Toshio Shigekiyo

Takayasu's Arteritis Associated with Antiphospholipid Antibodies Report of Two Cases

The authors describe 2 patients with Takayasus arteritis in whom lupus anticoagulant was positive and the titer of anticardiolipin antibody was elevated. One patient developed diffusely stenotic and occlusive changes in the multiple larger arteries. Histology of the small-sized arteries in another patient showed occlusive vasculitis without thrombosis, in addition to the findings in large-sized arteries compatible with Takayasus disease. These findings are uncommon in Takayasus arteritis. These findings suggest that antiphospholipid antibodies may have contributed to the pathogenesis of the extensive vasculopathy and may have triggered vasculitis in these patients.

Plasma fibronectin deficiency in eight members of one family

The proband, a 31-year-old female, had keloids at the sites of surgery and burns. Her plasma fibronectin level measured by Laurells method was only 10 mg/dl (mean +/- SD in 101 healthy controls 32.2 +/- 5.6 mg/dl) but the electrophoretic mobility was normal. Low levels of plasma fibronectin (range 11-17 mg/dl) were found in the probands mother, two uncles, two brothers, one daughter, and one nephew. Levels in her father and other family members examined were normal (range 32-51 mg/dl). The proband has been quite healthy, an haematological and haemostatic tests showed no abnormality except reduced phagocytosis by neutrophils. Other family members with low plasma fibronectin levels had no abnormalities on examination and no keloids.

Interferon Alpha-2a Therapy for Disseminated Intravascular Coagulation in a Patient with Blue Rubber Bleb Nevus Syndrome A Case Report

The authors present a sixteen-year-old girl with blue rubber bleb nevus syndrome (BRBNS) associated with disseminated hemangiomas involving the skin, oral cavity, skeletal muscle, and cerebrum. Although she denied neurologic symptoms, magnetic resonance imaging of the brain demonstrated dilatated cerebral veins and the Chiari I malformation. Examination of hemostasis revealed disseminated intravascular coagula tion (DIC) manifesting as Kasabach-Merritt syndrome, with the potential for life-threat ening bleeding or thrombosis in the central nervous system. Since successful management of life-threatening hemangiomas with interferon alpha-2a (IFN α-2a) has been reported, the authors administered IFN α-2a with an improvement in hemostasis. These findings suggest that IFN α-2a therapy is beneficial for relieving the life-threatening consumptive coagulopathy associated with BRBNS.

Acquired pial and dural arteriovenous fistulae following superior sagittal sinus thrombosis in patients with protein S deficiency: a report of two cases.

Two patients with protein S deficiency with acquired multiple pial and dural arteriovenous fistulae (AVFs) following superior sagittal sinus (SSS) thrombosis are reported. Case 1 is a 38-year-old male with protein S deficiency who developed generalized seizure due to SSS thrombosis. Local fibrinolysis was achieved in the acute stage. His 10-month follow-up angiogram revealed an asymptomatic acquired dural AVF arising from the middle meningeal artery and the anterior cerebral artery with drainage to the thrombosed cortical vein in the right frontal lobe. Furthermore, his 2-year follow-up angiogram revealed a de novo pial AVF from the middle cerebral artery in the Sylvian fissure with drainage to the cortical vein initially thrombosed. However, this asymptomatic pial AVF caused bleeding in the ipsilateral cerebral hemisphere 12 years after onset, whereas the dural AVF spontaneously disappeared. Surgical disconnection was successfully performed to eliminate the source of hemorrhage. Case 2 is a 50-year-old male with a past history of SSS thrombosis with protein S deficiency who developed pulsatile tinnitus and generalized seizure. His angiogram showed a cortical dural AVF in the left parietal lobe and a sporadic dural AVF involving the right sigmoid sinus. The parietal lesion was eliminated by transarterial embolization followed by craniotomy. However, a de novo pial AVF emerged from the middle cerebral artery adjacent to the previously treated lesion. Of four cortical AVFs in two patients, thrombosis of cortical veins caused by protein S deficiency might play an important role in their formation. Long-term follow-up is required because this peculiar disorder has an unusual clinical course.

