BACKGROUND: Eleven percent of severe hemophilia A patients and 5% of severe hemophilia B patients may develop inhibitors. We have conducted aPCC-based maintenance therapy for hemophilia patients with high levels of responding inhibitors and we analyzed the efficacy, safety, the factor consumption and the expense of this treatment, as compared to on-demand therapy. METHODS: Eleven hemophilia patients with high levels of responding inhibitors were eligible for the study. We tried to evaluate the longitudinal bleeding episodes, the inhibitor titers, the X-ray findings, the adverse events and the factor consumption between on-demand therapy and maintenance therapy. The bypassing agent in this study was aPCC having a longer half-life. The dosage was 30~50 U/kg, 3 times a week. RESULTS: The mean follow-up period was 6.8 months for on-demand therapy and 10.6 months for maintenance therapy. The mean dosage of aPCC was 45.2 U/kg. The episodes of hemarthrosis decreased by 61.4% (P=0.003) and other significant bleedings decreased by 45.2% (P=0.109). The inhibitor titers decreased in 7 patients and these increased in 4 patients, but anamnesis took place in only 1 patient. Radiologically, 2 patients improved, 1 patient got worse and 7 patients were stable. Neither adverse signs nor symptoms were noticed. The mean factor consumption changed from 55.8x10(3) U for aPCC and 48.6 mg for rFVIIa on-demand therapy to 216x10(3) U for aPCC and 4.8 mg rFVIIa for maintenance therapy. Maintenance therapy cost 67% more than on-demand therapy monthly (P=0.041). CONCLUSION: aPCC-based maintenance therapy for hemophilia patients with high responding inhibitors cost 67% more than on-demand therapy, but it reduced by 61.4% the episodes of hemarthrosis and 45.2% of the other significant bleedings. aPCC-based maintenance therapy can very effectively reduce the bleeding episodes of hemophilia patients with high levels of responding inhibitors.
Factor VIIa ; Follow-Up Studies ; Half-Life ; Hemarthrosis ; Hemophilia A ; Hemophilia B ; Hemorrhage ; Humans ; Hypogonadism ; Mitochondrial Diseases ; Ophthalmoplegia ; Prothrombin ; Recombinant Proteins

Hemophilia A (factor VIII deficiency) and Hemophilia B (factor IX deficiency) are the most common and serious congenital coagulation disorders. Accurate diagnosis is important and essential for effective management. A definitive diagnosis depends on factor assay to demonstrate the presence of factor VIII or factor IX. Bleeding should be treated with factor replacement therapy at the earliest moment possible, preferably within two hours from the onset of symptoms. In spite of improvements in hemophilia therapy, arthropathy remains as a significant clinical problem. Based on numerous recommendations, a major goal of hemophilia therapy is to prevent any joint disease, and prophylaxis is superior to on-demand therapy in delaying or preventing the development of hemophilic arthropathy. Prophylaxis is the administration of clotting factors at regular intervals to prevent bleeding. Currently the most commonly suggested protocol for prophylaxis is the infusion of 25~40 IU/kg of clotting factor concentrates three times a week for those with hemophilia A and twice a week for those with hemophilia B. The management of patients who have inhibitory antibodies against factor VIII or IX remains challenging. About 10~15% of hemophilia A patients and 1~3% of hemophilia B patients may develop persistent inhibitors rendering treatments with factor concentrates difficult. Alternative agents for hemophilia inhibitor patients include bypassing agents, such as recom-binant factor VIIa and prothrombin complex concentrates. Ultimately, immune tolerance induction to eradicate the inhibitor is desired.
Antibodies ; Blood Coagulation Factors ; Factor IX ; Factor VIIa ; Factor VIII ; Hemophilia A ; Hemophilia B ; Hemorrhage ; Humans ; Immune Tolerance ; Joint Diseases ; Prothrombin

Central venous access devices (CVAD) provide hemophilic patients, particularly children, with prolonged reliable venous access to promote routine factor replacement therapy. However, one of the significant complications of CVAD use is infection. We report the case of a severe hemophilia B patient with an inhibitor who developed septic arthritis and infective endocarditis associated with methicillin-resistant Staphylococcus aureus infection originating from a CVAD. Our patient had an underlying condition of congenital heart disease, one of the risk factors for infective endocarditis. Unfortunately, the antibiotic therapy did not have a significant effect. An echocardiogram revealed vegetation on the right ventricular moderate band and surgery was determined to be the best course of action. Septic arthritis and endocarditis rarely occur in hemophilia patients, however, they must be taken into account in hemophiliacs with continuing bacteremia.
Adolescent* ; Arthritis, Infectious* ; Bacteremia ; Child ; Endocarditis* ; Heart Defects, Congenital ; Heart Septal Defects, Ventricular ; Hemophilia A* ; Hemophilia B* ; Humans ; Methicillin-Resistant Staphylococcus aureus ; Risk Factors

