Immune tolerance induction in patients with severe hemophilia with inhibitors: expert panel views and recommendations for clinical practice

For hemophilia patients with inhibitors, immune tolerance induction (ITI) may help to restore clinical response to factor (F) VIII or FIX concentrates. Several ITI regimens and protocols exist; however, despite 30 yr of progressive investigation, the ITI evidence base relies mainly on observational data. Expert opinion, experience, and interpretation of the available evidence are therefore valuable to support clinical decision-making. At the Sixth Zürich Haemophilia Forum, an expert panel considered recent data and consensus to distill key practice points relating to ITI. The panel supported current recommendations that, where feasible, ITI should be offered early to children and adults (ideally ≤ 5 yr of inhibitor detection) when inhibitor titers are <10 Bethesda units (BU) and should be stopped when successful tolerance is achieved. For hemophilia A inhibitor patients, ITI can be founded on recombinant FVIII at high doses. The panel considered that patients with a high bleeding frequency should be offered additional prophylaxis with a bypassing agent. For patients with hemophilia B, there may be a benefit of genetic testing to indicate the risk for inhibitors. ITI is often less effective and associated with a greater risk of side effects in these patients. For high-titer inhibitor (≥ 5 BU) hemophilia B patients, the panel advised that bypassing agents could be offered on demand in addition to ITI. Within future ITI regimens, there may be a role for additional immunosuppressant therapies. Participants agreed that research is needed to find alternatives to ITI therapy that offer durable and sustained effects and reduced rates of complications.     

Immune complexes mediate rapid alterations in microvascular permeability: roles for neutrophils, complement, and platelets

OBJECTIVE: Immune complex-induced responses involve multiple cellular and molecular mechanisms. However, how these pathways interact in the initiation of immune complex-induced response is poorly understood. Therefore the aim of this study was to investigate the immediate response of the microvasculature to immune complex formation. METHODS: The reverse passive Arthus (RPA) model was applied to the mouse cremaster muscle. Intravital microscopy was used to examine alterations in florescein isothiocyanate (FITC)-dextran leakage from microvessels, and endothelial interactions of leukocytes and platelets in postcapillary venules. RESULTS: Immune complex deposition induced rapid increases in microvascular permeability and leukocyte adhesion and emigration. Inhibition of platelet-activating factor (PAF) and leukotrienes inhibited the increase in permeability. Depletion of C3 reduced immune complex-mediated leukocyte recruitment and permeability, and a similar effect on permeability was observed following inhibition of leukocyte adhesion. Mast cell stabilization reduced increases in leukocyte adhesion and emigration but accelerated the increase in microvascular permeability. Platelet-endothelial interactions also increased during the RPA response, and platelet depletion delayed the changes in permeability and inhibited leukocyte recruitment. CONCLUSIONS: This study demonstrates that immune complexes induce a rapid induction of complement-dependent leukocyte recruitment, and neutrophil-dependent microvascular dysfunction. Furthermore, this study identifies a role for platelets in promoting immune complex-induced leukocyte recruitment.     

Impaired immune function in hemophilia patients treated exclusively with cryoprecipitate: relation to duration of treatment

Recently, abnormalities of cell-mediated immunity were found in hemophiliac patients receiving factor VIII concentrate therapy. Contradictory results were reported concerning cellular immune functions in hemophiliacs treated only with cryoprecipitate or fresh frozen plasma. Therefore, we evaluated the immunological status of 15 Israeli patients with severe classic hemophilia-A who were treated only with cryoprecipitate and never exposed to factor VIII concentrate whether of commercial source or blood bank prepared. As a group, only mildly depressed cellular immune functions and slight reduction in the helper to suppressor cell ratio were found. However, when patients treated more than 15 years were analyzed separately, a significant reduction in proportion of T cells, T-helper cells, helper to suppressor ratio, and proliferative response to phytohemaglutinin and pokeweed mitogen were observed compared to patients treated for less than 15 years and normal controls. Proportion of T-suppressor cells, Con A-activated suppressor activity, and IgG and IgA levels were significantly elevated in patients treated for more than 15 years. These results may support the view that derangement of immune function in hemophiliacs results from infusion of foreign proteins or an ubiquitous virus rather than contracting AIDS infectious agent.     

