Acute upper gastrointestinal bleeding due to portal hypertension in a patient with primary myelofibrosis:A case report

BACKGROUND Acute upper gastrointestinal bleeding is a common medical emergency that has a 10%hospital mortality rate.According to the etiology,this disease can be divided into acute varicose veins and nonvaricose veins.Bleeding from esophageal varices is a life-threatening complication of portal hypertension.Portal hypertension is a clinical syndrome defined as a portal venous pressure that exceeds 10 mmHg.Cirrhosis is the most common cause of portal hypertension,and thrombosis of the portal system not associated with liver cirrhosis is the second most common cause of portal hypertension in the Western world.Primary myeloproliferative disorders are the main cause of portal venous thrombosis,and somatic mutations in the Janus kinase 2 gene(JAK2 V617F)can be found in approximately 90% of polycythemia vera,50% of essential thrombocyrosis and 50% of primary myelofibrosis.CASE SUMMARY We present a rare case of primary myelofibrosis with gastrointestinal bleeding as the primary manifestation that presented as portal-superior-splenic mesenteric vein thrombosis.Peripheral blood tests revealed the presence of the JAK2 V617F mutation.Bone marrow biopsy ultimately confirmed the diagnosis of myelofibrosis(MF-2 grade).CONCLUSION In patients with acute esophageal variceal bleeding due to portal hypertension and vein thrombosis without cirrhosis,the possibility of myeloproliferative neoplasms should be considered,and the JAK2 mutation test should be performed.

Portal hypertension secondary to myelofibrosis with myeloid metaplasia:A study of 13 cases

AIM:To describe the clinical presentation and complications of portal hypertension (PH) secondary to myelofibrosis with myeloid metaplasia (MMM).METHODS: Medical records for 123 patients with MMM were reviewed.RESULTS: Thirteen patients with PH secondary to MMM were identified. Median ages at time of MMM and PH diagnosis were 61 and 66 years, respectively. The interval from MMM diagnosis to presentation with one of the PH features ranged from 1 to 11 years. Variceal bleeding and ascites were the most common presentations. Of the eight patients who presented with variceal bleeding, six patients underwent endoscopic variceal ligation (EVL) with no variceal recurrence or hematological worsening during a 12-mo follow up period.CONCLUSION: Patients with MMM might develop PH. Exact mechanisms leading to PH in MMM are still controversial. As in other etiologies, variceal bleeding and ascites are the most common presentations. Anemia may correlate with, and/or predict, the severity of the PH presentation in these patients. EVL can successfully control variceal bleeding in MMM. Further clinical studies are required.

Multiple esophageal variceal ruptures with massive ascites due to myelofibrosis-induced portal hypertension

A 75-year old man had been diagnosed at 42 years of age as having polycythemia vera and had been monitored at another hospital. Progression of anemia had been recognized at about age 70 years, and the patient was thus referred to our center in 2008 where secondary myelofibrosis was diagnosed based on bone marrow biopsy findings. Hematemesis due to rupture of esophageal varices occurred in January and February of 2011. The bleeding was stopped by endoscopic variceal ligation. Furthermore, in March of the same year, hematemesis recurred and the patient was transported to our center. He was in irreversible hemorrhagic shock and died. The autopsy showed severe bone marrow fibrosis with mainly argyrophilic fibers, an observation consistent with myelofibrosis. The liver weighed 1856 g the spleen 1572 g, indicating marked hepatosplenomegaly. The liver and spleen both showed extramedullary hemopoiesis. Myelofibrosis is often complicated by portal hypertension and is occasionally associated with gastrointestinal hemorrhage due to esophageal varices. A patient diagnosed as having myelofibrosis needs to be screened for esophageal/gastric varices. Myelofibrosis has a poor prognosis. Therefore, it is necessary to carefully decide the therapeutic strategy in consideration of the patient's concomitant conditions, treatment invasiveness and quality of life.

