Marked Thrombocytosis Research Articles

Essential thrombocythaemia.

Essential thrombocythemia (ET) is a chronic Philadelphia-negative myeloproliferative neoplasm that has its main involvement in the megakaryopoietic lineage, generating sustained thrombocytosis in peripheral blood and an increase in the number of mature megakaryocytes in the bone marrow. In addition to marked thrombocytosis, it is characterized by increased thrombotic or hemorrhagic risk and the presence of constitutional symptoms. Patients with ET have a low but known risk of disease progression to myelofibrosis and/or acute leukemia. The diagnosis is made based on the 2016 WHO criteria. At present, available treatments for patients with ET are mainly aimed at minimizing the risk of thrombosis and/or bleeding.

Outbreak of Acute Clinical Mastitis in Primigravidae Ewes in the Immediately Pre-Partum Period

An outbreak of acute mastitis was investigated in a dairy sheep farm in Central Greece with a prevalence of 8.2%. Two animals were examined with symptoms of hyperacute inflammation in one of the two mammary glands. Affected glands presented swollen to grossly enlarged, warm and painful. In both animals, haematological examination revealed mild anaemia, increased leucocyte counts with mature neutropaenia and left shift, and marked thrombocytosis. Bacteriological examinations of mammary gland secretion yielded heavy growth of Streptococcus dysgalactiae and Escherichia coli from each of the two animals, respectively. Serological examination revealed a high percentage of positive samples for small ruminant lentivirus infection in both animals. The somatic cell count in the bulk-tank milk was 0.65 × 106 cells/mL. The housing conditions were inadequate with high levels of ammonia, intense stocking and muddy bedding. This pathological condition in nulliparous ewes was attributed to the extensive oedema of mammary gland and teat, the relaxation of immunity during the peri-parturient period and the heavily contaminated environment. These findings are in general agreement with corresponding incidents in heifers. Following our instructions for improving housing conditions, no other similar incidents were recorded.

Clinical characteristics of Japanese patients with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.

Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare disease, which presents with features of myelodysplastic syndromes with ring sideroblasts and essential thrombocythemia, as well as anemia and marked thrombocytosis. SF3B1 and JAK2 mutations are often found in patients, and are associated with their specific clinical features. This study was a retrospective analysis of 34 Japanese patients with MDS/MPN-RS-T. Median age at diagnosis was 77 (range, 51-88) years, and patients had anemia (median hemoglobin: 9.0g/dL) and thrombocytosis (median platelet count: 642 × 109/L). Median overall survival was 70 (95% confidence interval: 68-not applicable) months during the median follow-up period of 26 (range: 0-91) months. A JAK2V617F mutation was detected in 46.2% (n = 12) of analyzed patients (n = 26), while an SF3B1 mutation was detected in 87.5% (n = 7) of analyzed patients (n = 8). Like those with myelodysplastic syndromes or myeloproliferative neoplasms, patients often received erythropoiesis-stimulating agents and aspirin to improve anemia and prevent thrombosis. This study, which was the largest to describe the real-world characteristics of Japanese patients with MDS/MPN-RS-T, showed that the patients had similar characteristics to those in western countries.

Non-traumatic rupture of the spleen and marked post-splenectomy thrombocytosis associated with polycythemia vera

Non-traumatic rupture of the spleen and marked post-splenectomy thrombocytosis associated with polycythemia vera

Pro106Leu MPL mutation is associated with thrombocytosis and a low risk of thrombosis, splenomegaly and marrow fibrosis

The P106L mutation in the human myeloproliferative leukemia virus oncogene (MPL) was shown to be associated with hereditary thrombocythemia in Arabs. The clinical and bone marrow (BM) features of P106L mutation are unknown. Genetic databases at two tertiary hospitals in Saudi Arabia were searched to identify patients with the MPL P106L mutation. Clinical data were collected retrospectively and the BM aspirates and biopsies were independently reviewed by two hematopathologists. In total, 115 patients were included. Median age was 33 years of which 31 patients were pediatric and 65 were female. The mutation was homozygous in 87 patients. Thrombocytosis was documented in 107 patients, with a median platelet count of 667 × 109/L. The homozygous genotype was associated with a higher platelet count. Thirty-three patients had an evaluable BM and clustering of megakaryocytes was observed in 30/33 patients. At the time of last follow-up, 114 patients were alive. The median follow-up was 7.8 years from the time of thrombocytosis. No patients developed disease progression to myelofibrosis. The P106L mutation was associated with marked thrombocytosis at a younger age and with a low risk of thrombosis, splenomegaly, and marrow fibrosis. The BM demonstrated normal or hypocellular marrow with megakaryocyte clusters.