Immune complexes inhibit apoptosis of chronic lymphocytic leukaemia B cells

In the present study we examined the effect of immune complexes (IC) on the survival of chronic lymphocytic leukaemia (B-CLL) B cells. Our results showed that either precipitating IC (pIC), Ab-coated erythrocytes (E-IgG) or heat-aggregated IgG (aIgG) significantly inhibited spontaneous apoptosis of B-CLL cells, as well as that induced by fludarabine, chlorambucil or dexamethasone. After depletion of T lymphocytes, monocytes and NK cells, incubation with IC was no longer able to delay B-CLL cells apoptosis, suggesting that prevention of apoptosis depends on IC interaction with accessory leucocytes. The release of IFNgamma by non-malignant cells upon activation with IC was responsible, to some extent, for IC effects as shown by the fact that neutralizing anti-IFNgamma MoAb partially prevented their ability to inhibit B-CLL cells apoptosis. The observation that treatment with IC resulted in increased expression of HLA-DR on B-CLL cells suggests that inhibition of apoptosis is associated with cellular activation.     

Therapeutic choices for patients with hemophilia and high-titer inhibitors.

Effective treatment of bleeding episodes in hemophilia with high titer inhibitors (HTI) remains a challenge, despite the fact that the therapeutic armamentarium has expanded considerably over the past few years. Treatment safety has improved with the availability of porcine factor VIII (FVIII) and bypassing products such as recombinant factor VIIa (rFVIIa), and plasma‐derived activated Prothrombin Complex Concentrates (aPCCs) that are virally inactivated. The major drawbacks of rFVIIa and aPCCs are their unpredictable hemostatic effect, lack of laboratory assays to monitor efficacy and dosing frequency, and the risk of thrombosis. The proceedings of a one‐day workshop of physicians who specialized in treating patients with hemophilia held in Vienna on May 13, 2000 have been summarized. In making a decision regarding the choice of product, physicians often consider the type of bleeding episode (life or limb threatening), age of the patient, volume of the reconstituted product, previous exposure to plasma derived products, cost, efficacy, and safety. For plasma naïve patients, to achieve rapid hemostasis a majority of the panelists used porcine FVIII (for patients who lack porcine inhibitory antibodies) or rFVIIa. For patients previously treated with plasma derived factors, in addition to the above concentrates, aPCCs were recommended. Although no data exists regarding safety and efficacy, switching products was routinely practiced either because of availability or cost. Furthermore, the panelists were uncertain about the efficacy of bypassing agents in the prevention of joint disease in inhibitor patients. The workshop participants felt that future research offers the best solution to resolve some of the dilemmas faced by clinicians and may help individualise treatment in a hemophilia patient with a high titer inhibitor. Am. J. Hematol. 67:240–246, 2001. © 2001 Wiley‐Liss, Inc.     

Prevention of bleeds in hemophilia patients with inhibitors: emerging data and clinical direction

In patients with hemophilia, the development of high-responding inhibitors to factor VIII prevents adequate replacement therapy and results in increased risk of serious bleeding episodes, poor control of joint bleeding, and progressive, debilitating joint disease. Immune tolerance therapy can eradicate inhibitors, but it is not uniformly successful. Emerging data suggest that prophylaxis using activated prothrombin complex concentrates may be effective and safe in reducing the incidence of joint bleeding during immune tolerance therapy and for patients in whom immune tolerance induction fails. However, only controlled clinical trials will ultimately demonstrate whether prophylaxis can prevent joint bleeding and damage, and improve quality of life in patients with inhibitors.     

The Pennsylvania hemophilia program 1973-1978

In Pennsylvania, the prevalence of hemophilia is one per 10,000 males. Factor VIII deficiency is five times more frequent than Factor IX deficiency, and 34% of the patients have no relatives affected with the disease. The mean age is 23 years old, and 50% of the patients are less than 20 years old. Approximately one-third of the patients with Factor VIII deficiency and one fourth of the patients with Factor IX deficiency have levels of < 0.01 μ/ml. By clinical criteria, 55% of those with Factor VIII deficiency are severe compared to 45% of those with Factor IX deficiency. Factor VIII-deficient patients are treated an average of 18 times per year compared to ten times per year for patients with Factor IX deficiency. Hemarthroses account for 70% of the hemorrhages treated and for 40% of the concentrate usage. Home therapy patients use an average of 45,950 Factor VIII units per year at a cost of $4,170 per patient and their use accounts for 60% of the total Factor VIII usage of 1.7 million units. Less than five days per patient per year are lost from school or work because of bleeding, and patients are hospitalized for bleeding an average of only two to three days per patient per year. Adverse immediate reactions to therapy are infrequent. Five percent of patients have persistence of the hepatitis B virus, and 7.5% have inhibitors. The mortality rate is 0.04% per year, with half of the deaths being hemophilia-related.     

