What factors determine the pregnancy outcome in patients with essential thrombocythemia?

Objectives: Treatment of essential thrombocythemia (ET) is particularly challenging in pregnancy due to the increased risk of thromboembolic complications. Therefore, the use of antithrombotic regimens are recommended in pregnant women with ET.Methods: The study included 52 pregnancies in 27 patients diagnosed with ET, who were treated in Department of Haematology. The influence of anticoagulant, antiplatelet and cytoreductive therapy on the course and outcome of pregnancy was analysed. This study also examined if there was any correlation between molecular and clinical features such as mutational profile, blood count, presence of acquired von Willebrand syndrome (AvWS), the International Prognostic Score for Essential Thrombocythemia (IPSET) risk group and the IPSET-thrombosis risk group and pregnancy outcome.Results: Study participants who received antithrombotic therapy were significantly more likely to give birth to a healthy child. The best outcomes were observed in patients who received low dose acetylsalicylic acid (ASA) together with low-molecular-weight heparin (LMWH). There was a statistically significant correlation between classification to the high-risk group according to the IPSET-thrombosis score and incidence of miscarriage. Cytoreductive treatment with interferon-α2, as well as the presence of AvWS did not increase the likelihood of pregnancy loss. Blood counts and presence of specific gene mutations profile were also not found to be significant determinants of pregnancy outcome.Conclusion: To our best knowledge, this is the first clinical study investigating the correlation between risk group (according to IPSET and IPSET-thrombosis) and pregnancy outcome in women with ET.

Treatment of Essential Thrombocythemia with Anagrelide Is Associated with an Increased Risk of Worsened Kidney Function.

BACKGROUND AND PURPOSE: When choosing a cytoreduction method for patients suffering from essential thrombocythemia (ET), it is important to know the safety profile of the medicine used. Few articles have been published about the effects of hydroxycarbamide (hydroxyurea, HU) and anagrelide (ANA) on renal function in ET patients. This study is the largest analysis of nephrotoxicity of cytoreductive drugs used in ET therapy so far, which additionally includes risk factors for the progression of kidney disease and coexisting genetic mutation. EXPERIMENTAL APPROACH: The retrospective study included 310 patients diagnosed with ET. Demographic data, comorbidities, Cr, and estimated glomerular filtration rate (eGFR) were all taken into account prior to diagnosis and after 6 months of HU and ANA treatment. KEY RESULTS: A statistically significant difference was found between Cr and eGFR levels at baseline and after 6 months of treatment (p < 0.001). The applied treatment (HU and ANA) had the greatest impact on kidney function. ANA significantly increased the risk of worsening renal function in contrary to hydroxycarbamide after 6 months of treatment (eGFR change: median +1 mL/min/1.73 m2 [interquartile range (IQR) (-4)-(+7)] in the HU group vss. median -13 mL/min/1.73 m2 [IQR (-18)-(-6)] in the ANA group, odds ratio [OR] 7.92 95% confidence interval [95% CI] [4.17-15.08], p < 0.001). Lowering of eGFR <60 mL/min/1.73 m2 occurred in 31 patients (31.0%) from the ANA group and 10 people (4.8%) treated with HU (p = 0.000). In 1 patient from the ANA group, >50% decrease in eGFR was observed. The chance for an increase in Cr levels was higher in people with pre-existing arterial hypertension (OR 1.92 CI = 95% [1.21-3.05], p = 0.006). Sex, type of mutation found (JAK2 V617F or CALR), and previous renal impairment did not affect renal function after 6 months of treatment. In addition, there was no difference in the efficacy of ET treatment between HU and ANA (p = 0.998). CONCLUSIONS AND IMPLICATIONS: The observations indicate that ANA should be used in patients with ET with great caution and taking into account the risk of worsened kidney function.

The pathogenesis and available prevention options in patients with diabetic thrombophilia.

