附录:英文文献

附录:英文文献

A Preliminary Study of Age and Sex of People with Hemophilia

Yang Shaofang1,Ge Miao1,Liu Shanxi2,Liu Yiguo2,Cen Minyi1

Abstract Aim: This paper aims at providing more information of people with hemophilia for more targeted treatment.Methods: 1149 people with hemophilia are surveyed in 45 units, then established by EpiData software.Analyze the number of people with hemophilia in 9 age intervals for the male and female by Population pyramid and Pareto analysis.Results: It is found thatthe people with hemophilia are appearing in every age interval.Relative to the number of male patients, the number of female patients is extremely rare.Of 1134 male patients relative frequency for male ranked the first(23.0%), second(17.4%),third(17.2%)are 7-12, 2-3, 13-18 years old, respectively, while of 15 female patients relative frequency for female in these age intervals are only 13.3%, 13.3%, 6.7%, respectively.However, the most relative frequency of female patients is between 26-45 years old.Conclusion: There is a challenge of the aging hemophilia population.Most of male patients are between 7-12 and 2-3 years old.Most of female patients are between 26-45 years old.

Keywords hemophilia, survey, age, sex

1 Introduction

Hemophilia, an X-linked genetic blood disorder that affects boys and men primarily,is the most well-known[1-4].Women carry the gene and their sons develop the disease[5-6].Nowadays, hemophilia is harmful, distributed widely and lack of effective treatment measure[7].In order to supply assistance treatment information of hemophilia, many researchers have studied demographic characteristics, quality of life, age, sex, etc[8-13].Patricia A

etc.[8]

studied health information of 1,243 women with hemophilia aged 18-25 years.C.Hermans etc.[9]researched the clinical management of older people with hemophilia.However, there is no report on special age and sex of people with hemophilia[8-16].The present paper focuses on hemophilia patient's age and sex for providing more information for patients with hemophilia in order to get more targeted treatment.

2 Materials and Methods

The method of sampling survey is used in this study.The people with hemophilia from various administrative units(hospitals and research institutes)were collected in China.1149 people with hemophilia were tested in 45 units.The age of the volunteers ranged from 0-75 years old.These people with hemophilia were located in 256 cities and counties in China.

The database with 1149 cases is established by EpiData software[17]after finishing encoding data.

According to the United Nations age interval, the age interval is divided into juveniles(age ＜ 18 years), youth(age∈[18, 45)years), mid adults(age ∈[45, 59)years), and the elderly(age ∈[59, 75)years)(Table 1).

Table1　Relative Frequency of Patients in Different Age Interval

3 Results

Statistical analysis

A total of 1149 people with hemophilia have been researched, of which hemophilia A(HA)is 1000 cases, hemophilia B(HB)is 149 cases(table 2).

Table2　Relative Frequency of Types of People with Hemophilia

Table3　Relative Frequency of Patients in Different Age Interval

Table 3 presents most of the patients are juveniles aged 0-18 years old, which account for 68.4% of the total, followed by the youth aged 18-45 years old, which account for 29.4% of the total.Fewer patients are adults aged 45-59 and the elderly aged 60-75 years old.However, of 1149 people with hemophilia, 25 people are over 45 years old.It is a remarkable fact that there is more aging hemophilia population.

Table4　Relative Frequency of Patients in Different Age Intervals

In order to differentiate and comprehensive the number of each age intervalmore obviously.It is important to subdivide age intervals according to the United Nations ages and Chinese children ages.Table 4 shows relative frequency of patients in different age intervals.The most number of patients are in 7 - 12 age intervals which are 263 number of patients and constitute 22.9%, followed by the patients aged 1-3 years are 199 number of patients and constitute 17.3%.The least number of patients are in 60 - 75 age intervals which are 2 number of patients and constitute 0.2%.

Pareto analysis and Population pyramid analysis

Study the number of each age interval for male and female with Population Pyramid Analysis and Pareto Analysis[18].Table 5 presents relative frequency of patients in different age intervals for male and female.Figure 1 shows Pareto analysis summarizing the number of the male in different age interval and Pareto analysis based on the cumulative percentages.Figure 2 shows Pareto analysis summarizing the number of the female in different age interval and Pareto analysis based on the cumulative percentages.

Table5　Relative Frequency of Patients in Different Age Intervals for male and female

A total of 1149 patients are researched, of the 1134(98.7%)patients are male, and 15(1.3%)patients are female.For the male, the number ranked the first(261), second(197), third(195)are 7-12, 2-3, 13-18 years old, which relative frequency is 23.0%,17.4%, 17.2%.The least number is in 60-75 years old, which relative frequency is only 0.1%(Table 5, Figure 1).For the female, the relative frequency in 7-12, 2-3, 13-18 years old is only 13.3%, 13.3%, 6.7%, respectively.The most number is between 26-45 years old, which relative frequency is as much as 40.0%, while the least number is in 46-59 and 0-1 years old(Table 5, Figure 2).

Figure1　Pareto Analysis Summarizing the Number of the Male with Hemophilia in Different Age Interval and Pareto Analysis Based on the Cumulative Percentages

Figure2　Pareto Analysis Summarizing the Number of the Female with Hemophilia in Different Age Interval and Pareto Analysis Based on the Cumulative Percentages

Although from the point of single gender, the most number of female patients is in 26-45 years old, which relative frequency is as much as 40.0%.However, in contrast to the number of male patients, the number of female patients is extremely rare(Figure 3).