肝硬化 肝癌患者血清循环免疫复合物的研究

采用一种简单、敏感的放射免疫法测定了101例肝病患者(25例肝癌,17例肝硬化,26例慢迁肝,33例乙肝病毒携带着)的血清循环免疫复合物,并观察了各组肝功能的变化以及HBV标志.结果表明:肝癌组的IgG-CIC含量及γ-GT含量明显高于其它各组.IgG-CIC 5.21(PHC),3.43(LC),2.41(CPH)及1.92(ASC),P<0.01.γ-GT 262(PHC).63.1(LC),44.7(CPH)以及18.7(ASC),P<0.01.伴有HBV感染的肝癌组中有80%可检出IgG-CIC,而CPH及ASC组中仅有50%可检出IgG-CIC.研究结果还表明:肝癌组中,IgG-CIC含量随着AFP含量的升高而上升.但在AFP过度升高时,IgG-GIC反而降低.这可能提示:随着肿瘤的生长,IgG-CIC升高,AFP值随肿瘤恶化逐渐上升,致使IgG-CIC从结合补体转变成非结合补体,导致IgG-CIC的下降.根据结果提示:HBV感染与肝癌发生有着密切关系.     

Changes in coagulation parameters with exercise in patients with classic hemophilia

Vigorous exercise is known to increase VIII:C and VIIIR:Ag levels transiently in normal individuals. Although exercise programs are frequently advocated in the management of hemophilia, the effects of exercise on coagulation parameters in these patients have not been well studied. Eleven hemophiliacs were exercised on a bicycle ergometer to maximum voluntary effort as evidenced by an increase in pulse, blood pressure, and plasma catecholamine (norepinephrine and epinephrine) levels. The effects of this exercise on coagulation parameters, including functional and antigenic components of the factor VIII molecule, were determined. The entire group demonstrated a decrease in mean prothrombin time (11.7 to 11.2 sec). Four mild hemophiliacs demonstrated an increase in mean VIII:C (14.5% to 17.3%), and VIII:CAg (12% to 17.8%). Changes in VIII:C and VIII:CAg were not noted in the seven severe hemophiliacs. Both severe and mild patients demonstrated significant changes in fibrinogen, factor II, and factor VII after exercise. This study indicates that submaximal exercise modifies coagulation parameters in patients with hemophilia.     

The development of ankylosing spondylitis in a patient with familial hemophilia

Hemophilia is a rare inherited disease which causes bleeding due to Factor VIII or Factor IX deficiency. It is usually X-linked recessive and typically affects males. Arthropathy occurs as a result of cartilage damage and chronic synovitis due to recurrent intra-articular bleeding in hemophilic patients and is mostly seen in the knee, shoulder, hip and ankle joints. There are many other diseases that cause chronic synovitis ankylosing spondylitis (AS), which is a subtype of spondyloarthropathies that cause chronic low back pain, more common in men younger than 45 years of age. In addition to axial involvement, peripheral arthritis, uveitis, enthesitis and dactylitis can be seen. Although the etiology is not fully known, genetic and environmental factors are responsible for the pathogenesis. In this study, we aimed to present congenital hemophilia and AS coexistence in a 22-year-old male patient.     

Successful treatment of high titer inhibitors in mild hemophilia A with avoidance of factor VIII and immunosuppressive therapy.

We describe two patients with mild hemophilia A (MHA) who developed high titer inhibitor (HTI) following intensive recombinant factor VIII (rFVIII) concentrate replacement for surgery and trauma. Intranasal desmopressin was instituted shortly following immunosuppressive therapy (IST) and activated prothrombin complex concentrate (APCC) in one case, and following APCC alone in the second case. Avoidance of factor VIII (FVIII) coupled with intranasal desmopressin prophylaxis three times a week resulted in undetectable inhibitor levels. Both patients have had no further bleeding episodes and have been maintained on desmopressin prophylaxis prior to activity for the past 2 to 3 years. Recombinant factor VIIa (rFVIIa) was used successfully prior to a second surgery in one patient without complication.     

