Thrombohemorrhagic Complications Research Articles

Secondary malignancies in essential thrombocythemia and polycythemia vera: A retrospective analysis of 437 patients from a single institution.

6621 Background: Essential thrombocythemia (ET) and polycythemia vera (PV) are chronic myeloproliferative neoplasms (MPN). Patients (pts) are at risk of thrombohemorrhagic complications for which they are often treated with different agents. Previous studies suggested that the risk of secondary malignancy (SM) may be increased in pts with PV or ET treated with Hydroxyurea (HU) or Alkylating agents (ALK). We report the incidence of SM in pts with ET and PV at our institution and treatment received. Methods: We performed a retrospective chart review of all pts with ET and PV seen at MD Anderson (diagnosis according to WHO) between January, 1960 and September 2010, recorded the pathological diagnosis of SM, and performed an analysis to look for differences in risk of SM according to treatment received. Results: A total of 437 pts charts (ET 263, PV 174) were evaluated. 29 pts developed SM [12 ET (4.6%), 17 PV (9.8%)] with median time to diagnosis of 68 months (14-167) in ET pts and 76 months (1-247) in PV pts. 6 pts developed 2 SM. 23 Pts had 29 solid tumors [7 Skin cancers (ET 2, PV 5), 5 breast (ET 2, PV3), 4 lung (ET 3, PV1), 4 genitourinary (ET 2, PV 2), 2 Thyroid (PV 2) and 7 other cancers]. 6 pts had hematologic malignancy [4 AML (ET 2, PV 2), 1 CLL (ET) and 1 NHL (ET)]. 341 (78%) of the 437 pts [222 (84%) ET; 119 (68%) PV] received one or combination of: 1- HU: 259 (60%) pts [162(62%) ET; 97 (56%) PV]; 2- Anagrelide (AG): 145 (33%) pts [112 (43%) ET; 33 (19%) PV]; 3- interferon (INF): 69 (16%) pts [47 (18%) ET; 22 (13%) PV]; 4- ALK (busulfan, melphalan or chlorambucil): 23 (5%) pts [16 (6%) ET; 7 (4%) PV]. Median follow up (MFU) was 69 months (1-396) with 27% of pts followed > 10 y. Risk of SM was 7% in pts treated with HU (ET 6%; PV 8%), 5% with AG (ET 4%; PV 9%), 4% with INF (ET 6%, PV 0%), and none of the pts receiving ALK developed SM (perhaps due to low number of pts and short MFU). 8 (8%) of the 96 pts not receiving any treatment developed SM. No statistical difference in SM risk was observed among treated and non treated groups. Conclusions: Our analysis confirmed inherited risk of developing SM in pts with ET and PV. Contrary to previous reports, the type of therapy received did not increase that risk, perhaps due to a relatively short MFU.

Annual Clinical Updates in Hematological Malignancies: A Continuing Medical Education Series: Polycythemia vera and essential thrombocythemia: 2011 update on diagnosis, risk‐stratification, and management

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms primarily characterized by erythrocytosis and thrombocytosis, respectively. Other disease features include leukocytosis, splenomegaly, thrombohemorrhagic complications, vasomotor disturbances, pruritus, and a small risk of disease progression into acute leukemia or myelofibrosis. Diagnosis is based on JAK2 mutation status (PV and ET), serum erythropoietin (Epo) level (PV), and bone marrow histopathology (ET). The presence of a JAK2 mutation and subnormal serum Epo level confirm a diagnosis of PV. Differential diagnosis in ET should include chronic myelogenous leukemia and prefibrotic myelofibrosis. Current risk stratification in PV and ET is designed to estimate the likelihood of thrombotic complications: high-risk-age > 60 years or presence of thrombosis history; low-risk-absence of both of these two risk factors. Presence of extreme thrombocytosis (platelet count > 1,000 x 10⁹/L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. Risk factors for shortened survival in both PV and ET include age > 60 years, leukocytosis, history of thrombosis, and anemia. Survival is near-normal in ET and reasonably long in PV. The 10-year risk of leukemic/fibrotic transformation is < 1%/1% in ET and < 5%/10% in PV. In contrast, the risk of thrombosis exceeds 20%. The main goal of therapy is therefore to prevent thrombohemorrhagic complications and this is effectively and safely accomplished by the use of low-dose aspirin (PV and ET), phlebotomy (PV), and hydroxyurea (high risk PV and ET). Treatment with busulfan or interferon-a is usually effective in hydroxyurea failures.