Figure3　Population Pyramid Analysis the Number of Patients in Different Age Intervals

In figure 3,red represents the number of the male with hemophilia, green represents the number of the female with hemophilia.It shows that compared with the male, the number of women can slightly displayed only in 26 - 45 years old from nine age intervals.

4 Discussion

Our results show that hemophilia A is more common than hemophilia B, the number of the male with hemophilia is far more than the female, and most of patients are juveniles aged 0-18 years old, which coincide with the biology characteristics of hemophilia[1-4,19].

Before modern substitution treatment was introduced at the end of the 1960s, hemophilia often resulted in severe disability at a young age and premature death[1-3].However,in this study, there are some people with hemophilia in every age interval, such that there are 25 out of 1149 people aged over 45 years.The result at a societal level is that there are many more elderly people with hemophilia than in previous generations.It may be, life expectancy for people with hemophilia has improved and is now approaching that of the general population[9,20-21].

In order tofacilitate differentiate and comprehensive the number of each age interval,we subdivide age intervals and find that the male with hemophilia are most around 7-12 and 2-3 years old, whereas the female with hemophilia are most around 26-45 years old.For male patients, most around 7-12 and 2-3 years old, coincide with the epidemiological characteristics of hemophilia[1-4].The reason for female patients, most around 26-45 years old may be that: on the one hand, women who carry one copy of the abnormal gene also can experience heavy bleeding symptoms and have mild hemophilia[6].However, most of the women with a family history of hemophilia did not realize that they were at risk of bearing the gene[8].On the other hand, most women have married at the age of 26-45.They have formed their own family and had children.At this time, mild symptoms resulting from hemophilia can be more severe for women because of their associated effects on menstruation, pregnancy, childbirth[6,10,22-23].

These data provide useful evidence on the trends in a measurable outcome of hemophilia.In recent, though there is relatively small number of people with hemophilia, for meeting the challenge of the ageing hemophilia population, the management of hemophilia becomes more complex[9].We will have come a long way to supply assistance treatment information for discovering new characteristic rules and seeking new treatment strategies[24-26].One of the important challenging issues in the near future is registration available information for all affected individuals worldwide.

Conflict of interest statement

None of the authors have any financial or other potential conflict of interest for this study.

Acknowledgements

This work is supported by the Central College Fund(PhD)(No.GK201504015).

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Study on the Efficacy and Safety of Xueyou Mixture(血友合剂)in Treating Hemophilia

Liu Shanxi(刘陕西),Jiang Lin(江琳),Liu Yiguo(刘义国),

He Yueqin(贺乐琴), Liang Xin(梁鑫),Kong Weiwei(孔伟伟),

and Chen Jing(陈静)

Abstract Objective:To observe the effect of Xueyou Mixture(血友合剂,XYM)on blood coagulation factors and its safety in treating hemophilia.Methods:To the randomly selected 65 inpatients of hemophilia,XYM was administered accompanied with intravenous dripping of liver cell growth factor 60-100 mg once a day to protect the liver,with no blood products like concen trateed Ⅷand FⅨ factor or blood plasma given.The treatment lasted for 3 weeks.The short-term efficacy and adverse reactions were observed.The longterm efficacy in patients was observed in a follow-up study of 6-12 months after they were discharged from the hospital but continuously took XYM orally.Results: The short-term markedly effective rate in the patients was 95.38%(62/65).After they were treated for 3 weeks, the level of FⅧ factor activity increased in 56 patients of type A from(3.32±12.21)%to(4.18±12.23)%.and in 9 of type B from(4.92±1.81)% to(5.64±1.96)%.Compared with that before treatment, the difference significant in both of them(P＜0.01).No obvious adverse reaction was found in the treatment period.The follow-up study showed that in 22 patients of type A, the FⅧ fctor activity ratio increased from(3.32±2.11)% to(6.31±2.16)%,(8.36±1.05)%.and(16.38±2.71)%in the 2nd, 3rd and 6th month after discharge respectively, all showing significant difference to that before treatment P＜0.01); and in 4 patients of type B, it increased from(4.15±2.26)%to 7.8% and 11.6%(mean value)in the 2nd and 6th month respectively.Conclusion: XYM could raise the activity of factorsⅧ and Ⅸ in patients with hemophilia, and the degree of the rise is related with the duration of the therapy, with no obvious adverse re action, which strikes out a new path and new train of thinking for the treatment of the disease by non-blood preparation.

Keywords Xueyou Mixture, hemophilia, therapeutic efficacy

Hemophilia is a disease of deficiency in a group of hereditary coagulation factors, with its radical treatment still lacking in the whole world.Research in gene therapy is still at the bottom of the valley because of its low level of expression, shortness in effect-maintaining time, strong immune reaction to adenoviral vector and reproductive chain transferring,etc[2-4]; replacement therapy with blood preparation could be applied during hemorrhage,but could cause more harm than benefit gained due to the high occurrence of complication with hepatitis B and C.AIDS, and production of blood coagulation antibody, the last of which will, in particular, destroy the coagulation factors of the patients' own, lower their activity and thus affect the efficacy of hemostasis to form a vicious cycle.

