Hemophilia is an X-chromosomal companion recessive disorder with a positive family history and refusal to affect only males. Among the inherited coagulation factor deficiencies, vascular pseudhemophilia is the most common, followed by hemophilia, which requires satisfactory laboratory tests to confirm the diagnosis. The most rapid and major screening tests are prothrombin time doctor (PT) and activated or leukotonic partial thromboplastin-rich time (APTT or KPTT). In coagulation factor deficiency disorders bleeding significant time is generally normal on Thursday but in vascular pseudohemophilia (VWD) there is bleeding I want time prolongation too rarely because of the lack of vascular pseudohemophilia Vascular pseudohemophilia due to the cause of the disease (VWF) affects the stabilization of platelet function so that initial hemostasis is impaired (see vascular pseudohemophilia) How prothrombin time (PT) measures factor II, VII, IX and X activity Partial thromboplastin consultation Time (APTT or KPTT) measurement of factors Ⅻ Ⅺ Ⅸ Ⅷ and Ⅹ The pattern of prolonged PT APTT being corrected by condition normal plasma or serum may reflect the type of coagulation factor deficiency If correction is not possible then it reflects the presence of anticoagulant substances. Hemophilia A and hemophilia B Hemophilia A, traditionally known as hemophilia, is caused by a deficiency of factor VIII (F VIII:C). Hemophilia B (also known as Christmases’ disease and PTC deficiency) is caused by a deficiency of F IX. deficient coagulation factors. The incidence of arthropathy remains high in hemophiliacs. hemophilic arthritis is caused by frequent bleeding in the joint cavity of hemophiliacs leading to degeneration of cartilage and inflammation of the synovial membrane, (leading to fibrosis and damage to the joints, appearing) fibrotic damage to the joints, causing joint contracture, joint deformation, arthritis, and in turn leading to muscle atrophy, limitation of movement, osteoporosis and disability. arnold ( 1977) classified it into five stages based on clinical and radiographic manifestations: Stage I: X-rays show normal bones, and soft tissue swelling shadows can be seen in the form of blood accumulation in the joint or bleeding in the soft tissue around the joint. Stage II: Similar to subacute arthrosis. Osteoporosis, especially in the epiphysis, is significant. The joint gap is normal and there are no bone cyst changes. Stage III: joint destruction is obvious, articular cartilage is still intact, there is no obvious narrowing of the cartilage space, occasionally subchondral cystic cavity can be seen with the joint, the intercondylar fossa of the knee joint and ulnar talar notch are more widened. Stage IV; destruction of articular cartilage and narrowing of the interstitial space, more significant than in stage III. Stage V; disappearance of the interstitial space, enlargement of the epiphysis, and destruction of the articular structures. Due to the special nature of hemophilia, the choice of treatment is influenced by various factors, such as the stage of arthritis, the severity of joint involvement, pain, mobility, and the need for anti-hemophilic factors, etc. Especially, the choice of alternative complementary therapy and invasive treatment is not only limited by the patient’s own condition, but also by the difficulty of obtaining alternative factors, the patient’s economic condition, and the level of the hospital, and in terms of In terms of treatment alone, the efficacy of different methods has been reported differently. Considering that the choice of treatment options for patients with hemophilic arthritis at different times will affect the progression of the patient’s disease, the relief of joint pain, the effect of functional recovery, and the prognosis and quality of life of the patient’s condition, the choice of treatment methods for this particular patient is very important. 1, replenish the missing coagulation factors Hemophilia is a genetic disease caused by the deficiency of coagulation factors VIII, IX and D, bleeding is common, especially intra-articular bleeding, and the resulting inflammatory, proliferative synovitis leads to arthritis, hemophilic arthropathy. The pathogenesis of hemophilic arthropathy is multifactorial, and the exact mechanism is unclear. In patients with early hemophilia, routine supplementation of the deficient coagulation factors and reduction of intra-articular bleeding can slow or even end the progression of hemophilic arthritis. However, several studies have shown that although prophylactic clotting factor replacement in patients with severe hemophilia can improve joint function, the optimal timing and termination of therapy, as well as the dose selection and targeting of therapy, are major issues in supplemental replacement therapy. Continuous prophylactic coagulation factor supplementation is generally more difficult to achieve because of the high cost of coagulation factors. The ideal level of factor should be maintained at 25-50% of normal levels for 5-10 days. To achieve this goal, severe hemophilia requires 15-25u/kg, or 300-500u/l of factor IX, repeated over 2-3 days for major bleeding, and intravenous administration of 1u The intravenous administration of 1u/kg of factor VIII can increase the plasma concentration by 0.1u/l, while the same dose of factor IX can only increase by 0.1u/l. The second replacement therapy can usually be given within 24-48 hours. Alternatively, coagulation factors can be supplemented by fresh frozen plasma (, supplementation of