Platelets — From Function to Dysfunction in Essential Thrombocythaemia

Platelets are an important component of blood. The main biological role of platelets is to respond to vascular injury and promote thrombus formation to prevent bleeding. However, we now know that platelets also have additional functions in a variety of processes such as immunity, inflammation, coagulation, atherogenesis and tumour metastasis. Platelet disorders commonly lead to defects in haemostasis. Of particular interest is the myeloid proliferative disorder, essential thrombocythaemia (ET). In ET the increased number of platelets leads to an increased risk of blood clot formation and subsequent thrombohaemorrhagic complications. Here we provide a general review of platelet function and activation, as well as more detailed information on the dysfunction of platelets in patients with ET.

Rethinking Disease Definitions and Therapeutic Strategies in Essential Thrombocythemia and Polycythemia Vera

The seminal discovery of the JAK2V617F mutation, which is highly prevalent in Philadelphia-negative myeloproliferative disorders, now renamed neoplasms, triggered an almost unprecedented explosion of interest and data in the field. Descriptions of additional mutations in exon 12 of JAK2, at position 515 in MPL, and a number of other mutations at low frequency followed these discoveries. These advances in our understanding of molecular pathogenesis of these conditions coincided with the publication of results from two major clinical studies, ECLAP and PT-1, which contributed important clinical insights and facilitated significant correlative data collection. This article, focusing mainly upon essential thrombocythemia and polycythemia vera, reviews four major themes: the impact upon classification of these disorders considering a radical review of current terminology, and then three areas pertinent to clinical management: the indications for cytoreductive therapy in which the key targets are to reduce thrombohemorrhagic complications, relieve disease-related symptoms, and minimize the risk of transformation to secondary myeloid malignancy such as myelodysplasia, leukemia, and secondary myelofibrosis; and second reviewing current and, last, future therapeutic options, in particular interferon and JAK2 inhibitors.

Treatment related changes in antifibrinolytic activity in patients with polycythemia vera

Polycythemia vera (PV) is a clonal myeloproliferative disorder characterized by predominantly excessive erythrocyte production. During the course of the disease, bleeding or thrombosis may be observed. In PV patients, the influence of antifibrinolytic activities on development of thrombohemorrhagic complications remains to be elucidated. In the present study, alterations in antifibrinolytic activity of PV patients and the effects of treatments on these alterations were investigated. Newly diagnosed and therapy-naive 22 PV patients were included. Thrombomodulin (TM), plasmin-alpha 2-antiplasmin complex (PAP), plasminogen activator inhibitor-1 (PAI-1) and thrombin activable fibrinolysis inhibitor antigen (TAFIa) levels were measured in all individuals and after phlebotomy and 5-hydroxyurea (5-HU) therapy in PV patients. TM, PAP, PAI-1 and TAFIa values of the patient group were higher than those of the controls. After phlebotomy, no changes were detected in TM, PAI-1 and TAFIa values, but PAP values decreased. On the contrary, 5-HU treatment resulted in a marked decrease in TM, PAI-1, PAP and TAFIa levels. These findings suggested that the changes in antifibrinolytic activity and endothelial dysfunction might be contributed to formation of intravascular thrombosis in PV patients, even though not clinically overt. 5-HU in addition to phlebotomy affects antifibrinolytic activity and may have an influence on diminishing predisposition of thrombosis.

Thrombohemorrhagic complications of myeloproliferative disorders

Myeloproliferative disorders are commonly associated with thrombohemorrhagic manifestations. The current review highlights recent advances in understanding the epidemiology and pathogenetic mechanisms of thrombotic and bleeding complications. Therapeutic modalities and prophylactic interventions corresponding to the specific disease states are also discussed.

