Spleen tyrosine kinase (Syk) signaling is central to phagocytosis‐based, antibody‐mediated platelet destruction in adults with immune thrombocytopenia (ITP). Fostamatinib, an oral Syk inhibitor, produced sustained on‐treatment responses in a phase 2 ITP study. In two parallel, phase 3, multicenter, randomized, double‐blind, placebo‐controlled trials (FIT1 and FIT2), patients with persistent/chronic ITP were randomized 2:1 to fostamatinib (n = 101) or placebo (n = 49) at 100 mg BID for 24 weeks with a dose increase in nonresponders to 150 mg BID after 4 weeks. The primary endpoint was stable response (platelets ≥50 000/μL at ≥4 of 6 biweekly visits, weeks 14‐24, without rescue therapy). Baseline median platelet count was 16 000/μL; median duration of ITP was 8.5 years. Stable responses occurred in 18% of patients on fostamatinib vs. 2% on placebo (P = .0003). Overall responses (defined retrospectively as ≥1 platelet count ≥50 000/μL within the first 12 weeks on treatment) occurred in 43% of patients on fostamatinib vs. 14% on placebo (P = .0006). Median time to response was 15 days (on 100 mg bid), and 83% responded within 8 weeks. The most common adverse events were diarrhea (31% on fostamatinib vs. 15% on placebo), hypertension (28% vs. 13%), nausea (19% vs. 8%), dizziness (11% vs. 8%), and ALT increase (11% vs. 0%). Most events were mild or moderate and resolved spontaneously or with medical management (antihypertensive, anti‐motility agents). Fostamatinib produced clinically‐meaningful responses in ITP patients including those who failed splenectomy, thrombopoietic agents, and/or rituximab. Fostamatinib is a novel ITP treatment option that targets an important mechanism of ITP pathogenesis.

Primary immune thrombocytopenia (ITP) is a predominantly immunoglobulin G (IgG)-autoantibody-mediated disease characterized by isolated thrombocytopenia. Rozanolixizumab, a subcutaneously infused humanized monoclonal anti-neonatal Fc receptor (FcRn) antibody, reduced serum IgG in healthy volunteers. In this phase 2, multicenter, open-label study, patients with persistent/chronic primary ITP received 1 to 5 once-weekly subcutaneous infusions of rozanolixizumab (cumulative doses, 15-21 mg/kg). Primary objectives were safety and tolerability, and secondary objectives were clinical efficacy (change in platelet count) and pharmacodynamic effect (change in IgG). In all, 51 (77.3%) of 66 patients reported 1 or more adverse events (AEs), all mild-to-moderate, most commonly headaches (26 [39.4%] of 66), of which 15 were treatment related. Four patients had serious AEs, but none were treatment related. No AEs resulted in discontinuation of the study drug. No serious infections occurred. Platelet counts of ≥50 × 109/L were achieved at least once at any time after multiple infusions (5 × 4, 3 × 7, or 2 × 10 mg/kg: 35.7%, 35.7%, and 45.5% of patients, respectively) or single infusions (15 or 20 mg/kg: 66.7% and 54.5% patients, respectively). Minimum mean IgG levels and maximum mean platelet counts both occurred by day 8 in the higher (15 and 20 mg/kg) single-dose cohorts and maximum platelet count occurred by day 11 onward in the multiple-dose cohorts. No clinically meaningful changes occurred in IgA, IgM, IgE, or albumin levels. In patients with persistent/chronic primary ITP, rozanolixizumab demonstrated a favorable safety profile and rapid, substantial platelet increases concordant with substantial IgG reductions, especially with single doses. By day 8, in the 15 and 20 mg/kg single-dose cohorts, >50% patients achieved clinically relevant platelet responses (≥50 × 109/L), coinciding with the lowest mean IgG levels. These data support phase 3 development of rozanolixizumab in persistent/chronic primary ITP. This trial was registered at www.clinicaltrials.gov as #NCT02718716.