coagulation factors is the preferred indication for fresh frozen plasma). Fresh frozen plasma contains all the components of normal human plasma, including stable and unstable clotting factors, fibrinogen, and various proteins (, and can be used to supplement clotting factors). It is more effective when multiple coagulation factors are lacking; it can also be used when a single concentrated coagulation factor is lacking and temporarily unavailable. It is generally believed that the clotting factor of most patients can be increased to 25% of normal with a dose of 10~15 ml/kg of fresh frozen plasma transfusion, and the hemostatic function can be achieved. However, in cases of severe coagulation factor deficiency, plasma transfusion cannot achieve the effective concentration of a single coagulation factor. For example, in hypofibrinogenemia, the first dose of 60 mg/kg of fibrinogen is required to achieve an effective hemostasis level of 0.5 g/L, while 250 ml of plasma is equivalent to 1 g of concentrated product; in hemophilia A, the level of factor VIII required for effective hemostasis is 30%-40%, which should be increased to 80% and maintained at 30%-40% before surgery, but plasma transfusion can only rapidly increase it to 15%. Therefore, where possible, concentrated products can be used to achieve therapeutic effects that are not possible with whole blood plasma. At present, the following preparations are also available for supplementation: fresh whole blood Each ml of fresh whole blood contains 0.3u of AHG, and it is expected that the concentration of AHG in the patient’s blood can reach 4-6% of normal after application. Therefore, it is difficult to increase the blood concentration of AHG by applying whole blood, especially because of the progressive decrease of AHG in stock blood, and transfusion of whole blood can only supplement the blood volume but not increase the level of AHG. Cold precipitate Frozen plasma is frozen in a 4°C refrigerator for several hours, and a portion of the plasma protein remains in an insoluble state. This cold precipitate is rich in factor VIII and fibrinogen and can be separated out by centrifugation. The cold precipitate contains 3 to 5 u of factor VIII per milliliter, which is 16 times more than the fresh whole blood content. It contains 50% of factor VIII and 2 to 3% of the total amount of the original plasma protein, and it is expected that the blood concentration will increase to 60 to 80% of that of a normal person after application. Dried and frozen human AHG concentrate The content of dried and frozen AHG is 3-5u per ml, which is 4-6 times that of normal human plasma, and the blood concentration can reach 60-80% of normal human after use, which is the most ideal supplement. In case of intra-articular or intra-muscular bleeding, the lacking factor should be supplemented early, and the bleeding will stop after the blood AHG level reaches 5-15% of normal human for a few hours; in case of traumatic bleeding or major surgery, the blood AHG level should be increased to 40-50% of normal level until the wound is completely healed. decreases by 1/2, and after 24 hours only 1/4 (now). Therefore AHG in the blood will disappear rapidly after major surgery. In this case, multiple small inputs of supplementation are better than a single large dose. It is more reasonable to give 1 dose every 8 hours. Factor 9 has a half-life of 18 hours, so it is more reasonable to give it every 12 hours. The following complications can occur with large amounts of factor supplementation: development of antibodies, hemolytic anemia, hepatitis and AIDS. 2. Surgical synovectomy – open or under arthroscopy If the bleeding joint does not respond to coagulation factor replacement therapy, then it enters the stage of hemophilic synovitis, persistent synovitis or recurrent intra-articular bleeding, and after 3-6 months of ineffective conservative treatment, surgical intervention can be considered, which aims to control recurrent intra-articular bleeding, remove inflammatory synovium, maintain joint mobility as much as possible, and avoid further destruction of articular cartilage. Open synovectomy requires large amounts of preoperative coagulation factor supplementation and is indicated for patients with stage II or higher, good pain control, approximately 25% to 55% improvement in postoperative joint mobility, and complete control of bleeding. Its average hospital stay is about 23-26 days, but the operation is difficult, and about half of them have loss of mobility, patellar adhesions and fibrous joint ankylosis after surgery. Arthroscopic subsurface membrane resection: Intra-articular blood clots are slowly absorbed and can lead to synovitis. Arthroscopic flushing with large amounts of saline can flush out the accumulated blood and blood clots or remove them under direct arthroscopic vision. Arthroscopic subsurface membrane resection with the appropriate approach can effectively treat hemophilic arthritis because it reduces the occurrence of bleeding (, the use of replacement factors) and joint pain. Postoperative recovery is rapid, with less loss of joint mobility and less supplemental clotting factors. However, the equipment and technical requirements are high, and postoperative complications such as bleeding and infection may occur, and in severe cases, the role of arthroscopy is limited, and incision is still required at this time. 3, intra-articular injection of chemicals such as hormones, rifampin, etc. Intra-articular injection of chemicals such as hormones, rifampin, etc. is also