Importance of Rapid Diagnosis of Hemostatic Dysfunction in Patients with Injury and Acute Blood Loss

Examining the hemostatic system in 436 patients with injury and acute blood loss by an instrumental low-frequency piezoelectric hemocoagulation technique permits one to assess the likelihood of thrombohemorrhagic complications and multiple organ dysfunction syndrome in early stages of disease. Key words: acute blood loss, hemorrhagic shock, APACHE, disseminated intravascular coagulation, multiple organ dysfunction syndrome.

Src tyrosine kinase preactivation is associated with platelet hypersensitivity in essential thrombocythemia and polycythemia vera

AbstractPolycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative disorders characterized by an increased incidence of thrombo-hemorrhagic complications. The acquired somatic Janus kinase 2 (JAK2) V617F mutation is present in the majority of PV and ET patients. Because aberrant protein Tyr-phosphorylation has been associated with hematopoietic malignancies, the activity of the tyrosine kinases Src and JAK2 was analyzed in resting and thrombin-stimulated platelets from 13 PV and 42 ET patients. JAK2 was found inactive in healthy and pathological resting cells regardless of the V617F mutation. In addition, Src was inactive in all resting platelets, but in the pathological specimens it was present in a preactivated conformation as a consequence of anomalous dephosphorylation of its inhibitory phospho-Tyr527 residue, likely mediated by Src homology-2 domain-containing protein Tyr-phosphatase-2 (SHP-2), whose constitutive activity correlated with its recruitment to Src. Low thrombin concentration triggered a more rapid Src-signaling activation, higher [Ca2+]c increase, and aggregation in pathological platelets compared with controls. Thrombin-induced Src activation preceded JAK2 activation, which occurred simultaneously in normal and pathological platelets. Our results indicate that a constitutive Src kinase preactivation is implicated in platelet hypersensitivity and likely involved, at least partially, in the functional abnormalities of PV and ET platelets.

Haemostatic Profile of Patients with Type 2 Diabetes Mellitus in Northern Nigeria

Diabetes Mellitus is a major health problem that results in significant morbidity and mortality from diverse complications. Thrombo-haemorrhagic complications are well recognized among diabetic populations. Many of the previous haemostatic studies in diabetic Nigerians focused on patients from the west and south eastern parts with scanty information from northern Nigeria. A total of 50 diabetic subjects aged between 30 – 80 years attending the diabetic clinic of the Jos University Teaching Hospital were selected for the study. 50 aged and sex matched non – diabetic persons in the family medicine outpatient clinic of the same hospital were recruited as controls. Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT), Thrombin Time (TT) and fibrinogen weight were estimated using standard methods. There was significant prolongation of PT, APTT, TT of diabetics when compared with the non – diabetic controls (P<0.005). Also the mean fibrinogen weight was significantly higher in the diabetic patients than the controls (P<0.05). These findings suggest that despite the popular notion of a prothrombotic tendency in diabetes, diabetics may also be prone to developing haemonhagic complications. It is helpful to bear this in mind, and to include incorporate PT, APTT, TT and fibrinogen assay as routine investigations for better management of these patients.

Is RARS-T a new disease entity or a subtype of RARS or ET?

TO THE EDITOR: A recent report of V617F mutation in myelodysplastic syndrome, myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable, refractory anemia with ring sideroblasts with thrombocytosis, and acute myeloid leukemia by Jekarl DW et al. [1] has shown one patient with JAK2 V617F mutation among 7 patients with RARS-T. This 14.3% of JAK2 mutation rate seems to be lower than 58% of previously reported data in the review of Wardrop D and Steenma DP [2]. Fifty-four patients had JAK2 mutation among 93 patients with RARS-T in 10 serial studies. Additionally 2 of 27 JAK2 wild-type patients showed MPLW515 mutation. MPLW515 mutation is found in 5% of primary myelofibrosis and 1% of essential thrombocythemia (ET) cases [3]. But Jekarl DW et al did not report about this second mutation in their article. One more concern for this report was the incidence and the diagnosis of RARS-T. Seven patients were enrolled in this single-center study only for 3 years. Seven RARS-T patients seemed to be extraordinarily many, even when authors used WHO 2008 criteria which alleviates the criterion of thrombocytosis from 600,000/µL to 450,000/µL, and their center is one of the large tertiary hospitals in Korea. Also, there was no data on 7 RARS-T patients about the percentages of ring sideroblast (RS), and comorbidities which are necessary for the exclusion of other reacitve thrombocytoses such as inflammation or bleeding. The role of RS in the pathophysiology of RARS, RARS-T and RCMD-RS (this entity is recently combined with RCMD in WHO 2008 criteria) is not clearly elucidated now. Also the cut-off value of 15% is thought to be arbitrary. Seventy-three MDS patients with RS showed the wide range of RS between 1% and 86% [4]. The survival of patients with RARS-T was similar to that of patients with ET but better than that of patients with RARS [5]. The thrombohemorrhagic complications of patients with RARS-T had not been reported except in some case repots. The recommended approach to RARS-T is same as in ET although anemia and neutropenia could be aggravated by cytoreductive therapy. Therefore, RARS-T, a provisional and new entity in WHO 2001 and 2008 criteria should be reconsidered whether it will be kept its own entity or be integrated into ET or RARS as a subtype depending on the dysplastic features of marrow.

