[Hemophagocytic lymphohistiocytosis following mRNA-1273 COVID-19 vaccination].

A 34-year-old man with no medical history presented with fever 4 days after receiving the first dose of mRNA-1273 coronavirus disease 2019 (COVID-19) vaccine. He had no prior clinical evidence of severe acute respiratory syndrome coronavirus 2 infection and was negative for serial polymerase chain reaction testing. Ten days after vaccination, he was referred to our hospital because of no response to antibiotics and the emergence of neutropenia, thrombocytopenia, and liver dysfunction. Blood tests also showed elevated serum ferritin and plasma soluble interleukin-2 receptors. Serological and PCR testing excluded active infections of cytomegalovirus, Epstein-Barr virus, and hepatitis viruses. Blood culture yielded no growth. Computed tomography revealed mild hepatosplenomegaly and porta hepatis lymphadenopathy but no focus on infection. Bone marrow aspiration demonstrated hemophagocytosis but no infiltrating lymphoma cells. Immediately, 2-mg/kg intravenous methylprednisolone was commenced based on the presumptive diagnosis of hemophagocytic lymphohistiocytosis (HLH), leading to the rapid and durable improvement of his symptoms and laboratory data. Later, without other causes triggering hemophagocytosis, and with the close link between vaccination and disease onset, the final diagnosis of vaccination-induced secondary HLH was made. HLH after COVID-19 vaccination, though extremely rare, can occur regardless of the vaccine type. Therefore, clinicians should recognize and deal with this occasionally fatal adverse event.

[Chronic myeloid leukemia with an in-frame exon 4 deletion in ABL1 with acute abdomen due to an intrapelvic bulky mass as the initial symptom].

A 23-year-old woman was admitted to our hospital because of rapidly developing lower abdominal pain. Computed tomography revealed ascites, splenomegaly, and a huge mass that occupied the pouch of Douglas and surrounded her uterus. A markedly elevated white blood cell count of 495×109/l and the identification of the BCR-ABL1 fusion gene led to the diagnosis of chronic myeloid leukemia (CML). Although neither an increase in the blast percentage nor any additional chromosomal abnormality was observed in the patient, CML was considered in the blast phase because of extramedullary disease infiltration. Dasatinib was administered with the temporal use of hydroxyurea and VP-16, which resulted in rapid disappearance of her intrapelvic mass and complete hematologic response within 1 month. She refused to undergo allogeneic hematopoietic stem cell transplantation and continued to take dasatinib, achieving complete cytogenetic and major molecular responses within 5 and 11 months, respectively. CML cases initially presenting with extramedullary tumors are rare. Furthermore, in our case, a mutational analysis at diagnosis revealed an in-frame exon 4 deletion in ABL1, which is reported to decrease cell proliferation. This fact is intriguing because her clinical outcome was relatively favorable.

Reevaluation of platelet function in chronic immune thrombocytopenia: impacts of platelet size, platelet-associated anti-αIIbß3 antibodies and thrombopoietin receptor agonists.

Platelet function of immune thrombocytopenia (ITP) has been controversial because of methodological problems associated with low platelet counts. In this study, we evaluated platelet function in 21 patients with chronic ITP (cITP) using the recently developed flow cytometry (FCM)-based platelet aggregation assay (FCA) along with a PAC1/CD62P assay. Since ITP platelets are larger than controls, whole platelets (whole gating method) and size-adjusted platelets (size-adjusted method) were analysed in the PAC1/CD62P via FCM. We found that: (i) aggregation was equivalent [phorbol myristate acetate (PMA) or adenosine diphosphate (ADP)-induced] or enhanced [protease-activated receptor 1-activating peptide (PAR1AP)-induced] in cITP compared with control by FCA; (ii) PAC1 or CD62P was also equivalent or enhanced in cITP in the whole gating method; and (iii) in sharp contrast, the size-adjusted method revealed that ADP-, PAR1AP-, and collagen synthetic liquid reactive peptide (SRP)-induced PAC1 and ADP-induced CD62P were impaired in cITP. These data suggested that an increase in the number of larger-sized platelets may compensate for the impaired platelet function of cITP, leading to non-inferiority of overall platelet function in cITP. Furthermore, we revealed that ADP-induced aggregation was impaired in the patients with thrombopoietin receptor agonists (TPO-RAs) or platelet-associated anti-αIIbß3 antibodies compared with the control, suggesting that the presence of anti-αIIbß3 autoantibodies and/or administration of TPO-RAs may have a negative impact on platelet function.

