Postpartum inhibitor to factor VIII: treatment with high-dose immunoglobulin and dexamethasone

Spontaneous occurrence of an acquired inhibitor to factor VIII (FVIII) is a rare event. About 50% of cases are idiopathic. Among younger people, inhibitors are often found in the postpartum period. Treatment must be administered either to overcome haemorrhagic symptoms or to eradicate the inhibitor. Several approaches have been proposed for inhibitor eradication, based on immunosuppressive drugs such as corticosteroids, cyclophosphamide and azathioprine, with varying results. High-dose immunoglobulin (HDIg) has been recently proposed as first-line therapy. We report on four cases with acquired inhibitor to FVIII occurring 4-8 months after delivery. At diagnosis, inhibitor titre was < 5 Bethesda units mL(-1) (BU mL(-1)) in three cases and > 5 BU mL(-1) in one. Factor VIII coagulant activity (FVIII:C) was < 1 U dL(-1)> in three cases and 12 U dL(-1) in one. We treated the patients with HDIg (400 mg kg-1 day(-1) for 5 consecutive days) and dexamethasone (24 mg day(-1) for 5-7 consecutive days), administered at the same time. In three women, the inhibitor was suppressed in 2-50 weeks. After an off-therapy period ranging from 20 to 104 weeks, the FVIII:C was persistently normal and the inhibitor undetectable. The fourth woman remained unresponsive. In two cases, recombinant activated factor VII administration stopped the bleeding. Thus, intermediate- to high-dose dexamethasone and HDIg given at the same time could be a successful and safe therapeutic approach for a rapid and complete remission from the development of FVIII inhibitors.     

阿斯米亚联合治疗肺癌化疗所致胃肠道反应的临床观察

目的:评价阿斯米亚(盐酸格拉司琼氯化钠注射液)治疗肺癌化疗所致胃肠道反应。方法:86例随机分成3组：1)单用组(A组)：从化疗当日起，每天使用阿斯米亚100m1．静滴，连续6天；2)联用组(B组)：化疗第一日阿斯米亚100ml，而后灭吐灵30mg 地塞米松5mg，静滴，连续5天；3)对照组(C组)：只有灭吐灵30mg 地塞米松5ng。静滴，连续6天。结果:B组控制恶心呕吐的有效率与A组无明显差异。而明显高于C组。结论:阿斯米亚单次使用联合灭吐灵 地塞米松。疗效好，费用低，值得临床推广。     

High-dose intravenous immunoglobulin in the treatment of acute myocarditis. A case report and review of the literature

A few reports have suggested the beneficial effect of high-dose intravenous immunoglobulin (IVIG) in the treatment of acute myocarditis and cardiomyopathy. We describe a 49-year-old woman in which acute myocarditis was diagnosed on the basis of clinical and echocardiographic findings. Conventional treatment with captopril and frusemide was administered: intravenous heparin and, subsequently, oral anticoagulants were added because of the appearance of an apical thrombus. On the fifth day of hospitalization, treatment with high-dose (400 mg kg(-1) day(-1)) IVIG was started and prosecuted for 5 days. A dramatic improvement of clinical conditions was observed, with increase of the left ventricular ejection fraction (LVEF) from 30% to 75% within 1 week. One year after the diagnosis the patient is in good health, with steady normal LVEF. The rapid recovery, which was immediately subsequent to the administration of high-dose IVIG, suggests that this kind of treatment has been effective in our patient with acute myocarditis.     