AML-213 Unusual Presentation of Acute Myeloid Leukemia (AML-M2): A Case Report

Acute myeloid leukemia (AML) is rarely presented with thrombocytosis and marked thrombocytosis with a platelet count over 1.0×1012/L is an extremely rare phenomenon. A case of de novo AML with unusual presentation by extreme thrombocytosis. A case report. Hematology Unit at the Oncology Center Mansoura University, Egypt. A 37-year-old male patient with a history of sleeve gastrectomy in 2020, presented with oral mucositis, recurrent abscess, fever, and bilateral axillary lymphadenopathy. Initial complete blood count (CBC) showed a Hb level of 6 g/dL, a platelet count of 1.685×109/L, and a white blood cell (WBC) count of 19×109/L. Diagnosis of de novo AML (FAB-M2 AML) was confirmed by bone marrow aspiration, biopsy, and immunophenotyping. Cytogenetic study showed negative t(8;21)/inv 16/ t(9;22). A molecular study showed positive FLT-3 mutation and negative BCP/ABL1, JAK2, V617F, and CALR exon 9 mutations excluding blast transformation on top of myeloproliferative neoplasm (MPN) and myelodysplastic syndrome (MDS). The patient received induction chemotherapy including a course of 7-day-cytarabine along with 3-day-anthracycline on September 20th, 2021 but the patient was refractory as BMA showed blast cells 75%. The patient started salvage HAM (high-dose cytosine arabinoside and mitoxantrone) + Sorafenib on November 6th, 2021. Again, he could not achieve a response and received FLAG (high-dose cytosine arabinoside, fludarabine, and granulocyte colony-stimulating factors) + Sorafenib on December 18th, 2021, after recovery from COVID-19 infection. To shed light on fact that myeloid neoplasms as MPN, MDS, and de novo AML can share overlapping features. On January 25th, 2022, the last CBC showed a Hb level of 8.4 g/dL, a platelet Count of 395×109/L, and a WBC Count of 2.41×109/L with a differential Neutrophil count of 0.24×109/L. The patient lost follow-up since then. Only a few AML cases have been reported with thrombocytosis. Detailed molecular studies are mandatory to confirm the diagnosis of de novo AML patients with unusual presentation. Careful follow-up of those cases could help in establishing management guidelines for better outcomes as those patients usually have a poor prognosis.

P086 Kawasaki syndrome and Epstein Barr virus: a case report (again!)

Abstract Background Kawasaki disease (kDa), also known as mucocutaneous lymph node syndrome, is always updating. We present the case of a toddler boy with concomitant positive EBV serology. Material The infant is referred to the pediatric ward for stomatitis with cheilitis, fever> 40 ° C, asthenia, irritability evolving for 4–5 days. In addition, clinical examination revealed multiple, small cervical lymph nodes, < 1 cm. There is no conjunctivitis, no skin rash, nor reactivation of the BCG scar. Biology reveals hyperleukocytosis with very high ESR and CRP. ECG and Echo-heart, requested for suspicion of Kawasaki syndrome, are normal. Results Empirical treatment with Aciclovir—Cefalexin with topical care was started. Viral serologies return HSV (-), CMV (-), but EBV (+). Clinical improvement was noted within 36 h. However, inflammatory markers improve within 2–3 days. At 15 days, the child presents with typical convalescent peeling of the fingers and toes; associated with marked thrombocytosis. The diagnosis of Kawasaki Syndrome is definitively confirmed. Discussion The exact aetiology of Kawasaki syndrome remains unclear. Among the factors frequently encountered, the Epstein Barr Virus is reported for almost 30 years. The syndrome frequency is highest before the age of 5 years; similar to Infectious Mono-Nucleosis (due to EBV…). Our case depicts a concomitant Kawaski syndrome and positive EBV serology; without any detectable coronary artery abnormality. Conclusion Kawasaki syndrome is a real “chameleon” condition with possible cardiovascular complications. The viral aetiology springs up through “an old friend”: the Epstein Barr Virus ...Even without any aneurysm (also associated with EBV), the American Heart Association recommends long-term monitoring for all Kawasaki syndromes.

Severe Iron Deficiency Anemia Leading to Thrombocytosis With Arterial and Venous Thrombosis

A 45-year-old female who was a teacher by profession with a history of chronic asymptomatic anemia in the past presented to our hospital with complaints of intermittent fever for two weeks, cough with expectoration, dyspnea on exertion, and left upper limb edema for four days. She had a history of abdominal pain after food intake. She gave a history of having anemia for the past 23 years. Evaluation after admission showed raised inflammatory markers, marked thrombocytosis, and severe iron deficiency anemia. Further imaging in the form of a CT of the abdomen and thorax showed that she had a left-sided pleural effusion which showed an exudative picture, splenomegaly with a splenic infarct with a splenic abscess, and a suprarenal abdominal aorta thrombus. She was also found to have deep vein thrombosis (DVT) of the left subclavian and proximal internal jugular vein in a ultrasonogram (USG) Doppler. The workup done ruled out congenital and acquired causes of thrombosis and after extensive evaluation the patient was found to have unexplained thrombosis. The cause of unexplained thrombosis is the point of interest in this patient. Despite extensive workup, no precise cause for thrombosis, which was both arterial and venous in nature could be found out initially. Hence by exclusion, the possibility of secondary thrombocytosis causing the thrombosis was considered. Over the next few years, this patient underwent repeat esophageal endoscopies, colonoscopies, and capsule studies all without being able to pinpoint a diagnosis. Eventually three years later, a CT enteroscopy with biopsy showed the diagnosis of Crohn’s disease and the patient was started on appropriate immunosuppressive treatment for the same. There have been multiple case reports of thrombocytosis causing arterial or venous thrombus but not many have recorded both arterial and venous thrombosis in the same patient.

