acquired hemophilia
Introduction
Introduction to acquired hemophilia Acquired hemophilia (AH) refers to a hemorrhagic disease caused by the production of specific autoantibodies that inhibit factor VIII (FVIII) in vivo. Although there are often life-threatening severe bleeding, if the diagnosis is correct and the treatment is timely, an effective hemostasis effect will be achieved. The determination of the treatment regimen depends on the severity of the bleeding and the nature of the antibody. basic knowledge The proportion of illness: 0.0001%-0.0003% Susceptible people: no special people Mode of infection: non-infectious Complications: cerebral hemo
Cause
Acquired hemophilia
About 50% of AH patients are healthy and have no cause, and another 50% are secondary to other diseases. The most common diseases associated with AH are autoimmune diseases, perinatal, malignant tumors, drugs. Reactions (penicillin and its derivatives) and skin diseases. In recent years, it has been confirmed that surgery may be a triggering factor for AH. Rizza et al. investigated 240 patients with AH who were admitted to the Oxford Hemophilia Center for 10 years, and found that 98 patients had related diseases. Among them, 24 were malignant tumors, 16 were rheumatic diseases, and 11 were postpartum. Delgado et al studied 20 retrospective and prospective articles on AH collected by Medline in the past 15 years, summarizing the clinical features of 234 patients and finding tumor-related There were 43 cases (18%), 34 cases (15%) related to postpartum, 22 cases (9%) related to autoimmune diseases, and 135 cases (58%) with other reasons or unclear reasons.
Autoimmune disease (30%):
FVIII autoantibodies can be found in a variety of autoimmune diseases. The mechanism of antibody production: inflammatory activity associated with systemic autoimmune diseases causes acute phase response proteins to be presented to the immune system by antigen-presenting cells, resulting in the production of autoantibodies. FVIII is Such a protein may partially explain that acquired coagulation factor antibodies are more common in FVIII than other coagulation factors. FVIII autoantibody titers in patients with rheumatoid arthritis are usually higher and are not treated or treated with prednisone alone. Will not reduce, most patients need to add an alkylating agent to eliminate antibodies.
Postpartum immunity is low (15%):
Often primipara, accounting for 2.5% to 14%, manifested as bleeding within 1 to 4 months after delivery, and also reported bleeding 1 year after delivery. Most patients have lower autoantibody titers, with an average of about 20 Bethesda units ( BU), if the antibody titer is less than 5BU, the antibody will generally disappear on its own, no longer appear in pregnancy, such as titer greater than 10BU, the antibody can last for several years, and hormone, intravenous gamma globulin products, cytotoxic The drug treatment is ineffective. The mortality rate of this group of patients is low, 0-6%. The mechanism of antibody may be due to: 1 pregnancy causes the immune status of the body to change, and the FVIII from the embryo leaks through the placenta to the mother. Foreign antigens cause the mother to produce FVIII antibodies, 2 precursors to the emergence of autoimmune diseases, and 3 are related to factors secreted by the placenta.
Malignant tumors (20%):
About 10%, seen in solid tumors or hematological tumors, especially lymphoproliferative diseases including chronic lymphocytic leukemia (CLL), erythroleukemia, myelofibrosis, lymphoma, multiple myeloma, myelodysplastic syndrome, Castleman's disease, Antibody production mechanism: abnormal response of T cells to unknown antigens or interaction between B cells and T cells leads to immune dysfunction. For example, leukemia clones of CLL patients or tumor B cells of patients with low lymphoma produce abnormalities through unknown mechanisms. FVIII or antigen-stimulated organisms produce antibody responses against normal FVIII, and expansion of B cell subsets of CD5 in CLL patients leads to increased production of antibodies against FVIII, and it is also possible that B cells produce these antibodies, and leukemia patients are leukemia clones leading to T cells. And NK cell function regulation disorders, these cells, especially CD4 T cell subsets play an important role in the recognition of foreign antigens, monitoring antibodies produced by B cells, these abnormalities in the immune system can explain clonal diseases such as erythroleukemia and bone marrow Fibrosis, the presence of FVIII in the myelodysplastic syndrome The relationship between antibodies, AH and solid tumors is still controversial. Some authors believe that patients with solid tumors have no causal relationship with FVIII antibodies, because immunosuppressive therapy can eliminate antibodies in most patients, and surgical removal of tumors only makes a very small number of patients The disappearance of antibodies and the treatment of tumors cannot effectively eliminate antibodies. The efficacy of immunosuppressive therapy supports the hypothesis that FVIII autoantibodies are autoimmune responses of the body to tumors, because in the elderly or tumor patients, various factors can change the immune status of the body. The occurrence of autoimmune diseases, the reduction of immune tolerance leads to the proliferation of pathological clones or the production of autoantibodies. However, some authors believe that treatment of tumors can eliminate antibodies, such as the persistence of antibodies, because the tumor is in advanced stage or metastasis, is a The performance of paracancerous syndrome is also ineffective with immunotherapy.