Acute myocardial infarction in a patient with essential thrombocythemia who underwent successful stenting : A case report

Essential thrombocythemia (ET) can cause systemic vascular thrombosis, but involvement of coronary arteries in the setting of ET is rare. This report describes a case of acute myocardial infarction (MI) in a patient with ET. A 67-year-old man with ET complained of severe acute chest pain. Emergent coronary angiography revealed subtotal thrombotic occlusion of the left main trunk (LMT) coronary artery. Coronary angioplasty and stenting were performed successfully. Coronary angiography 4 weeks later revealed no significant restenosis. The patient has done well after primary coronary stenting with the use of only an antiplatelet agent to treat the thrombocythemia.

Increase in plasma thrombomodulin level in patients with vibration syndrome

To determine whether endothelial cells are injured in vibration syndrome, we measured plasma levels of thrombomodulin (TM) in 100 patients with this syndrome using one-step sandwich enzyme immunoassay. Plasma level of TM in patients with vibration syndrome was significantly higher than that in normal control (p < 0.0001). There was no significant difference in the plasma TM level between patients with vibration syndrome and those with collagen disease. Plasma TM concentration in chain-saw operators was significantly higher than that in rock-drill operators (p < 0.05). Plasma TM value did not significantly differ between patients with vibration-induced white finger (VWF) and those without VWF. These results suggest that endothelial injury is present in patients with vibration syndrome, the degree of endothelial injury in patients with vibration syndrome equals that in patients with collagen disease, and the endothelial injury in chain-saw operators is greater than that in rock-drill operators. However, there was no difference in the degree of endothelial injury between patients with VWF and those without VWF.

Bleeding tendency in chronic neutrophilic leukemia.

To define the clinical and pathologic features and natural history of chronic neutrophilic leukemia (CNL), as defined by the World Health Organization (WHO), Elliott critically reviewed the literature and identified a total of 34 patients meeting strictly defined WHO criteria for CNL [1]. Of the 34 patients, 9 died of intracranial hemorrhage and 3 demonstrated easy bruising. Elliot indicated that a disproportionate number of reports of intracranial hemorrhage must be considered in the context of an association with chemotherapy-induced thrombocytopenia during treatment of progressive disease. Furthermore, he described that excess hemorrhagic events were not a significant finding in chronic stable-phase disease in the absence of chemotherapy-induced thrombocytopenia. Here, we describe platelet dysfunction in a patient with CNL complicated by bleeding tendency. At the time this patient showed bleeding symptoms, she had not received chemotherapy and her platelet count was normal. On 20 August 2003, an 83-year-old Japanese woman was referred to our department for examination of bleeding tendency. She had a 3-year history of recurrent purpura and occasional nasal bleeding. Neither the patient nor any members of her family had a history of bleeding tendencies. On physical examination, purpura was detected on the face, back and extremities. A CT scan of the abdomen demonstrated splenomegaly. Peripheral blood showed: hemoglobin, 9.7 g/dl; platelets, 284 9 10/l; leukocytes, 29.0 9 10/l with 0.2% myelocytes, 0.6% metamyelocytes, 2.0% stabs, 90.8% segments, 1.0% eosinophils, 2.2% basophils, 1.2% monocytes and 2.0% lymphocytes. Neutrophil alkaline phosphatase (NAP) score was 352 (normal, 190–370). The serum concentration of granulocyte colonystimulating factor (G-CSF) was under 10.0 pg/ml. Immunoelectrophoresis did not show any M protein in serum or urine. The bone marrow was grossly hypercellular with marked myeloid hyperplasia and 1.0% blasts. There were no dysplastic features, minimal fibrosis, normal megakaryocytes and erythropoiesis. Chromosomal analysis demonstrated a normal karyotype. Reverse transcriptasepolymerase chain reaction (RT-PCR) studies failed to demonstrate the presence of BCR-ABL fusion. The patient was diagnosed as having CNL. Routine hemostatic tests demonstrated: bleeding time, more than 8 min (normal, 1–5 min); prothrombin time, 14.9 s (normal, 10.0–13.5 s); activated partial thromboplastin time, 39.8 s (normal, 25.0–40.0 s); plasma fibrinogen level, 295 mg/dl; plasma FDP concentration, 4.1 lg/ml (normal, below 10 lg/ml). Factor VIII activity was 180% (normal, 62–145%), von Willebrand factor antigen was 136% (normal, 50–150%), and ristocetin cofactor activity was 133% (normal, 50–150%). Activities of factor XIII and a2-plasmin inhibitor were 76% (normal, over 70%) and 86% (normal, 85–118%), respectively. Platelet aggregation induced by ADP, collagen, epinephrine or ristocetin was decreased when compared to that in the control. In contrast, arachidonic acid induced platelet aggregation was normal (Fig. 1). Similar patterns of abnormal platelet aggregation were repeatedly demonstrated on three different occasions. Flow cytometric analyses of her platelets for CD41 and CD42b expression showed normal patterns. These findings suggested that this patient had storage pool disease. In this disease, platelet aggregation induced by ADP, collagen, or epinephrine is impaired, but that induced by arachidonic T. Shigekiyo (&) J. Miyagi M. Chohraku K. Kawauchi E. Sekimoto A. Shirakami H. Shibata Department of Internal Medicine, Tokushima Prefectural Central Hospital, 1-10-3 Kuramoto-cho, Tokushima 770-0042, Japan e-mail: shigekiyo@tph.gr.jp