In order to seek new drugs for treatment of hemophilia.65 patients of hemophilia were treated by the authors using Xueyou Mixture(血友合剂,XYM), a Chinese herbal nonblood preration, as the dominantremedy combined with others for strengthening liver protection, and favorable effects have been obtained.

Methods

Diagnostic Standard

The diagnosis of hemophilia was made in reference to the standard for diagnosis and efficacy evaluation of hematopathy[5]with the activity of factorⅧ(FⅧ), FⅨ and FⅪ taken as the primary indexes and patients history of inheritance and clinical manifestations like spontaneous bleeding or traumatic bleeding that is hard to stop taken into consideration, but with acquired coagula- tion factor deficiency and von Willebrand disease(vWD)excluded.All the patients were classified into four grades according to the activity of FⅧ and FⅨ.In them:severe grade: ＜1%; moderate grade:(2% and ＜5%); mild grade≥5% and＜25%; and sub-clinical grade≥25 but＜50%.

General Materials

The 65 enrolled patients of hemophilia selected randomly from the inpatients came from the inparious areas of China, hospitalized in the authors' hospital with in the period from Jan.2006 to Sep.2006, 64 males and 1 female, aged 0.8-56 years, with the median age of 12.6 years.Eighteen(27.7%)of them had hereditary history, and whether the other 47(72.3%)had it or not was unknown.Among them, 56(86.2%)were of type A and the other 9(14.9%)of type B;their condition of disease was classified as of severe grade in 18(27.7%), moderate grade in 30(46.2%), mildgrade in 17(26.2%), with no case of sub-clinical grade.As to the three coagulation factors(FⅧ,FⅨandFⅪ), 45 patients(69.2%)suffered from deficiency in one, 15(23.1%)from deficiency in two and 5(7.7%)from deficiency in all the three.

28 patients had their activity of coagulation factor determined 1-4 times before, among whom the activity had been lowering continuously along with the growth in age in 18 patients(64.3%), unchanged in 9(32.1%)and increased in 1(3.6%).

48 patients(73.9%)had complications of hypocalcemia, 39(60.0%)with anemia, 44(67.7%)with hemophilic arthropathy, 6(9.2%)with hepatitis B, 3(4.6%)with hepatitis C and 3(4.6 %)with each of the following diseases of hematocyst, infected hematoma,renal stone, peripn heral nerve injury, contracture of muscular tendon and hydronephrosis,and none with AIDS or syphilopathy.Anti-factorⅧ antibody detection showed positive in 2 out of the 4 tested patients.

Treatment

XYM,which consists of 13 kinds of Chinese herbs, including Radix Rehmanniae praeparata, Radix Moromdae officinalis, Radix Ginseng, Radix Angelicae,Radix Notoginseng, Radix Rubiae and Radix Astragalus membranaceus, etc, was given 1 dose every day,decocted in water twice, with the 2 decoctions mixed(about 200 mL)for intake in 2 times in the morning and at evening.At the same time, liver cell growth factor(product of Beisheng Pharmaceutical Co, Ltd.)was given 60-100mg per day by intravenous dripping to strengthen liver protection.Instead of XYM, to children patients aged below 1 year, Xueyou Capsule(血友胶囊,of the constituents same to that of XYM, but made into powder,each gram containing ingredients equivalent to 5 g of crude drugs, and packaged in capsule, 0.25 g/capsule)was given orally after meal, 3 times a day, 4 capsules each time.

The treatment lasted for 3 weeks and the short-term effect of treatment was evaluated then.Blood preparation like concentrated factorⅧ and Ⅸ,or blood plasma was not allowed in the whole therapeutic course.

After the patients were discharged from the hospital, they would be asked to take XYM or its capsuleform continuously for 6-12 months, and then recheck of blood coagulation factor was performed in the locality every 3 months for long-term efficacy observation.

Detection of Coagulation Factors Activity

With the one-stage method adopted, the activity of 3 kinds of coagulation factors were detected with the coagulation factor deficient plasma purchased from Fisher Scientific International Inc, USA.

Detection of Adverse Reaction and Complications

The changes in clinical symptoms, ECG, liver and renal function, blood sugar, electrolytes and routine tests on blood and urine were observed and detected before and after treatment to assess the adverse reaction to the testing treatment.The complications such as varthropathy, hematoma and hematocyst were supervised with MRI and color ultrasonography.

Evaluation of Short-Term Efficacy

For the sake of excluding deviation from laboratory detection,and also for the observation of long-term effect, the therapeutic effect was evaluated after the 3-week treatment by a recheck of FⅧ or FⅨ activity.Increase of the activity by 0.3% over the baseline value was regarded as effective, otherwise as ineffective.

Statistical Analysis

Pairedt-test and χ2test were adopted for intergroup comparison with SPSS 11.0 Software.

RESLUTS

Short-term Efficacy

The treatment showed to be effective in 62 of the 65 patients, which accounted for 95.38%,and ineffective in 3(4.62%).Of the failed treated cases, one had anti-factor Ⅷantibody(0.75 UI/mL plasma), and the other two were treated for only 2 weeks.

Change in Coagulation Factors Activities

As shown in Table 1,after 3 weeks of treatment, the activities of FⅧ,FⅨand FⅪwere all elevated in the 56 patients of hemophilia type A, showing significant difference to those before treatment(P＜0.01),while in the 9 patients of type B, significance only showed in FⅨ activity(P＜0.01),but no significant changes were found the other two(P＞0.05).

