Kazuya Sakai

TAFRO syndrome successfully treated with tocilizumab: A case report and systematic review

Abstract Thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome is considered as a unique clinicopathologic variant of multicentric Castleman’s disease and is recently reported in Japan. This entity represents a severe inflammatory state leading to organ failures such as severe liver dysfunction seen in our case, and can be treated by immunosuppressive agents, steroids, and cyclosporine shown in several case reports. A systematic review and our case suggest the potential utility of tocilizumab as a treatment for TAFRO syndrome.

Hairy Cell Leukemia with Systemic Lymphadenopathy: Detection of BRAF Mutations in Both Lymph Node and Peripheral Blood Specimens

A 47-year-old woman with pancytopenia, excessive systemic lymphadenopathy and splenomegaly was referred to our hospital. The peripheral blood (PB) smear findings indicated neutropenia with lymphoid cells exhibiting hairy projections, while the histological findings of the cervical lymph node (LN) suggested hairy cell leukemia (HCL). In addition, the BRAF V600E mutation was detected, and the immunoglobulin gene rearrangement patterns were identical in both the cervical LN and PB specimens. Based on these findings, we diagnosed the patient with systemic lymphadenopathy due to HCL. This is the first report of a BRAF mutation detected in both the PB and LN at the onset of HCL.

Efficacy and safety of interferon alpha for essential thrombocythemia during pregnancy: two cases and a literature review

For pregnant women with essential thrombocythemia (ET), no standard approach for managing the platelet count has been established. We present the cases of two pregnant women with ET treated with interferon (IFN)-alpha. Each case showed a marked platelet decrease, from values within normal limits at the time of delivery, with no severe adverse events. To clarify the efficacy and safely of IFN alpha for ET during pregnancy, we performed a literature review. A total of 43 pregnant women with ET were ultimately identified from 12 articles and the present cases. IFN-alpha therapy decreased platelet counts to normal levels at birth in many cases, and there were no adverse events that required the discontinuation of IFN-alpha treatment. Overall, 93% of pregnant women with ET gave birth to healthy babies. We consider that, given its efficacy and safety, IFN-alpha therapy is a reasonable treatment option for pregnant women with ET.

Intravitreal injection of aflibercept, an anti-VEGF antagonist, down-regulates plasma von Willebrand factor in patients with age-related macular degeneration.

We investigated the association between von Willebrand factor (VWF) and exudative age-related macular degeneration (AMD) in 114 Japanese patients. Intravitreal injection of vascular endothelial growth factor (VEGF) inhibitor is the most effective therapy for AMD. Therefore, we analyzed changes of VWF antigen (VWF:Ag) and VWF multimers (VWFMs) after intravitreal injection of aflibercept, an anti-VEGF antagonist. The relationship between polymorphisms in complement factor H (p.Y402H and p.I62V) and AMD was previously reported. In our patients, p.I62V, but not p.Y402H, was significantly associated with an increased risk of AMD. Pre-treatment plasma levels of VWF:Ag in patients with AMD were significantly higher than those in controls. Unusually large VWFMs (UL-VWFMs) were detected in the majority of AMD patients with concurrent vitreous or subretinal hemorrhage. After intravitreal injection of aflibercept, plasma levels of VWF:Ag and VEGF-A were significantly decreased. UL-VWFMs disappeared after aflibercept injection in three cases, but persisted even 1 month after injection in the other five cases. In conclusion, plasma VWF:Ag levels were significantly elevated in patients with AMD, and decreased after intravitreal aflibercept injection. VWF may play an important role in the pathophysiology of AMD, and aflibercept might improve AMD by reducing plasma levels of VWF in addition to VEGF-A.

Effects of plasma glycosyltransferase on the ABO(H) blood group antigens of human von Willebrand factor

Von Willebrand factor (VWF) is one of the plasma protein carrying ABO(H) blood group antigens, but the combining process of these antigens is not clear. In the present study, we examined whether plasma glycosyltransferase affects the blood group antigens on VWF. VWF expressing H-antigen (H-VWF) from blood group O and bovine serum albumin conjugated with H-antigen (H-BSA) were incubated with recombinant α1-3-N-acetylgalactosaminyltransferase (rA-transferase) and A-plasma with or without an additional UDP-GalNAc. Transformed antigens were detected by western blotting and ELISA, using an anti-A antibody. Both H-VWF and H-BSA acquired the A-antigen after incubation with rA-transferase and UDP-GalNAc. Incubation with A-plasma very weakly converted the H-antigen on BSA and VWF to A-antigen only in the presence of supplemented UDP-GalNAc. This conversion was enhanced on desialylation of H-VWF. These results indicate that sugar chains of plasma VWF can be modified by the external glycosyltransferase, but that plasma glycosyltransferase has no effect on the blood group antigens of VWF due to its low activity and the lack of donor sugars. Further, sialic acid residues of VWF may exert a protective effect against post-translational glycosylation. Our results clearly exclude the possibility that blood group antigens of VWF are constructed extracellularly in plasma.