JAK2 V617F, MPL W515L and JAK2 Exon 12 Mutations in Chinese Patients with Primary Myelofibrosis

Objective： JAK2 V617F, MPL W515L and JAK2 exon 12 mutations are novel acquired mutations that induce constitutive cytokine-independent activation of the JAK-STAT pathway in myeloproliferative disorders （MPD）. The discovery of these mutations provides novel mechanism for activation of signal transduction in hematopoietic malignancies. This research was to investigate their prevalence in Chinese patients with primary myelofibrosis （PMF）. Methods： We introduced allele-specific PCR （AS-PCR） combined with sequence analysis to simultaneously screen JAK2 V617F, MPL W515L and JAK2 exon 12 mutations in 30 patients with PMF. Results： Fifteen PMF patients （50.0%） carried JAK2 V617F mutation, and only two JAK2 V617F-negative patients （6.7%） harbored MPL W515L mutation. None had JAK2 exon 12 mutations. Furthermore, these three mutations were not detected in 50 healthy controls. Conclusion： MPL W515L and JAK2 V617F mutations existed in PMF patients but JAK2 exon 12 mutations not. JAK2 V617F and MPL W515L and mutations might contribute to the primary molecular pathogenesis in patients with PMF.

Pseudohyperkalemia with Myelofibrosis after Splenectomy

SEUDOHYPERKALEMIA refers the serum potassiumlevel is higher than plasma potassium due tovarious reasons in vitro monitoring, but actualpotassium level in vivo is at the normal range. Aseries of inappropriate clinical interventions due to initialfailure to recognize it may actually decrease potassiumlevel，which could cause life-threatening condition. Here wereport a patient with myelofibrosis who occurred spurioushyperkalemia after splenectomy, aiming at emphasizingthe importance of recognizing pseudodyperkalemia.

Peritonitis in myelofibrosis:a cautionary tale

BACKGROUND: Primary myelofibrosis (PMF) is a myeloproliferative disorder characterized by bone marrow fibrosis. Extra-medullary hematopoiesis sometimes occurs even in the peritoneal cavity, apart from organs such as the liver, spleen, and lymph nodes. This may sometimes be complicated by spontaneous infection and complications. We report a rather unusual case of PMF, who presented as an emergency with spontaneous peritonitis to general surgery department and had a fulminant clinical course. METHOD: A clinical case note review was done and a literature search was undertaken. RESULTS: A rather unusual case of PMF, who presented as an emergency with spontaneous peritonitis to general surgery department. The patient underwent a laparotomy and had a fulminant clinical course. CONCLUSIONS: Peritonitis in myelofibrosis may have a number of causes. Clinicians need to be aware of them and provide conservative management prior to surgical treatment. (Hepatobiliary Pancreat Dis Int 2010; 9: 651-653)

Primary myelofibrosis with concurrent CALR and MPL mutations:A case report

BACKGROUND Primary myelofibrosis(PMF)is a myeloproliferative neoplasm(MPN)characterized by recurrent mutations in the JAK2,CALR,and MPL genes.The CALR and MPL co-mutation is very rare.To our knowledge,no more than five cases have been reported.Here,we report a case of PMF in which a CALR and MPL co-mutation was detected by next-generation sequencing(NGS)technology,and a literature review was performed.CASE SUMMARY A 73-year-old woman was admitted to our hospital in 2018 due to abdominal distension.The patient had splenomegaly,lymphadenopathy,leukopenia,anemia,and immature granulocytes in peripheral blood.There were dacrocytes and atypical megakaryocytes in bone marrow,and megakaryocytic proliferation was very active,accompanied by reticulin fibrosis grade 2.By NGS analysis of the bone marrow sample,we detected mutations in CALR,MPL,and PIK3RI,while JAK2 V617F and BCR-ABL were negative.Therefore,the patient was diagnosed with PMF and received oral ruxolitinib.However,the spleen and hematologic responses were poor.We review the literature,analyze previous reports of the mutation sites in our patient and differences between our patient and other reported cases of co-mutated CALR and MPL genes,and discuss the reason why the CALR and MPL co-mutations are rare and possible mechanisms and their impact on the prognosis of patients.CONCLUSION CALR and MPL mutations can be concurrent in MPN,but they are rare.The use of NGS may help to identify more patients with co-mutated CALR and MPL genes.This will help to further explore the mechanism and its impact on these patients to develop appropriate treatment strategies.