Thrombotic Complications and Risk of Myeloid Transformation in 164 Elderly Patients with Essential Thrombocythemia.

Abstract 2916Poster Board II-892 Introduction:Essential thrombocythemia (ET) is a myeloproliferative neoplasm associated with increased risk of both venous and arterial thrombosis, hemorrhage and transformation to other myeloid disorders such as myelofibrosis (MF), myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML). Although age greater than 60 years has been shown to be an independent risk factor for thrombosis, data regarding disease outcome and optimal therapy in the very elderly diagnosed with ET is limited. Our aim was to assess rates of thrombo-hemorrhagic complications and transformation in very elderly patients with ET at two tertiary care centers in Vancouver, British Columbia. Patients and methods:A retrospective chart review was conducted of all patients diagnosed with ET at age 60 years or older from 1982 to 2008. Data collected included baseline patient characteristics, arterial and venous thrombosis at diagnosis, cardiac risk factors, antiplatelet and cytoreductive therapy throughout the course of the disease, and thrombo-hemorrhagic complications or transformation to AML, MDS or MF during the follow-up period. The patients were separated into three age groups: 60 to 69 years, 70 to 79 years, and 80+ years. Chi-squared tests were used to compare the age groups in terms of baseline characteristics, treatment, thrombotic and hemorrhagic complications, and myeloid transformation. Kaplan-Meier curves for thrombosis and transformation-free survival were generated to follow rates of thrombosis and transformation over time. Results:We identified 164 patients diagnosed with ET at age 60 years or older, of which 68 were 60-69 years, 66 were 70-79 years and 30 patients were 80+ years. The median duration of follow-up was 2576 days for the 60-69 group, 1903 days for the 70-79 group, and 453 days for the 80+ group. The three groups were similar in baseline characteristics, including cardiac risk factors, baseline levels of haemoglobin, white blood cells and platelets, as well as the rates of thrombotic or hemorrhagic events at diagnosis. Treatment including the use of ASA (91% 60-69y, 80.3% 70-79y and 75.9% 80+y, p=0.10) and hydroxyurea therapy (67.2% 60-69y, 80.3% 70-79y and 73.3% 80+y, p=0.23) was comparable amongst the three age groups. The number of patients developing thrombotic events during follow up (30.9% 60-69y, 16.7% 70-79y and 13.3% 80+y, p=0.063) and the risk of thrombosis over time (Figure 1A) was similar across the three age groups (p=0.68). The number of patients with myeloid transformation during follow up was greater in the 60-69 age group (25% 60-69y, 9.1% 70-79y and 6.7% 80+y, p=0.013), but the risk of transformation over time was not significantly different (p=0.29) (Figure 1B). Conclusions:Age over 60 years has previously been shown to be a risk factor for thrombosis in patients with ET. The current study found no differences in the rates of thrombotic complications, nor myeloid transformation amongst three subgroups of elderly patients with ET. We also note that physicians' treatment approach does not seem to differ amongst these elderly subgroups. Although our data is limited by a small number of very elderly patients, we conclude that the disease course is not different amongst various age groups of elderly patients with ET. With currently available information, there is no reason to consider the disease differently in such patients. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

MiRNAs Expression Pattern in Essential Thrombocythemia and Polycythemia Vera Patients.

