Diagnosis Of Thrombocytopenia Research Articles

Novel THPO variant in hereditary thrombocytopenia: A potential candidate variant for predisposition to myeloid neoplasm.

Hereditary thrombocytopenia is a heterogeneous group of congenital disorders with a wide range of symptoms depending on the severity of platelet dysfunction or thrombocytopenia. Because of its clinical phenotypes and the bone marrow morphology associated with this condition, hereditary thrombocytopenia can be misdiagnosed as primary immune thrombocytopenia and myelodysplastic syndrome. Therefore, genetic evidence is necessary for the accurate diagnosis of hereditary thrombocytopenia. Refractory cytopenia of childhood is a subgroup of myelodysplastic syndrome that was added to the World Health Organization classification in 2008. To investigate the germline and somatic variants associated with refractory cytopenia of childhood, we performed targeted multigene sequencing in three patients with refractory cytopenia of childhood. Of the three patients, one progressed from megakaryocytic hypoplasia with thrombocytopenia, and targeted multigene sequencing revealed THPO variants in this patient and his sister. We propose that the monoallelic deletion of THPO is a potential candidate for germline predisposition to myeloid malignancy.

Thrombotic Thrombocytopenic Purpura in a Parturient Leading to Life-Threatening Thrombocytopenia and Neonatal Demise—A Case Report

Abstract Thrombocytopenia is common (up to 12%) in pregnancy; thrombotic thrombocytopenia is a rare cause of thrombocytopenia; however, it is immediately life-threatening to both mother and fetus and requires immediate intervention. This is compounded by the need to act on a presumptive diagnosis with high level of suspicion given the relatively long laboratory confirmation time. A 31-year-old gravida 3, para 1 parturient at 26 weeks of gestation presented to outside hospital with recent onset of easy bruising and blurry vision. A blood count was drawn and showed a platelet count of 19,000/μL. She was transferred to our institution for management where an initial diagnosis of preeclampsia with severe features was made based on thrombocytopenia and fetal growth restriction (<1%). Platelet count nadired at 14,000/μL and a blood smear showed schistocytes, suggesting microangiopathic hemolysis, prompting discussion of urgent cesarean delivery and anesthesia consult. An urgent hematology consult led to presumptively diagnosing thrombotic thrombocytopenic purpura and cesarean delivery was deferred after discussion with the patient and team. Plasma exchange and steroid therapy were started promptly, and her platelet count improved within 12 hours. Unfortunately, the patient experienced neonatal demise. Undetectable ADAMTS13 levels confirmed diagnosis of thrombotic thrombocytopenia. She was transitioned to rituximab, platelets recovered to baseline, and she continues to do well. Thrombotic thrombocytopenia is a rare, life-threatening cause of thrombocytopenia in pregnancy. Despite grim fetal prognosis, especially in early pregnancy, low threshold of suspicion, early anesthesia involvement, and multidisciplinary approach can facilitate diagnosis and timely intervention. In our case, it was likely lifesaving.

Development and internal validation of a clinical prediction model for the diagnosis of immune thrombocytopenia

BackgroundImmune thrombocytopenia (ITP) is a diagnosis of exclusion that can resemble other thrombocytopenic disorders. ObjectivesTo develop a clinical prediction model (CPM) for the diagnosis of ITP to aid hematogists in investigating patients presenting with undifferentiated thrombocytopenia. MethodsWe designed a CPM for ITP diagnosis at the time of the initial hematology consultation using penalized logistic regression based on data from patients with thrombocytopenia enrolled in the McMaster ITP registry (n = 523) called the Predict‐ITP Tool. The case definition for ITP was a platelet count less than 100 × 109/L and a platelet count response after high‐dose corticosteroids or intravenous immune globulin, defined as the achievement of a platelet count above 50 × 109/L and at least a doubling of baseline. Internal validation was done using bootstrap resampling. Model discrimination was assessed by the c‐statistic, and calibration was assessed by the calibration slope, calibration‐in‐the‐large, and calibration plot. ResultsThe final model included the following variables: (1) platelet count variability (based on three or more platelet count values), (2) lowest platelet count value, (3) maximum mean platelet volume, and (4) history of major bleeding (defined by the ITP bleeding scale). The optimism‐corrected c‐statistic was 0.83, the calibration slope was 0.88, and calibration‐in‐the‐large for all performance measures was <0.001 with standard error <0.001, indicating good discrimination and excellent calibration. ConclusionsThe Predict‐ITP Tool can estimate the likelihood of ITP for a given patient with thrombocytopenia at the time of the initial hematology consultation. The tool had high predictive accuracy for the diagnosis of ITP.

GESTATIONAL THROMBOCYTOPENIA: CASE REPORT AND APPROACH TO DIAGNOSIS

Thrombocytopenia (TCP) is a frequent observation in term obstetric populations. The majority of newly diagnosed instances of TCP are mild, asymptomatic, and discovered during regular prenatal screening. The diagnosis and treatment of thrombocytopenia during pregnancy and postpartum can be difcult due to the numerous potential reasons, some of which are directly related to the pregnancy and others that are not. There are no diagnostic laboratory tests for many of the causes. Management choices may carry the risk of major consequences for both mother and foetus, necessitating prompt delivery decisions, and there may be worries about foetal thrombocytopenia. Gestational thrombocytopenia (GT), preeclampsia,HELLPsyndrome, and immune-mediated thrombocytopenia are common causes at term (ITP). Preeclampsia/HELLPsyndrome has well-dened symptoms and test ndings, whereas the others are asymptomatic and indistinguishable. A25-year-old woman with new-onset TCPat 40 weeks gestation with 11000/Lplatelets recovered within 12 hours postnatally. After checking out other reasons of severe new-onset TCPat term, therapy should focus on hemostasis before delivery