Inhibition of Fibrin Monomer Polymerization by Bence Jones Protein in a Patient with Primary Amyloidosis

The mechanism of inhibition of fibrin monomer polymerization was studied in a patient with primary amyloidosis. Thrombin and reptilase times of the patients purified fibrinogen (Fbg) were remarkably prolonged, and polymerization of the patients fibrin monomer was disturbed. Fbg-Bence Jones protein (BJP) complex was demonstrated by immunoelectrophoresis and sodium dodecyl sulfate-polyacrylamide gel electrophoresis on the patients purified Fbg. The patients BJP not only prolonged the thrombin time of normal Fbg but also inhibited the polymerization of normal fibrin monomer. These results suggested that in this patient fibrin monomer polymerization was inhibited by binding of BJP to Fbg.

Treatment of acquired amegakaryocytic thrombocytopenic purpura with romiplostim

A standard treatment for acquired amegakaryocytic thrombocytopenic purpura (AATP) has not yet been established. Once AATP is diagnosed, a therapeutic trial of cyclosporine, with or without antithymocyte globulin (ATG), is indicated [1]. Allogeneic bone marrow transplantation (BMT) is considered to be an appropriate treatment for patients with refractory or progressive AATP, who are relatively young and have matched siblings [2]. Recently, successful treatment of AATP with a thrombopoietin (TPO) receptor agonist, eltrombopag, has been reported [3]. We herein describe a patient with AATP refractory to other therapies, including eltrombopag, who was successfully managed with another TPO receptor agonist, romiplostim. This publication was approved by the ethics committee of Tokushima Prefectural Central Hospital. A 55-year-old male was referred to us for thrombocytopenia in December 2004. He had a past history of myocardial infarction at 51 years of age, and had therefore been taking numerous drugs, such as aspirin, nicorandil, quinapril hydrochloride, carvedilol, candesartan cilexetil, azosemide, spironolactone, and allopurinol. He was not a heavy drinker. A physical examination revealed many petechiae and ecchymoses on the extremities and the abdominal wall. The peripheral blood results were as follows: Hb, 13.2 g/dl; RBC, 4.19 10/ml; WBC, 7.6 10/ml (seg., 63.5%; eos., 7.0%; baso., 1.5%; mono., 7.5%; lym., 23.0%) and PLT, 4 10/ml. His blood chemistry values, including total bilirubin, AST, ALT, ALP, LDH, BUN and creatinine, were all within the normal limits. The prothrombin time, activated partial thromboplastin time, plasma fibrinogen level, and plasma FDP concentration were all normal. The platelet-associated IgG level was 57.6 ng/10 cells (reference range, 5–25 ng/10 cells). Tests for rheumatoid factor and antinuclear antibody were negative. Screening assays for the human immunodeficiency virus, human T-cell leukemia virus type-1, hepatitis B virus, hepatitis C virus and human parvovirus B19 (IgM) were negative. Bone marrow aspiration showed normal cellularity and the absence of megakaryocytes, with a normal appearance of erythroid and myeloid elements (Figure 1A and B). A bone marrow cytogenetic study showed normal karyotypes. The patient was therefore diagnosed with AATP. Unfortunately, a bone