Purpura Fulminans Associated with Overwhelming Postsplenectomy Infection

A 37-year-old Japanese woman was referred to our institute with a 1-day history of a fever and altered mental status. Physical examinations revealed non-palpable purpura on her face, trunk, and extremities (Picture 1, 2). Blood tests revealed marked thrombocytopenia and hypofibrinogenemia. A detailed chart review showed that she had undergone splenectomy 10 years prior and had not been vaccinated against pneumococcus. A lumbar puncture revealed pleocytosis suggesting meningitis, and her blood cultures were positive for Streptococcus pneumoniae. A diagnosis of purpura fulminans (PF) and overwhelming postsplenectomy infection (OPSI) due to pneumococci was established. After therapy with ceftriaxone, she recovered, and the purpura diminished. Asplenic people are susceptible to severe infections due to encapsulated bacteria, such as S. pneumoniae, and develop OPSI, a life-threatening entity (1). Pneumococcus develops both PF and OPSI. PF and OPSI more frequently develop in septic patients with asplenia than in those with intact spleen (2). Physicians need to be aware that purpura may be the only sign of OPSI in asplenic patients.

Severe reduction of free-form ADAMTS13, unbound to von Willebrand factor, in plasma of patients with HELLP syndrome

Severely decreased ADAMTS13 unbound to VWF may play a key role in the pathogenesis of HELLP syndrome.A qualitative ADAMTS13 assay may be important for diagnosing HELLP syndrome.

Decreased activity of plasma ADAMTS13 are related to enhanced cytokinemia and endotoxemia in patients with acute liver failure

Deficient ADAM metalloproteinase with thrombospondin type-1 motif, member 13 (ADAMTS13) activity (ADAMTS13:AC) results in the accumulation of unusually large von Willebrand factor multimers (UL-VWFM) and causes microcirculatory disturbances and multiple organ failure, while endotoxins trigger the activation of a coagulation cascade. The objective of the present study was to explore the role of ADAMTS13 in endotoxemia in patients with acute liver failure (ALF). Plasma concentrations of endotoxin and cytokines, including interleukin (IL)-6 and IL-8, and activity of the plasma ADAMTS13 inhibitor were determined, along with ADAMTS13:AC, the VWF antigen (VWF:Ag) and UL-VWFM, in 27 patients with acute hepatitis (AH), 11 patients with ALF, and 10 healthy controls. IL-6 and IL-8 concentrations on admission were significantly higher in patients with ALF than in those with AH or in healthy controls. ADAMTS13:AC concomitantly decreased and VWF:Ag progressively increased with increasing cytokine concentrations from the normal range to >100 pg/ml. The inhibitor was detected in 8 patients with ALF (0.6 to 2.4 BU/ml) and 6 patients with AH (0.6 to 0.8 BU/ml). Patients with the inhibitor reported lower ADAMTS13:AC, higher VWF:Ag and lower functional liver capacity than those without the inhibitor. Collectively, the findings suggested that decreased ADAMTS13:AC and increased VWF:Ag may be induced by pro-inflammatory cytokinemia as well as the presence of the ADAMTS13 inhibitor, both of which may be closely related to enhanced endotoxemia in patients with ALF.

Myeloid blast crisis in chronic myeloid leukemia with a unique deletion near the BCR/ABL breakpoint

We describe a case of a 44-year-old man with chronic myeloid leukemia in blastic crisis phase based on peripheral blood smear findings, and the detection of BCR/ABL transcript signals by fluorescence in situ hybridization analysis. Our attempts to quantify the amount of the major BCR/ABL fusion gene revealed that some primers were unable to detect the gene, whereas other primers could detect the gene. We detected a unique deletion on the BCR area by cloning the sequence, which has not been reported previously. Our case suggests that direct sequencing is important when quantitative PCR yields ambiguous results.