Low-risk polycythemia vera treated with phlebotomies: clinical characteristics, hematologic control and complications in 453 patients from the Spanish Registry of Polycythemia Vera.

Hematological control, incidence of complications, and need for cytoreduction were studied in 453 patients with low-risk polycythemia vera (PV) treated with phlebotomies alone. Median hematocrit value decreased from 54% at diagnosis to 45% at 12 months, and adequate hematocrit control over time (< 45%) was observed in 36%, 44%, and 32% of the patients at 6, 12, and 24 months, respectively. More than 5 phlebotomies per year in the maintenance phase were required in 19% of patients. Worsening thrombocytosis, age > 60 years, and microvascular symptoms constituted the main indications for starting cytoreduction. Median duration without initiating cytoreduction was significantly longer in patients younger than 50 years (< 0.0001). The incidence rate of thrombosis under phlebotomies alone was 0.8% per year and the estimated probability of thrombosis at 10 years was 8.5%. The probability of arterial thrombosis was significantly higher in patients with arterial hypertension whereas there was a trend to higher risk of venous thrombosis in cases with high JAK2V617F allele burden. Rates of major bleeding and second primary neoplasm were low. With a median follow-up of 9 years, survival probability at 10 years was 97%, whereas the probability of myelofibrosis at 10 and 20 years was 7% and 20%, respectively. Progression to acute myeloid leukemia was documented in 3 cases (1%). Current management of low-risk PV patients is associated with low rate of thrombosis and long survival. New treatment strategies are needed for improving hematological control and, in the long term, reducing progression to myelofibrosis.

Cardiovascular Risk in Polycythemia Vera: Thrombotic Risk and Survival: Can Cytoreductive Therapy Be Useful in Patients with Low-Risk Polycythemia Vera with Cardiovascular Risk Factors?

BACKGROUND/AIMS: Cardiovascular risk factors are not considered in the current scores for evaluation of the thrombotic risk in myeloproliferative neoplasms, and in polycythemia vera (PV) in particular. Cytoreduction is currently not indicated in low-risk patients with PV, despite the absence or presence of cardiovascular risk factors. Our purpose is to highlight how cardiovascular risk factors in patients with PV increase the thrombotic risk both in low- and high-risk patients. METHODS: We collected and analyzed data from 165 consecutive patients with a diagnosis of PV followed at our institution and compared the frequency of thrombosis in subgroups of patients distinguished by the presence or absence of cardiovascular risk factors. The statistic tools used to obtain the results were the χ2 and the Kruskal-Wallis test for frequencies, and the Kaplan-Meyer method as well as the log-rank test for analysis of survival data. RESULTS: The major result obtained is that the frequency of thrombotic events in our population is strictly linked with the cardiovascular risk, and it increases with the number of risk factors. Moreover, survival significantly worsens with the number of cardiovascular risk factors, despite the classical PV risk stratification. CONCLUSION: It should be useful to design perspective studies to determine the real influence of cardiovascular risk factors on the thrombotic risk for patients with PV and on survival in order to evaluate the opportunity to develop new specific therapeutic recommendations.

Outcomes Following Posterior Lumbar Fusion in Patients with Polycythemia Vera.

BACKGROUND: Polycythemia vera (PV) is a chronic myeloproliferative neoplasm that is associated with increased risk for venous and arterial thromboembolism. The aim of this study was to evaluate outcomes following elective posterior lumbar fusion (PLF) and/or posterior interbody fusion (PLIF) among patients with PV. METHODS: Using PearlDiver retrospective national database, Medicare patients <85 years old who underwent elective primary PLF (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 81.07) and/or PLIF (ICD-9-CM code 81.08) for degenerative lumbar spine pathologies during 2006-2013 were identified. Patients included in the PLF and/or PLIF cohort were separated into patients with a prior diagnosis of PV (ICD-9-CM code 238.4) and a control cohort of patients without PV. Comparisons of postoperative outcomes were made between the PV patient group and matched control group. Significance was set at 0.05. RESULTS: Selected study participants included 1491 patients with PV and 29,056 patients in the matched control group. Patients with PV had a significantly increased rate of 90-day acute pulmonary embolism (1.9% vs. 1.2%, odds ratio [OR] 1.65, 95% confidence interval [CI] 1.10-2.38, P = 0.010), 90-day lower extremity deep vein thrombosis (3.4% vs. 1.9%, OR 1.81, 95% CI 1.33-2.40, P < 0.001), and 1-year diagnosis of surgical site infection (5.4% vs. 4.2%, OR 1.30, 95% CI 1.02-1.63, P = 0.027) compared with patients without PV. Nonetheless, PV was not associated with other major medical complications, including stroke, myocardial infarction, and mortality, following PLF and/or PLIF. CONCLUSIONS: Patients with PV undergoing elective PLF and/or PLIF have a significantly increased risk for pulmonary embolism, lower extremity deep vein thrombosis, and surgical site infection.