Drugs (15%):
For example, the relationship between antibiotics (penicillin, sulfonamides, chloramphenicol) and anticonvulsants (phenytoin) and FVIII autoantibodies has been confirmed. Usually, these antibodies appear after hypersensitivity reactions and disappear soon after stopping the drug. Autoantibodies were reported in patients with CML after treatment with IFN-. However, the pathophysiological mechanisms of such phenomena are unclear.
Surgery (10%):
The cause of FVIII autoantibody production by surgery may be: 1 related to trauma, tissue damage, 2 immune dysfunction with surgery, 3 reactions to anesthetics or other drugs.
Prevention
Acquired hemophilia prevention
Preventing bleeding is more important than alternative treatment, including:
(1) Strengthen missions, avoid strenuous activities, and encourage appropriate physical activity.
(2) Avoid using antiplatelet drugs.
(3) Avoid intramuscular injection.
(4) If surgery is required, the lack of clotting factors should be supplemented before surgery.
(5) Those who are eligible should regularly supplement the corresponding coagulation factors.
(6) Hemophilia is a contraindication to many invasive procedures, such as extraction, bone wear, and surgery. Avoid blind operation before giving clotting factor infusion intervention.
prevent disease
Prenatal diagnosis after pregnancy can be performed for prenatal and postnatal care. For hemophilia patients, especially female patients, genetic testing should be done. For women who have a family history but are not genetically carried, they can be safely delivered after pregnancy. For female carriers, it is best to do gender identification after pregnancy (usually within 12-14 weeks). If the fetus is female, you can do normal full-term delivery according to your heart. If the fetus is male, you need to perform amniocentesis. Extract DNA to detect the severity of hemophilia, or take a sample of umbilical cord blood (approximately 16-18 weeks after gestation) to determine the degree of clotting factor deficiency, and determine whether to perform a therapeutic abortion based on actual conditions, especially fetal clotting factors. Pregnant women who are deficient should terminate their pregnancy as soon as possible.
Complication
Acquired hemophilia complications Complications
The main surface of hemophilia is bleeding, complications caused by bleeding:
First, the complications of joint bleeding: joint damage caused by hemophilic arthritis.
Second, the complications of muscle bleeding: light can be naturally absorbed, heavy can not absorb will oppress blood vessels and nerves, causing numbness and activity.
Third, the complications of cerebral hemorrhage: similar to stroke.
Symptom
Acquired hemophilia symptoms Common symptoms Dysphagia, intracranial hemorrhage, venous thrombosis, hematuria
AH patients have no previous or family history of bleeding, and their clinical manifestations vary. Most patients present with sudden spontaneous hemorrhage, with soft tissue hematoma, intramuscular hemorrhage, extensive subcutaneous ecchymoses, gastrointestinal and genitourinary bleeding. Severe or life-threatening bleeding accounts for more than 80%, and the mortality rate is about 20%. Unlike HA, AH patients have less joint bleeding.
Bleeding performance, the most common clinical manifestations of AH patients are siltation, ecchymosis, muscle hematoma, accounting for 60%; hematemesis, melena, hematuria is also more common, intramuscular hemorrhage can lead to compartment syndrome, compression of neurovascular bundles, bleeding Patients with dysphagia and respiratory wheezing may also present with intracranial hemorrhage. Patients with AH may be accompanied by deep vein thrombosis and lupus anticoagulant. Some patients are due to or after surgery. Wound bleeding is diagnosed, and iatrogenic bleeding is common, often after intravenous intubation or intravesical intubation.
The bleeding performance of pregnant women with FVIII autoantibodies varies from person to person, usually occurs within 3 months after delivery, and there is bleeding symptoms only 1 year after delivery, which may be manifested as postpartum minor bleeding or bleeding, and the general hemostatic treatment measures are invalid; Or manifested as interstitial vaginal bleeding, with recurrent appearance of gross hematuria, sometimes due to diagnosis delay, severe bleeding requires removal of the uterus and even life-threatening, high mortality.
Examine
Acquired hemophilia check
1. Activated partial thromboplastin time (APTT)
Prothrombin time (PT) and platelet function tests When APTT is prolonged and PT and platelet function are normal, the presence or absence of autoantibodies should be considered. It is a screening test for autoantibodies.