Table1　Changes in Activities of Coagulation Factors(%,±s)h

Notes:∗P＜0.05, compared with BT in the same group; BT means before treatment.AT means after treatment.

Changes of Hemoglobin

After treatment, the level of hemoglobin(g/L)in the 65 patients increased from 110.52±18.17(40-135)to 122.09±13.32(90-140),the difference showing significance(P＜0.01).

Adverse Reaction

Except for dizziness and nausea that occurredin 4 cases(6.2%)due to the quick speed of dripping liver cell growth factor, which disappeared after the speed was slowed down; no patient s complained of evident discomfort in the treatment course.None of the examinations on liver and renal function,ECG,electrolytes, blood sugar and routine test of blood andurine before and after treatment showed to be abnormal.

Results of Follow-up

26 patients(40.0%)out of the 65 were followed-up for 6-12 months, and the results showed that the activity of FⅧ or FⅨ was increased in the follow-up period with the extent of raising related to the duration of medication(Figure 1).

In the 26 patients followed-up, the activity of FIE in the 22 patients of type A got

raised from(3.25±2.11)%to(6.31±2.16)%,(8.36±1.06)%and(16.38±2.71)% af

ter taking XYM continuously for 2, 3 and 6 months respectively, with the highest reaching 21.90%, showing significant difference to that before treatment(P＜0.01).

As for that in the 4 patients of type B, it increased from(4 .15±2.26)%to an average of 7.80% and 11.60% respectively after 2 and 6 months, but the data were not managed statistically because the size of the sample was too small.

Figure 1.Relationship between Coagulation Factors Activities and Duration of Therapy

DISCUSSION

Nowadays,the activities of FⅧ,FⅨ and FⅪin hemophilic patients are mostly detected by one-stage method at home and aboard,and the patients are divided,according to the fact that factor activity got reduced by＜50% of the relevant value, into A, Band C types.In this study, 69.2% of the 65 patients were of single factor deficiency, 23.1%of double factor deficiency and 7.7% of triple factor deficiency.The degree of the deficiency of the three factors in the latter two types was different, always with one dominating the other two.This fact indicated that in the patients of hemophilia, except the single factor deficiency type,there also exists complex coagulation factor deficiency.Besides, it also hints that in diagnosing hemophilia.patients for the first time,detection of the three coagulation factors should be performed simultaneously to avoid misdiagnosis.The etiology of the complex type may be related with gene mutation position and type of the coaguation factors.For women patients with bleeding mainly in the skin and mucous membrane and few in the joints and muscles, the diagnosis should be confirmed to exclude acquired coagulation factorⅧ deficiency and vWD through such tests as W factor antigen, vWD factor antigen and bleeding time.

In TCM theory, hemophilia belongs to the category of qi-blood deficiency and blood stasis,which is considered to be caused by congenital defect.Since Shen(肾)is the basic congenital foundation and Pi(脾)is the acquired constitution, Gan(肝)and Shen are of thesame source, so, the pathogenetic mechanism should be related with Gan, Pi and Shen in TCM.

XYM possesses the effects of nourishing Gan and Shen,strengthening Pi,supplementing qi, and generating and controlling blood.In the recipe, Radix Rehmanniae praeparata and Radix Moromdae Officinalisare used to reinforce Shen and generate blood; Radix Angelicae and Radix Paeoniae alba have effects in nourishing blood and softening Gan;Radix Ginseng and Radix Astragalus membranaceus are applied to supplement qi and control blood and Radix Notogin seng with Radix Rubiae can cool blood heat to stop bleeding and also dissipate stasis to reduce swelling.

Modern pharmacological study showed that saponins extracted from ginseng and astragalus have effects in promoting synthesis of DNA, RNA and protein in the liver and bone marrow, and also show an antimutation action.Thus, it would be help repair hemophilic deficient genes and mutation genes.The water extract of Radix Rubiae could shorten the coagulation time, promote the production of thrombokinase and thrombin as well as the fibrination, which is favorable to stop bleeding in patients.Radix Angelicae, Radix Paeoniae alba and Radix Rehmanniae praeparata have the functions of regulating immunity and inhibiting inflammatory response, therefore,showing good efficacy in treating hemophilic arthritis, Pigmentation Villio-nodular synovitis and for eliminating exudation and edema.

Clinical observation on the 65 patients showed that after 3 weeks of treatment, the short-term effective rate in the patients was 95.4%(62/65), and the 6-month follow-up study showed that the activity of FⅧor FⅨincreased exponentially with the extent related to the duration of medication, indicating that XYM has an effect of continuously elevating coagulation activity.As for the details of its mechanism, it remains to be studied further.

The cases followed up in the study were limited due to the difficulty in conducting rechecks of patients who were scattered to different places in the country, which needs to be strengthened in the future.Another report by us concerning the treatment of joint bleeding and arthropathy in hemophilia patients is about to be published.