Diabetes mellitus (DM), a growing health problem itself, is accompanied by an increased risk of cardiovascular and thrombotic complications. The imbalance between coagulation and fibrinolysis processes observed in patients with diabetes may be defined as diabetic thrombophilia. Several mechanisms are involved in the hypercoagulability state in diabetics, including endothelial cell damage, altered platelet structure and function, increased microparticle formation, different structure of fibrin clots, disturbances in the activity of coagulation factors, fluctuations in the concentrations of fibrinolysis activators and inhibitors, and qualitative changes of proteins due to glycation and oxidation processes. These all are the reasons why DM is the most common cause of acquired thrombophilia. Moreover, diabetes changes the efficacy of certain medications. Results of various trials seem to suggest that thrombolytic drugs are less effective in patients suffering from this disease. The impact of DM on the effectiveness of treatment with acetylsalicylic acid (ASA) remains unclear. Awareness of thrombotic complications in diabetic patients may enable earlier diagnosis and proper therapy.

Constitutional mutations of the CHEK2 gene are a risk factor for MDS, but not for de novo AML.

CHEK2 plays a key role in cellular response to DNA damage, and also in regulation of mitosis and maintenance of chromosomal stability. In patients newly diagnosed with myelodysplastic syndrome (MDS, n = 107) or acute myeloid leukemia (AML, n = 117) congenital CHEK2 mutations (c.444 + 1G > A, c.1100delC, del5395, p.I157 T) were tested by PCR and sequencing analysis. The karyotype of bone marrow cells of each patient was assessed at disease diagnosis using classical cytogenetic methods and fluorescence in situ hybridization. The CHEK2 mutations were strongly associated with the risk of MDS (p < 0.0001) but not with the risk of de novo AML (p = 0.798). In CHEK2-positive MDS patients, two times higher frequency of aberrant karyotypes than in CHEK2-negative patients was found (71% vs. 37%, p = 0.015). In CHEK2-positive patients with cytogenetic abnormalities, subtypes of MDS: refractory anemia with excess blasts-1 or 2, associated with unfavorable disease prognosis, were diagnosed two times more often than in CHEK2-negative cases with aberrations (78% vs. 44%). In conclusion, the congenital CHEK2 inactivation is strongly associated with the risk of MDS and with a poorer prognosis of the disease. However, the chromosomal instability in AML is not correlated with the hereditary dysfunction of CHEK2.

Application of the apparent diffusion coefficient in magnetic resonance imaging in an assessment of the early response to treatment in Hodgkin's and non-Hodgkin's lymphoma - pilot study.

PURPOSE: Lymphoproliferative neoplasms are the largest and most frequently diagnosed entities in the group of haematological malignancies. The aim of the study was to assess whether apparent diffusion coefficient (ADC) measured on the first day of the second cycle of chemotherapy could be a predictor of prognosis and of the final treatment's outcome. MATERIAL AND METHODS: The study included 27 patients with diagnosed Hodgkin's and non-Hodgkin's lymphoma, who had magnetic resonance (MR) performed with diffusion weighted imaging/apparent diffusion coefficient (DWI/ADC) before and on the first day of the second cycle of chemotherapy. Imaging was performed using a 1.5 T MR scanner. ADC was measured in lymphoma infiltration in the area of the lowest signal in the ADC map and the highest signal on ß 800 images in post-treatment study. After that, the corresponding area was determined in a pre-treatment study and an ADC value was measured. RESULTS: The difference between ADC values in pre-treatment (ADC = 720 mm2/s) and post-treatment (ADC = 1059 mm2/s) studies was statistically significant (p < 0.001). Cutoff values for estimating response to treatment were established at the level of ADC 1080 mm2/s, and ADC to muscle ratio at 0.82 in post-treatment study. Patients with ADC > 752 mm2/s before treatment manifested lower probability of progression than patients with ADC < 752 mm2/s. CONCLUSIONS: ADC measurement's before treatment and on the first day of the second cycle of chemotherapy can be used as a prognostic marker in lymphoma therapy. ADC values lower than 1080 mm2/s and an increase of the ratio after the treatment can be considered as a marker of disease progression.

Peripheral circulatory disorders in essential thrombocythemia.