Hyperinsulinemia and insulin resistance in a patient with type 2 diabetes complicated with myelofibrosis

Inflammation induces insulin resistance and hyperinsulinemia due to elevation of serum cytokines such as tumor necrosis factor-α and interleukins. Chronic myeloproliferative diseases including myelofibrosis show higher serum interleukin levels than healthy subjects, which has been suggested to be the useful markers for disease activity. However, an association between myelofibrosis and insulin resistance has not ever been discussed anywhere. Here we report a case of type 2 diabetes showing remarkable hyperinsulinemia and insulin resistance possibly due to myelofibrosis.

Acute Panmyelosis with Myelofibrosis: A Rare Subtype of Acute Myeloid Leukemia

Acute panmyelosis with myelofibrosis (APMF) is a subtype of acute myeloid leukemia (AML) classified among the category of “AML, not otherwise specified” in the WHO 2016 classification of hematopoietic tumors. It is a rare, fatal hematological neoplasm that is characterized by acute onset of cytopenias and bone marrow fibrosis in the absence of splenomegaly or fibrosis related morphological changes in the red blood cells. The difficulty of diagnosis and management explains why APMF is rarely reported in Africa. We report here the case of a 30-year-old man who presented with dizziness, palpitations and dyspnea. Diagnosis of APMF was retained on bone marrow histology and immunohistochemistry which showed bone marrow fibrosis and high cellularity with majority of myeloid blast cells. The patient was treated by low dose cytarabine monotherapy 30 mg/m2 per week. At 3 months of treatment, the patient was transfusion-independent, with normalization of hemoglobin and platelets counts. However, the death occurred after 8 months. This case highlights the diagnosis specificity and management of AMPF, knowing the number of potential differential diagnoses and difficulties of its therapeutic management.

Intestinal obstruction caused by extramedullary hematopoiesis and ascites in primary myelofibrosis

Primary myelofibrosis(PMF) is a clonal hematopoietic stem cell disorder. It is characterized by bone marrow fibrosis, extramedullary hematopoiesis with hepatosplenomegaly and leukoerythroblastosis in the peripheral blood. The main clinical manifestations of PMF are anemia, bleeding, hepatosplenomegaly, fatigue, and fever. Here we report a rare case of PMF with anemia, small bowel obstruction and ascites due to extramedullary hematopoiesis and portal hypertension. The diagnosis was difficult to establish before surgery and the differential diagnosis is discussed.

An exceptional case of myelodysplastic syndrome with myelofibrosis following combination chemotherapy for squamous cell lung cancer

A 60-year-old woman with squamous cell carcinoma in the right lung was successfully treated with four cycles of combination chemotherapy after surgery, and complete remission was achieved. However, the patient developed myelodysplastic syndrome (MDS) RAEB-2 with myelofibrosis after remission, possibly because of chemotherapy or DNA methylation. The patient responded well to dacitabine (Dacogen), suggesting that DNA hypomethylation agents can be a promising therapy to retard the progression of a second tumor or carcinoma.

Turner syndrome with primary myelofibrosis,cirrhosis and ovarian cystic mass:A case report

BACKGROUND Turner syndrome(TS)with leukemia is a complicated clinical condition.The clinical course and outcome of these patients are poor,so the treatment and prognosis of TS with hematological malignancies deserve our attention.CASE SUMMARY Here,we report a case of a 20-year-old woman diagnosed with TS,primary myelofibrosis(PMF),cirrhosis,and an ovarian cystic mass.This is the first report on the coexistence of TS and PMF with the MPL and SH2B3 mutations.The patient was diagnosed with cirrhosis of unknown cause,splenomegaly and severe gastroesophageal varices.Additionally,an ovarian cystic mass caused the patient to appear pregnant.The patient was treated with the JAK2 inhibitor-ruxolitinib according to peripheral blood cells,although myelofibrosis was improved,the splenomegaly did not reduce.Moreover,hematemesis and melena occasionally occurred.CONCLUSION Ruxolitinib may clearly reduce splenomegaly.Though myelofibrosis was improved,cirrhosis and splenomegaly in this case continued to worsen.Effective treatment should be discussed.