Conclusively, the clinical observation showed that XYM is a good Chinese herbal preparation with high safety for treatment of hemophilia, which opens up a new path of treatment with non-blood preparation and provides a new train of thinking for prevention and treatment of hemophilia.[原载于Chin J Integr Med, 2007,13(2):141-144]

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Five in One Therapy for Graded Treatment of Haemophilic Arthritis

S.X.Liu∗, P.B.Li, Y.G.Liu, P.H.Wang

SHAANXI YIDA HEMOPHILIA INSTITUTE

Abstract Haemophilic arthritis is the most universal clinical appearance of haemophilia.Treatment of this disease has become an important and difficult issue worldwide until recently.The aim of the study was to investigate the efficacy and safety of five in one therapy for graded treatment of haemophilic arthritis.Haemophilic arthritis was classified into grades Ⅰ-Ⅳ according to severity and the standards of De Palma and Cotle.The effect of five in one therapy(intra-articular cavity drug injection, oral drug preparation, physiotherapy, and prevention of haemorrhage and infection evoked by puncture)was observed in 1572 affected joints of 750 cases of haemophilic arthritis.After 20 days treatment, all grade I andⅡ, 94.98% of grade Ⅲ and 56.16% of grade Ⅳ affected joints were completely relieved;5.02% of grade Ⅲ and 41.47% of grade Ⅳ affected joints were basically relieved; and 2.38% of grade Ⅳ were partially relieved.This resulted in short-term complete and basic relief of 98.56%(1505/1527)of all affected joints.After follow-up of 1-6 years,86.97% of the affected joints were completely relieved, without any adverse reaction or complication.The results suggest that five in one therapyis safe and effective for treatment of haemophilic arthritis, and provides a convenient, cost-effective way of preventing and treating deformity caused by haemophilic arthritis.

Key words five in one therapy; graded treatment; haemophilic arthritis

Introduction

Haemophilic arthritis is the most universal clinical appearance of haemophilia.The condition causes repeated swelling and pain, induces synovitis(arthromeningitis), and finally results in severe deformity of the load joint[1,2].This affects work and quality of life,and is a major burden for patients, their families, and society.Treatment of this disease has become an important and difficult issue worldwide.Human coagulation factor preparations and synovial resection for treatment of haemophilic arthritis were chronically administrated to reduce suffering[1,2]However, these therapieshave been discontinued due to induce severe complications.Currently, gene therapy is still undergoing research due to the low level of gene expression, short-term curative effect, severe immunological reactions against adenoviral carriers, and vertical transmission.Therefore,treatment of haemophilic arthritis has become a major problem in patients with joint malformation and deformity.

Since 2006, we have investigated the pathogenesis and treatment of haemophilic arthritis.According to preliminary data, we assume that articular bleeding may only be the initial feature of haemophilic arthritis.Inflammation mediated by immunological factors may be essential for repeated onset, exacerbation and deformity of haemophilic arthritis.To address the assumption, we observed the efficacy and safety of five in one therapy(intra-articular cavity drug injection, oral drug preparation, physiotherapy, and prevention of haemorrhage and infection evoked by puncture)for graded treatment of haemophilic arthritis in hospitalized patients at our institution.

Materials and Methods

Diagnostic standard

The“Standard for Diagnosis and Classification of Hemophilia”of the World Federation of Hemophilia(WFH)classifies haemophilia into two types: i.e., haemophilia A, with deficiency of coagulation factor FⅧ, and haemophilia B, with deficiency of coagulation factor FⅨ.Depending on the level or activity of FⅧ or FⅨ, haemophilia is classified into three further types: serious(FⅧ or FⅨ activity ＜1% or level ＜0.01 U/mL); medium(activity 1%-5% or level 0.01-0.05 U/mL); and mild(activity 5%-40% or level 0.05-0.4 U/mL).

Haemophilic arthritis was classified into four grades according to the standard of Palma and Cotler.Grade Ⅰ: bleeding and/or light synovitis.Grade Ⅱ: persistent synovitis.GradeⅢ: chronic arthritis with joint deformationand muscular atrophy.Grade Ⅳ: joint ankylosis.

Hospitalized patients were randomly enrolled with complete clinical and laboratory data.These patients were given five in one treatment for 20 days without application of any blood preparations.Other joint diseases such as joint tuberculosis and suppurative arthritis were excluded by iconography, joint cavity fluid puncturing, erythrocyte sedimentation rate, and tuberculosis antibody.

General data

We enrolled 750 patients with 1527 affected joints who were hospitalized between January 2006 and December 2013.The patients came from various parts of China and there were 747 male and 3 female patients, with a mean age of 15.28 years(range: 6-83 years).630 patients had haemophilia A, with a mean of FⅧ activity of 2.65±3.16%, and 120 had haemophilia B, with a mean of FⅨ activity of 4.16±5.27%.The number of affected joints were: 778 knees(50.95%), 361 ankles(23.64%), 299 elbows(19.58%), 59 hips(3.86%)and 30 shoulders(1.96%)(Table 1).The classification of haemophilic arthritis of the 1527 affected joints was: Grade Ⅰ, 42(2.75%); Grade Ⅱ, 101(6.62%); GradeⅢ, 458(29.99%); and Grade Ⅳ, 926(60.64%)(Table 2).

Verification of haemophilic arthritis

Joint puncturing was performed on all 1527 affected joints in 750 patients with haemophilic arthritis.Arthrorrhagia was seen in only 91(5.96%)joints, and the majority(1436;94.04%)had no blood.