Visual Diagnosis: Abnormal Behavior in a 2-month-old Boy.

Visual Diagnosis: Abnormal Behavior in a 2-month-old Boy.

Von Willebrand Factor Levels in Polycythemia Vera Are Not Reduced and Can be Predicted By Erythrocyte Counts

Introduction . Polycythemia Vera (PV) is a myeloproliferative neoplasm (MPN) whose major features are peripheral erythrocytosis and increased thrombotic risk, affecting morbidity and mortality. Essential Thrombocythemia (ET), a MPN characterized by high platelet generation rate, has been shown to be associated with a reduction in von Willebrand factor (vWf) large multimers and activity which depends on platelet turnover (Lancellotti et al, JTH 2015;13:1226-37). The acquired vWf type 2A defect in ET is thought to influence bleeding rate. Data on vWf and on a possible acquired von Willebrand deficiency in PV are less clear. Previous studies included PV patients with marked thrombocytosis, with bleeding history or included treated and untreated patients, with heterogeneous results. Therefore, the phenotypic features of vWf in PV patients with well-controlled haematocrit, routinely accessing the outpatient clinics remain largely undefined. In addition, whether the acquired vWf defect is similar between PV and ET remains poorly defined.Methods . This is an observational, cross sectional study on consecutive PV patients diagnosed according to the 2008 WHO criteria, treated to keep the hematocrit <45% and on antithrombotic prophylaxis with low-dose aspirin, according to current recommendations. VWF:antigen (VWF:ag) and WVF:activity (VWF:act) were measured by chemiluminescence assays (Instrumentation Laboratory, Milan, Italy). Routine hematochemistry, genotype, clinical characteristics and medications were also recorded. To compare vWF-associated phenotype in PV and ET, we selected age- and sex-matched ET patients from a cohort of 69 patients previously-published from our group (Lancellotti et al., JTH 2015; 13:1226-37). PV and ET plasma samples were measured in the same laboratory with the same methods.Results . Forty-one consecutive PV patients gave their written consent (age 66±11 years, 32% females). Mean (±SD) haematologic values were: hematocrit 43.9±2.9%, leukocytes 9.5±4.6x103/µl, platelets 353±260x103/µl. vWf:ag levels averaged 120±24%, vWf:act 115±21%, the act/ag ratio was 0.96±0.06. VWf:ag and vWf:act were significantly correlated (rho=0.98, p<0.001). On univariate analysis, both vWf:ag and vWf:act significantly and positively correlated with male sex, blood groups (higher in non-0 vs. 0 blood groups), hydroxyurea treatment, JAK2V617F allelic burden, and inversely correlated with erythrocytes and platelets. Multivariable analysis confirmed erythrocyte count (inversely, p<0.001, Figure), blood group (p=0.01) and JAK2V617F allele burden (p=0.02) as significant predictors of vWf:ag (adj Rsqr for the entire model=0.54). Erythrocyte count (inversely, p<0.001) and blood group (p=0.02) independently predicted vWf:Act as well (adj Rsqr for the entire model=0.49).We then compared vWf:ag and vWf:act between these PV patients and 41 ET patients (age 64±11 years p=0.4 vs. PV patients, 38% females). As compared to ET patients, PV patients showed similar levels of vWf:ag (120±23 and 136±57% in PV and ET, respectively; p=0.4), but significantly (p<0.01) higher levels of vWf:act (114±20 and 86±47%, in PV and ET, respectively) and act/ag ratios (0.9±0.06 and 0.6±0.2, in PV and ET, respectively).Conclusions. PV patients treated according to current recommendations do not show evidence for acquired vWf defect. In PV patients vWf levels seem dependent on erythrocyte count (inversely), blood groups (as in the normal population) and JAK2V617F allelic burden, with features different from age- and sex-matched ET patients. Future studies are needed to investigate the pathophysiological mechanisms linking eytrhocytes and vWf levels in PV. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Hematopoietic expression of a chimeric murine-human CALR oncoprotein allows the assessment of anti-CALR antibody immunotherapies in vivo.

