.

Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms.

PURPOSE: Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to develop acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Using population-based data from Sweden, we assessed the role of MPN treatment and subsequent AML/MDS risk with special focus on the leukemogenic potential of hydroxyurea (HU). METHODS: On the basis of a nationwide MPN cohort (N = 11,039), we conducted a nested case-control study, including 162 patients (153 and nine with subsequent AML and MDS diagnosis, respectively) and 242 matched controls. We obtained clinical and MPN treatment data for all patients. Using logistic regression, we calculated odds ratios (ORs) as measures of AML/MDS risk. RESULTS: Forty-one (25%) of 162 patients with MPNs with AML/MDS development were never exposed to alkylating agents, radioactive phosphorous (P(32)), or HU. Compared with patients with who were not exposed to HU, the ORs for 1 to 499 g, 500 to 999 g, more than 1,000 g of HU were 1.5 (95% CI, 0.6 to 2.4), 1.4 (95% CI, 0.6 to 3.4), and 1.3 (95% CI, 0.5 to 3.3), respectively, for AML/MDS development (not significant). Patients with MPNs who received P(32) greater than 1,000 MBq and alkylators greater than 1 g had a 4.6-fold (95% CI, 2.1 to 9.8; P = .002) and 3.4-fold (95% CI, 1.1 to 10.6; P = .015) increased risk of AML/MDS, respectively. Patients receiving two or more cytoreductive treatments had a 2.9-fold (95% CI, 1.4 to 5.9) increased risk of transformation. CONCLUSION: The risk of AML/MDS development after MPN diagnosis was significantly associated with high exposures of P(32) and alkylators but not with HU treatment. Twenty-five percent of patients with MPNs who developed AML/MDS were not exposed to cytotoxic therapy, supporting a major role for nontreatment-related factors.

Multiplex and quantifiable detection of nucleic acid from pathogenic fungi using padlock probes, generic real time PCR and specific suspension array readout.

A new concept for multiplex detection and quantification of microbes is here demonstrated on a range of infectious fungal species. Padlock probe methodology in conjunction with qPCR and Luminex technology was used for simultaneous detection of ten fungal species in one single experiment. By combining the multiplexing properties of padlock probes and Luminex detection with the well established quantitative characteristics of qPCR, quantitative microbe detection was done in 10-plex mode. A padlock probe is an oligonucleotide that via a ligation reaction forms circular DNA when hybridizing to specific target DNA. The region of the padlock probe that does not participate in target DNA hybridization contains generic primer sequences for amplification and a tag sequence for Luminex detection. This was the fundament for well performing multiplexing. Circularized padlock probes were initially amplified by rolling circle amplification (RCA), followed by a SybrGreen real time PCR which allowed an additive quantitative assessment of target DNA in the sample. Detection and quantification of amplified padlock probes were then done on color coded Luminex microspheres carrying anti-tag sequences. A novel technique, using labeled oligonucleotides to prevent reannealing of amplimers by covering the flanks of the address sequence, improved the signal to noise ratio in the detection step considerably. The method correctly detected fungi in a variety of clinical samples and offered quantitative information on fungal nucleic acid.