Immunosuppressive Treatment in Haemophiliacs with Inhibitors to Factor VIII and Factor IX

9 patients with severe haemophilia A and inhibitors (inhibitor levels between 0.1 to 5.8 U/ml) and 3 patients with severe haemophilia B and inhibitors (inhibitor levels between 0.1 to 11 U/ml) were treated on a total of 16 and 13 occasions, respectively, with a large dose of antigen (factor VIII or factor IX) and cyclophosphamide (10–15 mg/kg b.w. i.v. initially and then 2–3 mg/kg b.w. orally for 7–10 days) in connection with severe bleeding and surgery. All the patients had proved not to respond to treatment with factor VIII or factor IX concentrate alone, and all except one had shown strong secondary antibody increases. In 6 of the patients with haemophilia A the treatment (11 occasions) had a satisfactory haemostatic effect and even permitted neurosurgery without bleeding complications. The inhibitor level remained at zero for 5–10 days, after which it gradually began to return towards its original level. In these cases it was possible to give factor VIII in amounts which neutralised the inhibitor and afterwards raised the factor VIII initially to at least 50%. In the 3 patients with haemophilia B treatment (13 occasions) was successful except on one occasion, and surgery was performed without abnormal bleeding. The factor IX level was initially raised to at least 50% except in the one failure. The inhibitor level remained at zero for 12 days to 3 months, after which it gradually rose towards its original level. One patient was treated on 8 occasions.     

Antiemetic efficacy of granisetron plus dexamethasone in bone marrow transplant patients receiving chemotherapy and total body irradiation

Few trials exist regarding the antiemetic efficacy of granisetron in bone marrow transplant (BMT) recipients conditioned with high-dose chemotherapy and total body irradiation (TBI). In this single-center, open-label, prospective, trial, the antiemetic efficacy and safety of granisetron plus dexamethasone were evaluated in 26 patients conditioned with cyclophosphamide-containing regimens (the majority receiving 60 mg/kg per day on 2 consecutive days), and TBI (12 Gy divided over 4 days). Daily intravenous doses of granisetron 1 mg plus dexamethasone 10 mg were given 30 min prior to chemotherapy or radiation, and continued for 24 h after the last conditioning treatment for a median of 6 days (range 3-9). Emetic control was defined by the number of emetic episodes occurring within a 24 h period, or the requirement for rescue medication for nausea or vomiting. A total of 25 patients completed 186 evaluable treatment days. Response (emetic control by treatment days) was complete in 50% of patients, major in 48%, minor in 2%, and there were no failures. Adverse effects were minor, with diarrhea (15%), headache (14%), and constipation (11%) reported most often. Based on these results, the antiemetic regimen of granisetron plus dexamethasone appears effective and well tolerated during BMT conditioning with high-dose cyclophosphamide and TBI.     

Characterisation of the tolerant state in a patient with haemophilia B after removal of high-titre factor IX antibodies

In a patient with severe haemophilia B and antibodies against factor IX in high titre, and known for many years to be a really high responder, it was possible to suppress the secondary antibody response after treatment with high doses of intravenous IgG (Gammonativ, KabiVitrum AB) combined with factor IX and cyclophosphamide. After 2 further treatments, including IgG, a total disappearance of the IX:C inhibitor was noted. The patient now treats himself at home with weekly infusions of only factor IX concentrate. Survival of IX:C is normal, though IX antigen (IX:Ag), as measured with the original antibody in an immunoradiometric assay, persists for at least a week after concentrate infusion. We have not been able to demonstrate an antiidiotypic antibody. Instead the antigenic factor IX material circulates complexed to a 'new' antibody without anticoagulant activity. Theoretically at least, the persistence of such immune complexes may be important for sustaining the patient's tolerance to the anticoagulant antibody's epitope. The initial IgG treatment appears as a crucial factor for induction of tolerance in this case.     

Effectiveness of high-dose intravenous immunoglobulin in a case of acquired von Willebrand syndrome with chronic melena not responsive to desmopressin and factor VIII concentrate.