Pseudotumor of hemophilia in the orbit: the role of radiotherapy in management

A case of pseudotumor of hemophilia is presented that occurred in the right orbit of a boy with severe factor VIII deficiency and an inhibitor. After a period of observation and conservative management, low-dose radiotherapy (750 rads) and Proplex was used. Eighteen months after radiotherapy significant healing had occurred. The role of radiotherapy in the treatment of hemophilic pseudotumor is reviewed.     

Immune thrombocytopenic purpura associated with hepatitis A

Summary A 23 year-old man developed thrombocytopenic purpura at the end of the second week of the clinical evolution of hepatitis A confirmed by viral markers. The bone marrow of this patient showed megakaryocytic hyperplasia. Circulating in his serum immune complexes were demonstrated by solid phase conglutinin enzymo-immunoassay. Platelet-reactive serum factors were also detected by an indirect immunofluorescence test using fresh donor platelets as targets. The evolution of both the hepatitis and the purpura were benign with no therapy other than bedrest. Platelet count normalized within five weeks of the onset of purpura, and IgM antibodies against hepatitis A virus as well as circulating immune complexes dropped to normal levels. It is postulated that the thrombocytopenia of this case was caused by nonspecific deposition of immune complexes at the platelet surface.     

Health status and health-related quality of life associated with hemophilia

The hemophilias are a group of disorders associated with a chronic burden of morbidity and early mortality. Improvements in these adverse features have been achieved by the use of clotting factor concentrates within comprehensive centers of specialized care providing home infusion programs. Offsetting effects from transfusion-transmitted hepatitis and HIV infection are in recent decline. The net impact of these changes merits assessment. To test the a priori hypotheses that increasing severity of factor VIII deficiency would be associated with an increasing burden or morbidity and that hepatitis and HIV positivity would impair health status further, a cross-sectional study of a population-based cohort was undertaken in a regional hemophilia program in Ontario, Canada. A survey was made of mild, moderate, and severe hemophiliacs over 13 years of age who self-reported their health status using a standard 15-item questionnaire. The responses were converted to levels in the Health Utilities Index Mark 2 (HUI2) and Mark 3 (HUI3) health status classification systems to form multi-element vectors from which single-attribute morbidity and overall health-related quality of life utility scores were determined. The burden of morbidity was greater in hemophiliacs than in the general population and correlated with the category of disease (mild < moderate < severe). Hepatitis and HIV positivity conferred additional burdens of morbidity, which were mainly in the attributes of mobility (HUI2), ambulation (HUI3), and pain (HUI2/3), all of these differences reaching levels of statistical significance. Despite demonstrable improvements in the safety, effectiveness, and utilization of clotting factor concentrates, hemophiliacs continue to experience an important burden of morbidity. Measurement of this burden, as reported here, provides a basis for future economic evaluation of the costs and consequences of health care interventions provided to this population.     

Up-regulation of platelet activation in hemophilia A

Background

Platelets are an underappreciated factor in the classification of the bleeding tendency of patients with hemophilia. In this cross-sectional study, we investigated platelet activation status and responsiveness in relation to residual factor VIII activity and, within the group with severe hemophilia (<1% residual factor VIII activity), to annual factor VIII consumption.

Design and Methods

Twenty-one patients with mild-moderate hemophilia A, 13 with severe hemophilia A and 21 healthy controls were studied. The basal level of platelet activation and platelet responsiveness to activation and inhibition were determined by the measurement of platelet P-selectin expression and soluble platelet activation markers.