2. Plasma mixing test
When only APTT is prolonged, a plasma mixing test should be performed to determine APTT to determine the presence of antibodies. For example, APTT is prolonged by 5s or more for the presence of antibodies. When a factor (FXII, FXI, FIX, FVIII) is lacking in the internal coagulation pathway, Normal plasma and patient plasma can be mixed to correct prolonged APTT; however, when there is antibody, the extended APTT after equal plasma mixing cannot be corrected. For low titer antibodies, patient plasma and normal plasma should be used. Incubate for 1 to 2 h at °C to enhance the effect of autoantibodies on FVIII (in a time- and temperature-dependent manner) because high titers of FVIII autoantibodies can non-specifically inhibit coagulation factors in the internal coagulation pathway (FIX, FXI, FXII), so it is necessary to serially dilute the patient's plasma and mix it with undiluted normal plasma. Since the antibody is diluted, the activities of FXII, FXI, and FIX are normal, while FVIII:C is still inhibited.
3.Bethesda test
Once the presence of autoantibodies is determined, antibodies should be quantified to assess the severity and risk of bleeding. The usual method is the Bethesda method, which measures the ability of a patient to inactivate FVIII in normal plasma. A Bethesda unit is defined as the remaining in the test system. Patient plasma dilution at 50% FVIII activity, however, this method lacks sensitivity, especially when antibodies are low titers. In addition, the Bethesda method is established to detect alloantibodies present in HA patients. Detection of autoantibodies in patients with AH is not an ideal method, however, quantification of autoantibodies by this method predicts the severity of bleeding in patients with low titers of autoantibodies.
4. Improved Bethesda test
The patient's plasma is incubated with the normal human plasma diluted with the buffer to ensure the pH of the system is constant, and the normal human plasma diluted with the buffer is incubated with the spent FVIII plasma as a control, and the improved method improves the sensitivity. It is especially suitable for the detection of low titer antibodies. Therefore, it is recommended as the preferred method for detecting inhibitory antibodies. However, like the Bethesda method, this method cannot detect non-inhibitory FVIII antibodies, and the plasma used in FVIII is not used. There should be a FVIII antibody; the control and mixed plasma should be the same source.
5. ELISA method
Coated with recombinant FVIII, overnight at 4 ° C, sealed with non-specific sites of fish gelatin, added to diluted patient plasma and incubated at 37 ° C, then added horseradish peroxidase-labeled rabbit anti-human IgG, tetramethyldihydrochloride Benzidine (TMB) as a chromogenic substrate, terminated by hydrochloric acid, absorbance at 450 nm (A), this method can detect all anti-FVIII antibodies, including inhibitory and non-inhibitory autoantibodies and alloantibodies, which are sensitive The sex is 10 times higher than that of the Bethesda method. However, the FVIII source used as the standard antigen in the test has a great influence on the sensitivity of antibody detection. The highest detection rate when using recombinant FVIII as an antigen, the plasma-derived FVIII factor. Containing high levels of von Willebrand Factor (vWF), the detection rate is the lowest, so clinical use of recombinant FVIII as antigen in the detection of FVIII antibodies.
6. Immunoprecipitation (IP)
The patient's diluted plasma was incubated with the A1, A2, C2, and light chain fragments of the 125I-labeled FVIII molecule, and then the protein G-sephrose-bound magnetic beads were added; the bound radioactivity was measured by a gamma counter, and the result was expressed as an immunoprecipitation unit. /ml, calculated as: 1- (combined radioactivity / total radioactivity - background radioactivity) × plasma dilution factor × 16.7, the sensitivity and specificity of this method is the same as ELISA, can also detect all anti-FVIII antibodies, including Inhibitory and non-inhibitory autoantibodies and alloantibodies, clinically, when tested for FVIII antibodies, Bethesda and ELISA or IP assays should be performed simultaneously.
7.FVIII
The C-test Phase I method cannot determine whether FVIII:C reduction is caused by FVIII autoantibodies or lupus anticoagulant substances. The second phase rule can be identified because FVIII:C levels are normal or even increased in the presence of lupus anticoagulant substances; Identification with test or diluted RVVT.
8. According to the condition, clinical manifestations, symptoms, signs, choose to do ECG, B-ultrasound, X-ray, CT, MRI, biochemistry and other tests.
Diagnosis
Diagnosis and diagnosis of acquired hemophilia
diagnosis
If the patient has no previous or family history of bleeding and sudden bleeding, only APTT is prolonged, plasma mixed test proves the presence of autoantibodies, Bethesda test or ELISA, immunoprecipitation for antibody quantification, FVIII: C reduction, can clearly diagnose AH.
Differential diagnosis
AH should be differentiated from hemophilia A, hemophilia B and other congenital coagulation factor deficiency, other factors other than FVIII, such as acquired antibodies, except for patients with congenital clotting factor deficiency, family history, since childhood In addition to the characteristics of bleeding in the joints and other parts, the differential diagnosis depends mainly on laboratory tests and related clotting factor activity tests.