Myeloproliferative neoplasms (MPNs) are characterized by a pathologic expansion of myeloid lineages. Mutations in JAK2, CALR and MPL genes are known to be three prominent MPN disease drivers. Mutant CALR (mutCALR) is an oncoprotein that interacts with and activates the thrombopoietin receptor (MPL) and represents an attractive target for targeted therapy of CALR mutated MPN. We generated a transgenic murine model with conditional expression of the human mutant exon 9 (del52) from the murine endogenous Calr locus. These mice develop essential thrombocythemia like phenotype with marked thrombocytosis and megakaryocytosis. The disease exacerbates with age showing prominent signs of splenomegaly and anemia. The disease is transplantable and mutCALR stem cells show proliferative advantage when compared to wild type stem cells. Transcriptome profiling of hematopoietic stem cells revealed oncogenic and inflammatory gene expression signatures. To demonstrate the applicability of the transgenic animals for immunotherapy, we treated mice with monoclonal antibody raised against the human mutCALR. The antibody treatment lowered platelet and stem cell counts in mutant mice. Secretion of mutCALR did not constitute a significant antibody sink. This animal model not only recapitulates human MPN but also serves as a relevant model for testing immunotherapeutic strategies targeting epitopes of the human mutCALR.

Thrombocytosis as a Marker of Allograft Rejection in Lung Transplantation: A Case Series

<h3>Introduction</h3> Thrombocytosis (platelet count ≥450 × 10⁹/L) in the early postoperative period after lung transplantation has been correlated with acute cellular rejection (ACR). However, we have also observed significant elevations in platelet counts in the setting of reduced lung function secondary to allograft dysfunction in the late postoperative period. Herein, we describe a case series of three lung transplant recipients with thrombocytosis coincident with episodes of ongoing allograft rejection. <h3>Case Report</h3> Three bilateral lung transplant recipients - a 21-year-old female with trauma-related acute respiratory distress syndrome (patient A), 68-year-old male with interstitial lung disease (patient B), and 60-year-old male with inherited emphysema (patient C) - each presented with few days' history of exertional dyspnea at 4-months, 36-months, and 28-months post-transplant, respectively. Chest computed tomography revealed multifocal bilateral pulmonary consolidations and ground glass changes in patient A, mild upper lobe reticular changes in patient B, and subtle nodular opacities in the upper lobes in patient C. Bronchoscopy with transbronchial lung biopsy revealed influenza virus and grade A2 ACR in patient A. Biopsies in patient B and C showed no evidence of ACR, but revealed focal lung injuries. Marked thrombocytosis was observed on peripheral blood smear in all three patients at the time of admission, and complete blood count showed elevated platelet counts of 525 × 10⁹/L, 626 × 10⁹/L, and 681 × 10⁹/L. Trends of patients' platelet counts and corresponding lung function measures are shown in Figure 1. <h3>Summary</h3> We observed waxing and waning thrombocytosis which corresponded with gradual decline in lung function that ultimately trended towards accelerated chronic lung allograft dysfunction in all three patients. Exploration of this hematologic phenomenon in the setting of late postoperative allograft dysfunction is warranted.

Chronic myeloid leukaemia with marked thrombocytosis.

Chronic myeloid leukaemia with marked thrombocytosis.

LSD1 Inhibition with IMG7289 (bomedemstat) Rebalances Megakaryopoiesis and Erythropoiesis in a Patient with MPN/MDS with Refractory Anemia with Ringed Sideroblast and Marked Thrombocytosis with JAK2 and SF3B1 Mutations