A patient with benign monoclonal IgG lambda paraproteinemia, acquired von Willebrand syndrome (AVWS), and chronic melena successfully responding to high-dose intravenous immunoglobulin (lvlg) is reported. Coagulation parameters at admission were APTT (ratio) 1.68; VIII:C 11 IU/dL; vWF:Ag 7 IU/dL:Ricof less than 3 IU/dl. RIPA was greater than 1.8 mg/ml, and bleeding time (BT) was prolonged (18 min). No evidence for an in vitro inhibitor against the VIII/vWF complex was observed. VIII/vWF measurements showed a short-lived increase after both DDAVP and Hemate P, and BT was transiently normalized. After intravenous Ig (1 g/kg for 2 days), VIII/vWF measurements, hemostatic parameters and multimeric pattern were completely corrected (VIII/C 106 IU/dl, vWF:Ag 168 IU/dl, RiCof 147 IU/dl, APTT ratio 0.89, BT 5'), with a return to pre-infusion values after 15 days. Hemoccult test became negative and packed red cell transfusions, of which 130 units were administered during the last year, were no longer required. After 18 months the patient is on maintenance treatment with repeated courses of Ig, at 3 to 4-week intervals based on VIII/vWF and BT monitoring.     

Long-term treatment of refractory thrombocytopenia in a patient with Wiskott-Aldrich syndrome with vincristine, immunoglobulin, and methylprednisolone.

We report a child with Wiskott-Aldrich syndrome with severe, refractory, symptomatic thrombocytopenia who achieved an excellent response to combination therapy with vincristine 1.5 mg/m(2) x 1 day, intravenous immunoglobulin 1 g/kg x 3 days, and methylprednisolone 25 mg/kg x 3 days (VIM) for 7 years after failing multiple treatments. He did not have a histocompatible donor for bone marrow transplantation. When the patient ceased to respond to this regimen, he was rescued with pulse dexamethasone. Vincristine, immunoglobulin, and methylprednisolone might serve as a novel treatment option for the patient with refractory thrombocytopenia. Our patient had a sustained remission of symptomatic thrombocytopenia without toxicity. Furthermore, pulse dexamethasone might be an alternative treatment option to which patients with Wiskott-Aldrich syndrome may respond.     

A technique for specific removal of factor IX alloantibodies from human plasma: partial characterization of the alloantibodies

A method for specific removal of large amounts of factor IX:C alloantibodies by a resin to which highly purified factor IX was linked (factor IX CH-Sepharose) is described. Factor IX was isolated from human plasma by a three-step procedure, including barium citrate adsorption and elution, DEAE-Sepharose CL-6B chromatography, and dextran sulfate agarose chromatography. Approximately 100 mg factor IX was obtained from 60 liters of plasma. The preparation was about 95% pure as judged by SDS-PAA gel electrophoresis. Its specific coagulant activity was 160 U/mg (IX) and its factor IX clotting antigen (IX:Ag) 500-600 U/mg. Essentially quantitative coupling of the factor IX preparation to activated CH-Sepharose 4B was obtained (4 mg factor IX/ml gel; 2300-3000 U/IX:Ag/ml). This resin bound 1500-2000 U factor IX inhibitor/ml gel and could be re-used at least 5 times without any loss in binding capacity. The binding capacity was dependent on the flow rate. No signs of activation of the coagulation, fibrinolytic, or complement system were observed in vitro. Using this factor IX resin, factor IX alloantibodies were isolated and found to consist of two portions, one minor bound to the resin only in the presence of Ca2+ and another major portion Ca2+ independent. The specific inhibitory activity/milligram IgG of the Ca2+-dependent alloantibodies was about 5 times higher in the presence of Ca2+. It is concluded that 25 ml of the factor IX resin described can remove about 40,000 factor IX inhibitor units (comparable to 120,000 Bethesda U) in one run, provided the flow rate does not exceed 20 ml/hr. By using such a technique for removal of antibodies it seems feasible to convert hemophilia-B patients complicated with inhibitors against factor IX into ordinary hemophilia- B patients for treatment at an emergency or in association with major surgery.     