Clinicopathological Features of Isolated Thrombocytopenia Associated with SRSF2 Mutations: A Case Series

Introduction: Mutations of SRSF2, a gene involved in RNA splicing, are identified across a heterogenous group of myeloid neoplasms including MDS, CMML, and MPN. SRSF2 mutations have been associated with thrombocytopenia in MDS, but not in the case of MDS/MPN overlap conditions. When co-mutated with TET2, SRSF2 is associated with monocytosis and a myeloproliferative phenotype. SRSF2 mutations are also identified in normal individuals and in those with clonal cytopenias of undetermined significance (CCUS). Studies have examined genotype-phenotype correlations in myeloid malignancies, but similar analysis of the heterogeneity amongst patients with CCUS are lacking. Although dysplasia is not a defining feature of CCUS, sub-diagnostic dysplasia can be seen in CCUS and this subset notably had a higher proportion of spliceosome mutations. Here we describe the clinical and pathological features of a series of CCUS patients with prolonged, isolated thrombocytopenia and a SRSF2 mutation. Methods: We conducted a retrospective review of the electronic medical records of patients seen in the outpatient Hematology Clinic at the University of Southern California Norris Comprehensive Center between May 2014 and December 2021. Patients with persistent (> 6 months) isolated thrombocytopenia, a SRSF2 pathogenic mutation identified on a myeloid molecular panel, and absence of WHO-defined dysplasia or hematologic neoplasm on initial bone marrow biopsy were included. A work-up for alternative etiologies of thrombocytopenia was completed based on the clinical judgment of the treating physician. Bone marrow biopsies were reviewed by 2 independent hematopathologists. This study was approved by the Institutional Review Board of the University of Southern California. All patients signed informed consent. Results: Five patients met criteria for inclusion. All patients were male. Median age at diagnosis of thrombocytopenia was 61 years (56-74). Two patients were Asian and 3 were Caucasian. The median time from diagnosis of thrombocytopenia to the identification of a mutation on a myeloid molecular panel was 4 years (3-12). No patients had a family history of hematologic malignancy. Initial bone marrow biopsies did not meet WHO-defined thresholds for morphologic dysplasia. However, all patients had megakaryocytic hyperplasia and megakaryocytes with hyperchromasia and high nuclear-cytoplasmic ratio in 20% of megakaryocytes (Figure 1). Two patients who had CD34 staining showed positive staining in 30% of megakaryocytes. Four patients had normal cytogenetics and 1 patient had monosomy 7. Median bone marrow cellularity was 65% (30-80%). Two patients had intermittent peripheral monocytosis but did not meet the diagnostic criteria for CMML. No monocyte proliferation or immature monocytes were seen on bone marrow. SRSF2 mutations were P95H in 3 patients and P95L in 2 patients. Average variant allele frequency was 37.3% (range 28 - 50.2). Four patients had a co-occurring TET2 mutation; other co-mutated genes included RUNX1 (3 pts.), ASXL1 (1 pt.), DNMT3A (1 pt.), and NF1 (1 pt.). Median number of co-occurring mutations was 2 (0-3). Three patients were treated empirically for immune thrombocytopenia and had no response to IVIG and/or steroids. Three patients were treated with thrombopoietin receptor agonists (2 eltrombopag, 1 romiplostim) and had minimal transient platelet count increases not meeting the IWG MDS criteria for response. One patient was treated with hypomethylating agents for 4 months before progressing to MDS or AML. Four patients required as-needed platelet transfusions. To date, 4 have progressed to MDS or AML with a median time from diagnosis to progression of 6.3 years (range 5-10). Three patients have received allogeneic hematopoietic stem cell transplant. Conclusion: This series describes a subset of CCUS patients with isolated thrombocytopenia associated with SRSF2 mutations. We also describe atypical megakaryocytic findings which do not meet current WHO diagnostic criteria for dysmegakaryopoiesis; however, the uniform presence of these findings in this cohort suggests an association with thrombocytopenia and CCUS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Role of Platelet Indices and Thrombopoietin (TPO) Serum Levels in the Differential Diagnosis of Thrombocytopenia