Lysine-specific demethylase-1 (LSD1) is a histone H3 K4 demethylase that plays a critical role in hematopoietic progenitor cell differentiation, in particular, the production of megakaryocytes and erythrocytes from their common classical bi-potent progenitor (MEP). LSD1 is recruited to chromatin by the transcription factor GFI1B to license the maturation of megakaryocyte-erythrocyte progenitor cells (MEPs). Anemia is a common and serious complication of primary myelofibrosis (PMF), which is often refractory to conventional therapy. We report here the effect of IMG-7289 (bomedemstat), an LSD1 inhibitor, on skewing the fate of MEPs favoring the production of red cells over platelets and producing a complete hematologic remission in a JAK2V617F-positive PMF patient who had developed a refractory anemia with ringed sideroblasts. A 63 year old woman presented in 2016 with a 1 year history of with fatigue significantly compromising her lifestyle. She denied fever, night sweats, or weight loss. The physical examination was unremarkable with no palpable splenomegaly. Laboratory studies showed a hemoglobin (Hb) of 11.3 g/dL, a total white blood cell count (WBC) of 20.3k/µL with leukoerythroblastosis with 1% circulating blast cells, and a platelet count of 1,192k/µL. A bone marrow biopsy (BMB) showed a hypercellular marrow with increased dysmorphic megakaryocytes but without dyserythropoiesis. There were no ringed sideroblasts with Perls stain, and silver staining showed grade 2 reticulin fibrosis. The karyotype was del(7)(q11.2) and genotyping identified a JAK2V716F allele (VAF not known). The patient was considered to have PMF. Initial treatment consisted of hydroxyurea but without any improvement in her symptoms. Financial constraints initially prevented access to ruxolitinib but the patient was eventually started on 15 mg BID in January 2018. She tolerated therapy well but discontinued therapy a year later owing to no improvement in her fatigue and opted for observation alone. Over the next year, her hemoglobin fell to the range of 9.0-9.5g/dl and she developed drenching night sweats. A BMB in August 2019 showed a hypercellular marrow with increased dysplastic megakaryocytes but now with 76% ringed sideroblasts. Reticulin stain showed grade 2-3 fibrosis. No other dysplastic features were observed. Additional genotyping was declined by insurance and the patient was considered to have an MPN/MDS overlap syndrome. Accordingly, the patient was enrolled in clinical trial IMG-7289-CTP-102 (NCT03136185), a study of the LSD1 IMG-7289. On entry, her Hb was 9.5 gm/dL with an absolute reticulocyte count of 129K/µL. The WBC was 22.7k/µL with 69% neutrophils and 11% monocytes. The platelet count was 1,585k/µL with a mean platelet volume (MPV) of 8.1 fL. Genotyping showed a JAK2V617F VAF of 27%, a new SF3B1K700E mutation with a VAF of 26%, and a DNMT3A mutation with a VAF of 95%. Spleen volume by imaging was 283.3 cm³. The starting IMG-7289 dose was 40 mg po QD. At week 12, the Hb rose to 13.8 g/dL while the absolute reticulocyte count fell to 40K/µL. The platelet count was 271k/µL with the MPV increasing to 10.5 fL. The WBC was 5.2k/µL with 58% neutrophils and 18% monocytes. The mutant JAK2 allele burden had dropped to 14%. The spleen volume was 223 cm³. The IMG-7289 dose was reduced to 35 mg QD after complaints of fatigue. At Week 24, Hb was 11.7 g/dL, WBC was 12.1k/µL and platelets were 743k/µL. The total symptom score (MPN SAF TSS) was reduced by 31% from baseline. The expected pharmacodynamic effects of LSD1 inhibition on hematopoiesis were evident in this patient: monocytosis with a decrease in neutrophils and a marked reduction in the platelet count. Most striking was the concurrent improvement in the patient's anemia which was associated with a persistent reticulocytosis present at the start of treatment but with a significant increase in red blood cells in the setting of a SF3B1 mutation. MEP fate decisions hinge on the balance between KLF1 and FLI1 with the former favoring an erythroid fate, the later, megakaryocytes. The transcription factor complex of FLI1, GATA1, FOG1 which recruits the LSD1-containing NuRD complex is essential for megakaryocyte function; IMG-7289 likely disrupts that complex favoring erythropoiesis over megakaryopoiesis. The inhibition of LSD1 may, therefore, in the setting of thrombocytosis and anemia, rebalance the fate of MEPs to ameliorate both abnormalities. Disclosures Yacoub: Novartis: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company; Roche: Other: Support of parent study and funding of editorial support. Rienhoff:Imago BioSciences: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents &amp; Royalties.

Clinicopathological Description from the Largest Series of Patients with the Novel Pro106Leu MPL gene Mutation Associated with Hereditary Thrombocythemia