Abstract 1912Poster Board I-935 Background:Essential Thrombocythemia (ET) and Polycythemia Vera (PV) are myeloproliferative neoplasms (MPN) arising from a multipotent hematopoietic stem cell characterized by an unregulated production of platelets, red cells and white cells alone or in combination, a tendency to clonal evolution and an increased risk of thrombohemorrhagic complications. MicroRNAs (miRNA) are negative regulators of genes involved in cellular proliferation, apoptosis and/or carcinogenesis. Aim:To analyze the expression pattern of miRNA between PV and ET patients and to find distinctive signatures in ET patients according to JAK2V617F and c-MPL mutational status. Material and Methods:Total RNA was extracted from peripheral blood granulocytes of 50 ET patients, 10 PV patients and 10 controls. Median age of patients was 57 years (range, 20-88); males 36%. The JAK2V617F mutation was present in 23 (46%) of 50 ET patients and in all PV patients. MPL mutations were present in 5 (18%) of 27 JAK2V617F negative cases (3 cases MPLW515L, 1 case MPLW515K and 1 case MPLS505N). miRNA expression was profiled in 384 miRNA via Taqman Low Density Array in ABI PRISM 7900. Expression data was normalized with RNU48 and relative quantification was calculated with the 2–σσCt method. The data were presented as log10 of relative quantity of target miRNA. Median of normal controls was used as calibrator for all samples. Data were analyzed by means of Significant Analysis of MicroArrays (SAM), Prediction Analysis of MicroArrays (PAM) and Class Comparison methods using BRB array tools version 3.7.0 and TIGR multiexperiment viewer version 4.3. Results:We found a general downregulation of miRNA in ET and PV patients respect to normal controls. A set of 29 miRNA allowed us to discriminate between ET and PV versus normal controls; three of these miRNA were up-regulated and 16 down-regulated in PV and ET vs. normal controls with a >2 fold change and p value <0.01. A distinctive signature of 79 miRNAs differentiated ET, PV and controls and a hierarchical clustering analysis defined miRNA expression profiles of the three particular groups. When we compared miRNA differentially expressed between PV and ET patients, we found nine miRNA, 4 up-regulated and 5 down-regulated in ET with respect to PV patients (p<0.01). Statistical comparisons between ET JAK2V617F-positive and ET JAK2V617F-negative cases showed a distinctive signature of 13 miRNA that allowed us to discriminate between the two groups. In addition, we also found in JAK2V617F cases 19 miRNA differentially expressed between MPL positive and MPL negative patients, with a >2 fold change and p<0.01. Finally, an increased expression of miR-142-5p correlated with JAK2V617F allele burden in ET patients Conclusions:Our study demonstrates that ET and PV can be defined by specific signatures of miRNA. In ET, some miRNA allow us to discriminate cases according to JAK2V617F mutational status and also between MPL-positive and MPL-negative JAK2V617F-negative patients. Research Funding:FIS EC07/90791 Disclosures:No relevant conflicts of interest to declare.

Spontaneous Bilateral Renal Subcapsular Hematoma as a Possible Complication of Myeloproliferative Disorders

A 64-year-old male had bilateral renal subcapsular fluid accumulation evident on abdominal sonography performed during postoperative follow-up after surgery for a hepatoma. There were no clinical symptoms, and he had no history of trauma or receiving anticoagulant medication. Spontaneous bilateral renal subcapsular hemorrhage was diagnosed after a series of examinations. He did have an underlying myeloproliferative disorder (MPD), and had received incomplete cytoreductive treatment. Platelet aggregation in MPD is often abnormal, and both bleeding and hypercoagulation complications have been reported. Here we report a rare case of MPD with possible thrombohemorrhagic complications presenting as spontaneous bilateral renal subcapsular hematomas.