Background: The differential diagnosis of an isolated thrombocytopenia may be challenging, especially when it comes to differentiate immune thrombocytopenia (ITP) and an isolated thrombocytopenia in the context of bone marrow (BM) failure, in particular myelodysplastic syndromes (MDS); in such cases a BM examination is usually performed. It is known that thrombopoietin (TPO) serum levels are low in patients with ITP, while they are increased in case of amegakaryocytic thrombocytopenia. Furthermore, some platelet indices such as immature platelet fraction (IPF) may help to discriminate between hyporigenerative and consumption thrombocytopenia. Aim: The aim of this study was to compare TPO serum levels and platelet indices in patients with thrombocytopenia of different etiologies. Based on pathogenesis, we chose 3 groups of patients: ITP, amegakaryocytic thrombocytopenia (aplastic anemia (AA) or post-chemotherapy (CHT)) and thrombocytopenia in MDS and acute myeloid leukemia (AML). Although the diagnosis of amegakaryocytic thrombocytopenia and AML is straightforward with BM examination, we included patients with these diseases as a proof of concept and training set for our findings. Methods: This was a monocentric, retrospective, explorative study. Blood samples of patients with a platelet count < 100x109/L were collected. IPF, mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), platelet large cell ratio (P-LCR) were obtained using Sysmex XN-1000 hemocytometer (Sysmex Corporation). TPO serum levels were measured with a quantitative sandwich ELISA (R&D Systems). Microsoft Excel software was used for descriptive statistical analysis. Anova and Student's t-test were used for comparisons between groups. A p-value <0.05 was considered statistically significant. Results: We enrolled 84 patients: 50 ITP, 22 AML/MDS (13 AML, 9 MDS), 12 AA/post-CHT (4 AA, 8 post-CHT). Results are reported in Table 1. Neither mean platelet count (p=0.20) nor PCT (p=0.44) were significantly different between the three groups. Mean TPO serum levels were higher in patients with AA/post-CHT compared to ITP and AML/MDS groups (p<0.001). All patients in AA/post-CHT group had a TPO serum level >500 pg/mL, this value was never reached in patients with ITP and AML/MDS. TPO serum levels were higher in AML/MDS patients compared to ITP patients (p<0.001). While TPO serum levels were available for all patients, platelet indices were not, due to technical issues. IPF was available in 46/50 ITP patients, 20/22 AML/MDS and 8/12 AA/post-CHT, and it was higher in ITP patients if compared to AA/post-cht (p=0.021) and AML/MDS (p=0.0045). MPV, PDW and P-LCR were available in 27/50 ITP patients, 12/22 AML/MDS and 9/12 AA/post-CHT: they were higher in ITP patients than in the other groups (AML/MDS p=0.0185, AA/post-CHT p=0.017). In our cohort, patients with TPO ≥250 pg/mL and IPF <12% had a higher probability to belong to AML/MDS group (TPO: OR 0.08, 95% CI 0.02-0.32; IPF: OR 0.19, 95% CI 0.06-0.59). These findings were confirmed by multivariate analysis (IPF: p-value = 0.0185, CI 0.8647-0.9868; TPO: p-value = 0.004, CI 1.002-1.011). The other platelet indices were not included in this analysis due to the paucity of data. No correlation was found between platelet count, TPO and IPF in ITP patients. Of note, no differences were observed in terms of platelet count, TPO serum levels ad IPF between patients with AML and MDS. Conclusions: Our findings confirm that, in patients with the same platelet count, those with consumptive thrombocytopenia have higher IPF and lower TPO levels, while patients with amegakaryocytic thrombocytopenia have higher TPO levels and lower IPF. While TPO levels alone can distinguish amegakaryocytic thrombocytopenia from other etiologies, these preliminary data suggest that by combining IPF and TPO, patients with consumptive thrombocytopenia can be distinguished from MDS patients. This could be useful to spare BM examination in selected cases, or as an additional tool when the diagnosis remains uncertain also with BM examination. These data need to be confirmed in larger cohorts. The role of the other platelet indices, and the technical issues in their determination, needs further studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Isolated Thrombocytopenia in Older Adults Is Associated with the Diagnosis of Hematologic Malignancy: A Population-Based Study

Background: In older patients, performing a bone marrow aspirate/biopsy (BM) during consideration of the diagnosis of immune thrombocytopenia (ITP) is controversial, and international hematology societies conflict in their recommendations due to limited evidence. Although ITP is more common in patients older than 60 years, the prevalence of hematologic malignancy also rises with age. The objective of this study was to determine whether isolated thrombocytopenia in patients aged 60 years and older is associated with the diagnosis of a hematologic malignancy, compared to matched patients without thrombocytopenia. Methods: We performed a retrospective population-based propensity-matched cohort study using linked health administrative data in Ontario, Canada. We included patients aged 60 years and older. Exposed patients were those with an internist or hematologist billing a consultation for thrombocytopenia, with laboratory-documented thrombocytopenia (platelet count <100x109/L) within 6 months prior to the consultation date (index date). Unexposed patients were those who never had specialist consultation for thrombocytopenia, who had all platelet counts >100x109/L within 6 months prior to index date. Patients were excluded if they had an abnormal hemoglobin or white blood cell count at index date, or a history of cancer, cirrhosis, or inherited bleeding or coagulation disorder. Exposed and unexposed patients were matched 1:4 on age at index (within 1 year), sex, and a propensity-score (within 0.2 standard deviations). The primary outcome was diagnosis of hematologic malignancy using a competing-risk of death model. The secondary outcome was all-cause death. We performed pre-specified stratified analyses on the primary outcome by age (<80; >80 years), sex, duration of thrombocytopenia prior to specialist consultation (<1; >1 year), severity of thrombocytopenia at index date or closest laboratory test prior to index date (<30x109/L; >30x109/L), and patients treated with corticosteroids (prednisone or dexamethasone) within 2 weeks of index date versus patients not treated with corticosteroids. We also performed pre-specified sensitivity analyses on the primary and secondary outcome to compare hazard ratios (HR) among exposed patients stratified by platelet count on index date or closest platelet count prior to index date (<10x109/L, 10-29x109/L, 30-49x109/L, 50-99x109/L). Results: We matched 4,390 exposed to 17,556 unexposed patients from January 1, 2009 to December 31, 2019. Among exposed patients, 378 (8.6%, 95% CI 7.8-9.5; 19.1/1000 person years (PY), 95% CI 17.1-21.0) were diagnosed with hematologic malignancy over 3.91 years of follow-up, compared to 204 unexposed patients (1.2%, 95% CI 1.0-1.3; 2.5/1000PY, 95% CI 2.2-2.8) over 4.05 years of follow-up. In the first year after consultation, the HR for being diagnosed with a hematologic malignancy was 15.5 (95% CI 11.3-21.4, p<0.0001, Figure 1) in exposed patients compared to unexposed. In subsequent years the HR was 5.3 (95% CI 4.4-6.6, p<0.0001, Figure 1). This relationship persisted in stratified analyses by sex, age, severity or duration of thrombocytopenia, and patients treated with corticosteroids within 2 weeks of consultation. Among exposed patients, the majority of hematologic malignancy diagnoses in the first year after index date were registered within 6 weeks of a BM (88%), while in subsequent years 45% of diagnoses were registered within 6 weeks of a BM. The most common hematologic cancer diagnosed in exposed patients was MDS (31%) (Table 1). Over half of cases of hematologic malignancy found in the exposed cohort would have been immediately actionable with disease-specific therapy. In terms of overall survival, 1,277 exposed patients (29.1%, 95% CI 27.8-30.5; 61.1/1000PY, 95% CI 57.8-64.5) and 3,663 unexposed patients (20.9%, 95% CI 20.3-21.5; 44.7/1000PY, 95% CI 43.3-46.2) died during the follow-up period (HR 1.4; 95% CI 1.3-1.5, p<0.0001). In a sensitivity analysis, there was no difference in the rate of hematologic malignancy diagnosis or rate of death based on severity of thrombocytopenia. Conclusions and Relevance: This population-based study demonstrates a strong association between thrombocytopenia and hematologic malignancy in patients aged 60 years and older. These data support the use of BM upfront in outpatient specialist consultation for isolated thrombocytopenia in older patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cyclic Thrombocytopenia: A Case Report