Acquired hemophilia A (AHA) is a rare bleeding disorder, especially in adolescents and young adults (AYAs) attributable to the development of autoantibodies against coagulation factor VIII (FVIII). AHA diagnosis is difficult; patients lack any history of coagulopathy. We report here on an AYA with AHA who responded well to treatment. A 19-year-old woman visited our hospital with painful swelling of the right lower leg. She had no past or familial history of a bleeding disorder. The initial laboratory data revealed a prolonged activated partial thromboplastin time and an uncorrected mixing test result. The FVIII activity was below 1% and the FVIII antibody level 22.4 Bethesda units. She was diagnosed with AHA and treated with recombinant activated coagulation factor VII, activated prothrombin complex concentrates and an oral steroid. After 9 months, FVIII antibody level was negative and the FVIII activity was normalized. AHA is very rare especially in AYAs, but physicians must be suspicious about the disorder and plan specialized coagulation tests to diagnose the disease. An early diagnosis of acquired bleeding disorders should be done for initiating the adequate treatment immediately by both controlling the acute bleeding episode and eliminating FVIII antibodies.

Inhibitor development is one of the major adverse events associated with increased morbidity and mortality in patients with congenital hemophilia. Recent treatment for them is immune tolerance induction (ITI), which involves the administration of high doses of factor concentrates over a prolonged period, sometimes combined with immunosuppressive agents. We report a case of inhibitor elimination with Rituximab, and high-dose factor VIII concentrates in a 5-year-old boy with hemophilia A. The patient improved clinically, with fewer bleeding episodes. However, he continued to have low immunoglobulin levels, which led to recurrent infections. After an infusion of intravenous immunoglobulin, inhibitor titers increased rapidly and his ITI was deemed a failure. In conclusion, even though it failed in the present study, Rituximab may be an alternative adjuvant therapy to eliminate the inhibitor in patients with hemophilia. The appropriate schedule and long-term side effects need further investigation.
Appointments and Schedules ; Child, Preschool ; Factor VIII ; Hemophilia A ; Hemorrhage ; Humans ; Immune Tolerance ; Immunoglobulins ; Immunosuppressive Agents ; Male ; Mortality ; Rituximab

PURPOSE: Intestinal vascular ischemia is the most probable pathogenesis in the development of necrotizing enterocolitis in prematures. The authors studied the histology of intestinal mucosal damage by clamping the superior mesenteric artery in 35 rats, and, analyzed the histologic scores between young rats(I) and adult rats(II) groups according to clamping times(15, 30 and 60 minutes) and compared the effect of interleukin-10(IL-10) in five subjects. METHODS: The superior mesenteric artery supplying the small intestine was clamped by a small vessel clamp. IL-10 was applied subcutaneously every three days. All rats were killed on the third day after clamping, and were evaluated pathologically by histologic scoring scale adapted from Chiu, et al. RESULTS: The histologic score of group I was significantly higher than that of group II(P<0.05). When groups I & II were compared in terms of ischemic time, histologic scores showed significant statistical differences in the 60 minute group(9.2+/-1.304, 6.6+/-1.14, respectively, P<0.05). In young rats, the histologic score of the 30 minute group was significantly higher than that of the 15 minute group(P<0.05). Also in adult rats, the histologic score of the 60 minute group was significantly higher than that of the 30 minute group(P<0.05). The histologic score of the IL-10 treated-group was significantly lower than that of the non-treated group(P<0.05). CONCLUSION: More rapid and severe mucosal damage by ischemia was found in young rats than adult rats. We also expect that IL-10 may have an effect on treatment and prevention of ischemic change, but more extensive study is required.
Adult ; Animals ; Constriction ; Enterocolitis, Necrotizing ; Humans ; Interleukin-10* ; Intestine, Small ; Intestines ; Ischemia* ; Mesenteric Artery, Superior ; Models, Animal ; Rats