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Angiogenesis plays an important role in the biology of hematological malignancies, including essential thrombocythemia (ET) and polycythemia vera (PV). Some data suggests that it has a role in the pathogenesis of thrombosis, the major clinical problem in ET and PV. The number of different subpopulations of circulating endothelial cells (CECs), plasma levels of vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor 1 and 2 (sVEGFR-1,2) and placenta growth factor (PlGF) were determined in 30 patients with ET and 16 patients with PV. Correlations between angiogenesis and JAK2-V617F mutational status, risk factors for thrombosis and coagulation activation markers were also assessed. The number of CEC subpopulations, were markedly higher in ET and PV patients, irrespective of JAK2-V617F status, when compared to the control group. The median values of activated CECs were markedly higher in PV patients with WBC >8.7 (x10(9)/l). Significantly higher VEGF plasma levels were found in ET patients and a similar trend was seen in PV patients in relation to healthy volunteers. The plasma levels of sVEGFR-1 were significantly higher, and PlGF levels markedly lower, in the ET and PV group than in controls. Our study also demonstrated markedly increased levels of D-dimer and TAT complexes in the patient groups. In conclusion, we found that angiogenesis, as measured by CEC numbers, is increased in ET and PV patients regardless of JAK2-V617F mutational status. Our results demonstrated that angiogenic cytokines interact with known thrombotic risk factors. We confirmed the coagulation activation in ET and PV patients but found no differences in levels of coagulation activation markers in relation to JAK2-V617F mutational status.

This is especially important, since, as with other new oral anticoagulants (NOACs), no specific antidote exists for the reversal of its anticoagulant effect in the case of severe bleeding [6].It has to be emphasized that no single laboratory hemostasis test has shown any direct correlation between rivaroxaban plasma levels and either anticoagulant efficacy or the risk of bleeding. Nevertheless, anti-FXa chromogenic assays seem to be better than prothrombin time (PT) assessment for the quantitative measurement of Xarelto plasma Rivaroxaban (Xarelto), a direct, specific Factor Xa (FXa) inhibitor, is nowadays broadly used for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation, as well as the prevention and treatment of venous thromboembolism (VTE) in various clinical settings [1][2][3]. Although rivaroxaban does not require routine coagulation monitoring, measurement of its plasma concentration is highly recommended in certain situations, including overdoses, drug accumulation or during the period before urgent surgery [4,5]. AbstractBackground. Rivaroxaban (Xarelto) does not require routine coagulation monitoring; however, in certain clinical situations (overdose, drug accumulation, urgent surgery) measurement of its plasma concentration is highly recommended. Currently, there is no single hemostasis test that shows a direct correlation between rivaroxaban plasma levels and anticoagulant efficacy. Objectives. This study was intended to assess the value of ROTEM in determining rivaroxaban administration. Material and Methods. Thirteen patients with venous thromboembolism and 13 healthy volunteers were compared with regard to certain ROTEM parameters and anti-FXa activity. The tests were done before the administration of 20 mg rivaroxaban (i.e. 24 h after previous administration) and 2.5 h afterwards.Results. The study group demonstrated residual activity of rivaroxaban in plasma (20 ± 11.3 ng/mL) 24 h following the previous administration, which did not cause marked changes in clotting assays compared to controls. In the group, 2.5 h after rivaroxaban administration, prolongation of PT (PTratio 1.51 ± 0.22), APTT (APPTratio: 1.30 ± 0.14) and ROTEM CT (CTratio -EXTEM: 2.45 ± 1.06, CTratio -INTEM: 1.32 ± 0.21) were observed. The cut-off values for particular tests were created to determine if the patient had achieved desirable anticoagulant effect after rivaroxaban administration. The mean anti-FXa values were significantly lower in patients before rivaroxaban dosing than after. Conclusions. PT demonstrated better diagnostic value than APTT in rivaroxaban administration. The ROTEM clotting time (CT) according to EXTEM may be used to determine the anticoagulation effect of rivaroxaban, but is not sensitive enough to measure the residual activity of this drug (Adv Clin Exp Med 2015, 24, 6, 995-1000).