Introduction Cyclic thrombocytopenia (CTP) is a rare disorder characterized by episodes of oscillating platelet counts. It is usually associated with another primary hematologic disorder but there are idiopathic cases in the literature. Patients with CTP have similar clinical features and symptoms with idiopathic thrombocytopenic purpura (ITP), so they are often misdiagnosed as ITP and treated accordingly. In general, CTP does not respond to ITP therapies, so it should always be considered when treatments are not effective. It is more common in females. However, in our case report we present a 93-year-old male with CTP who was initially mistaken for ITP. Case description A 93-year-old male patient with a past medical history of hypertension was initially thought to have idiopathic thrombocytopenia (ITP) presenting with mucosal gum bleeding and a petechial rash. He was found to have isolated thrombocytopenia, and no evidence of other cytopenias. He did trials of multiple medications such as corticosteroids and intravenous immunoglobulin (IVIG) with no response. He was not a surgical candidate for splenectomy. He also deferred a bone marrow biopsy, though peripheral blood testing with flow cytometry showed a small monoclonal B cell population. Peripheral blood myeloid sequencing panel showing ASXL1 and EZH2. He was started on Eltrombopag, a thrombopoietin (TPO) agonist with significant lability in the platelet count, from 8,000 per microliter (mcL) to over 1,000,000 per mcL. Romiplostim, another TPO agonist also gave similar results. A diagnosis of cyclic thrombocytopenia was suspected. A Helicobacter pylori antibody was positive, and treated with antibiotics with no improvement in platelet count oscillations. Thyroid function was within normal limits. T-cell gene rearrangement was negative. Thrombopoetin (TPO) levels were checked and these were found to be in discordance with the platelet count, consistent with a CTP diagnosis. He was started on cyclosporine 150 milligrams twice daily with significant improvement in fluctuations of platelet counts. Discussion Cyclic hematopoietic disorders are rare and have regular predictable oscillations of one or more cellular components of the blood. Physiologically, there is a complex interplay between thrombopoietic stimulation and feedback inhibition in order to maintain the circulating platelets within the normal range. An error in any of these steps results in oscillation of the platelet counts (cyclic thrombocytopenia). Many mechanisms are behind the pathophysiology of this disease, such as: autoimmune destruction of platelets, hypoplasia of megakaryocytes, a defect in regulating platelet formation and an infectious or hormonal etiology. There are many reports linking T-lymphocytes proliferation and clonal TCR gene rearrangement to cyclic thrombocytopenia. We noticed in the literature that there can be variable responses to TPO agonists, but often can result in very high platelet counts. Due to its rarity, there are only case reports which show reports of remission after hormone therapy with danazol and immune suppressant therapies, such as cyclosporine. Further studies are needed to determine the mechanism responsible for cycling phenomena and optimal treatments for this disorder. In conclusion, any presumed ITP case that does not respond well to the standard therapy of ITP should be reevaluated for the possibility of cyclic thrombocytopenia.

Immune thrombocytopenia in a small cell lung cancer patient treated with atezolizumab: a case report

Immune checkpoint inhibitors (ICIs), an enormous oncological breakthrough in the last 10 years, have become the standard treatments for several types of solid cancers. Although ICIs are generally well tolerated and result in favorable outcomes, they also cause unique immune-related adverse events (irAEs) across bodily systems and organs. Compared to most common irAEs, which occur in the endocrine, skin, pulmonary system, and gastrointestinal tract, haematological irAEs (haem-irAEs) are relatively rare but potentially life-threatening events that are occasionally irreversible and refractory. Currently, haem-irAEs are not sufficiently understood, management, and lack consensus, while other common irAEs have well been characterized and managed. The reports of ICI-related thrombocytopenia in small cell lung cancer (SCLC) are rarely seen. Hence, we reported a rare case of severe steriod-resistant ICI-related thrombocytopenia after received chemotherapy plus anti-PD-L1 inhibitor in SCLC patient. Our case exemplifies the diagnosis, diagnosis of exclusion, treatment, and prognosis of thrombocytopenia in the pattern of combination therapy, meanwhile, the subject of diagnosis, therapies, therapeutic strategies for refractory type and incidence, potential biomarkers, mechanisms and prognosis in ICI-related thrombocytopenia have been fully discussed. Herein, we present a 64-year-old man diagnosed advanced SCLC developed refractory immune-related severe thrombocytopenia, who achieved favorable outcomes of cancer following chemotherapy combined with atezolizumab administrated. Routine blood re-examination on the third day of 6th therapy showed a thrombocyte count of 11×109/L. Combined the medical history and the results of laboratory tests, the diagnosis of ICI-induced thrombocytopenia was confirmed. Despite large doses of methylprednisolone, immunoglobulin, and rituximab, intermittent platelet transfusion, thrombopoietin being administrated to the patient, there were no signs of platelet count and hemoglobin improvement. Currently, this is the first case about atezolizumab induced thrombocytopenia in SCLC patient, while there is extremely rare haem-irAEs reported in SCLC. Although ICI-related severe thrombocytopenia is rare, it may persist or even be fatal. Clinicians should pay more attention to its diagnosis and prompt treatment. Once developed thrombocytopenia, large doses of methylprednisolone, ntermittent platelet transfusion, thrombopoietin should be timely administrated, also plasma exchange or rilzabrutinib, other immunosuppressive drugs, or IL-6 inhibitor warrant apply if steriod-resistant.

