I use the hematological, morphological and molecular criteria recently established by the World Health Organization to diagnose essential thrombocytemia. In these patients, major causes of morbidity ...and mortality are represented by thrombosis and bleeding, whereas progression to myelofibrosis and transformation to acute leukemia are more rare. Myelosuppressive therapy can reduce the rate of vascular complications, but there is some concern about treatment-related toxicity. Therefore, I follow a risk-oriented therapeutic approach to avoid inappropriate exposure to cytotoxic drugs on one side or suboptimal treatment on the other. Established predictors of cardiovascular events are represented by older age and previous thrombosis, whereas recent data suggest a prognostic role for novel risk factors, including leukocytosis and JAK2V617F mutational status. There is no indication for therapeutic intervention in asymptomatic, low-risk patients, while I treat high-risk patients with hydroxyurea (HU) first. Other therapeutic options, such as interferon alpha or anagrelide, may find place in selected patients including those who are resistant or intolerant to HU. I follow a risk-oriented approach also for management of pregnancy. Low-risk women are given low-dose aspirin throughout pregnancy and prophylactic low-molecular-weight heparin (LMWH) post partum, whereas LMWH throughout pregnancy and/or interferon-alpha can be required in high-risk cases.
Abstract Clinical evidence supports the need of changing the diagnostic criteria of the 2008 updated WHO classification for polycythemia vera (PV), essential thrombocythemia (ET) and primary ...myelofibrosis (PMF). In JAK2 -mutated patients who show characteristic bone marrow (BM) morphology, clinical studies demonstrated that a hemoglobin level of 16.5 g/dL in men and 16.0 g/dl for women or a hematocrit value of 49% in men and 48% in women are the optimal cut off levels for distinguishing JAK2 -mutated ET from “masked/prodromal” PV. Therefore BM morphology was upgraded to a major diagnostic criterion. Regarding ET the key issue was to improve standardization of prominent BM features enhancing differentiation between “true” ET and prefibrotic/early primary myelofibrosis (prePMF). These two entities have shown a different epidemiology and clinical outcomes. Concerning prePMF a more explicit clinical characterization of minor criteria is mandated for an improved distinction from ET and overt PMF and accurate diagnosis and outcome prediction.
Under the auspices of an International Working Group, seven centers submitted diagnostic and follow-up information on 1545 patients with World Health Organization-defined polycythemia vera (PV). At ...diagnosis, median age was 61 years (51% females); thrombocytosis and venous thrombosis were more frequent in women and arterial thrombosis and abnormal karyotype in men. Considering patients from the center with the most mature follow-up information (n=337 with 44% of patients followed to death), median survival (14.1 years) was significantly worse than that of the age- and sex-matched US population (P<0.001). In multivariable analysis, survival for the entire study cohort (n=1545) was adversely affected by older age, leukocytosis, venous thrombosis and abnormal karyotype; a prognostic model that included the first three parameters delineated risk groups with median survivals of 10.9-27.8 years (hazard ratio (HR), 10.7; 95% confidence interval (CI): 7.7-15.0). Pruritus was identified as a favorable risk factor for survival. Cumulative hazard of leukemic transformation, with death as a competing risk, was 2.3% at 10 years and 5.5% at 15 years; risk factors included older age, abnormal karyotype and leukocytes ≥15 × 10(9)/l. Leukemic transformation was associated with treatment exposure to pipobroman or P32/chlorambucil. We found no association between leukemic transformation and hydroxyurea or busulfan use.
Primary antithrombotic prevention with aspirin is not indicated in asymptomatic patients with confirmed antiphospholipid (aPL) positivity without systemic autoimmune disorders because: a) the ...estimated prevalence of thrombosis in unselected cases is about 1% patient-years (range 0–2.8); b) this level of thrombotic risk is equivalent to that of major bleeding associated with the use of aspirin and therefore the expected benefit does not outweigh the risk; c) these expectations have been confirmed by at least one randomized clinical trial, although with methodological limits. The management of modifiable thrombotic risk factors can be an alternative and safer strategy, considering that many vascular events occur in the presence of concomitant non-aPL triggering conditions. Whether primary prophylaxis with aspirin may be useful for some subsets of aPL patients at particularly high thrombotic risk, such as those with overt systemic autoimmune disorders or with special patterns of antibodies (‘triple positivity’), remains to be established.
Major causes of morbidity and mortality in polycythemia vera (PV) and essential thrombocythemia (ET) are represented by thrombosis and bleeding, progression to myelofibrosis and transformation to ...acute leukemia. Myelosuppressive therapy, preferentially with hydroxyurea, can reduce the rate of vascular complications, but there is some concern about an increased rate of leukemic transformation with this agent. Therefore, management of these disorders poses a significant challenge, and a risk-oriented therapeutic approach should be strictly followed to avoid inappropriate exposure to cytotoxic drugs on one side or suboptimal treatment on the other. Established risk factors for cardiovascular events are represented by older age and previous thrombosis, whereas impact of novel biological factors, including leukocytosis and JAK2V617F mutational status and/or mutational burden, is under active investigation. Low-risk PV patients should be managed only with phlebotomy and aspirin, whereas high-risk patients should also receive cytotoxic therapy. Regarding the management of ET, there is no clear indication for intervention in low-risk patients, whereas high-risk patients should be managed with chemotherapy. Other therapeutic options, such as interferon-alpha or anagrelide, may find place in selected patients including those who are resistant/intolerant to hydroxyurea. Finally, there is great expectation for novel drugs targeting the constitutively active JAK2/STAT pathway.