Defining targets in myeloproliferative disorders: reflecting on what is important

The current lack of curative options for essential thrombocythaemia (ET) leads to the goal of reducing the risk of potentially life-threatening thrombohaemorrhagic complications with long-term treatment. The setting of relevant treatment targets is an important consideration in this process, allowing the monitoring of disease control. Recent revisions to the World Health Organization (WHO) diagnostic criteria for the chronic MPDs 1 have implications not only for the diagnosis of patients, but also for the management of their disease and the continuing assessment of their progress. The purpose of this article is to discuss recent revisions to the WHO guidelines, and their influence on the setting of treatment targets in patients with ET.

Second malignancies in essential thrombocythemia (ET): a retrospective analysis of 331 patients with long-term follow-up from a single institution

Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by an indolent clinical course, with a median survival exceeding 20 years. A minority of patients undergo thrombohemorrhagic complications, which might be prevented by cytoreductive treatment in high risk categories. Alkylating agents (ALK) have been demonstrated to increase the risk of acute leukemia and myelodysplastic syndromes in patients with myeloproliferative disorders, whereas the potential oncogenicity of hydroxyurea (HU) remains a matter of debate. In this study, we retrospectively investigated long-term development of hematological and non-hematological second malignancies in 331 patients with ET, analyzing possible associations with chemotherapy treatments. Median follow-up was 108 months. Of the 194 patients who were treated with chemotherapy, 116 (60%) received only HU, 38 (19·5%) only ALK (busulfan or melphalan) and 40 (20·5%) ALK followed by HU. After a median time of 87 months from the diagnosis of ET, 43 patients developed a second malignancy, hematological in 15 and non-hematological in 28, for an overall cumulative incidence of 13%. According to the type of treatment, second malignancies were documented in 11·2% of patients treated with only HU, in 26·3% of patients who received only ALK, and in 25% of those treated with ALK followed by HU. Ten cases (7·3%) were recorded among the 137 patients who did not receive any treatment. Our analysis revealed a significant association between treatment with alkylating agents and an increased risk of developing second hematological malignancies, whereas no such association was detected with regard to treatment with hydroxyurea single agent in our ET population. In addition, different treatment strategies did not affect the risk of developing second solid cancers.

The Mevalonate Pathway as a Therapeutic Target in the Ph-Negative Chronic Myeloproliferative Disorders

The Ph-negative chronic myeloproliferative disorders (CMPDs) polycythaemia vera, essential thrombocytosis and idiopathic myelofibrosis are acquired stem cell disorders, which pathophysiologically are featured by clonal myeloproliferation and accumulation of myeloid cells, the latter being consequent to decreased apoptosis. Myelofibrosis and neoangiogenesis in the bone marrow and spleen are the histopathological hallmarks of idiopathic myelofibrosis but may develop in the other diseases as well. In patients with myelofibrosis elevated levels of circulating CD34+ cells are highly characteristic being partly explained by a proteolytic bone marrow mileu owing to excessive release of various proteases with ensuing extracellular matrix degradation and constitutive mobilisation of CD34+ cells into the peripheral blood. Thrombohaemorrhagic complications are major clinical problems contributing significantly to morbidity and mortality. Based upon in vitro and in vivo studies of the effects of statins (antithrombotic, antiproliferative, antiangiogenic, antiproteolytic) and zoledronic acid (antiproliferative antiproliferative, antiangiogenic, antiproteolytic) this review focusses on the translation of these effects into potential clinical benefits of combinational therapy with these agents in patients with CMPDs.

Update on the treatment of polycythemia vera with recombinant interferon alfa or imatinib mesylate

Polycythemia vera is a myeloproliferative disease, which, if untreated, leads to thrombohemorrhagic complications and eventually to progressive myelofibrosis, anemia, and splenomegaly. Two newly available drugs, interferon alfa and imatinib mesylate, may alter the course of this disease. Used as single agents, each produces lasting remissions in about 75% of patients with polycythemia vera. Of significance, change in JAK2 expression has been reported after treatment with both agents.

72 Thrombohemorrhagic complications during pregnancy and delivery in patients with hereditary connective tissue disorders

72 Thrombohemorrhagic complications during pregnancy and delivery in patients with hereditary connective tissue disorders

What role do coagulation disorders play in the pathogenesis of leptospirosis?