Immune Thrombocytopenia (Itp) In Emergency Medicine

Immune Thrombocytopenia (ITP) is an autoimmune disorder characterised by a low platelet countless than 100? ×? 10^9/L, purpura, and hemorrhagic episodes induced by antiplatelet autoantibodies without anemia or leukopenia. Immune thrombocytopenia (ITP) occurs in 2 to 4/100? 000 adults. A wide range of signs and symptoms, from modest mucocutaneous petechiae to severe, life-threatening organ haemorrhage, are seen in ITP patients. they may present to the emergency department (ED) with life-threatening bleeding as a result of their thrombocytopenia. ITP has two distinct clinical syndromes, manifesting as an acute condition in children and a chronic condition in adults. IgG autoantibodies make circulating platelets more sensitive. It causes these cells to be removed more quickly by antigen-presenting cells (macrophages) of the spleen, and occasionally the liver or other components of the monocyte-macrophage system. Current evidence supports alternatives to splenectomy for second-line management of patients with persistently low platelet counts and bleeding. By increasing platelet production, bone marrow compensates for platelet breakdown. Immune Thrombocytopenia most commonly arises within a few weeks after a viral infection in healthy children and young adults. Immunosuppressive treatment is usually effective in treating ITP. Many patients with ITP require no emergent treatment. However, the emergency physician should start treatment with a platelet transfusion, corticosteroids, and intravenous immune globulin (IVIG) as soon as the patient with suspected ITP arrives at the ED with serious haemorrhage.The diagnosis is usually made by ruling out all known causes of thrombocytopenia. This review aims to summarize current evidences regarding prevalence, causes, diagnosis and management of immune thrombocytopenia. Keywords:,,,

Diagnosis and treatment of immune thrombocytopenia in Poland

Immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by an isolated platelet count of less than 100,000/μL caused by destruction and reduced production of platelets. Systemic steroid therapy is a mainstay of first-line treatment; however, additional treatment lines are usually necessary due to the very high recurrence rate after therapy completion and steroid resistance. Standard treatment options for steroid resistance or steroid dependence include splenectomy, rituximab or thrombopoietin receptor agonists. The article presents current data on the diagnosics and therapy of ITP, considering the limited access to some forms of treatment in Poland.

Diagnostic value of multigene sequencing for inherited thrombocytopenia.

Multigene testing for inherited thrombocytopenia can detect an unexpected diagnosis as demonstrated in the case report from Ming-Ping et al., where the mode of inheritance and clinical phenotype did not point towards dominant Schlafen family member 14 (SLFN14) moderate thrombocytopenia. They describe two siblings with very severe thrombocytopenia due a pathogenic SLFN14 variant and gonosomal mosaicism in their healthy mother. In their paper Ming-Ping et al. describe two siblings with severe thrombocytopenia (platelets counts <15 × 109/l) and bleeding symptoms, born from healthy non-consanguineous parents.1 The first child died at the age of 5 months due to intracranial haemorrhage. This child also had larger platelets, while this was not found for his affected sister. She has received regular platelet transfusions since birth. Neonatal and immune thrombocytopenia were ruled out. Their diagnosis was made after using whole-exome sequencing with the detection of a heterozygous pathogenic SLFN14 variant that is responsible for dominant thrombocytopenia. Interestingly, gonosomal mosaicism for this variant was detected in the mother who has normal platelet counts. This case report nicely demonstrates the power of multigene sequencing for the diagnosis of inherited thrombocytopenia, which is an extremely heterogenous disorder with already 40 diagnostic-grade genes as potential underlying cause (Figure 1).2, 3 Using only textbook knowledge, the diagnosis of SLFN14-related thrombocytopenia could probably never have been made for these patients. Based on the clinical phenotypes present in the family members, a recessive form of inherited (macro)thrombocytopenia was expected as parents have a normal platelet count. In addition, SLFN14-related thrombocytopenia is an ultrarare disorder and clinical and laboratory data have only been described for four unrelated pedigrees.4 All patients with pathogenic SLFN14 variants have platelet counts >65 × 109/l (moderate thrombocytopenia) and highly variable degrees of bleeding symptoms and International Society of Thrombosis and Haemostasis (ISTH) bleeding scores ranging between 2 and 20. The children in this case report have a much more severe phenotype and still they carry the same genetic variant as previously described.4 In the past, several diagnostic algorithms have been proposed to assist clinicians in the differential diagnosis of inherited thrombocytopenia. The classification of inherited thrombocytopenia was typically driven by the presence or absence of other clinical features besides a platelet defect (syndromic versus non-syndromic), the mode of inheritance (recessive, dominant and X-linked) and the platelet size (macro, micro and normal size platelets) (Figure 1).5 Applying such an algorithm was very useful, as the numbers of genes implicated in inherited thrombocytopenia was less than half of the genes we know today. However, this algorithm would have missed the diagnosis in the family. Since the discovery of many novel genes for inherited thrombocytopenia using next-generation sequencing approaches over the last decade, phenotype–genotype associations for this disorder have become very complex.6 In addition, the mode of inheritance has expanded for well-known genes (e.g., dominant mild Bernard–Soulier syndrome versus the classical recessive form and recessive Fli-1 proto-oncogene, ETS transcription factor [FLI1] and growth factor-independent 1B transcriptional repressor [GFI1B] variants versus the known dominant forms of this type of thrombocytopenia). To date, multigene panel testing is typically used to diagnose inherited thrombocytopenia by investigating all the known genes involved in this pathology in a single analysis.7 Providing detailed clinical and laboratory information to genetic laboratories remains very important for the interpretation of this test as it assists in the variant classification to decide if a variant is pathogenic or not. The major drawbacks of performing a multigene panel test for inherited thrombocytopenia are the detection of many variants of unknown significance than cannot be used for clinical management and unsolicited findings. If for example pathogenic variants are detected in either RUNX family transcription factor 1 (RUNX1), ETS variant transcription factor 6 (ETV6) or ankyrin repeat domain-containing 26 (ANKRD26) in a patient with thrombocytopenia without a family history of leukaemia, such variants can be considered as an unsolicited finding if the patient was not aware about these genetic risk factors for leukaemia before initiating the multigene test. On the other hand, a multigene test allows the detection of ‘the unexpected diagnosis’. This case report provides such an example as a SLFN14 defect was not really expected based on the known disease phenotypes associated with pathogenic variants in this gene.