Thromboembolic events (TEE) are a serious clinical problem in multiple myeloma (MM) patients receiving thalidomide (T). Thirty-one MM patients were tested on diagnosis and after 2 and 4 weeks of therapy with T alone, or T in combination with dexamethasone (TD). Closure time (CT) in PFA-100 and P-selectin expression were assessed, as well as plasma levels of thrombin-antithrombin complexes (TAT), D-dimer (DD), soluble thrombomodulin (sTM) and von Willebrand factor antigen (vWF:Ag), along with the activity of coagulation factor VII and factor VIII. The concentration of vascular endothelial growth factor and its type 1 and 2 receptors were also assayed. On diagnosis, significantly prolonged median CT with both used cartridges, elevated P-selectin expression, DD concentration, TAT, vWF:Ag and factor VIII and factor VII activity were seen in the patient group as compared to controls. Therapy with these regimens caused marked shortening of CT with both cartridges. Treatment with TD leads to the significant increase in CD62P expression on platelets. Median TAT value increased significantly in relation to baseline after therapy with both regimens. Factor VIII activity exceeded 150 % in all patients after 2 weeks of TD therapy and was markedly elevated compared to baseline. One month of TD therapy significantly increased sTM concentration. These results demonstrate the enhanced platelet and coagulation system activation already present in MM patients on diagnosis, which is further increased by antimyeloma therapy. These changes are more pronounced after TD therapy and may promote TEE. Tested angiogenesis marker levels are elevated already on diagnosis, do not change after therapy and have no significant impact on the coagulation system in patients with MM.

Recent studies have shown that angiogenesis plays an important role in the biology of hematological malignancies including essential thrombocythemia (ET). Using cytofluorimetric analysis, the levels of angiogenic factors, as well as the number of circulating endothelial cells (CECs), were determined in 65 patients with ET, including 33 previously untreated and 32 receiving cytoreductive therapy. Correlations between markers of angiogenesis and JAK2-V617F mutational status were also assessed. We found significantly higher levels of vascular endothelial growth factor (VEGF) and markedly decreased levels of placental growth factor in untreated patients with ET with respect to control subjects. VEGF levels were significantly increased in patients with white blood count >8.7 (x 10(9)/L) vs. <8.7 (x 10(9)/L). Furthermore, the levels of VEGF in patients on hydroxyurea (HU) therapy were markedly lower than in untreated patients. It was also demonstrated that the number of all CEC subpopulations (resting, activated, apoptotic, and circulating precursor endothelial cells) was increased in patients with ET in relation to controls, regardless of the JAK2-V617F status, and was not affected by cytoreductive treatment. In conclusion, our study highlights the possible role of angiogenesis in the pathophysiology of ET. It provides evidence that the number of CECs is elevated independently of JAK2-V617F status and is not down-regulated by HU or anagrelide therapy. Our data suggest that VEGF levels are particularly elevated in patients with high leukocytosis. Further investigation should be undertaken to determine the possible role of antiangiogenic therapy in ET.

Coagulation disorders are often the reason for fatal bleeding in acute promyelocytic leukemia. Their occurrence as well as pathogenesis and prognostic significance in other subtypes of acute myelogenous leukemia and acute lymphoblastic leukemia is less known. Tests were carried out in 70 patients including 49 with AML and 21 with ALL. In all patients thrombin-antithrombin complexes (TAT), D-dimer (DD) and plasmin-antiplasmin complexes (PAP), antithrombin III activity, fibrinogen/fibrin degradation products, APTT and PT were determined. The tests were performed on diagnosis and after cytostatic treatment. The level of TAT, DD and PAP was elevated in 83% of the patients on diagnosis and in 90% after treatment. The highest values were observed in AML M3 patients. Among leukemic patients with normal levels of TAT, DD and PAP at diagnosis, cytostatic treatment had a negligible effect on the level of these markers. During remission the levels of these markers returned to the normal values while in patients without remission they were either elevated or returned to normal values. No correlation between the levels of activation markers and remission rate was reported. DIC was diagnosed in 13 patients including three after chemotherapy. The DIC was acute or subacute in AML and chronic in ALL patients. In the majority of acute leukemia patients there were already changes on diagnosis indicating coagulation activation. Except for AML M3, these usually had a subclinical course. The TAT, DD and PAP tests are not reliable markers of remission in acute leukemias.