Francisca Ferrer-Marín

Assessment and prognostic value of the European LeukemiaNet criteria for clinicohematologic response, resistance, and intolerance to hydroxyurea in polycythemia vera

Criteria of response and definition of resistance and intolerance to hydroxyurea (HU) in polycythemia vera (PV) were proposed by the European LeukemiaNet (ELN). Such criteria were evaluated in 261 PV patients (median follow-up, 7.2 years) treated with HU for a median of 4.4 years. Complete response, partial response, and no response were observed in 24%, 66%, and 10% of patients, respectively. Achieving ELN response (complete or partial) or hematocrit response did not result in better survival or less thrombosis and bleeding. On the contrary, having no response in leukocyte count was associated with higher risk of death (HR, 2.7; 95% confidence interval [CI], 1.3%-5.4%; P = .007), whereas lack of response in platelet count involved a higher risk of thrombosis and bleeding. Resistance and intolerance to HU was registered in 11% and 13% of patients, respectively. Resistance to HU was associated with higher risk of death (HR, 5.6; 95% CI, 2.7%-11.9%; P < .001) and transformation (HR, 6.8; 95% CI, 3.0%-15.4%; P < .001). In summary, fulfilling the ELN definition for response to HU was not associated with a benefit in the clinical outcome in PV, whereas response in platelet and white blood cell counts were predictive of less thrombohemorrhagic complications and better prognosis, respectively. Resistance to HU was an adverse prognostic factor.

Developmental differences in megakaryocytopoiesis are associated with up-regulated TPO signaling through mTOR and elevated GATA-1 levels in neonatal megakaryocytes

Multiple observations support the existence of developmental differences in megakaryocytopoiesis. We have previously shown that neonatal megakaryocyte (MK) progenitors are hyperproliferative and give rise to MKs smaller and of lower ploidy than adult MKs. Based on these characteristics, neonatal MKs have been considered immature. The molecular mechanisms underlying these differences are unclear, but contribute to the pathogenesis of disorders of neonatal megakaryocytopoiesis. In the present study, we demonstrate that low-ploidy neonatal MKs, contrary to traditional belief, are more mature than adult low-ploidy MKs. These mature MKs are generated at a 10-fold higher rate than adult MKs, and result from a developmental uncoupling of proliferation, polyploidization, and terminal differentiation. This pattern is associated with up-regulated thrombopoietin (TPO) signaling through mammalian target of rapamycin (mTOR) and elevated levels of full-length GATA-1 and its targets. Blocking of mTOR with rapamycin suppressed the maturation of neonatal MKs without affecting ploidy, in contrast to the synchronous inhibition of polyploidization and cytoplasmic maturation in adult MKs. We propose that these mechanisms allow fetuses/neonates to populate their rapidly expanding bone marrow and intravascular spaces while maintaining normal platelet counts, but also set the stage for disorders restricted to fetal/neonatal MK progenitors, including the Down syndrome-transient myeloproliferative disorder and the thrombocytopenia absent radius syndrome.

Distinct differences in platelet production and function between neonates and adults: implications for platelet transfusion practice

Thrombocytopenia is a common problem among sick neonates admitted to the neonatal intensive care unit. Among neonates, preterm infants are the subgroup at highest risk for thrombocytopenia and hemorrhage, which is frequently intracranial. Although there is no evidence of a relationship between platelet (PLT) count and occurrence of major hemorrhage, preterm infants are commonly transfused prophylactically when PLT counts fall below an arbitrary limit, and this threshold is usually higher than for older infants or adults. This liberal practice has been influenced by the observation that, in vitro, neonatal PLTs are hyporeactive in response to multiple agonists. However, full‐term infants exhibit normal to increased primary hemostasis due to factors in neonatal blood that enhance the PLT–vessel wall interaction. Additionally, cardiorespiratory problems are considered the main etiologic factors in the development of neonatal intraventricular hemorrhage. In this review, we will discuss the developmental differences that exist in regard to PLT production and function, as well as in primary hemostasis in preterm and term neonates, and the implications of these developmental differences to transfusion medicine. PLT transfusions are not exempt of risk, and a better understanding of the PLT function and the hemostatic profile of premature infants and their changes over time and in response to illness is the starting point to design randomized controlled trials to define optimal use of PLT transfusions in premature neonates. Without these future trials, the marked disparities in PLT transfusion practice in neonates between hospitals and countries will remain over time.