Use of PLT-F channel and immature platelet fraction parameters in differential diagnosis of thrombocytopenia

Establishing the true causes of thrombocytopenia is of paramount importance, since the tactics of managing patients depend on it. Obtaining information about the activity of thrombocytopoiesis until recently was possible only after examining the bone marrow, but modern laboratory diagnostic capabilities make it possible to evaluate thrombocytopoiesis by a comprehensive clinical blood test performed on a hematological analyzer using a fluorescent optical method (PLT-F). At the same time, in addition to the number of platelets in peripheral blood, information is available on the number of immature platelets (IPF) in absolute and relative terms. Objective: to evaluate the possibility of using the PLT-F channel and IPF parameters in the differential diagnosis of thrombocytopenia. We reviewed three clinical cases with different pathogenetic variants of thrombocytopenia (immune thrombocytopenia, thrombocytopenia in DIC and thrombocytopenia associated with bone marrow damage). In all cases, a clinical blood test was performed on a Sysmex XN 1000 hematological analyzer using the PLT-F channel. When using the PLT-F channel, parameters are available to differentiate thrombocytopenia according to the mechanism of pathogenesis. The absolute value of IPF is a criterion for the activity of thrombocytopoiesis in the bone marrow, while the relative value of IPF, namely the increase in this parameter, is a criterion for the loss of platelets in the peripheral bloodstream (destruction or increased consumption of platelets). The availability of obtaining diagnostic information about the activity of thrombocytopoiesis and loss of platelets in the peripheral bloodstream using a clinical blood test using the PLT-F channel on Sysmex XN hematological analyzers is of great clinical importance, since a clinical blood test, being a routine study, does not require special conditions for sampling biomaterial, and can be performed not only at the stage of diagnosis, but also during therapy monitoring.

MPN-386 Real-World Ruxolitinib Treatment Pattern in Myelofibrosis Patients With Thrombocytopenia.

Ruxolitinib, the standard treatment for patients with myelofibrosis to reduce splenomegaly and improve myelofibrosis-associated symptoms, is associated with high rates of cytopenia effect. Thrombocytopenia, common in myelofibrosis patients, is associated with poor clinical outcomes, and its treatment confers a unique challenge. This real-world study characterized the disease and ruxolitinib treatment pattern in myelofibrosis patients with thrombocytopenia using US insurance claims data. Data from the IBM MarketScan® Medicare Supplemental Database were retrospectively analyzed to identify patients aged ≥18 years with ≥1 claim for ruxolitinib and ≥2 non-diagnostic medical claims for myelofibrosis from 2017 to 2019. The first ruxolitinib claim on or after the first myelofibrosis claim defined the index date. Patients who continuously enrolled in a health plan for 3 months before and 6 months after the index date were included. Clinical characteristics and ruxolitinib treatments were compared in myelofibrosis patients with or without a history of thrombocytopenia prior to ruxolitinib initiation. Overall, 136 myelofibrosis patients who received ruxolitinib treatment were included in the analysis. The median age was 61 years, 61% were male, 62% had primary myelofibrosis, and 38% had post-polycythemia vera or essential thrombocythemia myelofibrosis. Prior to ruxolitinib treatment, 57% of patients had a diagnosis of splenomegaly, 56% had anemia, 25% had thrombocytopenia, 19% had received RBC transfusion, and 7% had neutropenia. During ruxolitinib treatment, 25% of patients had a new diagnosis of thrombocytopenia, 22% had neutropenia, and 19% had anemia. Patients with versus without history of thrombocytopenia had more anemia (79% vs. 48%, P=0.001), more red blood cell transfusions (44% vs. 11%, P<0.001), and a lower mean starting dose of ruxolitinib (20 mg vs. 27 mg, P=0.005). History of anemia, leukocytosis, neutropenia, myelofibrosis type, and splenomegaly had no effect on the ruxolitinib starting dose. Myelofibrosis patients with versus without history of thrombocytopenia continued ruxolitinib treatment at lower doses. During ruxolitinib treatment, 57% of patients with versus 42% without history of thrombocytopenia experienced anemia (OR=1.88, P=0.43). History of thrombocytopenia was a major factor influencing ruxolitinib dose and was associated with history of anemia and neutropenia. Our findings underscore the need for more treatment options to manage myelofibrosis patients with thrombocytopenia.