Results

Patients with severe hemophilia A had a higher percentage of activated platelets at baseline (15.9%) when compared to patients with mild-moderate hemophilia A (8.2%, P=0.014) and controls (6.4%, P<0.001). Both patients with mild-moderate hemophilia A and those with severe hemophilia A had higher levels of the soluble platelet activation markers platelet factor 4 (1.4 and 1.8 pg/10⁶ platelets), CXCL7 (65.8 and 48.2 pg/10⁶ platelets) and RANTES (12.8 and 9.5 pg/10⁶ platelets), compared to controls (platelet factor 4: 0.3 pg/10⁶ platelets, P<0.001 and <0.001; CXCL7 20.0 pg/10⁶ platelets, P<0.001 and <0.001; RANTES 4.5 pg/10⁶ platelets, P<0.001 and =0.003, respectively). In support of these observations, we found clinical evidence that higher platelet P-selectin expression correlates with lower factor VIII consumption in patients with severe hemophilia (Spearman’s r −0.65, P=0.043).

Conclusions

This study indicates that platelets from patients with severe hemophilia A are in a pre-activated state and that this pre-activated state is associated with factor VIII consumption.     

老年人Ig、CIC和auto－Ab相互关系的研究

本文对不同年龄组健康人血清免疫球蛋白（Ｉｇ）、循环免疫复合物（ＣＩＣ）和游离自身抗体（ａｕｔｏ－Ａｂ）的含量进行同步测定。结果发现，血清ＩｇＧ含量随增龄无明显改变，老年组ＩｇＡ明显高于青壮年组和老年前期组，而ＩｇＭ从４５岁便开始下降，老年人降低更为显著；老年组血清ＩｇＧ含量与ＣＩＣ－ＩｇＧ、ａｕｔｏ－Ａｂ－ＩｇＧ含量呈明显正相关；ＣＩＣ－ＩｇＧ／血清ＩｇＧ明显高于其他年龄组，提示其体内有免疫复合物滞留。这说明，评价老年人体液免疫功能时，不仅要测定血清Ｉｇ含量，而且要测定ＣＩＣ－Ｉｇ和ａｕｔｏ－Ａｂ－Ｉｇ的含量。     

Results of secondary prophylaxis in children with severe hemophilia

In this study, 13 children with severe hemophilia were given routine replacement infusions of factor VIII or IX to treat arthropathy. The children who had a mean age of 6.9 years (range 2.0–12.5) at initiation of prophylaxis had experienced an average of 43 acute hemorrhages (range 8–127) in the year prior to prophylaxis, of which a mean of 24 (range 5–46) were into joints. Therapy was begun in five children, using factor VIII concentrate at 20 U/kg three times a week, and one boy received factor IX concentrate 40 U/kg twice a week. This dose schedule was inadequate for three factor VIII-deficient boys and for the one factor IX-deficient boy. Two of three factor VIII-deficient boys responded to an increase to 30 U/kg prior to the 3-day interval. The dose frequency was increased to three times a week for the factor IX-deficient boy, but he continued to bleed and was taken to synovectomy. One of the original five factor VIII-deficient boys plus seven other factor VIII-deficient boys were begun on factor VIII 20 U/kg every other day; 3 boys ceased bleeding. Trough factor VIII levels were measured 24 hr after an infusion in the five boys who continued to bleed. Factor VIII dosage was adjusted to achieve a trough level of >1%; 4 responded to an increase in the dose of factor VIII; 1 had an adequate trough but, due to compliance issues, was taken to synovectomy. Serial clinical and radiographic assessments determined stabilization of joint disease in more than one-half of the boys. No child showed reversal of abnormal radiographic findings. Institution of aggressive factor VIII and IX concentrate in children with established hemophilic arthropathy does not reverse joint disease but may alter the clinical course of hemophilia. Future studies to compare this intervention with primary prophylaxis instituted prior to the onset of recurrent joint hemorrhage are warranted. © 1994 Wiley-Liss, Inc.     

The management of hemophilia in elderly patients

After the increasing rate of deaths observed during the 1980s due to human immunodeficiency virus (HIV) infection, the health-related quality of life and life expectancy of persons with hemophilia have improved, mainly due to the progresses of replacement therapy and antiviral drugs and to the improvement of the global comprehensive care provided by specialized centers. As a consequence, an increasing number of hemophiliacs have reached an older age and nowadays physicians in hemophilia centers find that they must handle age-related clinical problems never previously observed in this population. The management of elderly persons with congenital hemophilia is discussed in the first part of this review. The second part describes the general aspects of acquired hemophilia due to anti-factor VIII autoantibodies, focusing on the clinical management of elderly patients, one of the groups most frequently affected by this acquired bleeding disorder.