Successful treatment using high-dose intravenous immunoglobulin in a patient with rapidly progressive interstitial pneumonia associated with dermatomyositis

A 36-year-old male patient with dermatomyo-sitis (DM) associated with rapidly progressive interstitial pneumonia (IP) was successfully treated by high-dose intravenous immunoglobulin (IVIG). He suffered from myopathy, skin lesions, and IP. In spite of the treatment with a high-dose corticosteroid, IP progressed rapidly. Then high-dose intravenous immunoglobulin (20 g/day, 4 days) was administered. The skin lesions, myopathy, and pulmonary lesions improved. High-dose IVIG was considered to be a relatively safe and effective treatment for progressive IP associated with DM. Received: October 9, 1999 / Accepted: May 24, 2000     

Immune tolerance induction in haemophiliacs with inhibitor to FVIII: high- or low-dose programme

Summary. In 1993–94, 15 high responders were treated in our centre according to the Malmo protocol which was modified as follows: serial plasmapheresis was performed instead of extracorporeal adsorbtion to protein A for reducing inhibitor levels and, after the bolus dose to neutralize the inhibitor, factor VIII concentrate was administered by a continuous infusion. Thus, this regimen included continuous infusion of factor VIII(FVIII) for 1–4 weeks, iv cyclophosphamide for 2 days and orally for 8–10 days, and intravenous immunoglobulin (IVIG) from the fourth day for 5 days. All patients had been qualified for the treatment when the antibody level was < 15 BU mL⁻¹. Tolerance was induced in 10 patients (66.6% very good and good results). The treatment failed in five cases in which, due to a high inhibitor level, it was not possible to maintain a measurable factor VIII:C concentration throughout the whole period of infusion. We compared these results with results of our low-dose regimen: 25 IU FVIII kg⁻¹ b.w. twice a week (1985–89, 11 high responders). The modified Malmo Protocol is much shorter than the low-dose programme and this is a method of first choice in patients undergoing surgery in the near future.     

硼替佐米为主化疗方案治疗初治与复发难治多发性骨髓瘤近期疗效分析

目的:分析硼替佐米为主化疗方案治疗初治与复发难治多发性骨髓瘤(MM)患者的临床疗效和不良反应.方法:初治MM患者11例,复发、难治MM患者7例均采用VD方案化疗:硼替佐米1.0～1.3 mg/m2第1、4、8和11天快速静脉注射,地塞米松20 mg第1～4天(7例复发难治予地塞米松40 mg)静脉滴注,3周为1疗程,所...     

Acquired inhibitor to factor VIII: report of two unusual cases

Summary . The present report describes two unusual cases of bleeding due to development of inhibitor against factor VIII. One of the patients was known to have severe haemophilia B (factor IX < 1%) and the other, a healthy male of 46 years, spontaneously started to bleed and was found to have developed inhibitors to factor VIII:C along with other autoantibodies. Development of inhibitors to coagulation factors is a serious clinical problem in de-veloped countries and is more so in developing countries where treatment options are often limited.     

Studies on immunological assay of vitamin-K dependent factors.

Two-site immunoradiometric assays (IRMAs) for factor IX antigen (IX:Ag) were developed using a monoclonal antibody (RFF-IX/1) on the solid-phase and either another monoclonal antibody (RFF-IX/4) or a human polyclonal inhibitor antiserum as tracer (M-M and M-I IRMA respectively). The lower sensitivity limits of these two assays for IX:Ag in normal reference plasma were 4 X 10(-4) (M-M IRMA) and 2 X 10(-4) (M-I IRMA) units/ml. In 20 samples of normal plasma, levels of factor IX coagulation activity (IX:C) and of factor IX antigen measured by both IRMAs were highly correlated. Mean values of approximately 1.0 units/ml were obtained in all three assays. In normal serum, IX:Ag levels were lower with means of 0.84 (M-M IRMA) and 0.83 (M-I IRMA) units/ml. 4/25 patients with haemophilia B were CRM neg., two were CRM + and the remaining 19 patients were CRMr variants. In two of these, IX:Ag was detectable by M-I IRMA whilst IX:C and IX:Ag measured by M-M IRMA were undetectable. In plasma from a fetus subsequently terminated on eugenic grounds, IX:C and IX:Ag by both M-M and M-I IRMA were undetectable. In warfarin-treated plasma (n = 12), the level of IX:C was low (mean 0.39 units/ml). The levels of IX:Ag measured by M-M IRMA (mean of 0.80 units/ml) and by M-I IRMA (0.70 units/ml) showed a discrepancy. M-M IRMA reflects the real amount of IX:Ag in warfarinized plasma because both monoclonal antibodies bind to epitopes distant from the light chain carboxylated region. Western blotting of denatured factor IX demonstrated that RFF-IX/1 binds an epitope that is lost after XIa activation. RFF-IX/4 binds the heavy chain. Antigen measured after activation but without denaturing showed loss of 60% reactivity after XIa activation but no change after RVV activation. These data indicate a binding site for RFF-IX/1 within the activation peptide (residues 146-180).     