Frequency and utility of bone marrow examination in relapsed/refractory immune thrombocytopenia

BackgroundThe diagnosis of immune thrombocytopenia (ITP) is one of exclusion. Although guidelines recommend against routine bone marrow examination (BME) at time of ITP diagnosis, the role of BME in relapsed/refractory ITP is unclear. ObjectivesTo examine the frequency and predictors of BME in relapsed/refractory ITP. Patients/MethodsThis multicenter retrospective cohort study included adults with ITP who received second‐line therapy in Alberta, Canada from 2012 to 2019. We calculated the frequency of BME and rate of abnormal marrow findings. Logistic regression was performed to assess predictors of BME and predictors of bone marrow pathology. ResultsOf 324 patients with presumed ITP, 181 (56%) underwent BME. We observed a marked decline in the rates of BME among patients >60 years over the past decade, but not in patients younger than age 60 years. On multivariable logistic regression, older age (adjusted OR [aOR] 1.03, p = .0001), anemia (aOR 2.5, p = .01), splenomegaly (aOR 3.2, p = .01), splenectomy (aOR 2.4, p = .02), and lack of splenectomy response (aOR 3.4, p = .04) were significant predictors of BME. Abnormal marrow findings were found in eight (2% of overall cohort; 4% of BME): four myelodysplastic syndrome, one aplastic anemia, one chronic lymphocytic leukemia, one metastatic cancer, and one megaloblastic anemia. Seven (88%) underwent BME for bicytopenias/pancytopenias. Macrocytosis (aOR 9.6, p = .03) and rural residence (aOR 6.7, p = .02) were independent predictors of abnormal bone marrow findings. ConclusionsAlthough routine BME is frequently performed in relapsed/refractory ITP, abnormal findings are rare. Future prospective studies are needed to help identify a subgroup of relapsed/refractory ITP who may benefit from BME.

Mikroangiopathien in der Schwangerschaft

Das Wissen um die Differentialdiagnose der Mikroangiopathien ist auch für Geburtshelfer:innen wichtig. So ist die Kombination aus einer Thrombopenie und Hämolysezeichen wegweisend in der Erkennung der Erkrankung. Es sollten die Differenzialdiagnosen bekannt sein, da diese zu unterschiedlichen Therapienotwendigkeiten führen und Langzeitschäden, beispielsweise für die Niere, vermieden werden müssen. Die Differenzialdiagnosen der Thrombopenie stellen den Einstieg für die weitere Diagnostik dar. In der Kombination mit Hämolysezeichen und Veränderungen der Erythrozytenmorphologie (Fragmentozyten) liegen unterschiedliche Ursachen für die Mikroangiopathie vor. Eine thrombotisch-thrombozytopenische Purpura (TTP) kann während der gesamten Schwangerschaft, aber insbesondere im letzten Trimenon, die Ursache für solche Veränderungen sein. Bei dieser finden sich häufig gastrointestinale oder auch zusätzliche neurologische Symptome. Die Präeklampsie, insbesondere beim HELLP(„hemolysis, elevated liver enzymes, and a low platelet count“)-Syndrom, kann ebenfalls zu einer Mikroangiopathie führen, dieses i.d.R. mit entsprechender Erhöhung des Blutdrucks und insbesondere mit einer deutlichen Erhöhung der Lebertransaminasen, ebenfalls typischerweise im letzten Trimenon kombiniert. Wenn entsprechende Veränderungen nach der Geburt auftreten und diese neben der Hämolyse mit einem Nierenversagen verbunden sind, kann es sich hierbei um ein atypisches hämolytisch-urämisches Syndrom (aHUS) handeln, das spezifisch durch Antikörper therapiert werden sollte. Neben der typischen Gerinnungsaktivierung im Sinne einer Thrombosierung findet sich bei COVID-19 („corona virus disease“) auch das gesamte Bild einer entsprechenden Mikroangiopathie, zum Teil durch entsprechende Aktivierung des Gerinnungssystem, zum Teil durch eine Verstärkung der anderen Mikroangiopathien. Für alle Bereiche werden die Differenzialdiagnosen und mögliche Therapien skizziert.

Spurious Thrombocytopenia in an Automated Platelet Quantitation: A Dilemma with the Regular Laboratory Tasks

Spurious thrombocytopenia is a very rare condition, in which the actual number of platelets circulating in the body is substantially lesser than the number of platelets that automated cell counters record. It is crucial to be aware of this event since spurious thrombocytopenia might result in the incorrect diagnosis of thrombocytopenia, which would then necessitate additional expensive and time-consuming testing in the laboratory and the wrong course of treatment. In this article, actual knowledge of this uncommon event and the clinically significant laboratory will be compiled and reviewed based on the literature that has been published. The pathophysiological and laboratory aspects, important information on the identification and avoidance of false thrombocytopenia, and potential methods for determining the corrected platelet count were discussed.

Thromboelastography in guiding preventive platelet transfusion in patients with haematologic diseases.