Polycythemia Vera Management and Challenges in the Community Health Setting.

Patients with polycythemia vera (PV) experience shortened survival, increased risk of thromboembolic and hemorrhagic events, and burdensome symptoms. For all patients with PV, treatment with aspirin and hematocrit control with phlebotomy are recommended. In addition, patients with high-risk status or poor hematocrit control benefit from cytoreductive therapy with hydroxyurea, although approximately 1 in 4 patients develops resistance or intolerance. For patients who are resistant to or intolerant of hydroxyurea, studies have shown that ruxolitinib, a Janus kinase 1/2 inhibitor, provides hematocrit control, reduces spleen size, normalizes blood counts, and improves PV-related symptoms. For many patients, PV is managed in a community health setting, and it is important that community hematologists, oncologists, and internists are familiar with the contemporary management of PV to improve patient outcomes, including management for patients who present with unique health-care needs. This review provides an overview of current treatment options for patients with PV and discusses challenging circumstances encountered by community providers in the management of PV, including symptom assessment, identification of hydroxyurea resistance/intolerance, pregnancy, elective surgeries, concomitant immunosuppressants, and managing patients in areas with limited access to specialized hematologic care.

Pharmacobiological Approach for the Clinical Development of Ruxolitinib in Myeloproliferative Neoplasms.

Ruxolitinib, a JAK1 and JAK2 inhibitor drug, has recently been approved for the treatment of patients with high- or intermediate-risk myelofibrosis with symptomatic splenomegaly. Ruxolitinib is the first clinically useful targeted therapy in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). The aim of this paper is to indicate pharmacobiological aspects of ruxolitinib within the potential context of MPNs. Pharmacobiological assessments, in addition to knowledge of the risk profile for ruxolitinib in MPNs, are required. We propose hypotheses based on our experience in a splenectomized MPN patient with hyperproliferative bone marrow and moderate fibrosis receiving ruxolitinib. We believe that a true clinical development approach for this drug should include pharmacobiological assessments for ruxolitinib in addition to the disease risk profile of MPNs.

Perioperative blood product administration and thromboembolic events in patients with treated polycythemia vera: a case-control study.

BACKGROUND: Patients with polycythemia vera (PV) have historically been considered to be at high risk for perioperative hemorrhagic and thromboembolic complications. However, no recent studies have compared these outcomes between treated PV patients and patients without PV undergoing similar procedures. STUDY DESIGN AND METHODS: Patients with PV who underwent surgery with anesthesia from June 1, 2006, to May 31, 2011, were randomly matched (sex, age, type of surgical procedure, surgical year) at a ratio of 1:4 with control patients without PV. Conditional logistic regression analysis adjusting for surgical duration, preoperative hemoglobin, platelet count, and cardiovascular disease was used to assess the association between PV and blood product transfusions, thromboembolism, and other major cardiovascular and pulmonary complications. RESULTS: Fifty-six PV patients who underwent 79 surgeries were matched with 312 controls. During hospitalization, 35 (44.3%) and 82 (25.9%) PV and control patients, respectively, were transfused with blood products. PV patients were at increased risk for transfusion intraoperatively (odds ratio [OR], 4.35; 95% confidence interval [CI], 1.79-10.57; p = 0.001) and during hospitalization (OR, 4.35; 95% CI, 1.84-10.31; p < 0.001). The likelihood of thromboembolic complications and/or other major complications did not differ between the two study groups (thromboembolic-OR 1.53, 95% CI 0.39-6.02, p = 0.540; other major complications-OR 2.15, 95% CI 0.93-4.96, p = 0.073). CONCLUSIONS: Medically managed PV patients had an increased likelihood of receiving blood products perioperatively. Given the low number of observed thromboembolic events, we cannot make definitive conclusions regarding the association between PV and thromboembolism.

The role of parathyroidectomy in JAK2 mutation negative polycythemia vera.