Kinetic aspects of the removal of IgG and inhibitors in hemophiliacs using protein A immunoadsorption.

Seven patients with hemophilia A and B and 3 patients with acquired hemophilia were treated on 13 and 4 occasions, respectively, with protein A immunoadsorption to reduce anti-factor VIII or IX antibodies. Usually the patients were treated on 2 consecutive days. On each treatment day an average of 3 (range: 1.02-5.83) plasma volumes were processed in the congenital patients and 1.5 (range: 1.02-2.90) in those with acquired hemophilia. Plasma levels of IgG decreased from 18.9 +/- 1.9 to 3.1 +/- 1.2 g/l in the congenital group, and from 11.5 +/- 2.3 to 2.3 +/- 0.6 g/l in the acquired group. In the congenital hemophiliacs a corresponding reduction in inhibitor level of 70-95% was regularly seen; in 1 exceptional patient the inhibitor was reduced from 4,350 to 12 Bethesda Units/ml (BU/ml) during 5 days of treatment. In the congenital hemophiliacs immunoadsorption was followed by factor infusion to peak levels between 8 and 215 IU/dl. In the patients with acquired hemophilia a satisfactory reduction in inhibitor levels was obtained in 2 of the 4 treatments, which were followed by DDAVP or factor infusion. Some recommendations for the use of protein A immunoadsorption in the treatment of hemophilic patients will be given.     

Celecoxib prevents juxta-articular osteopenia and growth plate destruction adjacent to inflamed joints in rats with collagen-induced arthritis

The effect of celecoxib, a selective cyclooxygenase-2 inhibitor, on juxta-articular osteopenia and growth plate destruction adjacent to inflamed joints was investigated in rats with collagen-induced arthritis. Forty rats were assigned to the following six groups: (1) an untreated arthritis group; (2–5) arthritis rats receiving indomethacin (3 mg/kg per day), dexamethasone (0.2 mg/kg per day), or celecoxib (5 or 50 mg/kg per day), and (6) normal control rats. Drugs were administered for 2 weeks from the onset of arthritis. Then the hind paws were measured. Juxta-articular osteopenia and growth plate destruction adjacent to inflamed joints were also assessed using plain radiography, bone mineral density measurement, histology, and histomorphometry. Each treatment reduced inflammation, but only dexamethasone and high-dose celecoxib prevented bone loss adjacent to inflamed joints and significantly decreased bone resorption. In contrast, no treatment affected bone formation parameters. Growth plate destruction adjacent to inflamed joints was prevented by indomethacin, dexamethasone, and high-dose celecoxib. Although dexamethasone abolished inflammation, growth plate destruction was still observed. In conclusion, among the various drugs tested, only celecoxib had a preventive effect on both growth plate destruction and bone loss adjacent to inflamed joints in this arthritis model.     

Bradycardia after high-dose intravenous methylprednisolone therapy

In 5 consecutive patients with rheumatoid arthritis who received intravenous high-dose methylprednisolone (MP) therapy (1 g daily for 2 or 3 consecutive days), a decline in pulse rate was observed, most pronounced on day 4. In one of the 5 patients the bradycardia was associated with complaints of substernal pressure. Reversal to normal heart rate was found on day 7. Electrocardiographic registrations showed sinus bradycardia in all cases. No significant changes in plasma concentrations of electrolytes were found. Careful observation of patients receiving high-dose MP is recommended. High-dose MP may be contraindicated in patients with known heart disease.     