This study analysed the relationships between the main thromboelastography (TEG) parameters, the platelet (PLT) count and clinical bleeding in patients with blood diseases. We explored the threshold of the relevant parameters in the pathological condition of bleeding, aiming to scientifically guide clinical prophylactic PLT transfusion. In total, 268 patients with clear diagnoses of blood diseases and thrombocytopenia were enrolled and divided into five groups, A, B, C, D and E, corresponding to PLT counts of 0-10 × 109 /L, 11-20 × 109 /L, 21-30 × 109 /L, 31-50 × 109 /L and 51-100 × 109 /L, respectively. TEG and routine blood testing were performed simultaneously, the main TEG parameters and the PLT count were analysed, and the thresholds of the main TEG parameters in each group when the patient had bleeding were obtained. The maximum amplitude (MA) in groups A, B and C increased gradually, with a significant difference between each pair of these groups (P < 0.05). In groups A, B, C, D and E, the corresponding MA at the time of bleeding was 43.5 mm, 39.6 mm, 38.0 mm, 35.2 mm and 50.5 mm, respectively, with statistically significant differences (P < 0.05). The MA can be used as a reference indicator for preventive PLT transfusion to a certain extent. When the PLT count is within different ranges, the MA threshold for preventive PLT transfusion also differs. It is recommended that different PLT counts be correlated with different MA thresholds to guide clinical prophylactic PLT transfusion.

P1044: REAL-WORLD RUXOLITINIB TREATMENT PATTERN IN MYELOFIBROSIS PATIENTS WITH THROMBOCYTOPENIA

Background: Ruxolitinib (RUX) is the standard treatment for patients (pts) with myelofibrosis (MF) to reduce splenomegaly and improve MF-associated symptoms. RUX treatment is titrated based on platelet counts and is associated with high rates of cytopenia effect. The incidence of moderate thrombocytopenia (platelet count <100 x 109/L) is about 25% in newly diagnosed MF pts; however, the prevalence is about 67% in all MF pts. Low platelet count has been identified as an important surrogate marker of survival in MF pts with associated poor clinical features. Thrombocytopenia is also an independent predictor in the Dynamic International Prognostic Scoring System plus (DIPPS plus), with an actual 1.4-fold increased risk of death. Thus, treatment of MF pts with thrombocytopenia confers a unique challenge and unmet medical need. Real world studies will provide a perspective on the current management of MF pts with thrombocytopenia. Aims: To characterize the disease and RUX treatment pattern in MF pts with thrombocytopenia using de-identified insurance claims data in the US. Methods: The IBM MarketScan® Medicare Supplemental Database data was retrospectively analyzed to identify pts aged ≥18 years with ≥1 claim for RUX and ≥2 non-diagnostic medical claims for MF (ICD-10 D47.4, D7581) from 2017–2019. The first RUX claim on or after the first MF claim defined the index date. Pts who continuously enrolled in a health plan for 3 months before the index date and 6 months after the index date were included. Clinical characteristics and RUX treatments were compared in MF pts with or without a history of thrombocytopenia prior to RUX initiation. Results: The database contained 136 MF pts who had received treatment with RUX. Median age was 61 years, 61% were male, 62% of pts had primary MF, and 38% had post-polycythemia vera or essential thrombocythemia MF. Prior to initial RUX treatment, 57% of pts had a diagnosis of splenomegaly, 56% had anemia, 25% had thrombocytopenia, 19% had received RBC transfusion, and 7% had neutropenia. During RUX treatment, 25% of pts had a new diagnosis of thrombocytopenia, 22% had neutropenia, and 19% had anemia. Pts with a history of thrombocytopenia also had more anemia (79% vs 48%, p=0.001) and more RBC transfusions (44% vs 11%, p<0.001) than those without a history of thrombocytopenia. History of thrombocytopenia was associated with a lower starting dose of RUX (average starting daily dose 20 mg vs 27 mg, p=0.005), whereas history of anemia, leukocytosis, neutropenia, MF type, and splenomegaly were found to have no difference in the RUX starting dose. In addition, MF pts with history of thrombocytopenia continued RUX treatment at lower doses compared with those without a history of thrombocytopenia. During RUX treatment, 57% of pts with history of thrombocytopenia experienced anemia compared with 42% in pts without history of thrombocytopenia (OR 1.88, p=0.43). Summary/Conclusion: In this real-world data analysis, history of thrombocytopenia was a major factor influencing the RUX dose for treatment of MF pts, consistent with prescribing data that RUX dose is adjusted based on platelet counts. These data show that pts with thrombocytopenia were treated with lower doses of RUX in clinical practice. Additionally, history of thrombocytopenia was associated with history of anemia; thus, these MF pts may be more prone to develop anemia during RUX treatment compared with pts without a history of thrombocytopenia. Our findings underscore the need for more treatment options to manage MF pts with thrombocytopenia. *Equal contribution.

Diagnosis of immune thrombocytopenia, including secondary forms, and selection of second-line treatment.

This article summarizes our approach to the diagnosis of immune thrombocytopenia (ITP), its secondary forms, and choice of second-line treatment options. We very briefly summarize first-line treatment and then utilize a case-based approach. We first explore persistent, chronic ITP in a younger female. We consider many possibilities beyond primary ITP e.g., hypogammaglobulinemia, chronic infection, and anemia, and how to approach their diagnosis and management. The journey continues throughout pregnancy and the post-partum period and eventually includes fourth-line treatment after a late relapse. We then consider an older male, emphasizing differences in diagnostic considerations and management. The focus is on initiation and continuation of second-line treatment, the pros and cons of each option, and briefly the impact of treatment choices related to the endemic presence of severe acute respiratory syndrome coronavirus 2. During the review of potential second-line treatment options, we also briefly touch upon novel treatments. Finally, there is a short section on refractory disease drawn from our previous extensive review published in February 2020.1 The clinical nature of the discussions, replete with figures and tables and with the interspersion of pearls regarding efficacy and toxicity at different ages and genders, will serve the reader in the management of “typical” adult patients who develop persistent and chronic ITP.