marrow biopsy was not carried out. Of the drugs that the patient had received, both aspirin and allopurinol had previously been given to patients with AATP [1, 3, 4]. However, since it was impossible to show that none of the other drugs were associated with AATP, all medications were discontinued [5]. Pulse therapy with methylprednisolone (1 g/day 3), followed by prednisolone (1 mg/kg/day), was conducted at the same time, but his platelet count remained low for one month. Cyclosporine (5 mg/kg/day) was initiated in January 2005, but his thrombocytopenia had not improved after two months. Horse ATG (1 g/day 5) was administered in March 2005. His platelet count oscillated between 15 10/ml and 470 10/ml in 35–39-day intervals, but became consistently low in December 2005. Bone marrow aspiration in March 2006 gave the same results as in December in 2004 (data not shown). Rabbit ATG (0.5 g/day 5) was administered in March 2006. The change in his platelet count was similar to that after the administration of horse ATG. Danazol (300 mg/day) treatment was initiated in October 2006, but his thrombocytopenia had not improved after three months. Although he was referred to a hospital for allogeneic BMT in May 2007, he was refused a transplant because of his age, complications and the absence of related donors. Cyclophosphamide hydrate (1 and 2 g) was intravenously administered in June and August 2007, respectively, with no improvement of his thrombocytopenia. Since successful treatment of AATP with rituximab (375 mg/m intravenously, weekly, for two consecutive weeks) in a patient with systemic lupus erythematosus was reported, he was given rituximab (375 mg/m) twice in November 2008 [6]. However, his platelet count did not increase at all. When a test dose of horse ATG was given in March 2009, he developed hypotension and a skin rash. We therefore abandoned a second course of both horse and rabbit ATG. Intravenous immunoglobulin was not tested due to its potential risk of thrombosis [7]. Eltrombopag was initiated at 12.5 mg/day in September 2011, and was increased by 12.5 mg/day every two weeks. After one month of treatment Keywords

Factor VII Tokushima: the first case of factor VII Cys22Gly with the development of myocardial infarction in the proband receiving recombinant factor VIIa replacement therapy.

An 81-year-old man was referred to our department because of suspected factor VII (FVII) deficiency. His FVII activity was under 1%, whereas the FVII activity levels of his son and granddaughter were 65 and 109%, respectively. The nucleotide at position 3886 of his FVII gene was homozygous for G. A single T to G substitution results in the replacement of wild-type Cys at residue 22 by Gly. His son was heterozygous for G and T at position 3886, whereas his granddaughter was homozygous for wild-type T. These results suggest that he was homozygous for FVII Cys22Gly. He underwent radiofrequency ablation (RFA) for hepatocellular carcinoma, receiving 20 &mgr;g/kg of recombinant FVIIa prior to RFA and 10 &mgr;g/kg of recombinant FVIIa twice after RFA. He showed no bleeding tendency; however, a myocardial infarction was diagnosed and percutaneous coronary intervention was performed.