The relationship between polycythemia vera (PV) and primary hyperparathyroidism is not well understood. Remission or improvement of PV following parathyroidectomy in the setting of primary hyperparathyroidism has previously been described; however, long-term outcomes are not well characterized. We describe a patient with JAK2 mutation negative PV and primary hyperparathyroidism, with a dramatic, but ultimately transient, improvement in hemoglobin following resection of a parathyroid adenoma. While screening for hyperparathyroidism may be useful in the setting of PV, indications for parathyroidectomy should be driven by symptomatology or established criteria, not the desire to affect the clinical course of PV.

An exceptional case of renal artery restenosis in a patient with polycythaemia vera.

Polycythaemia vera represents a rare chronic myeloproliferative neoplasm characterized by an increased thrombotic risk. Previous case reports have documented a link between primary or secondary polycythemia and the presence of renal artery stenosis and renovascular hypertension. Herein, we report an exceptional case of renal artery restenosis leading to uncontrolled hypertension in a patient with PV and high haematocrit levels. A 52-year-old female patient with a history of polycythaemia vera under treatment with hydroxyurea and phlebotomy presented in our outpatient clinic with newly diagnosed hypertension caused by left renal artery stenosis. Six months after stenting, patient returned for a follow-up visit due to uncontrolled hypertension and high haematocrit levels. Total restenosis of the left renal artery was found. Patient received optical medical treatment and was prescribed to higher doses of hydroxyurea by her treating haematologist. Since then, blood pressure and Hct levels remain adequately controlled. As described by earlier case reports, renal artery stenosis, hypertension and polycythemia often coexist. However, renovascular hypertension may not only lead to secondary erythrocytosis but also be a thrombotic complication of primary erythrocytosis. Thus, patients with polycythaemia vera should be carefully evaluated and optimally managed when hypertension or impaired renal function coexist.

Successful liver transplantation in a patient with splanchnic vein thrombosis and pulmonary embolism due to polycythemia vera with Jak2v617f mutation and heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin treatment resulting in a severe acquired thrombophilic condition with an associated mortality of about 10 %. We report the first case of successful urgent liver transplantation (LT) in a patient with end-stage liver disease due to a Budd-Chiari syndrome, portal vein thrombosis and pulmonary embolism due to acquired thrombophilia associated to polycythemia vera carrying JAK2V617F gene mutation and HIT in the acute phase. Lepirudin was used to provide anticoagulation in the LT perioperative period that was performed without haemorrhagic and thrombotic complications despite the donor received heparin during liver explantation.

Splenic extramedullary hematopoietic proliferation in Philadelphia chromosome-negative myeloproliferative neoplasms: heterogeneous morphology and cytological composition.

We studied 24 spleens with extramedullary hematopoietic proliferation (EMHP), a key feature of advanced-stage Philadelphia chromosome-negative myeloproliferative neoplasms, obtained from 24 patients (14 primary myelofibrosis, 7 polycythemia vera and 3 unclassifiable). Hematoxylin and eosin, reticulin and trichrome stains, and immunohistochemical stains for myeloperoxidase, glycophorin-C, CD42b, CD34, CD117, CD8, nerve growth factor receptor and smooth muscle actin were evaluated. Clinical information was correlated with the morphological findings. Three distinct histological patterns of EMHP were recognized: diffuse (12), nodular (5), and mixed-nodular and diffuse (7). The preponderant lineage was granulocytic in diffuse, trilineage in nodular and erythroid in mixed EMHP. Erythropoiesis was largely intravascular, granulopoiesis was within the splenic cords and megakaryopoiesis was observed in both locations. The stromal changes paralleled the histological pattern with preservation of the splenic stromal and vascular architecture in the diffuse areas as opposed to areas of nodular EMHP. The morphological features of the splenic EMHP did not correlate with specific subtypes of myeloproliferative neoplasms. The mean duration of follow-up from initial diagnosis was 80 months. A total of 15 of the 24 patients died of disease: 8 of 12 (67%) with diffuse, 2 of 5 (40%) with nodular and 5 of 7 (71%) with mixed growth patterns. The mean duration from diagnosis to splenectomy was shorter in patients with diffuse (83 months) as compared with those with nodular EMHP (127 months). Our study demonstrates that splenic extramedullary hematopoietic proliferation in Philadelphia chromosome-negative myeloproliferative neoplasms shows distinct histological patterns that do not correlate with disease subtypes, but appear to suggest a trend between the histological patterns and clinical behavior. These results suggest a different biology of the disease in the nodular and diffuse extramedullary hematopoietic proliferation groups.

Right hepatic artery thrombosis in an essential polycythemia vera patient following pancreato-biliary surgery for severe pancreatitis.