Primary myelofibrosis with thrombophilia as first symptom combined with thalassemia and Gilbert syndrome:A case report

BACKGROUND A 46-year-old Han man first had sigmoid sinus and transverse sinus venous thrombosis at the age of 42.At the age of 44,he once again developed thrombosis.Genetic testing showed heterozygous SERPINC1 mutation,bone marrow biopsy showed fibrosis grade 1(MF-1),and JAK2 V617F mutation was positive,accompanied by UGT1A1 mutation andβ-thalassemia gene mutation.CASE SUMMARY A 46-year-old Han man was first found to have sigmoid sinus and transverse sinus venous thrombosis at the age of 42 but had no individual or family thrombosis history,and he had been regularly taking warfarin anticoagulant therapy for a long period of time.At the age of 44,venous thrombosis reappeared in parts of the intrahepatic vein,main portal vein,splenic vein,and superior mesenteric vein,and his spleen was obviously enlarged.He had a history of jaundice for many years,and genetic testing revealed that he carried a heterozygous SERPINC1 mutation.Bone marrow biopsy showed multifocal fibrous tissue hyperplasia among trabeculae and focal fibrosis.He was positive for the JAK2 V617F mutation.At the same time,UGT1A1 andβ-thalassemia gene mutations existed,and a SERPINC1 mutation and UGT1A1 mutation were both found in his parents.CONCLUSION The patient in this case had thrombophilia as the primary symptom,JAK2V617-positive myeloproliferative neoplasm(MPN)was the main potential cause,and hereditary AT-III deficiency may have been one of multiple secondary causes.It remains to be determined whether UGT1A1 andβ-thalassemia gene mutations are related to thrombophilia.However,the clinical features of MPN in this patient were hidden,and the relevant clinical features of coexisting thalassemia and hereditary Gilbert syndrome,reported here for the first time domestically and abroad,were complicating factors,causing great difficulties for a clear diagnosis.Thus,when thrombophilia has been determined,it is necessary to screen the relevant latent problems overall.When the clinical features cannot be perfectly explained by one etiology,a relevant comprehensive examination should also be initiated from the perspective of multiple etiologies.

Advances in the Study of High-Risk Gene Mutations for Primary Myelofibrosis

Primary myelofibrosis is a kind of MPNs due to clonal appreciation of hematopoietic stem cells. With the development of second-generation sequencing, high-risk mutation (HMR) genes such as ASXL1, EZH2, SRSF2, and IDH1/2 have been shown to be associated with disease prognosis and progression, and although allo-HSCT remains the only possible treatment for PMF, with the development of JAK inhibitors, there is an increasing interest in the study of inhibitors of these mutant loci.

Leukocytosis at Diagnosis in Patients with Essential Thrombocythemia Is a Risk Factor for Transformation into Myelofibrosis

Myelofibrosis (MF) represents the major long-term complication of essential thrombocythemia (ET). There is evidence that leukocytosis at diagnosis is associated with poorer survival in patients with ET. In this study, we retrospectively evaluated 143 patients with ET, diagnosed in agreement with WHO criteria, followed in a single centre over >10 years. Nine of them transformed into MF (post-essential thrombocythemia-myelofibrosis PET-MF). We compared PET-MF data at diagnosis with that of the remaining 134 patients (ET-1) and with a selected sub-group of ET-1 (ET-2, 19 pats) sex, age and follow-up duration matched to PET-MF. The PET-MF evolution rate was 4.6 per 1000 person-years;white blood cells count (WBC) count, haemoglobin levels and hematocrit were higher in PET-MF than in ET-1 (P = 0.01) while only WBC was higher than in ET-2 (P = 0.01). With multivariate analysis, only WBC count retained its signifi-cance. Our study highlights the prognostic relevance of leukocytosis on myelofibrotic transformation of ET.