Background: Hereditary thrombocythemia (HT) has been reported in Japanese and African populations in association with S505N, and N35K c-Mpl mutations, respectively. A novel Pro106Leu germ-line mutation in the c-Mpl gene has recently been shown to be associated with HT in Arabic population. Clinical and bone marrow (BM) features of Pro106Leu mutation are largely unknown. Methods: The molecular genetic databases at two tertiary hospitals in Riyadh, King Abdulaziz medical city (KAMC) and King Saud University medical city (KSUMC), were searched to identify all patients (pts) with MPL Pro106Leu mutation. Clinical and pathological data were retrospectively collected. BM aspiration and biopsy were independently reviewed retrospectively by two consultant hematopathologists and agreement was reached by a consensus review. Simple descriptive statistics were used to summarize the results. A univariate subgroup analysis, comparing the hematologic parameters between the homozygous and heterozygous genotypes was conducted using Pearson Chi-Square and t-tests. Results: A total of 115 pts with Pro106Leu MPL mutation were included, 86 (75%) from KAMC and 29 (25%) from KSUMC. All pts were ethnically Arabs. Median age was 33 years (yrs) (range: 0.4-68), 65 (56.5%) were female, and 31 (27%) were pediatric pts (age &amp;lt;18 yrs). MPL Pro106Leu mutation was homozygous in 87 (75.7%) pts, and heterozygous in 28 (24.3%). Spleen was enlarged in 3 (3%) pts, not documented in 15 (13%), and normal in 97 (84%). History of bleeding was documented among 11 (10%) pts. Thrombosis history was positive in 5 (4%) pts only, unavailable in 6 (5%), and negative in 104 (90%). Family history of thrombocytosis was reported in 46 (40%), but family history was not documented in 20 (17%). Common comorbidities include: autoimmune disease in 33 (29%), diabetes 21 (18%), and hypertension 20 (17%). Reasons for MPL testing was: abnormal routine blood work 79 (69%), family history of thrombocytosis 23 (20%), or others 13 (11%). Thrombocytosis [platelet (plt) counts &amp;gt; 450 x109/L] was documented in 107 (93%) pts, normal in 4 (3.5%), and low in 4 (3.5%) at the time of diagnosis of Pro106Leu mutation. See figure 1. The median plt count at the time of diagnosis of MPL Pro106Leu mutation was 667 x 109/L (range: 13-1473). The median mean plt volume was 8 fL (range 6.1-10.2), white blood cell count 8.4 x 109/L (2.46-68.35), absolute neutrophil count 5 x 109/L (1.01- 21.19), hemoglobin 132 gm/L (85-148), mean corpuscular volume 84.1 fL (57-117.3), mean corpuscular hemoglobin 27.7 pg (18-37.5), mean corpuscular hemoglobin concentration 327 g/dL (300-351), and red cell distribution width 13.6 (10.9-22.8). Ferritin less than 30 was seen in 40 (35%) pts, 27 of whom were women. No ferritin done in 14 pts. Iron stores (based on bone marrow, ferritin and iron saturation) were adequate in 56 (49%), inadequate in 49 (43%), and not documented in 10 (9%). BCR-ABL, JAK2 and CALR were only detected in 1 pt each. One pt was not tested for CALR mutation. All other pts were negative for the three mutations. Out of all 115 pts, 33 (29%) had an evaluable BM. BM cellularity ranged from 20-100 %, 12/33 (36%) were hypocellular, 17/33 (52%) normocellular, and 4/33 (12%) hypercellular. Megakaryocyte (meg) morphology revealed dysplastic changes in 20 (60%) (hypolobated megs or with separated lobes), only 7 (21%) of cases had cloudlike megs but none had staghorn or giant megs as described in essential thrombocythemia. BM megs were increased in 29 (87%). Small size megs were seen in 15/33 (45%). Clustering of megs was seen in the majority of the cases 30/33 (90%) of whom, 29(87%) had loose and 20 (60%) dense clusters. On univariate analysis (see tables 1-2), homozygous genotype was associated with higher plt count. Total of 65 (57%) pts were prescribed aspirin, and 16 (14%) hydroxyurea. At the time of last follow-up 114 (99%) of pts were alive. The median follow-up was 7.8 yrs from the time of thrombocytosis (ranged from 0-24.8). No case developed disease progression to myelofibrosis. One pt was diagnosed with T-lymphoblastic lymphoma and later died from treatment complications and another pt was diagnosed with CML. Conclusion: Pro106Leu mutation is associated with marked thrombocytosis at a younger age with a low risk of thrombosis. Homozygous genotype is associated with a significantly higher plt count. BM usually shows either normo- or hypocellular marrow with increased megs proliferation, and clustering. Disclosures No relevant conflicts of interest to declare.

Postpartum vertebral artery dissection: case report and review of the literature

BackgroundHypertensive disorders of pregnancy are associated with vascular complications, including ischemic stroke and cervical artery dissection. Vertebral artery dissection (VAD), however, is rare. We describe a 31-year-old female who presented with vertigo, nausea, and vomiting and was found to have a VAD. In addition, we discuss the presentation, differential diagnosis, and pathogenesis of this uncommon but clinically significant vascular event and summarize other cases of vertebral artery dissection described in the medical literature.Case presentationA 31-year-old Hispanic woman presented 10 days postpartum with a one-day history of vertigo, nausea, vomiting, and frontal headache. The patient’s pregnancy course had been complicated by preeclampsia, chorioamnionitis, and iron-deficiency anemia, and her delivery was complicated by acute hemorrhage. Physical examination was significant for left leg ataxia. Laboratory studies showed marked thrombocytosis. Emergent computed tomography (CT) scan of the head was obtained and revealed a left cerebellar ischemic large vessel stroke. Subsequent CT angiography of the head and neck showed a left VAD. Based on correlation of the clinical history and laboratory and imaging findings, a diagnosis of vertebral artery dissection secondary to reactive (secondary) thrombocytosis from overlapping iron-deficiency anemia and acute hemorrhage was established. The patient was started on a heparin infusion and experienced significant improvement after a four-day hospitalization.ConclusionVAD is a rare but important cause of neurologic symptoms in the postpartum period and should be considered in the differential diagnosis for women who present with headache and/or vertigo. Women aged 30 years or older and those with a history of a hypertensive disorder of pregnancy are at particularly high risk. Prompt diagnosis and management of VAD is essential to ensure favorable outcomes.