Hepatic artery thrombosis (HAT) remains one of the major causes of graft failure and mortality in liver transplant recipients. But it is a very rare in non-transplantation patient with the complication of HAT. We reported herein a case of successful urokinase intra-arterial thrombolytic treatment for HAT in an essential polycythemia vera patient following pancreato-biliary surgery. This patient underwent debridement and T-tube drainage in common bile duct for severe pancreatitis and acute suppurative obstructive cholangitis. Significant elevation of liver transaminases and white blood cell counts was noted 30 days after operation and HAT was confirmed by CT-angiography and digital subtracted angiography. Apart from malena and malaise, this patient had scarcity of evident symptoms. The only obvious risk factor relating to HAT is thrombocytosis. This patient was continuously characterized by an excess of platelets from its admission to the onset of HAT. This patient was treated successfully with continuous transcatheter arterial thrombolysis using urokinase. The symptom including malena and malaise disappeared 3 days after thrombolysis. And the patient was treated with hydroxyurea for polycythemia vera thereafter. In conclusion, physicians should be alerted that HAT can be happened in non-transplantation patients especially in those of having hypercoagulability.

Splenectomy normalizes hematocrit in murine polycythemia vera.

Splenic enlargement (splenomegaly) develops in numerous disease states, although a specific pathogenic role for the spleen has rarely been described. In polycythemia vera (PV), an activating mutation in Janus kinase 2 (JAK2(V617)) induces splenomegaly and an increase in hematocrit. Splenectomy is sparingly performed in patients with PV, however, due to surgical complications. Thus, the role of the spleen in the pathogenesis of human PV remains unknown. We specifically tested the role of the spleen in the pathogenesis of PV by performing either sham (SH) or splenectomy (SPL) surgeries in a murine model of JAK2(V617F)-driven PV. Compared to SH-operated mice, which rapidly develop high hematocrits after JAK2(V617F) transplantation, SPL mice completely fail to develop this phenotype. Disease burden (JAK2(V617)) is equivalent in the bone marrow of SH and SPL mice, however, and both groups develop fibrosis and osteosclerosis. If SPL is performed after PV is established, hematocrit rapidly declines to normal even though myelofibrosis and osteosclerosis again develop independently in the bone marrow. In contrast, SPL only blunts hematocrit elevation in secondary, erythropoietin-induced polycythemia. We conclude that the spleen is required for an elevated hematocrit in murine, JAK2(V617F)-driven PV, and propose that this phenotype of PV may require a specific interaction between mutant cells and the spleen.

Subacute intestinal obstruction associated with a case of polycythemia vera--a rare combination.

Primary Polycythemia Vera (PV) is difficult to diagnose due to its varied and atypical 1 presentation. It is a myeloproliferative disorder which is managed conservatively. We submit a case report of a patient who was admitted in surgery with subacute intestinal obstruction due to compression by a massive splenic cyst. The investigations showed PV causing splenomegaly.

Symptomatic splenomegaly in polycythemia vera: a review of the indications for splenectomy and perioperative considerations.

Polycythemia vera is a condition that surgeons do not commonly encounter. Advances in medical management have largely led to avoidance of surgical intervention in most patients. Indications and timing of splenectomy have been the subject of debate since the disease was first described in the late 19th century. Though anemia and thrombocytopenia associated with polycythemia vera only transiently respond to splenectomy, painful splenomegaly with infarction or compression of surrounding viscera are presently accepted indications for surgery. Special consideration must be given to polycythemia vera patients both preoperatively and postoperatively due to altered coagulation and anatomy. We present a review of the pathophysiology, medical treatment, indications for surgical intervention, and perioperative considerations for polycythemia vera.

Massive intraventricular thrombus in polycythemia vera.

Polycythemia vera is a chronic myeloproliferative disorder which is prone to thrombotic complications. However, thrombosis of the cardiovascular system is an extremely rare complication of polycythemia vera. We describe a 76-year-old male patient who developed congestive heart failure due to massive intraventricular thrombus with pulmonary valvular involvement. Surgical treatment under cardiopulmonary bypass proved to be the sole solution for such a condition.

Choosing between stem cell therapy and drugs in myelofibrosis.