Leptospirosis is a zoonosis of worldwide distribution, spread by the urine of infected animals. It is a major public health problem, especially in developing countries, where circumstances for transmission are most favourable. The clinical picture varies from mild disease to a severe illness with haemostatic derangements and multiorgan failure eventually leading to death. Although the haemorrhagic complications of severe disease are serious, the pathophysiology is scarcely elucidated. The complex mechanisms involved in inflammation-induced coagulation activation are extensively studied in various infectious diseases, i.e. Gram-negative sepsis. Tissue factor-mediated coagulation activation, impairment of anticoagulant and fibrinolytic pathways in close concert with the cytokine network are thought to be important. But for human leptospirosis, data are limited. Because of the growing interest in this field, the impact of leptospirosis, and the availability of new therapeutic strategies, we reviewed the evidence regarding the role of coagulation in leptospirosis and provide suggestions for future research.

Phenotypic Differences amongst Subgroups of Patients with Myelofibrosis with Myeloid Metaplasia (MMM): Analysis of 458 MMM Patients.

Background: Debate continues as to the clinical relevance of subclassifying patients with the myeloproliferative disorder (MPD) MMM into the subgroups of agnogenic myeloid metaplasia (AMM), post-polycythemic myeloid metaplasia (PPMM), and post-thrombocythemic myeloid metaplasia (PTMM). We looked to validate previously described phenotypic variability amongst subtypes, and explore relevant and differences in constitutional symptoms.Methods: An detailed analysis of patients with MMM whom responded to an international web based survey of MPD patients which registered responses regarding diagnosis, disease course, complete blood counts, co-morbidities (Charlson Co-morbidity index), symptoms, and fatigue (Fact-An and Brief Fatigue Inventory (BFI)).Results: A total of 456 patients self described as MMM responded of which 32.3% had AMM (n = 148), 38.0% % had PPMM (n = 174), and 29.7% had PTMM (n = 136). Detailed breakdown of differences in demographics, clinical course, current laboratory studies, treatment history, and current symptoms are outlined in the table below.Phenotypic Variability Amongst 458 MMM PatientsCategoryAMM (N=148; 32.3%)PPMM (N=174; 38.0%)PTMM (N=136; 29.7%)MMM Total (N=458)Δ between groups (p = )Age (Median)615757580.09Sex (% Males)60%49%30%47%<0.01Yrs from MPD Dx5686<0.01Labs/ Prior HistoryHb (g/dL)11.013.711.612.1<0.01% with RBC Tx43%6%11%20%<0.01Leukocytes (×10(9)/L)8.07.67.27.70.64Platelets (×10(9))/L)200352396321<0.01% with Splenomegaly76%49%41%54%<0.01% with Prior Thrombosis10%22%31%21%<0.01% with Prior Bleed16%20%31%22%0.01Treatment History for the MMM% with Prior Tx for MPD64%88%77%77%<0.01% Medical Therapy57%70%75%67%<0.01# Meds (Median (Range))1 (0–8)2 (0–6)2 (0–6)2 (0–8)<0.01% with Splenectomy8%5%6%6%0.48% with SCT6%1%1%3%<0.01MMM Associated Constitutional Symptoms% with Fatigue85%81%85%84%0.56% with Bone Pain51%46%44%47%0.51% with Fevers19%17%18%18%0.87% with Pruritus39%69%39%50%<0.01% with Night Sweats55%58%53%56%0.67% with Weight Loss30%15%16%20%<0.01Hb = Hemoglobin; SCT = Stem Cell TransplantOverall the data suggests patients with AMM are more likely male, with greater burdens of anemia, splenomegaly, and weight loss. However they are less likely to have experienced thrombohemorrhagic complications and have received fewer MPD medications. In contrast PPMM patients (not unsurprisingly) have little trouble from anemia, but have the most pruritus. Patients with PTMM are most likely female, with the highest platelet counts, and the greatest likelihood of thrombohemorrhagic complications. Additionally, all three subgroups of MMM had significant fatigue compared to published controls for both fatigue instruments (P<0.0001) yet there was no difference between MMM subtypes for the severity of fatigue.Conclusions: A large unselected series of MMM patients supports that although constitutional symptoms are significant and similar amongst MMM subgroups, these patients have variable burdens of other MPD manifestations.