Treatment and outcome of acquired haemophilia A with a standard conventional regimen in a cohort without associated conditions

Acquired haemophilia A (AH) is a rare bleeding disorder with significant risk of mortality. We conducted a study on the treatment and outcomes of patients with AH diagnosed between 1998 and 2004 in our institution. Fourteen patients (age range 17-89, median 64) were followed-up from between 10-64 months (average 32 months). Inhibitor levels ranged from 5 to 450 BU. Ten patients required either recombinant activated factor VIIa or prothrombin complexes for control of bleeding. All patients received a standard immunosuppressive regimen of prednisolone 1 mg kg day(-1) and oral cyclophosphamide 50-100 mg day(-1). In addition, nine patients received intravenous immunoglobulin. Complete remission (CR) was achieved in 88% (eight of nine evaluable patients) over durations ranging from 5-78 days (average 35 days). There were three mortality; from bleeding, sepsis and cerebral infarct. Two patients were lost to follow-up. There were no relapses among patients achieving CR. Conditions associated with AH were not identified at diagnosis or subsequent follow-up in all patients. This series represent one of the largest aetiologically and treatment-wise, uniformed cohort of AH patients. Despite toxicity concerns, the combination of prednisolone and cyclophosphamide remain an effective regimen and should be among the first line of treatment choices, with careful patient selection.     

The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized, double-blind, multicenter crossover trial

BACKGROUND: In patients with hypogammaglobulinemia, substitution with immunoglobulin is the treatment of choice to reduce both frequency and severity of bacterial infections. Even with treatment, however, infections still occur in these patients. OBJECTIVE: To determine whether doubling the standard dose of intravenous immunoglobulin would affect the incidence and duration of infections. DESIGN: Multicenter, double-blind, randomized, crossover study. SETTING: 15 outpatient clinics in the Netherlands. PATIENTS: 43 patients with primary hypogammaglobulinemia, 41 of whom completed the protocol. INTERVENTION: Patients received standard-dose immunoglobulin therapy for 9 months, followed by a 3-month washout period, and high-dose intravenous immunoglobulin therapy for 9 months, or vice versa. MEASUREMENTS: The primary outcome measures were total number and duration of infections. Other measures were periods of fever, hospital admissions, use of antibiotics, absence from school or work, and trough levels of serum immunoglobulin. Side effects from the study medication were also recorded. RESULTS: Compared with the standard dose of intravenous immunoglobulin (adults, 300 mg/kg of body weight every 4 weeks; children, 400 mg/kg every 4 weeks), high-dose therapy (adults, 600 mg/kg every 4 weeks; children, 800 mg/kg every 4 weeks) significantly reduced the number (3.5 vs. 2.5 per patient; P = 0.004) and duration (median, 33 days vs. 21 days; P = 0.015) of infections. Trough levels of IgG increased significantly during high-dose therapy. The incidence and type of side effects did not differ significantly for the two dosages. CONCLUSION: In patients with hypogammaglobulinemia, doubling the standard dose of intravenous immunoglobulin significantly reduced the number and duration of infections.     

Successful use of etanercept in the treatment of acute lupus hemophagocytic syndrome

Hemophagocytic syndrome has been reported to be associated with systemic lupus erythematosus. A 25-year-old woman with systemic lupus erythematosus developed hemophagocytic syndrome that was refractory to the combination therapy with high-dose corticosteroid, cyclosporine, and high-dose intravenous immunoglobulin, and successfully treated with the tumor necrosis factor inhibitor, etanercept. This case report provided the first observation that etanercept may be useful for the treatment of hemophagocytic syndrome associated with systemic lupus erythematosus refractory to conventional therapy.