[The frontline of TMA management].

Thrombotic microangiopathy (TMA) is a pathological condition characterized by platelet thrombi-induced generalized microvascular occlusion, thrombocytopenia, and microangiopathic hemolytic anemia. TMA includes the life-threatening diseases thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS). TTP is different from HUS in that it has a severe deficiency in ADAMTS13 activity. Congenital TTP is caused by a lack of plasma ADAMTS13 activity caused by genetic mutations, and acquired TTP is caused by a secondary deficiency caused by autoantibodies. In Japan the only product approved for the treatment of congenital TTP is fresh frozen plasma containing ADAMTS13. Recombinant ADAMTS13 may provide a new treatment option for congenital TTP. The first-line treatment for acquired TTP is plasma exchange. Rituximab treatment should be considered for patients who are refractory or have relapsed. Caplacizumab is a nanobody that specifically targets von Willebrand factor. ISTH recently published guidelines recommending that caplacizumab be added to the initial treatment for acquired TTP. Atypical HUS (aHUS) is related with the dysregulation of the complement alternative pathway. Eculizumab, a monoclonal antibody that inhibits C5, was the first drug approved for aHUS, and it was found to be well-tolerated by patients and effective in clinical use. TMA is classified based on its etiology, and specific treatments for targeting various etiologies are now available.

Anti-Ma-associated paraneoplastic cerebellar degeneration in a patient with nodular lymphocyte-predominant Hodgkin lymphoma: a case report.

BACKGROUND: Paraneoplastic cerebellar degeneration (PCD) is a devastating paraneoplastic syndrome that occasionally occurs in patients with Hodgkin lymphoma (HL). Anti-Ma2 is a well-characterized onconeuronal antibody and one of the causes of PCD. There has been only one previous report of anti-Ma2-associated paraneoplastic syndrome as a complication of HL. Here we present a rare case of anti-Ma2-associated PCD in a patient with nodular lymphocyte-predominant HL (NLPHL). CASE PRESENTATION: A 77-year-old man with a 3-month history of gait instability and a 2-month history of oscillopsia was referred to our hospital for further investigation. On examination, his cognition was normal. He had nystagmus in all directions of gaze; specifically, he had horizontal and rotatory nystagmus in the primary position, downbeat nystagmus after right, left, and up gaze, and upbeat nystagmus after down gaze. Although his limb ataxia was mild, his trunk ataxia was so pronounced that he was unable to walk without support. We strongly suspected paraneoplastic syndrome and tested for neuronal autoantibodies. The anti-Ma2 antibody was strongly positive in the blood and cerebrospinal fluid but other antineuronal autoantibodies were negative. Computed tomography showed an enlarged lymph node in the right axilla but no masses. Biopsy confirmed a diagnosis of NLPHL. The NLPHL cells stained with anti-Ma-2 antibody in the cytoplasm, suggesting these abnormal cells contained protein that was cross-reactive with Ma-2. CONCLUSIONS: To the best of our knowledge, this is the first case of anti-Ma2-associated PCD in a patient with NLPHL that was confirmed using immunostaining of the lymph node tissue with anti-Ma2 antibody. Our case confirms an association between anti-Ma2-associated PCD and NLPHL.

Intractable bleeding tendency due to acquired von Willebrand syndrome after Jarvik 2000 implant.

A 61-year-old man was implanted with a Jarvik 2000, a continuous axial flow type left ventricular assist device (LVAD), for end-stage heart failure due to dilated cardiomyopathy. One month later, his postoperative course was complicated with intractable oozing-type gastrointestinal bleeding from multiple small shallow ulcers and erosions in the colon. In addition, repeated bleeding episodes were encountered at around thoracentesis site for pleural effusion. Hematological examination showed that platelet counts and coagulation factors were kept within normal ranges. We, thereafter, revealed remarkable loss of the large multimers of von Willebrand factors (VWFs), which might be closely associated with his intractable bleeding tendency.

HIV-associated CD8+ T-cell Skin Infiltrative Disease and EBV-associated Polymorphic B-cell Lymphoproliferative Disorder in an AIDS Patient Who Improved Dramatically with Antiretroviral Therapy Alone.

Human immunodeficiency virus (HIV)-associated CD8+ T-cell skin infiltrative disease with severe erythroderma has rarely been reported. While HIV-positive patients are prone to develop lymphoma, which is often associated with Epstein-Barr virus, polymorphic lymphoproliferative disorder is rare, accounting for <5% of cases. We herein report a 41-year-old HIV-positive man who presented with a fever, erythroderma, and lymphadenopathy and was diagnosed with the coexistence of both diseases. His condition improved significantly with continued antiretroviral therapy. This case suggests that HIV-induced immunodeficiency is central to the pathogenesis of both entities and that improvement of the immunodeficient state is an effective treatment.

Persistent ADAMTS13 inhibitor delays recovery of ADAMTS13 activity in caplacizumab-treated Japanese patients with iTTP.