Knock-in mice bearing constitutively active αIIb(R990W) mutation develop macrothrombocytopenia with severe platelet dysfunction.

BACKGROUND: To date, several mutations that induce constitutive activation of integrin αIIbß3 have been identified in congenital macrothrombocytopenia. Of these, αIIb(R995W) is the most prevalent mutation observed in Japanese patients with αIIbß3-related congenital macrothrombocytopenia. OBJECTIVE AND METHODS: The present study aimed to explore the effects of constitutive activation of the αIIb(R995W) mutation on platelet production, morphology, and function. We generated αIIb(R990W) knock-in (KI) mice corresponding to human αIIb(R995W). RESULTS: Platelet counts of heterozygous (hetero) and homozygous (homo) KI mice were decreased by ~10% and ~25% relative to those of wild-type (WT) mice, respectively, with increase in platelet size. Decrease in absolute reticulated platelet numbers in steady state, delayed recovery from thrombocytopenia induced by anti-platelet antibody and impaired response to exogenous thrombopoietin administration suggested impaired platelet production in KI mice. WT and KI mice showed no significant differences in the number of megakaryocytes and ploidy of megakaryocytes, whereas proplatelet formation was significantly impaired in homo mice. We observed a slight but significant reduction in platelet lifespan in homo mice. The homo mice showed dramatic reduction in αIIbß3 expression in platelets, which was accompanied by severe in vivo and in vitro platelet dysfunction. CONCLUSION: The αIIb(R990W) KI mice developed macrothrombocytopenia, which was primarily attributed to impaired proplatelet formation. In addition, homo KI mice showed marked downregulation in αIIbß3 expression in platelets with severe impaired platelet function, similar to Glanzmann thrombasthenia.

Protease-activated receptor-4 (PAR4) variant influences on platelet reactivity induced by PAR4-activating peptide through altered Ca2+ mobilization and ERK phosphorylation in healthy Japanese subjects.

BACKGROUND: Thrombin belongs to the most potent platelet agonists and activates human platelets through GPIbα and two protease activated receptors (PARs), PAR1 and PAR4. However, the details of thrombin receptor system, especially the role of PAR4 on human platelet activation is still not clear. OBJECTIVES: We found a significant difference in PAR4-activating peptide (PAR4-AP)-induced, but not PAR1-AP, platelet aggregation between healthy Japanese subjects. Sequencing analysis revealed a single nucleotide change in PAR4 gene F2RL3 (SNP rs773902) leading to Ala120Thr variant. To elucidate the role of PAR4 in human platelet activation, we examined if platelet activation induced by PAR4-AP may be associated with PAR4 genotype. METHODS: Platelets from 202 healthy Japanese volunteers were genetically analyzed and determined the genotype frequency of rs773902. Agonist induced platelet aggregation, integrin αIIbß3 activation, granule release, Ca2+ mobilization, and activation of ERK and MLC were evaluated. The specificity of effects observed in platelets was confirmed in 293T cells transfected PAR4-Thr120 or Ala120. RESULTS: The frequencies of PAR4 variant Thr/Thr120, Ala/Thr120, and Ala/Ala 120 were 5.9, 37.1, and 57.0%, respectively. Platelets with Thr/Thr120 showed significantly higher reactivity in PAR4-AP-induced platelet aggregation, αIIbß3 activation and granule release compared to platelets with Ala/Ala120. PAR4-AP induced higher Ca2+ mobilization and ERK activation in platelets with Thr/Thr120 than Ala/Ala120. Ca2+ mobilization and ERK activation were also increased in 293T cells transfected with PAR4-Thr120 compared to Ala120. CONCLUSION: Our data suggested that PAR4-AP-induced platelet reactivity between PAR4 rs773902 was associated with altered intensity of Ca2+ mobilization and ERK activation.

Autoimmune bullous disease and Hashimoto's disease complicated by acquired hemophilia A.