Effects of in vitro adult platelet transfusions on neonatal hemostasis

Summary.  Background: Thrombocytopenia is frequent among neonates, and 20–25% of affected infants are treated with platelet transfusions. These are frequently given for mild thrombocytopenia (platelets: 50–100 × 109 L−1), largely because of the known hyporeactivity of neonatal platelets. In tests of primary hemostasis, however, neonates have shorter bleeding and closure times (CTs) than adults. This has been attributed to their higher hematocrits, higher von Willebrand factor (VWF) concentrations, and predominance of longer VWF polymers. Objective: To determine whether the ‘transfusion’ of adult (relatively hyperreactive) platelets into neonatal blood results in a hypercoagulable profile. Methods: Cord blood (CB) and adult peripheral blood (PB) were separated (with a modified buffy coat method) to generate miniaturized platelet concentrates (PCs) and thrombocytopenic blood. PB‐derived and CB‐derived PCs (n = 7 per group) were then ‘transfused’in vitro into thrombocytopenic CB and PB. The effects of autologous vs. allogeneic (developmentally mismatched) ‘transfusions’ were evaluated with whole blood aggregometry, a platelet function analyzer (PFA‐100), and thromboelastography (TEG). Results: Adult platelets aggregated significantly better than neonatal platelets in response to thrombin receptor‐activating peptide, ADP, and collagen, regardless of the blood into which they were transfused. The ‘transfusion’ of adult platelets into thrombocytopenic CB resulted in shorter CTs‐EPI (PFA‐100) and higher clot strength and firmness (TEG) than ‘transfusion’ of neonatal autologous platelets. Conclusions: In vitro‘transfusion’ of adult platelets into neonatal blood results in shorter CTs than ‘transfusion’ with neonatal platelets. Our findings should raise awareness of the differences between the neonatal and adult hemostatic system and the potential ‘developmental mismatch’ associated with platelet transfusions for neonatal hemostasis.

Neonatal Thrombocytopenia and Megakaryocytopoiesis

Thrombocytopenia is common among sick neonates, affecting 20% to 35% of all patients admitted to the neonatal intensive care unit (NICU). While most cases of neonatal thrombocytopenia are mild or moderate and resolve within 7 to 14 days with appropriate therapy, 2.5% to 5% of NICU patients develop severe thrombocytopenia, sometimes lasting for several weeks and requiring >20 platelet transfusions. The availability of thrombopoietic agents offers the possibility of decreasing the number of platelet transfusions and potentially improving the outcomes of these infants. However, adding thrombopoietin (TPO) mimetics to the therapeutic armamentarium of neonatologists will require careful attention to the substantial developmental differences between neonates and adults in the process of megakaryocytopoiesis and in their responses to TPO. Taken together, the available data suggest that TPO mimetics will stimulate platelet production in neonates, but might do so through different mechanisms and at different doses than those established for adults. In addition, the specific groups of thrombocytopenic neonates most likely to benefit from therapy with TPO mimetics need to be defined, and the potential nonhematological effects of these agents on the developing organism need to be considered. This review summarizes our current understanding of neonatal megakaryocytopoiesis, and examines in detail the developmental factors relevant to the potential use of TPO mimetics in neonates.

The International Prognostic Scoring System does not accurately discriminate different risk categories in patients with post-essential thrombocythemia and post-polycythemia vera myelofibrosis

Myelofibrotic transformation is a well-recognized complication of essential thrombocythemia (ET) and polycythemia vera (PV).[1][1],[2][2] However, information is scarce on the life expectancy and prognostic factors of patients developing this complication.[1][1],[3][3]–[5][4] Prognostic models

Increasing platelets without transfusion: is it time to introduce novel thrombopoietic agents in neonatal care?

The Food and Drug Administration recently approved two novel thrombopoiesis-stimulating agents, Romiplostim (AMG-531, Nplate) and Eltrombopag (Promacta), for the treatment of adults with immune thrombocytopenic purpura. For physicians taking care of critically ill neonates, this offers the opportunity of decreasing platelet transfusions and potentially improving the outcomes of neonates with severe and prolonged thrombocytopenia. However, several developmental factors need to be taken into consideration. First, the population of thrombocytopenic neonates likely to benefit from these agents needs to be carefully selected. Second, the mechanisms underlying neonatal and adult thrombocytopenia differ from each other and are incompletely understood, and pre-clinical evidence suggests that the response of neonates to thrombopoietic factors might be different from that of adults. Finally, the potential non-hematopoietic effects of thrombopoietin have not been well established. Here, we will discuss these issues in detail, and will highlight the critical developmental differences between neonates and adults that need to be considered as we think about introducing these agents into neonatal care.