A significant number of patients with essential thrombocythemia (ET) complain of symptoms including distal parts of the extremities (e.g., paresthesias or Raynaud's phenomenon). The aim of the present study was to examine peripheral circulation in the upper extremities of individuals with ET. The study included 45 ET patients and 30 control subjects. All participants were subjected to thermography, photoplethysmography, impedance plethysmography, and applanation tonometry pulse wave analysis. The patients with ET differed significantly from the control subjects in terms of 3rd finger skin temperature (mean 31.04 vs. 32.45°C), skin temperature gradient (mean 1.82 vs. 0.11°C), photoplethysmographic amplitude (median 0.25 vs. 0.74%), and pulse waveform in the radial artery (more frequent occurrence of type B waveform). Pulse wave parameters correlated with the skin temperature gradient. The study findings imply the altered regulation of peripheral circulation in ET, including a decreased flow and an increased resistance.

Stage of liver fibrosis in patients with congenital bleeding disorders and infected with hepatitis C virus.

INTRODUCTION: Hepatitis C virus (HCV) is the major cause of chronic liver disease in patients with hemophilia. However, since liver biopsy should not be routinely used in these patients, the accurate assessment of the stage of fibrosis has been limited so far. OBJECTIVES: The aim of this study was to determine the stage of liver fibrosis in HCV­infected patients with hemophilia by using noninvasive methods of fibrosis assessment, and to analyze the influence of risk factors on liver fibrosis. PATIENTS AND METHODS: The study included 71 HCV­infected patients with hemophilia and other congenital bleeding disorders. Patients were divided into 3 groups: HCV-RNA negative after successful treatment, HCV-RNA negative after spontaneous elimination of infection, and HCV­RNA positive. Liver fibrosis was measured with shear wave elastography and FibroTest. The risk factors for liver fibrosis were analyzed, including demographic factors, HCV genotype, coinfections, and comorbidities. RESULTS: Cirrhosis or significant fibrosis (METAVIR score >F2) was observed in 26.8% of the patients. The stage of fibrosis was associated with age and estimated duration of infection (P <0.001). Active and past HBV infection did not affect fibrosis. The stage of liver fibrosis was lower in patients with spontaneous clearance of HCV (P = 0.007). CONCLUSIONS: Patients in our study had a similar stage of liver fibrosis to that reported by other studies on hemophilia. The older age and long duration of infection are the main risk factors for advanced fibrosis. Noninvasive methods such as shear wave elastography and FibroTest may allow a proper assessment of the fibrosis stage in hemophilia patients, particularly when used together and in correlation with other clinical parameters. They may also be useful in other groups of HCV­infected patients.

Co-Infection of the Hepatitis C Virus With Other Blood-Borne and Hepatotropic Viruses Among Hemophilia Patients in Poland.

BACKGROUND: The prevalence of HCV infection in people with hemophilia is substantially higher than that in the general population (63% - 98%). Multiple transfusions and substitutive therapy have also been linked to a high risk of HBV and HIV transmission. However, the prevalence of other blood-borne viral infections in this population is less well known. OBJECTIVES: This study aimed to assess the prevalence of co-infection with HBV and other blood-borne viruses in Polish HCV-infected hemophiliacs. METHODS: Seventy-one individuals, the majority of whom were male (94.36%), who had congenital bleeding disorders (60 had hemophilia A, five had hemophilia B, and six had other factor deficiencies) and HCV infection, which was defined as the presence of positive anti-HCV antibodies, were included in this study. The study group was divided into two subgroups according to the year in which blood donors were first tested for HBsAg in Poland. The serological markers were screened using commercially available enzyme immunoassays according to the manufacturer's instructions. The molecular tests were performed using real-time PCR technology with commercial assays according to the manufacturer's instructions. RESULTS: The spontaneous elimination rate of HCV RNA was 29.6%. The HCV genotype 1 was detected in 28 patients (65.1%), genotype 2 in one patient (2.3%), genotype 3 in 11 patients (25.6%), genotype 4 in two patients (4.7%), and a mixed infection with genotypes 1 and 4 was detected in one person (2.3%). Fifty-three patients (74.6%) were anti-HBc positive. Among the seven HBsAg(+) patients, three individuals were HBV-DNA positive. No occult hepatitis B was detected. In six HBsAg positive patients, the HCV RNA was positive, while one patient was also infected with HIV. The prevalence rate of past infection with HAV in the study group was 30.9%, with a tendency for a higher prevalence in older patients. The prevalence of CMV and EBV infection was high and similar to that seen in the general population. All the patients were HGV and HTLV-1 negative. CONCLUSIONS: The diagnostics and management of infections with hepatotropic viruses, particularly HBV, are neglected in hemophilic patients. All patients with coagulation disorders and a history of exposure to non-inactivated blood products should be screened for blood-borne infections. The prevalence of other potentially blood-borne viral infections exhibited a pattern similar to that observed in the general population.