A 67-year-old man was admitted with a 1-month history of spontaneous hematoma in his right back and severe anemia. He had suffered from rashes with blisters involving both legs for 10 years, which had shown worsening and extended to his entire body concurrently with the hematoma. APTT was markedly prolonged to 119 seconds, and Factor VIII:C and FVIII inhibitor levels were less than 1% and 153.1 BU/ml, respectively, confirming the diagnosis of acquired hemophilia A (AHA). Skin biopsy revealed his rashes to be caused by autoimmune bullous disease (ABD), and laboratory and physical findings showed that he also had autoimmune hypothyroidism (Hashimoto's disease). Recombinant FVIIa was effective for management of his bleeding; in addition, FVIII inhibitor reduction and FVIII:C recovery, in parallel with improvement of the skin lesions, were achieved by administering prednisolone and cyclophosphamide. To our knowledge, this is the first report of AHA associated with ABD and Hashimoto's disease.

Dramatic response of chemotherapy for cancer of unknown primary origin of sarcomatoid carcinoma producing granulocyte colony-stimulating factor.

Cancer of unknown primary origin (CUP) which is usually diagnosed based on the histological type of metastatic site has marked heterogeneous characteristics. Sarcomatoid carcinoma defined as CUP has not been reported according to our literature survey. A 59-year-old man presented with enlarged multiple thoracic lymph nodes, huge splenomegaly and nodules in left temporal lobe of the brain. The histopathological diagnosis of lymph node and spleen was sarcomatoid carcinoma. However, all extensive diagnostic examinations could not detect a site of primary origin. The laboratory data showed marked leukocytosis with increased serum granulocyte colony-stimulating factor (G-CSF). Therefore, the patient was finally diagnosed of CUP of sarcomatoid carcinoma producing G-CSF. After gamma knife treatment for brain metastases, two regimens of taxan-based chemotherapy (carboplatin and paclitaxel, gemcitabine and docetaxel) were administered, with no effect but further tumor progression. Splenectomy for avoiding splenic rupture was performed. As the third line chemotherapy, the combination consisting of doxorubicin and ifosfamide was administered and showed a good therapeutic effect and normalized white blood cell count and serum G-CSF level. He achieved complete remission after three cycles. Herein we present an extremely rare case of CUP of sarcomatoid carcinoma producing G-CSF. Our case suggests the importance of chemotherapy including doxorubicin and ifosfamide, and multimodal therapeutic strategy for this aggressive disease.

[Development of chronic myelogenous leukemia during treatment with TPO receptor agonist for ITP].

We report a 77-year-old Japanese man with idiopathic thrombocytopenic purpura (ITP) which developed into chronic myelogenous leukemia (CML) during treatment with eltrombopag, a thrombopoetin (TPO) receptor agonist, because the disease was refractory to prednisolone. Eltrombopag can induce a good reaction in terms of the platelet count. However, CML in the chronic phase developed in about 19 months in our present case. Dasatinib was administered because he had diabetes. However, a blastic crisis immediately occurred. He died despite switching to Nilotinib. Recently, the occurrence of myelofibrosis and hematological malignancies due to long-term use of TPO receptor agonists has become a concern. This is the first report of a TPO receptor agonist possibly contributing to CML onset and crisis.

Stress affects a gastrin-releasing peptide system in the spinal cord that mediates sexual function: implications for psychogenic erectile dysfunction.

BACKGROUND: Many men suffering from stress, including post-traumatic stress disorder (PTSD), report sexual dysfunction, which is traditionally treated via psychological counseling. Recently, we identified a gastrin-releasing peptide (GRP) system in the lumbar spinal cord that is a primary mediator for male reproductive functions. METHODOLOGY/PRINCIPAL FINDINGS: To ask whether an acute severe stress could alter the male specific GRP system, we used a single-prolonged stress (SPS), a putative rat model for PTSD in the present study. Exposure of SPS to male rats decreases both the local content and axonal distribution of GRP in the lower lumbar spinal cord and results in an attenuation of penile reflexes in vivo. Remarkably, pharmacological stimulation of GRP receptors restores penile reflexes in SPS-exposed males, and induces spontaneous ejaculation in a dose-dependent manner. Furthermore, although the level of plasma testosterone is normal 7 days after SPS exposure, we found a significant decrease in the expression of androgen receptor protein in this spinal center. CONCLUSIONS/SIGNIFICANCE: We conclude that the spinal GRP system appears to be a stress-vulnerable center for male reproductive functions, which may provide new insight into a clinical target for the treatment of erectile dysfunction triggered by stress and psychiatric disorders.