von Willebrand disease (VWD) is the most common hereditary bleeding disorder. The treatment of VWD consists mainly of desmopressin and plasma-derived von Willebrand factor (pd-VWF) concentrate. We report on the first patient with VWD to be treated with recombinant VWF (rVWF) concentrate in Korea. Our patient was diagnosed with type 2 VWD at 10 months of age and suffered persistent severe epistaxis despite therapeutic levels of VWF activity and factor VIII (FVIII). At 34 months of age, rVWF was initiated and administered a total of 15 times in the following 8 months. No drug-related adverse events were observed and the patient was neither admitted nor given any transfusions during this period. Unlike pd-VWF/FVIII concentrates, rVWF did not increase FVIII to the excessively high levels that constitute a risk factor for thromboembolism, and was also preferable to pd-VWF/FVIII concentrates in that it contains ultra-large multimers of VWF. This is the first reported case in Korea in which rVWF was used to treat VWD. rVWF may be well tolerated and effective in VWD patients, especially those with refractory bleeding.

The purpose of this study is to evaluate an antioxidative effect of estrogen on the bone in oophorectomized rats. Thirty Sprague-Daley rats were equally divided into 3 groups; group 1 as control group with sham operation, group 2 as experimental group with oophorectomy, and group 3 as oophorectomized group treated with estrogen. Estradiol (5mg/kg BW) was administered three times per week from first to sixth week after oophorectomy. Left tibia was obtained to measure the amount of protein carbonyls as an index of oxidative stress and the activity of antioxidant enzymes. The results were as follows: trahecular bone area in proximal tihia decreased after oophorectomy, which increased in response to estrogen administration. The level of protein carbonylation in hone was not significantly different among all groups. Activity of antioxidant enzymes such ais glutathione reductase(GR), glutathione peroxidase(GP) and glutathione transferase(GST) in bone was not significantly different among all groups. However, the activity of catalase in bone markedly increased in group 3 compared with that in group 1 and group 2. In summary, bone trabecular area increased after admin- istration of estrogen. And estrogen induced the activitv of catalase, which might contrihute to prevent the oxidative damage. However, the glutathione utilizing enzymes such as GR, GP and GST were not significantly affected by estrogen status.
Animals ; Catalase ; Estradiol ; Estrogens* ; Female ; Glutathione ; Ovariectomy ; Oxidative Stress ; Protein Carbonylation ; Rats* ; Tibia

Hemophilia, an inherited bleeding disorder, is caused by a deficiency of coagulation factor VIII or IX. Most of patients with hemophilia need vascular procedure, which can lead to complications. Even though these complications can also occur in normal people, hemophilia and coagulopathy are particular risk factors. We reviewed medical records of patients with hemophilia who underwent vascular procedures and investigated its complications. Vessel-related complications occurred in five patients. Three patients had pseudoaneurysms after radial arterial puncture. All patients underwent coagulation factor replacement or ultrasound-guided compression and showed improvement. Neuropathy developed in one patient due to a hematoma that occurred after blood sampling. The hematoma improved, but motor and sensory deficits remained and neuropathy was confirmed. One patient died of uncontrolled bleeding after angiography. Vascular procedures require more attention in patients with hemophilia. Caution and prevention of complications is essential, even before the patient is diagnosed with hemophilia.
Aneurysm, False ; Angiography ; Blood Coagulation Factors ; Factor VIII ; Hematoma ; Hemophilia A ; Hemorrhage ; Humans ; Medical Records ; Punctures ; Risk Factors

Spinal epidural hematoma (SEH) is a rare neurosurgical emergency in which pressure on the spinal cord leads to acute neurological deficits, and is a rare complication in children with hemophilia. We report three cases of SEH in severe hemophilia A. An 8-month-old boy who presented with non-traumatic acute-onset irritability was found to have SEH and was later diagnosed with hemophilia. The two other patients presented with neck pain and magnetic resonance imaging confirmed the diagnosis of SEH. Two patients who received conservative management fully recovered, however the patient who presented with progressive neurological abnormalities at the time of diagnosis, received surgery but later developed breathing difficulties and quadriplegia. Early diagnosis and immediate, aggressive, clotting factor replacement therapy are crucial when managing SEH in children with hemophilia. Immediate and aggressive factor replacement, accompanied by both neurological monitoring and early imaging, are essential for hemophiliac with suspected SEH.
Child* ; Diagnosis ; Early Diagnosis ; Emergencies ; Hematoma ; Hematoma, Epidural, Spinal* ; Hemophilia A* ; Humans ; Infant ; Magnetic Resonance Imaging ; Male ; Neck Pain ; Quadriplegia ; Respiration ; Spinal Cord