Altered plasma fibrin clot properties in essential thrombocythemia.

Patients with increased thromboembolic risk tend to form denser fibrin clots which are relatively resistant to lysis. We sought to investigate whether essential thrombocythemia (ET) is associated with altered fibrin clot properties in plasma. Ex vivo plasma fibrin clot permeability coefficient (Ks), turbidimetry and clot lysis time (CLT) were measured in 43 consecutive patients with ET (platelet count from 245 to 991 × 10(3)/µL) and 50 control subjects matched for age, sex and comorbidities. Fibrinolysis proteins and inhibitors together with platelet activation markers were determined. Reduced Ks (-38%, p < 0.0001) and prolonged CLT (+34%, p < 0.0001) were observed in ET. The differences remained significant after adjustment for fibrinogen and platelet count. ET was associated with a slightly shorter lag phase (-5%, p = 0.01) and higher maximum absorbency of the turbidimetric curve (+6%, p < 0.001). The ET patients had higher plasma P-selectin by 193% (p < 0.00001) and platelet factor 4 (PF4) by 173% (p < 0.00001), with higher P-selectin observed in 19 (44%) patients with JAK-2 gene V617F mutation. Higher t-PA (+20%, p < 0.001), 23% higher plasminogen activator inhibitor-1, PAI-1 (+23%, p < 0.01) and unaltered thrombin-activatable fibrinolysis inhibitor, plasminogen and α2-antiplasmin activity were found in the ET group. Ks inversely correlated with fibrinogen, PF4 and C-reactive protein. CLT positively correlated only with PAI-1. Patients with ET display prothrombotic plasma fibrin clot phenotype including impaired fibrinolysis, which represents a new prothrombotic mechanism in this disease.

Current Possibilities to Assess the Degree of Liver Fibrosis in Patients with Haemophilia Infected with HCV--Review.

Haemophilia is an entity, wherein the HCV infection rate is greater than in the general population and ranges between 70-90%. The majority of HCV infections were acquired by hemophiliacs in the 1980s, by the use of infected cryoprecipitate or fresh frozen plasma preparations. It is therefore highly likely that many of them, more than twenty years after the infection, have developed advanced liver disease. Until recently, in order to assess its severity, it was necessary to perform a liver biopsy. Currently, we observe rapid developments of non-invasive methods that are particularly useful in patients with bleeding disorders. The most popular include elastography (Fibroscan, SWE) and the algorithms based on measurements of the relevant blood parameters (e.g. FibroTest, Fibrometer, APRI index). Ease of implementation of these studies, no need for hospitalization of the patient or specific preparation for surgery, allow for quick and minimally invasive assessment of liver disease progression and classification of the patient to the appropriate antiviral therapy.

A risk of essential thrombocythemia in carriers of constitutional CHEK2 gene mutations.

Germline mutations of the CHEK2 gene have been reported in some myeloid and lymphoid malignancies, but their impact on development of essential thrombocythemia has not been studied. In 16 out of 106 (15.1%) consecutive patients, newly diagnosed with essential thrombocythemia, we found one of four analyzed CHEK2 mutations: I157T, 1100delC, IVS2+1G>A or del5395. They were associated with the increased risk of disease (OR=3.8; P=0.002). The median age at ET diagnosis among CHEK2+/JAK2V617F+ patients was seven years lower than that among CHEK2-/JAK2V617F+ (52 vs. 59 years; P=0.04), whereas there was no difference in the medians of hematologic parameters between these groups. The results obtained suggest that CHEK2 mutations could potentially contribute to the susceptibility to essential thrombocythemia. The germline inactivation of CHEK2, as it seems, has no direct impact on the development of disease, but it could cause disruption of cell cycle checkpoints and initiate or support the cancerogenic process of essential thrombocythemia at a younger age.