We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis ...(SVT). Budd-Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors.
The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To ...tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9-8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8-7.3) on VKA and 8.9 (95% CI: 5.7-13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2-8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3-20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19-5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1-4.5) on VKA and 0.7 (95% CI: 0.08-2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.
Progression to acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) is a possible evolution of polycythemia vera (PV), but whether some patients are at increased natural risk for this ...complication and how much the contribution of pharmacologic cytoreduction can affect the natural course of the disease remain uncertain. The European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) prospective project included 1638 patients with PV. AML/MDS was diagnosed in 22 patients after a median of 2.5 years from recruitment in the study and a median of 8.4 years from the diagnosis of PV. Variables associated with progression to AML/MDS were assessed using different models of multivariate analysis. Older age was confirmed as the main independent risk factor (hazard ratio HR, 4.30; 95% confidence interval 95% CI, 1.16-15.94; P = .0294), whereas overall disease duration failed to reach statistical significance (more than 10 years: HR, 1.91; 95% CI, 0.64-5.69; P = .2466). Exposure to P32, busulphan, and pipobroman (HR, 5.46; 95% CI, 1.84-16.25; P = .0023), but not to hydroxyurea (HU) alone (HR, 0.86; 95% CI, 0.26-2.88; P = .8021), had an independent role in producing an excess risk for progression to AML/MDS compared with treatment with phlebotomy or interferon.
The optimal intensity of oral anticoagulation for the prevention of recurrent thrombosis in patients with antiphospholipid antibody syndrome is uncertain. Retrospective studies show that only ...high-intensity oral anticoagulation target international normalized ratio (INR) >3.0 is effective but a recent randomized clinical trial comparing high (INR range 3.0-4.0) vs. moderate (INR 2.0-3.0) intensities of anticoagulation failed to confirm this assumption.
We conducted a randomized trial in which 109 patients with antiphospholipid syndrome (APS) and previous thrombosis were given either high-intensity warfarin (INR range 3.0-4.5, 54 patients) or standard antithrombotic therapy (warfarin, INR range 2.0-3.0 in 52 patients or aspirin alone, 100 mg day(-1) in three patients) to determine whether intensive anticoagulation is superior to standard treatment in preventing symptomatic thromboembolism without increasing the bleeding risk.
The 109 patients enrolled in the trial were followed up for a median time of 3.6 years. Mean INR during follow-up was 3.2 (SD 0.6) in the high-intensity warfarin group and 2.5 (SD 0.3) (P < 0.0001) in the conventional treatment patients given warfarin. Recurrent thrombosis was observed in six of 54 patients (11.1%) assigned to receive high-intensity warfarin and in three of 55 patients (5.5%) assigned to receive conventional treatment hazard ratio for the high intensity group, 1.97; 95% confidence interval (CI) 0.49-7.89. Major and minor bleeding occurred in 15 patients (two major) (27.8%) assigned to receive high-intensity warfarin and eight (three major) (14.6%) assigned to receive conventional treatment (hazard ratio 2.18; 95% CI 0.92-5.15).
High-intensity warfarin was not superior to standard treatment in preventing recurrent thrombosis in patients with APS and was associated with an increased rate of minor hemorrhagic complications.
The efficient use of microalgae to convert sun light energy into biomass is limited by losses during high light illumination of dense cell cultures in closed bioreactors. Uneven light distribution ...can be overcome by using cell cultures with smaller antenna sizes packed to high cell density cultures, thus allowing good light penetration into the inner sections of the reactor. We engineered a new small PSII antenna size
Chlamydomonas reinhardtii strain with improved photon conversion efficiency and increased growth rates under high light conditions. We achieved this goal by transformation of a permanently active variant NAB1* of the LHC translation repressor NAB1 to reduce antenna size via translation repression. NAB1* expression was demonstrated in
Stm6Glc4T7 (T7), leading to a reduction of LHC antenna size by 10–17%.
T7 showed a ∼50% increase of photosynthetic efficiency (ΦPSII) at saturating light intensity compared to the parental strain.
T7 converted light to biomass with much higher efficiencies with a ∼50% improved mid log growth phase. Moreover,
T7 cultures reached higher densities when grown in large-scale bioreactors. Thus, the phenotype of strain
T7 may have important implications for biotechnological applications in which photosynthetic microalgae are used for large-scale culturing as an alternative plant biomass source.
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