Clinical Features and Outcomes of Patients With Chronic Myeloid Leukemia Presenting With Isolated Thrombocytosis: A Systematic Review and a Case From Our Institution.

Chronic myeloid leukemia (CML) represents a common condition in the spectrum of myeloproliferative disorders (MPD). It classically exhibits leukocytosis, but rarely presents with isolated thrombocytosis. This paper is designed to review the clinicopathologic features, treatment, and outcomes of patients with CML who present with isolated thrombocytosis.We searched PubMed, MEDLINE®, ScienceDirect, and Scopus for English-language articles about case series and case reports for the period 2000-2020 with the terms “chronic myeloid leukemia” and “thrombocytosis” and pooled them with a case from our institution. Cases were also incorporated from the reference list and screened for inclusion. A total of 20 cases were included in the final cohort. The male-to-female ratio was 1:1.86. The mean age of the patients at the time of initial diagnosis was 40.5 years (range: 9-77 years). Out of 17 cases with available data, seven (41%) were asymptomatic and found to have thrombocytosis incidentally upon routine blood work. Five cases (29.4%) either had a history of thrombotic events or presented with severe thrombotic complications, including ischemic cerebrovascular accidents (CVA), myocardial infarction (MI), pulmonary embolism (PE), and/or miscarriages. Four cases (23.5%) had more than one symptom at presentation, including headache, syncope, and bruising. The average platelet count was 1,923 × 109/L (range: 584-8,688 × 109/L), and one case (5%) had anemia. The bone marrow (BM) examination showed normal cellularity and normal myeloid to erythroid (M/E) ratio in seven (50%) and 11 (84.6%) out of the 14 and 13 cases with reported data, respectively. Moreover, megakaryocytes in the BM were small in 10 cases (71.4%), pleomorphic in three cases (21.4%), and dysplastic in one case (7.1%).Accurate differentiation among MPD subtypes and the exclusion of CML is critical in reaching a proper diagnosis to decide on proper therapy and eventually modify outcomes. Prompt evaluation for the precise diagnosis of patients presenting with isolated marked thrombocytosis will help expedite their diagnosis and initiation of a specific tyrosine kinase inhibitor (TKI) therapy, thereby promptly inducing remission, preventing thrombotic complications, and avoiding adverse drug events, which would eventually improve outcomes.

EXPERIMENTAL ULCERATIVE COLITIS: TGF-Β AS A DIAGNOSTIC MARKER

Previous studies stated that TGF-β is a pleiotropic cytokine, abundant in mammalian intestine, regulates multiple cellular functions as a suppressor of the immune response, cell proliferation, and oncogenesis. Studyaims: Here, we investigated the value of TGF-β as a diagnostic marker of ulcerative colitis disease (UC) in experimental UC model. Materials& Methods: Acute & chronic UC was induced in mice by using (3% and 1.5% respectively) DSS in drinking water. The induction of UC was confirmed by histopathological examination. Proteins and mRNA expression of both TGF-β and TNF-α were analyzed by western blot and real time PCR respectively. Complete blood count (CBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR). Results: A marked elevation occurred in proteins and mRNA expression of both TGF-β and TNF-α in UC tissues in acute and chronic groups vs. healthy group. Furthermore, significant elevation in both CRP and ESR of diseased groups was recorded in comparison to normal group . Blood count revealed marked leukocytosis, thrombocytosis and marked decrease in red blood cell counts with severe anemia in both acute and chronic UC groups compared to healthy control group . Conclusion: Increased levels of TGF-β protein and mRNA expression in UC disease might have a diagnostic value side by side with inflammatorybiomarkers (TNF-α, CRP & ESR), leukocytosis, thrombocytosis, bloody diarrhea and histopathological changes.

The Essential Thrombocythemia in 2020: What We Know and Where We Still Have to Dig Deep.

The Essential Thrombocythemia is a Chronic Philadelphia-negative Myeloproliferative Neoplasm characterized by a survival curve that is only slightly worse than that of age- and sex-adjusted healthy population. The criteria for diagnosis were reviewed in 2016 by WHO. The incidence varies from 0.2 to 2.5:100 000 people per year, with a prevalence of 38 to 57 cases per 100 000 people. The main characteristics of ET are the marked thrombocytosis and the high frequency of thrombosis. The spectrum of symptoms is quite wide, but fatigue results to be the most frequent. Thrombosis is frequently observed, often occurring before or at the time of diagnosis. The classification of thrombotic risk has undergone several revisions. Recently, the revised-IPSET-t has distinguished 4 risk classes, from very low risk to high risk. Driver mutations seem to influence thrombotic risk and prognosis, while the role of sub-driver mutations still remains uncertain. Antiplatelet therapy is recommended in all patients aged ⩾ 60 years and in those with a positive history of thrombosis or with cardiovascular risk factors, while cytoreductive therapy with hydroxyurea or interferon is reserved for high-risk patients.