[Mastocytosis--diagnostic criteria and treatment]. / Mastocytoza--rozpoznawanie i leczenie.

Mastocytosis is a heterogeneous group of rare diseases characterized by the proliferation and accumulation of mast cells in one or more organs such as the skin, bone marrow, liver, spleen, and lymph nodes. According to the WHO classification, mastocytosis is divided into seven subvariants. The symptoms are associated with mediator release and impaired organ function due to infiltration by neoplastic mast cells. There is a higher risk of anaphylactic shock; therefore education of the patients is very important. Patients may be asymptomatic. Symptomatic treatment is used in cutaneous mastocytosis and in indolent systemic mastocytosis. More aggressive subvariants of mastocytosis are treated with chemotherapy, targeted therapy, and bone marrow transplantation.

31P MRS analysis of the phospholipid composition of the peripheral blood mononuclear cells (PBMC) and bone marrow mononuclear cells (BMMC) of patients with acute leukemia (AL).

The aim of this study was to evaluate the phospholipid concentration in acute leukemia (AL) blast cells from peripheral blood (PBMC) and bone marrow (BMMC). In vitro 31P Nuclear Magnetic Resonance Spectroscopy (31P MRS) was used. The integral intensities of the resonant peaks and the phospholipid concentrations in PBMC and BMMC were analyzed. Differences in the phospholipid concentrations in cells from myeloblastic or lymphoblastic lines were also evaluated. This investigation was carried out on phospholipid extracts from PBMC and BMMC from 15 healthy volunteers and 77 patients with AL (samples taken at the moment of diagnosis). A significant decrease in sphingomyelin (SM) and phosphtidylserine (PS) was observed in the PBMC of patients with AL relative to the results for the healthy volunteers. For ALL, we found a significant decrease in the concentration of phosphatidylcholine plasmalogen (CPLAS), SM, PI+PE (phosphatidylinositol + phosphatidylethanolamine) and PS in comparison with the results for healthy volunteers and patients with AML. Experiments with BMMC cells revealed a significant decrease in the concentration of CPLAS, SM, PI+PE, and PS in ALL relative to AML. Additionally, a significant decrease in phosphatidylcholine (PC) concentration was observed in ALL compared to AML. If the phospholipid extracts were taken simultaneously from the same patient, there were no significant differences in the integral intensities and phospholipid concentrations between PBMC and BMMC.

Lipid changes occuring in the course of hematological cancers.

The relationship between plasma lipid levels and mortality from cardiovascular diseases has been shown in many studies, but there has been far less investigation into their relationship to non-cardiovascular diseases. The aim of this study was to investigate the lipid profile of individuals with hematological malignancies and its relationship to disease activity. 238 patients were included in the study: 84 with acute leukemia, 62 with non-Hodgkin lymphoma, 35 with Hodgkin's lymphoma, 32 with multiple myeloma, and 25 with myeloproliferative syndrome. The HDL cholesterol level of the patients differed to that of the individuals in the control group in the active disease period for all the analyzed disorders, but only remained statistically significant in the acute leukemia and non-Hodgkin lymphoma groups during the remission period. Smaller differences were observed for the remaining lipid fractions, except for the triglyceride level, which increased in the active disease period in all the analyzed disorders except non-Hodgkin lymphoma. The most pronounced changes in the lipid fractions occurred in the HDL cholesterol level, and were the most remarkable for acute leukemia.

Platelet-activating factor changes in phospholipid extracts from the plasma, peripheral blood mononuclear cells and bone marrow mononuclear cells of patients with acute leukemia--a 31P MRS in vitro study.

The aim of this investigation was to evaluate the changes in PAF concentrations in the plasma, PBMC and BMMC of patients with acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML). The plasma was from 23 healthy volunteers (HV) and 44 patients with AL (16 ALL, 28 AML). The PBMC were from 15 HV and 55 patients with AL (18 ALL, 37 AML), and the BMMC from 40 patients with AL (11 ALL, 29 AML). Methanol-chloroform phospholipid extraction from 60 x 10(6) cells (PBMC or BMMC) was performed according to a modified version of Folch's method. (31)P MRS data was obtained on an AMX 300 Bruker spectrometer (7.05 T). The PAF concentration in the plasma of the patients with ALL or AML was lower than that for the healthy volunteers. The PAF concentration in the plasma of the patients with ALL did not differ significantly from that of the patients with AML. In the case of both the PBMC and BMMC, the PAF concentration was significantly diminished in patients with ALL relative to the concentration for those with AML and for the healthy volunteers. No differences were observed in the PAF concentrations for the AML patients and the healthy volunteers.