called chemical synovectomy. This method is especially suitable for children and small joint lesions without obvious X-ray changes, which can reduce the amount of supplemental coagulation factors, and the operation is simpler and has good pain control. Postoperative rehabilitation is required to promote the recovery of joint mobility. The disadvantages are poor bleeding control, short effective time, frequent complaints of pain after surgery, which can lead to a certain degree of functional loss and ankylosis, and repeated injections that can easily lead to intracavitary infection. One of the antibiotics that can be used to treat non-infectious joint injuries is rifampicin, which has been used with good results. It was initially used to treat rheumatoid arthritis and was later used in hemophilic arthritis. Caviglia et al. in Argentina observed that rifampicin was more effective in small joints (elbow, ankle) than in large joints (knee). The results of animal experiments showed that the treatment pattern of rifampicin is similar to that of NSAIDs. Radioactive synovectomy: (rhenium-186-sulfide colloid, beta radionuclide, p-32, etc.) Radioactive synovectomy has been used to treat synovitis in individual joints for more than 50 years, and its usefulness has been recognized and is commonly used to treat chronic hemophilic arthritis. This procedure was initially used to treat rheumatoid arthritis to relieve pain and reduce inflammation, and as an alternative to surgical synovectomy in rheumatoid arthritis and other inflammatory joint diseases such as osteoarthritis and hemophilic arthritis. Compared to surgical synovectomy, radiosynovectomy can achieve the same results and has the advantages of being less costly, preserving the patient’s ambulatory function, and being reproducible. In addition, topical drops of radiopharmaceuticals can be effective in reducing post-prosthetic graft exudation. Radiation necrosis of the skin is a known but rare complication, (with cases demonstrating this known complication,) and the recent finding by Dunn et al. that two cases of leukemia have been reported in patients treated with two or more joint radioisotopes has led to a reevaluation of the use of this method. The pros and cons should be weighed before use on patients and the long-term side effects of this operation should be monitored. Some efficacy has been reported by Klett et al. in Germany for radioactive synovial irradiation of synovial hypertrophy and inflammation presenting with rhenium- 186-sulfide colloids in rheumatoid arthritis, osteoarthritis, hemophilic arthritis, and spondyloarthropathies. Although the therapeutic effect has not been confirmed by the most stringent standards of today’s clinical studies. However, the available data suggest that rhenium-168 radiation therapy can be used as a second-line treatment for patients who have failed other treatments. In contrast, intra-articular injection of beta radionuclides can be used definitively in rheumatoid arthritis, seronegative spondyloarthritis and post-surgery in choroidal nodular synovitis and in the prevention of bleeding in hemophilic arthropathy. Soroa et al. in Argentina took monthly treatment with methylene diphosphonate (p32) irradiation while monitoring subjects with routine blood, x-ray, ultrasound, and 3D bone scan, and concluded by random clinical assessment (including degree of joint involvement, pain, mobility, antihemophilic factor requirement, amount of hormones and analgesics) and follow-up that with p32 there was neither systemic or local There was neither a systemic or local reaction nor leakage. 80% of the patients after radiosynovectomy had improved mobility of the joint, disappearance of the joint cavity, and reduced use and frequency of anti-hemophilic factors. Although the use of p 32 irradiation was effective in reducing the rate of intra-articular bleeding, the persistence of the response is uncertain and may also be classified as a late intervention. For advanced cases, periarticular osteotomy has been used to correct joint deformities. Wallny et al. performed periarticular osteotomy of the knee in 52 patients with hemophilic arthropathy between 1974 and 1984 and followed 45 patients for an average of 11.6 years. However, in almost all patients there was no significant postoperative improvement in joint mobility. Even with significant radiographic joint destruction, the stricture osteotomy showed acceptable long-term clinical results, suggesting its feasibility. Younger patients in particular benefit more from it, as it may avoid joint replacement altogether, or at least allow its extension to a later stage. It has also been suggested that the choice of periarticular osteotomy should be made with caution and must be viewed on an individual basis, and that patients must be fully informed of the advantages and disadvantages of this operation. 