Pathological examination of synovial membrane biopsy showed that,under light microscopy, the synovium tissue with apparent hyperplastic epithelium formed a papillary structure that was uneven in size.The cells were arranged in strata with abundant cytoplasm and contained many black pigmentation granules.The nuclei were oval and uniform in size,and the chromatin had a fine grainy appearance.Vascular proliferation could be seen in villous stroma accompanied with significant inflammatory cell infiltration.The pathological appearance was concordant with a diagnosis of pigmented villous nodular synovitis(Fig.1).

Inflammatory index showed that complement component C3 was increased in 54 of 55(98.18%)patients, and C-reactive protein was positive in 458 of 611(74.96%) patients,supporting the theory of immune-mediated arthritis.

Testing drugs and treatment

Five in one therapy was administered for 20 days for graded treatment of haemophilic arthritis as follows.

(1)Compound

arthritis

capsule(National Intellectual

Property Office,ZL201410128057.6; 1.2 g, three times daily, orally)was a Chinese medical preparation for anti-inflammatory activity, apocatastasis, tendon relaxation, pain relief and inhibition of immunoreactivity.

(2)Intra-articular cavity injection of anti-inflammatory mixture: 10 mg triamcinolone acetonide acetate(Shanghai Xudong-Haipu Pharmaceutical Co.Ltd, H20063226), plus methotrexate(Shanxi Pude Pharmaceutical Co.Ltd, H14022462), 2.5 mg twice weekly,for grades Ⅰ-Ⅳ haemophilic arthritis.Rifampicin injection(Chongqing Huabang Pude Pharmaceutical Co.Ltd., H20041320), 0.45 g, once or twice weekly for inhibition of periosteal proliferation in Grade Ⅱ haemophilic arthritis.Sodium hyaluronate(Shanghai Haohai Biotechnology Co.Ltd., H20051838), 30 mg, once or twice weekly for anti-inflammatory activity, lubrication, and cartilage repair, in Grades Ⅲ and Ⅳ haemophilic arthritis.

(3)Physiotherapy: MC-B-Ⅱ pulse magnetic therapeutic apparatus, local irradiation,20 min, once daily for 7~10 sessions, for Grades Ⅰ and Ⅱ haemophilic arthritis.Therapeutic Instrument of Digital Intermediate Frequency, local treatment for pain relief, anti-inflammatory activity, and promotion of blood circulation, 20 min, once daily for 7-10 sessions, for Grades Ⅲ and Ⅳ haemophilic arthritis.Ultrashort Wave Diathermy Apparatus,local treatment for anti-inflammatory activity and apocatastasis, 20 min, once daily for 7-10 sessions, for Grades I and II haemophilic arthritis.Physical sports therapy: separation of musculotendinous adhesions, muscle strengthenning, and tendon relaxation and lengthening, for Grades Ⅲ and Ⅳ haemophilic arthritis.Orthotic device, for tendon lengthening,for Grades Ⅲ and Ⅳ haemophilic arthritis with knee or elbow deformity.

(4)Prevention of joint puncture-evoked bleeding: haemostatic mixture, including etamsylate(Hubei Tianyao Pharmaceutical Co.Ltd, H42020039), 2.0 gin adults,plus tranexamic acid(Harbing Sanjing-Tongtai Pharmaceutical Co.Ltd., H23020968), in adults, 0.1 g added to 250 mL 5% glucose, once or twice daily by intravenous drip.

(5)Prevention of joint puncture-evoked infection: clindamycin(Cleocin; Guangzhou Beiyunshan, Tianxin Pharmaceutical Co.Ltd., H20063575), 1.2 g, once daily by intravenous drip, or cefazolin sodium(Harbing Group Pharmaceutical Factory, H23020945), in adults, 4.0 g once or twice daily by intravenous drip.

Treatment according to grade was as follows.Grade I: joint puncture; haematological draining; flushing of joint cavity; intra-articular injection of anti-inflammatory mixture; and magnetotherapy of affected joint.Grade Ⅱ: injection of rifampicin and anti-inflammatory mixture into joint cavity; and ultrashort wave therapy.Grades Ⅲ and Ⅳ: injection of sodium hyaluronate and anti-inflammatory mixture into joint cavity; intermediate frequency therapy; and physical sports therapy.Grade Ⅳ treatment also included correction of joint deformity with an orthotic device.All grades Ⅰ-Ⅳ were treated with oral compound arthritis capsule.

Items and methods of observation

Joint swelling, pain, tenderness and activity were measured in 1527 joints from patients with haemophilic arthritis before and after treatment to evaluate the short-term curative effect.The long-term curative effect was evaluated after 6 months follow-up.

Joint swellingwas determined by measuring the joint circumference: for knee and elbow joints, measuring at the patella and olecranon level; for ankle joints, measuring below the medial and lateral malleolus; for hip joints, measuring at the thigh root; and for shoulder joints, measuring at the roots of the upper limb.The circumference size was shown in centimetres.

Joint pain and tenderness were evaluated by a five-point oral grading scale: painless,mild pain, moderate pain, severe pain, intense pain, and extreme pain were scored as 0,1, 2, 3, 4 and 5, respectively.