Non-Hodgkin's lymphoma as a rare manifestation of immune reconstitution disease in HIV-1 positive patients.

Combination antiretroviral therapy (cART) can improve immune system function through suppression of HIV-1 replication. However, paradoxical immune response may develop in some patients as a result of effective therapy followed by immune restoration. The phenomena is known as IRS, immune reconstitution syndrome/immune recovery syndrome. IRS can develop within weeks to months after cART is commenced and the time is related to the type of the disease. There are but scant reports concerning IRS-NHL (non-Hodgkin's lymphoma) in HIV-1 positive subjects. We observed 4 (33%) cases of IRS-NHL out of 12 patients in whom NHL was diagnosed. As a result of potent cART they reached viral suppression in a mean time of 15 weeks followed by a rise in CD4(+) T cells within 16.5 weeks. The diagnosis of NHL was established at a mean time of 36 weeks after cART was introduced and 20 weeks after the CD4 T cell increase was achieved. This may indicate that the immune reconstitution as a result of cART was a predisposing factor for the development of NHL in our patients. There was prompt progression of the disease and the outcome was fatal in all cases. IRS-NHL should be suspected in any case of lymphadenopathy, generalized or limited to the abdomen or periphery, which develops after immune recovery due to potent cART within a few months.

[The biology of HDL lipoprotein and its antisclerotic activity]. / Biologia lipoproteiny HDL i jej przeciwmiazdzycowe dzialanie.

Clinical and epidemiological studies showed an inverse relationship between the level of high-density lipoprotein (HDL) cholesterol and the development of atherosclerosis. This fact aroused more interest in HDLs and it was found that these lipoproteins have significance in malignant diseases. In this review the biochemical classification of plasma lipoproteins, the structure of HDL, and the structural characterization of HDL-apolipoproteins are presented. The synthesis of HDL cholesterol and factors that regulate their structure and function are also considered. We discuss the antiatherogenic activity of HDL through its reverse cholesterol transport and antioxidant, anti-inflammatory, antithrombotic, and profibrinolytic effects.

[Factor VII deficiency--case report]. / Niedobór czynnika VII--opis przypadku.

We describe the hypoproconvertinemia - a hereditary factor VII deficiency, diagnosed in 55-years-old female. Prolonged menstruations resulted in planned hysterectomy. Both her sons also have agent VII deficiency, however without any symptoms of hemorrhagic diathesis.

Diffuse malignant lymphoma type B with optic chiasm infiltration, visual disturbances, hypopituitarism, hyperprolactinaemia and diabetes insipidus. Case report and literature review.

The case is reported of a 55-year-old man with diffuse malignant lymphoma type B associated with transient optic chiasm infiltration and visual disturbances but with persistent hypopituitarism, hyperprolactinaemia and diabetes insipidus. The patient was administered chemotherapy and radiotherapy. Repeated MR and CT scans showed optic chiasm infiltration, which disappeared in the course of the chemotherapy but then recurred, changed its appearance and finally disappeared again. In the meantime visual disturbances occurred and disappeared during the therapy. Hypopituitarism, diabetes insipidus and hyperprolactinaemia were diagnosed and replacement therapy was administered. Later on abdominal pain occurred, and a CT scan revealed bilateral kidney masses and enlarged retroperitoneal lymph nodes. These were diffuse malignant lymphoma with regional lymphonodulitis in histology. Finally, hydrothorax and hydroretroperitoneum were diagnosed. The patient died as a result of systemic complications of the disease. The length of survival time documented following the hypothalamochiasmatic infiltration and diagnosis of lymphoma makes the case an unusual one for patients with CNS lymphoma. Hormonal disturbances accompanying the suprasellar region infiltration are very important from the practical point of view.