Myelofibrosis: Prognostication and cytoreductive treatment

Myeloproliferative neoplasms include three diseases: polycythemia vera, essential thrombocythemia and primary myelofibrosis(PMF), currently diagnosed according to the 2008 World Health Organization criteria. Patients with PMF may encounter many complications, and, among these, disease progression is the most severe. Concerning prognostication of Myelofibrosis(MF), the International Prognostic scoring system(IPSS)(International Prognostic Scoring System) model at diagnosis and the Dynamic IPSS(DIPSS) anytime during the course of the disease may be useful to define survival of MF patients. The IPSS and the DIPSS are based on age greater than 65 years, presence of constitutional symptoms, hemoglobin level less than 10 g/d L, leukocyte count greater than 25 × 109/L, and circulating blast cells 1% or greater. Cytogenetic profile and mutational analysis seem to be the next step to implement MF prognostication. Concerning treatments, hydroxyurea has been considered until now the drug of choice when an anti-myeloproliferative effect is needed, but recent data on JAK inhibitors demonstrated a significant effect of these drugs on splenomegaly and symptoms.

A New Observation of Bone Marrow Involvement by Diffuse Large B-Cell Lymphoma Mimicking Myelofibrosis

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma, characterized by high clinical and biological heterogeneity. Patients typically present with progressive lymphadenopathy, extranodal disease and may also experience fever, night sweats and unexplained weight loss. We report here the case of a 16-year-old female with osteoarticular pain, dizziness, and dyspnea on exertion. Clinical examination showed no lymphadenopathy. Complete blood count (CBC) revealed pancytopenia and marrow smears found to be hypocellular. Initial diagnosis favored secondary myelofibrosis. Diagnosis of bone marrow involvement by DLBCL was retained on bone marrow histology and immunohistochemistry which showed infiltration of large B lymphoid cells. The patient was treated by immunochemotherapy R-CHOP regimen. This case highlights a very rare and atypical circumstance of discovery of DLBCL with myelofibrosis as an initial symptom. Prognosis value of this presentation and management difficulties are also discussed.

Overview of dyslipidemia and metabolic syndrome in myeloproliferative neoplasms

Myeloproliferative neoplasms(MPNs)occur due to the abnormal proliferation of one or more terminal myeloid cell lines in peripheral blood.Subjects suffering from MPNs display a high burden of cardiovascular risk factors,and thrombotic events are often the cause of death in this population of patients.Herein,we provide a brief overview of dyslipidemia and metabolic syndrome and their epidemiology in MPNs and examine the common molecular mechanisms between dyslipidemia,metabolic syndrome,and MPNs,with a special focus on cardio-vascular risk,atherosclerosis,and thrombotic events.Furthermore,we investigate the impact of dyslipidemia and metabolic syndrome on the occurrence and survival of thrombosis in MPN patients,as well as the management of dyslipidemia in MPNs,and the impact of MPN treatment on serum lipid concentrations,particularly as side/adverse effects reported in the context of clinical trials.

Efficacy and safety of JAK inhibitor INC424 in patients with primary and post-polycythemia vera or post-essential thrombocythemia myelofibrosis in the Chinese population

A phase II study （A2202） was performed to evaluate the efficacy and safety of JAK inhibitor ruxolitinib in 63 Chinese MF patients. Ruxolitinib was given twice a day （bid） at a starting dose of 15 mg （n = 25） or 20 mg （n = 38） based on a baseline platelet count. About 94.7% of the patients achieved a reduction in spleen size, 27.0% of which exhibited significant reduction （≥35%） at week 24. Significant improvement in debilitating constitutional symptoms, as assessed by MFSAF v2.0, was observed in patients treated with ruxolitinib. Ruxolitinib treatment was generally weli tolerated by Chinese patients. Although the treatment was associated with an increase in certain adverse events （AEs） that were established as identified risks （anemia and thrombocytopenia）, these AEs were considered manageable in this clinical setting. Ruxolitinib provided substantial reductions in splenomegaly and improvements in symptoms, and was well-tolerated by Chinese patients with MF.

Hemoglobin E/beta-thalassemia with Massive Myelofibrosis

HbE is the most common hemoglobin variant in the world.In compound heterozygotes,the interaction of HbE with othermutations in the β-globin gene results in HbE/β-thalasse-mia disease,which shows great variation in severity,includingcases that require blood transfusions just like the β-thalasse-mia major patients.Many hematologic disease could developmyelofibrosis.However,HbE/β-thalassemia with myelofibro-