The High Mobility Group A1 Chromatin Regulator Is Required for Pathologic Megakaryocyte Development and Progression to Myelofibrosis in JAK2V617F Murine Models

Introduction: JAK2V617F-positive myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell (HSC) disorders characterized by unregulated JAK2/STAT signaling and increased risk of transformation to myelofibrosis (MF). Pathologic JAK2/STAT signaling of the thrombopoietin/thrombopoietin receptor pathway in HSC, progenitors, and megakaryocytes drives megakaryocytic proliferation, megakaryocytic hypertrophy, thrombocytosis, HSC niche damage, osteosclerosis, myelofibrosis, and extramedullary hematopoiesis (EMH). The High Mobility Group A1/2 (HMGA1/2) genes encode oncogenic chromatin remodeling proteins that foster aberrant STAT3 signaling in diverse contexts. In murine models, Hmga1/2 overexpression drives clonal expansion and deregulated proliferation. In patients with MPN, HMGA1/2 genes are overexpressed with disease progression to MF. We therefore sought to: 1) elucidate mechanisms mediated by HMGA1/2 in JAK2V617F-associated MF transformation and 2) test the hypothesis that HMGA proteins are rational therapeutic targets for MF progression. Methods: We used a JAK2V617F transgenic murine model (VF) in which 13 copies of the human JAK2V617F cDNA are driven by the Vav promoter (Blood 2008; 111:5109-5117). To elucidate the function of Hmga1 or Hmga2 in the JAK2V617F context, we crossed VF mice onto a background deficient for Hmga1 or Hmga2 to generate VF/Hmga1+/- and VF/Hmga2+/- progeny. We also generated a tissue specific model whereby Hmga1 was deleted in HSC via Vav-cre (Vav-cre Hmga1+/-) and crossed these mice onto the VF model (VF/Vav-cre Hmga1+/-). Serial blood counts, histology of marrow and spleen, and immunohistochemistry with CD61 antibodies were compared in each model at 8, 16, and/or 40 weeks of age. We also performed flow cytometric analysis of HSC and progenitor populations in mice with these genotypes. Results: The VF mice develop an MPN phenotype by 8 weeks with marked thrombocytosis and erythrocytosis. By 33 weeks, VF mice progress to MF characterized by anemia, splenomegaly due to extramedullary hematopoiesis (EMH), marked megakaryocytic hyperplasia, megakaryocytic hypertrophy, increased platelet size, and osteosclerosis with reticulin fibrosis (Figure A and B). ). The VF mouse also develops an expansion of megakaryocyte-erythroid progenitors (MEP) compared to wildtype mice (P&amp;lt;0.01). Neither mice with Hmga1deficiency (Hmga1+/- or Hmga1-/-) nor Hmga2+/- mice develop thrombocytopenia or other blood count abnormalities at one year of age, and preliminary data suggests that the MEP compartment is normal in Hmga1+/- and Hmga1-/- mice. However, VF/Hmga1+/- mice had reduction of both megakaryocyte hypertrophy and hyperplasia, bone marrow fibrosis, and osteosclerosis compared to VF mice at corresponding age ranges (Figure A). Further, there was mitigation of thrombocytosis, reduction in platelet size, and decreased spleen weight in VF/Hmga1+/- mice compared to VF mice at corresponding age ranges (Figure B). Importantly, VF/Hmga1+/- mice fail to develop anemia which occurs after 33 weeks in the VF model (VF hemoglobin 12.9 g/dl, VF/Hmga1+/- hemoglobin 15.1 g/dl, P&amp;lt;.05). In VF/Hmga1-/- mice, there was no expansion in MEP. The MPN progression to MF was prevented by both global or HSC-specific heterozygous Hmga1 deficiency, demonstrating that the effects of Hmga1 are specific to the hematopoietic cell context rather than the bone marrow microenvironment. In addition, similar degrees of mitigation were observed in VF mice with heterozygous or homozygous Hmga1 deficiency. In contrast, Hmga2 deficiency failed to prevent progression in the VF model. Unexpectedly, Hmga2 deficiency exacerbated megakaryocyte hypertrophy and reticulin fibrosis in VF mice. Conclusions: In a JAK2V617F murine model, heterozygous deficiency of Hmga1 prevents MPN progression to MF, interrupting both the development of megakaryocytic hyperplasia and fibrosis, which are hallmarks of murine and human JAK2V617F disease. While Hmga1 is not required for megakaryocyte or platelet development under steady state conditions, it is critical to the amplification of aberrant signaling in MF associated VF. Further, our findings underscore a key role for HMGA1 as a mediator of aberrant JAK2/STAT3 signaling and a therapeutic target to quell myeloproliferation and prevent MF progression. Disclosures Duffield: Boston Biomedical/Sumitomo Dainippon Pharma Co., Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; MedImmune: Consultancy.