Optimal clinical management of patients with primary myelofibrosis and post-essential thrombocythemia/polycythemia vera myelofibrosis is a challenge, given the typically advanced age of presentation and variability of the disease course and prognosis. Current medical therapeutic options have not demonstrated an impact on the disease course, which exceeds the palliation of disease-related extramedullary hematopoiesis and alleviation of cytopenias. In contrast, allogeneic stem cell transplantation (SCT) can lead to 'cure' but is limited due to patient's age or comorbidities. Currently, in patients, who are reasonable candidates, SCT (frequently with a reduced intensity conditioning regimen) is employed for intermediate- to high-risk disease. Current pharmaco-medical therapy is used as a bridge to transplant, or instead of transplant in poor transplant candidates. Pathogenetic insights, especially the discovery of the Janus kinase (JAK)2(V617F) mutation, have ushered in a host of new potential therapeutic agents that may augment the role of medical therapy. Similarly, the boundaries of transplantation continue to alter with strategies that decrease conditioning-related toxicity, improved antimicrobial prophylaxis and decreased graft-versus-host disease. The potential for continued improvements in both medical and transplant therapy suggests that for the immediate future the optimal choices for an individual patient will remain potentially volatile and present complex decisions.

Postsurgery outcomes in patients with polycythemia vera and essential thrombocythemia: a retrospective survey.

A multicenter retrospective analysis was performed to estimate the frequency of thrombosis and hemorrhage after surgical procedures in patients with polycythemia vera (PV) and patients with essential thrombocythemia (ET). Data from 105 patients with PV and 150 patients with ET were analyzed, for a total of 311 surgical interventions. An emergency procedure was performed in 25 (8.1%) patients; 194 surgeries were done under general anesthesia, and 21 (23%) of 91 abdominal interventions were done under laparoscopy; 155 (50.1%) were major surgeries. Subcutaneous heparin was administered in 169 (54.3%) of 311 cases and antiplatelet therapy in 48 (15.4%) of 311 case interventions. One hundred eighty-eight (74%) of 255 patients were on cytoreductive therapy before surgery. No events were observed in 259 (83.2%) of 311 procedures during 3 months of follow-up; there were 12 arterial and 12 venous thrombotic events, 23 major and 7 minor hemorrhages, and 5 deaths. Arterial thromboses were more frequent in ET (5.3% vs 1.5%; P=.08), venous events were more frequent in PV (7.7% vs 1.1%; P=.002). There was not a correlation between bleeding episodes and the type of diagnosis, use of antithrombotic prophylaxis, or type of surgery. A high proportion of PV and ET surgeries was complicated by vascular occlusion (7.7%) or by a major hemorrhage (7.3%). Prospective investigations analyzing the optimal prophylaxis in these patients are suggested.

Hematoma of a congenitally bicuspid aortic valve in a patient with polycythemia vera and the antiphospholipid antibody syndrome.

We present a novel case of a hematoma involving a congenitally bicuspid aortic valve. The patient was a 47-year-old woman with polycythemia vera and antiphospholipid antibody syndrome. She was treated with anagrelide for thrombocytosis. The patient developed a valvular hematoma which caused clinically significant aortic stenosis and regurgitation. Consequently, the patient underwent surgery with insertion of a porcine bioprosthesis. Eighteen months postoperatively the patient developed a large prosthetic thrombus with severe aortic stenosis requiring reoperation.

Regression of myelofibrosis and osteosclerosis following hematopoietic cell transplantation assessed by magnetic resonance imaging and histologic grading.

Myelofibrosis is a reactive, often inhomogeneous process in the marrow cavity, and sampling errors on biopsies obtained to diagnose and monitor the course of myelofibrosis have been a constant problem in hematopathology. We investigated the potential utility of magnetic resonance imaging (MRI) of the lumbar spine, pelvis, and femora as a diagnostic and monitoring technique for assessment of myelofibrosis. Findings on serial marrow biopsies were correlated with T1-weighted spin-echo and short inversion time inversion recovery (STIR) images in patients with chronic idiopathic myelofibrosis or myelofibrosis developing from polycythemia vera or essential thrombocythemia who underwent hematopoietic cell transplantation (HCT). Thirty-five patients were studied before HCT; 11 were followed for 3 months and 10 patients for >/=1 year after HCT with sequential marrow biopsies and MRI studies. MRI allowed direct visualization of the biopsy sites and correlation of histologic and MRI findings. MRI also provided assessment of the extent and degree of myelofibrosis in a large volume of the skeletal marrow. There was good correlation between biopsy results and MRI findings at specific biopsy sites and between successful HCT and resolution of fibrosis and osteosclerosis as determined by MRI. We conclude that in patients with myelofibrosis, MRI of the skeleton provides a comprehensive assessment of the pattern and extent of fibrosis and allows for correlation with biopsy findings. In patients undergoing HCT, MRI accurately reflects response or progression of marrow disease.