Oral anticoagulation to prevent thrombosis recurrence in polycythemia vera and essential thrombocythemia.

It is unclear whether anticoagulation guidelines intended for the general population are applicable to patients with polycythemia vera (PV) and essential thrombocythemia (ET). In the present study, the risk of thrombotic recurrence was analyzed in 150 patients with PV and ET treated with vitamin K antagonists (VKA) because of an arterial or venous thrombosis. After an observation period of 963 patient-years, the incidence of re-thrombosis was 4.5 and 12 per 100 patient-years under VKA therapy and after stopping it, respectively (P < 0.0005). After a multivariate adjustment for other prognostic factors, VKA treatment was associated with a 2.8-fold reduction in the risk of thrombotic recurrence. Notably, VKA therapy offset the increased risk of re-thrombosis associated with a prior history of remote thrombosis. Both the protective effect of VKA therapy and the predisposing factors for recurrence were independent of the anatomical site involved in the index thrombosis. Treatment periods with VKA did not result in a higher incidence of major bleeding as compared with those without VKA. These findings support the use of long-term anticoagulation for the secondary prevention of thrombosis in patients with PV and ET, particularly in those with history of remote thrombosis.

Frequency and prognostic value of resistance/intolerance to hydroxycarbamide in 890 patients with polycythaemia vera.

The clinical significance of resistance/intolerance to hydroxycarbamide (HC) was assessed in a series of 890 patients with polycythaemia vera (PV). Resistance/intolerance to HC was recorded in 137 patients (15·4%), consisting of: need for phlebotomies (3·3%), uncontrolled myeloproliferation (1·6%), failure to reduce massive splenomegaly (0·8%), development of cytopenia at the lowest dose of HC to achieve a response (1·7%) and extra‐haematological toxicity (9%). With a median follow‐up of 4·6 years, 99 patients died, resulting in a median survival of 19 years. Fulfilling any of the resistance/intolerance criteria had no impact on survival but when the different criteria were individually assessed, an increased risk of death was observed in patients developing cytopenia [Hazard ratio (HR): 3·5, 95% confidence interval (CI): 1·5–8·3, P = 0·003]. Resistance/intolerance had no impact in the rate of thrombosis or bleeding. Risk of myelofibrotic transformation was significantly higher in those patients developing cytopenia (HR: 5·1, 95% CI: 1·9–13·7, P = 0·001) and massive splenomegaly (HR: 9·1, 95% CI: 2·3–35·9, P = 0·002). Cytopenia at the lowest dose required to achieve a response was also an independent risk factor for transformation to acute leukaemia (HR: 20·3, 95% CI: 5·4–76·5, P < 0·001). In conclusion, the unified definition of resistance/intolerance to HC delineates a heterogeneous group of PV patients, with those developing cytopenia being associated with an adverse outcome.

Risk of thrombosis according to need of phlebotomies in patients with polycythemia vera treated with hydroxyurea.

Hematocrit control below 45% is associated with a lower rate of thrombosis in polycythemia vera. In patients receiving hydroxyurea, this target can be achieved with hydroxyurea alone or with the combination of hydroxyurea plus phlebotomies. However, the clinical implications of phlebotomy requirement under hydroxyurea therapy are unknown. The aim of this study was to evaluate the need for additional phlebotomies during the first five years of hydroxyurea therapy in 533 patients with polycythemia vera. Patients requiring 3 or more phlebotomies per year (n=85, 16%) showed a worse hematocrit control than those requiring 2 or less phlebotomies per year (n=448, 84%). There were no significant differences between the two study groups regarding leukocyte and platelet counts. Patients requiring 3 or more phlebotomies per year received significantly higher doses of hydroxyurea than the remaining patients. A significant higher rate of thrombosis was found in patients treated with hydroxyurea plus 3 or more phlebotomies per year compared to hydroxyurea with 0–2 phlebotomies per year (20.5% vs. 5.3% at 3 years; P<0.0001). In multivariate analysis, independent risk factors for thrombosis were phlebotomy dependency (HR: 3.3, 95%CI: 1.5–6.9; P=0.002) and thrombosis at diagnosis (HR: 4.7, 95%CI: 2.3–9.8; P<0.0001). The proportion of patients fulfilling the European LeukemiaNet criteria of resistance/intolerance to hydroxyurea was significantly higher in the group requiring 3 or more phlebotomies per year (18.7% vs. 7.1%; P=0.001) mainly due to extrahematologic toxicity. In conclusion, phlebotomy requirement under hydroxyurea therapy identifies a subset of patients with increased proliferation of polycythemia vera and higher risk of thrombosis.