ABSTRACT: For patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP), caplacizumab, a nanobody against von Willebrand factor A1 domain, has become crucial. Delayed normalization of ADAMTS13 activity during caplacizumab therapy has been identified. In a retrospective analysis, we compared platelet count, ADAMTS13 activity, its inhibitor, and anti-ADAMTS13 immunoglobulin G (IgG) levels in acute iTTP cases treated with caplacizumab (n = 14) or without it (n = 16). The median time from initial therapeutic plasma exchange (TPE) to the first rituximab administration was 12 days in the caplacizumab group (n = 11) and 10 days in the group without caplacizumab (n = 13). We evaluated ADAMTS13-related parameters at onset and once a week until day 28 after the first TPE. The number of days until the platelet counts reached ≥150 × 109/L was significantly shorter in the caplacizumab group than in the non-caplacizumab group. The median ADAMTS13 activity levels on days 14, 21, and 28 were significantly lower in the caplacizumab group. The median titers of the ADAMTS13 inhibitor and anti-ADAMTS13 IgG on the same days were significantly higher in the caplacizumab group. Furthermore, the median number of days from the first TPE until finally achieving an ADAMTS13 activity of ≥10% was significantly longer in the caplacizumab group than in the non-caplacizumab group (42 vs 23 days, P = .014). We observed delayed ADAMTS13 activity recovery and continued inhibitor and anti-ADAMTS13 IgG detection in patients with acute iTTP on caplacizumab, possibly because of the decreased number of TPEs and delayed frontline rituximab.

Cryobiopsy for Pneumocystis jirovecii pneumonia secondary to adult T-cell lymphoma/leukaemia.

A 79-year-old woman presented to the emergency department with a 1-week history of progressively worsening dyspnoea on exertion. Chest computed tomography (CT) showed bilateral consolidation. On laboratory findings, the line blot assay for human T-cell leukaemia virus type 1 was positive, the white blood cell count was 33,000/µl (atypical lymphocytes 8500/µl, 26% of the total white blood cell count) and ß-d-glucan was increased to 391.1 pg/ml. In bronchoalveolar lavage fluid, there was a small number of atypical lymphocytes, and the polymerase chain reaction for Pneumocystis jirovecii was positive. Sulfamethoxazole-trimethoprim and corticosteroid were administered, but the lung shadows remained. Adult T-cell lymphoma/leukaemia (ATLL) cell infiltration was suspected, and transbronchial lung cryobiopsy was performed, which showed no infiltration of lymphoma cells into the lung. The lung shadow showed an improving trend on chest CT. She was diagnosed with chronic type ATLL and discharged without chemotherapy.

Complete Bone Marrow Necrosis with Charcot-Leyden Crystals Caused by Myeloid Neoplasm with Mutated NPM1 and TET2.

Bone marrow necrosis (BMN) has various underlying diseases. In hematological malignancies, both lymphoid and myeloid neoplasms have been shown to cause BMN. Charcot-Leyden crystals (CLCs) are bipyramidal crystals that have been found in patients with immune system diseases, tumors, skin diseases, asthma, infections, and intestinal diseases. Because the combination of CLCs and acute myeloid leukemia (AML) is rare, the relationship between BMN, CLCs, and AML remains largely unexplored. We herein report a suspected case of AML that was difficult to diagnose morphologically because of complete BMN with CLCs but achieved complete hematologic remission with treatment similar to that for AML.

Extracorporeal membrane oxygenation in Stenotrophomonas maltophilia pneumonia during acute myeloid leukemia: A case report.

Stenotrophomonas maltophilia (S. maltophilia) is a Gram-negative, multidrug-resistant organism that both opportunistically infects the bloodstream and leads to pneumonia in immunosuppressed patients, including those with hematologic malignancies. In patients with severe respiratory failure, venovenous extracorporeal membrane oxygenation (VV ECMO) can stabilize the respiratory status. However, whether ECMO in patients with hematologic malignancies improves the clinical outcomes is still controversial because ECMO increases the risk of the exacerbation of sepsis and bleeding. We report a case of a 46-year-old man with Stenotrophomonas maltophilia hemorrhagic pneumonia acquired during consolidation chemotherapy for acute myeloid leukemia in whom VV ECMO lead to a good clinical outcome. The stabilization of his respiratory status achieved with VV ECMO allowed time for trimethoprim-sulfamethoxazole antibiotic therapy to improve the pneumonia. We suggest the background of patients, including comorbidities and general conditions, should be taken into account when considering the clinical indications of ECMO.

Association between the severity of acquired von Willebrand syndrome and gastrointestinal bleeding after continuous-flow left ventricular assist device implantation.

OBJECTIVES: Acquired von Willebrand syndrome, characterized by the reduction in von Willebrand factor (vWF) large multimers, has recently been considered as one of the causes of gastrointestinal bleeding (GIB). It remains unclear whether its haematological severity is linked with susceptibility to bleeding because the definition of the haematological severity of acquired von Willebrand syndrome has not been precisely determined. This study sought to establish a quantitative methodology to assess the haematological severity of acquired von Willebrand syndrome and to define the threshold for occurrence of GIB in patients implanted with left ventricular assist devices (LVADs). METHODS: In total, 41 patients treated with continuous-flow LVAD implanted between 2011 and 2017 at Tohoku University Hospital were investigated. vWF large multimers were quantitatively evaluated using the 'vWF large multimer index' defined as the ratio of a large multimer proportion in total vWF derived from a patient to that from a normal control. Using this index, the amount of vWF large multimers was expressed as a percentage of its normal control value obtained with a simultaneous analysis of each time measurement. RESULTS: Twelve (29%) patients developed GIB events during follow-up periods (median 591 days) after an LVAD implantation. The vWF large multimer index in patients with GIB was significantly lower than that in those without GIB (25.0 ± 10.3% vs 37.5 ± 17.8%, P = 0.008). Most importantly, all patients experiencing GIB exhibited a vWF large multimer index below 40%. CONCLUSIONS: Patients with GIB exhibited a more severe loss of vWF large multimers. The vWF large multimer index may dictate the risk of GIB after an LVAD implantation. Clinical trial registration number: UMIN000018135.