6. Arthroplasty The introduction of coagulation factor concentrate preparations has made it possible to use artificial joint replacement to treat hemophilic arthritis. Arthroplasty not only eliminates pain and improves function, but also completely removes the bleeding synovium and reduces the chance of joint bleeding. Therefore, the use of arthroplasty is no longer a contraindication for young patients with hemophilic arthritis. Some authors have even suggested that arthroplasty should be performed before severe joint deformities occur to reduce bleeding and save joint function. Although postoperative recovery of joint function is not yet ideal, its positive significance in relieving pain and improving quality of life has been generally recognized by professionals and has gained some clinical experience. The indications are mainly severe joint pain leading to loss of joint function, and such pain has not been treated with regular medical therapy, while simple joint flexion and extension disorders or flexion contractures are not indications. Contraindications to surgery include: joint ankylosis; recent history of infection; long-term drug addiction; and positive F-VIII antibody. Based on the experience of Ruijin Hospital, the following clotting factor replacement protocol is used. Hemophilia A: On the day of surgery, 50 IU/kg of factor VIII was infused at 0:00, 25 IU/kg was given at 6:00, and factor VIII was tested at 8:00. If the level of coagulation factor VIII activity (F VIII:C) was >50%, surgery could be performed. From 1 to 3 d after surgery, 25 IU/kg was given every 8 h. From 4 to 7 d after surgery, 15 IU/kg was given every 8 h. Later, the amount of coagulation factor supplementation was reduced according to bleeding and factor VIII levels. Hemophilia B: Preoperative activated partial thromboplastin time (APTT) should be in the normal range (35-45 s) and coagulation factor IX activity (F IX:C) level >40% for surgery. Because factor IX has a longer half-life compared to factor VIII, the treatment regimen is different from the former. Factor IX concentrate is given 1 to 2 d before surgery and on the day of surgery, 40 to 50 IU/kg every 12 h; 1 day after surgery, 40 to 50 IU/kg every 12 h; 2 to 3 d after surgery, 30 to 40 IU/kg every 12 h; 4 to 7 d after surgery, 20 to 30 IU/kg every 12 h; 8 to 15 d after surgery, 15 to 20 IU/kg every 12 h, for the whole course of 2 weeks. Postoperatively, the APTT should be maintained at 50-60 s, the coagulation factor IX activity (FIX:C) level at 20%-30%, and the absence of clinical bleeding should be maintained. Fan Yongqian et al. hoped that factor VIII levels would reach 50% on the day of surgery, and that factor VIII levels would be maintained at >30% 1 to 3 days after surgery and >20% 4 to 14 days after surgery. Factor IX levels were maintained at 20%-25% 1 to 3 days after surgery and 15%-20% 4 to 14 days after surgery, which is a more economical solution than the other protocols. However, due to the high risk, total arthroplasty must be performed under strict surgical indications. 7. Oral D-penicillamine hydrochloride: In the advanced stages of hemophilic arthropathy, which is more similar to degenerative than inflammatory arthropathy, Corrigan et al. supplemented oral D-penicillamine hydrochloride with the above comprehensive treatment in 16 patients with advanced hemophilic arthritis, and their findings suggest that D-penicillamine hydrochloride is an effective and safe drug for the treatment of hemophilic chronic synovitis. (Deleted) Treatment is supplemented with oral penicillamine D-hydrochloride, which is given in the following dosing regimen: a single dose of DC penicillamine hydrochloride is given 1 hour before breakfast each day. The dose for children is 5-10 mg/kg body weight, not exceeding 10 mg/kg , and for adults 750 mg per day. They found from patients taking this drug for more than 1 week that it eliminated significant synovial-associated pain, pressure and reduced bleeding frequency, and that the dosing regimen was safe, with only 4 patients experiencing associated side effects: proteinuria in 1 case; rash in 2 cases; and vomiting in 1 case. All patients’ side effects disappeared after discontinuation of the drug, and there were no other side effects. Patients generally started to show effects within 3 months. They concluded that in addition to the more durable benefit of 3-12 months of treatment over short-term hormone therapy in all patients investigated, D-penicillamine also had a significant cost advantage over prophylactic infusion of the relevant factor or performing surgery. However, the mechanism of action of this drug is not clear. It has been suggested that D-penicillamine is a Cu2+ chelator and that the penicillamine-Cu2+ complex has superoxide dismutase activity, and that the anti-inflammatory effect of this drug may be related to its superoxide dismutase activity, which scavenges free radicals. The use of recombinant activating factor VII (rFVIIa; NovoSeven) is an effective treatment for sudden life-threatening hemorrhage in hemophiliacs with inhibitory factors, and it has also been successfully used in the surgical treatment of such patients. In a review by Obergfell A et al, rFVIIa provided a safe and effective method of hemostasis for orthopedic surgery in this group of patients without bleeding complications. However, the choice of dosing method and mode of administration remains to be confirmed in further controlled trials. 9. Outlook: With the last 20 years with extensive operations and various successes and endurance, great progress has been made in arthropathies. There are numerous approaches to treating hemophilic arthritis, each of which has its advantages and disadvantages, and the treatment of choice varies among different types and stages of hemophilia. Early treatment and prevention of chronic synovitis and progressive arthropathy are key. When advanced arthropathy occurs and severe disability develops, the goal is to minimize the risk while providing durable, functional reconstruction, but in general, the treatment of patients with hemophilic arthritis requires close collaboration between hematologists, orthopedic surgeons, rehabilitation physicians, and physical therapists.