Joint function was evaluated by using the neutral 0 degree method, i.e., using a protractor to measure the changes of joint angles before and after treatment and using a 5-point scoring method to evaluate the joint activity.On the basis of the measured angle between joint unbending and most flexion, it was divided into five equal parts, each part was scored as 1.If the joint activity completely recovered to a normal level, it was scored as 5.The measure of every joint activity was described in detail in the report published by Zhi Jiening and Sun Lei in 2007 [3].

The curative effect was determined by measuring joint swelling, pain, tenderness and activity as follows.(1)Complete remission: joint circumference returned to normal levels;pain and tenderness disappeared, with a score of 0; and joint activity returned to normal,with a score of 5.(2)Basic remission: joint circumference returned to normal levels; pain and tenderness disappeared, with a score of 0; and joint activity significantly increased more than 1, but not to normal level(＜5).(3)Partial remission: joint circumference returned to normal levels; pain and tenderness disappeared, with a score of 0; and joint activity increased less than1.(4)No remission: joint swelling, pain, tenderness and activity not obviously changed compared with before treatment.

Adverse reactions and complications of puncturing

Liver and kidney function, electrolytes, electrocardiography, blood glucose, and routine blood and urine analysis were examined before and after treatment to observe any adverse reactions.Joint puncture was examined to determine whether there was fresh bleeding and/or infection, as well as aggravation of pain and tenderness after treatment.

Statistical analysis

All data are shown as mean ± SD.Statistical analysis was carried out using SPSS version 11.0.Thet test, c2test and rank-sum test were performed to analyze the difference between two groups.P＜ 0.05 was considered to be statistically significant.

Results

Therapeutic effect

A total of 1527 affected joints in 750 patients with haemophilic arthritis were treated with the five in one graded therapy for 20 days, without auxiliary treatment with coagulation factors and plasma preparations.Joint circumference was significantly reduced compared with that before treatment(P＜0.001 in knees, elbows and ankles; P＜0.01 in hips; but P＞0.05 in shoulders).Pain and tenderness completely disappeared in the all affected joints(P＜0.001)and the joint activity significantly increased or returned to normal levels(P＜0.001)(Table 1).

Further analyses indicated that complete remission was obtained in 1098 affected joints(71.91%), basic remission in 408(26.72%), and partial remission in 22(1.44%), and no joints show ed no remission.The results suggest that the complete and basic remission rate of haemophilic arthritis was 98.63%, as shown in Table 2 and Fig.2.

Adverse reactions and complications evoked by puncturing

The 1527 affected joints were punctured on 9162 occasions and there were no complications, such as infection, fresh bleeding and pain aggravation.There were no adverse reactions throughout the course of treatment.Liver and kidney function, electrolytes, electrocardiography, blood glucose and routine blood and urine analysis all showed normal results.

Outcome of follow-up study

After 1-6 years follow-up, there was relapse in 33 joints with Grade Ⅲ and 166 with Grade Ⅳ(13.03%)haemophilic arthritis.Continuous remission was observed in the other 1328(86.9%)affected joints.These results suggest that the five in one therapy for graded treatment of haemophilic arthritis has a long-term therapeutic effect.

Discussion

Haemophilia is a haemorrhagic disease with a high bleeding rate, mortality and disability.In particular, haemophilia-induced arthritis can cause a disability rate of ≤80%[1,2].Therefore, control and management of haemophilic arthritis have become key issues for alleviating patient suffering, improving quality of life, and reducing the burden on families and society.Clinicians routinely administrated human blood coagulation factors to treat haemophilic arthritis for a long time.However, the use of blood coagulation factors for treatment of haemophilic arthritis could produce some serious complications, especially FVIII/FIX antibody, which aggravates mortality and disability in patients[4-7].Therefore, developing a novel therapy for haemophilic arthritis became a matter of urgency.

Recently, it was considered that arthrorrhagia is only the initiating factor in the pathogenesis of haemophilic arthritis, while immune-mediated inflammation is the essential cause induced the joint swelling and pain, bone hyperplasia, cartilage destruction, joint deformity, and disability.The pathogenesis of haemophilic arthritis is closely related to erythrocyte damage, release of iron ions and hemosiderin, and inflammatory cell infiltration(CD4 T cells, macrophages, and monocytes), as well as release of inflammatory factors(tumour necrosis factor-α, and interleukins 1, 6, 15, 17 and 21-23).These factors stimulate synovial cells, fibroblasts and osteoclasts, and several signalling pathways to induce arthritis in patients with haemophilia[8-10].Clinicians have developed some other methods of treatment,such as synovectomy and radionuclide therapy, but the curative effect was not satisfactory.In addition to the expense, many complications, such as, postoperative joint dysfunction, paediatric long bone dysplasia, recessive cancer, local necrosis and haemorrhage, seriously hindered the clinical application of these treatments in haemophilic arthritis.

We found that arthrorrhagia was only present in a small number(6%)of the affected joints, as verified by joint puncture.Pathological assessment of synovial biopsy indicated that the pigmentary villous nodular synovitis in the affected joints were similar to those of rheumatoid arthritis.The systemic inflammatory index indicated that complement component C3 increased in most(98%)of the patients with haemophilic arthritis, and C-reactive protein was positive in 75%.These observations provided support for the idea that haemophilic arthritis is a feature of immune-mediated arthritis.According to this idea, we used the five in one therapy for graded treatment of haemophilic arthritis and obtained good therapeutic results.The joint swelling, pain and tenderness gradually disappeared, and joint activity improved in most of the patients during 20 days treatment.There were no complications,such as infection, fresh bleeding and pain aggravation, or any adverse reactions.Follow-up of 1-6 years indicated that most of the patients with haemophilic arthritis achieved better long-term therapeutic effects than those treated with synovectomy or radionuclide therapy.

In conclusion,our results suggest that five in one therapyis safe and effective for graded treatment of haemophilic arthritis, and provides a convenient, cost-effective way of preventing and treating deformity caused by haemophilic arthritis.

Acknowledgments

This project was supported by China-Japan Research Center for Prevention and Treatment of Hemophilia.There are no any conflicts of interest in the studies reported in the paper.(原载 Hemophilia,2015,1-6,doi:10.111/hac.12746)

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Study on Graded Therapy of Hemophilic Arthritis by Integrative Traditional Chinese and Western Medicine

Liu Shanxi(刘陕西),Jiang Lin(江琳),Liang Xin(梁鑫),

Kong Weiwei(孔伟伟),Chen Jing(陈静),Liu Yiguo(刘义国),

and He Leqin(贺乐琴)

ABSTRACT Objective: To study the effect and safety of graded therapy featuring integrative traditional Chinese and Western medicine for the treatment of hemophilic arthritis.Methods: Forty patients with hemophilic arthritis were hospitalized randomly, with their blood coagulation factor activity determined by one-stage method and their arthritis classified into 4 stages.The treatment was applied according to the stage of arthritis and finding of intra-articular cavity puncture.For stage I,based on the principle of RICE(rest,ice,compression and elevation),1.8 g of Xuefuda(血府达)was medicated orally once per day, intravenous dripping of 250 mL of hemostasis mixture twice a day and 1.2 g of clindamycin per day were also given for hemostasis and anti-inflammation.For stage Ⅱ-Ⅲ,Kangyanling(抗炎灵)was additionally administered via intra-articular cavity injection twice a week, 2 mL every time, for 5-6 times in total.For stage Ⅳ, the drug for intra-articular cavity injection was replaced with 25 mg of sodium hyaluronate and the frequency of injection reduced to every two weeks, for 5-6 times in total.Coagulation factors Ⅲ and Ⅳas well as blood plasma were not given in the whole treatment course.Short-term therapeutic effects and adverse reaction in patients were evaluated, and the long-term effects were followed-up after patients left the hospital with 6-month consolidation therapy by Xuefuda.Results: After a 3-week treatment, 33 patients(82.5%)were completely remitted; 5(12.5%)were partially remitted and 2(5.0%)unremitted, setting the short-term effective rate at 95.0%(38 cases).The 6-month follow-up showed that except for a relapse in 2 and 4 patients of stage Ⅲ and Ⅳ respectively, long-term remission displayed in all the other 34 patients, with the remission sustaining rate being 85.0%.No complication such as an infection, bleeding or aggravating pain occurred in the 215 times intra-articular puncturing conducted in the 40 patients.Normal figures were shown in liver and kidney function, electrolytes, ECG, blood glucose and routine test of blood and urine throughout the course.Conclusion: The graded treatment of integrative medicine for hemophilia with non-blood preparation has a favorable effect and is safe or without any adverse reaction, which opens a high efficacy and new safe path and thinking for the treatment of and deformity prevention in the hemophilic patients.

Key words integrative traditional Chinese and Western medicine, treatment, hemophilic arthritis, effect

Hemophilia is a hemorrhagic disease caused by the deficiency of a group of chain genetic coagulation factors.The condition could result in bleeding in the load joint to induce synovitis, and severe deformity of the joint, affecting work and quality of life(QOL)in patients.Currently there is no radical therapy on the disease worldwide[1].Gene therapy is now still in the valley stage of research due to the low level of gene expression, short sustaining time, severe immunological reactions against adenoviral carriers and its reproductive chain transmission[2-4].Therefore, the treatment of hemophilic arthritis becomes the key problem for joint malformation and deformity.The graded treatment with integrative traditional Chinese and Western medicine(ICWM)was adopted by the authors' institute for treating 40 patients with hemophilic arthritis, reportedly yielding a favorable effect.

METHODS

Diagnostic Standard

Hemophilia was diagnosed and typed referring to the“Standard for Diagnosis and Efficacy Evaluation of Blood Disease”[5].The condition of hemophilic arthritis was classified into 4 stages[6,7].Stage I : transient synovitis with no hemorrhage-caused sequelae, X-ray only showed changes in soft tissue; Stage Ⅱ: persistent synovitis with swollen joint, thickened synovial membrane and limited motion, X-ray showed first grade of pathological change with mini-change on single facet of epiphysis; Stage Ⅲ: chronic arthritis with the clinical manifestations of stage Ⅱ and complicated with deformation of joint orientation and muscular atrophy.X-ray showed abnormal osteoepiphysis hypertrophy, narrowed joint gap,different degrees of inconsistent joint facets and subcartilaginous cyst formation; Stage IV:fibrous or osseous ankylosis, X-ray showed joint deformation.

Patients were enrolled in the observation and analysis, randomly hospitalized, given the ICWM graded treatment for 3 weeks without application of any blood preparation and with complete laboratory data.Joint diseases such as joint tuberculosis and pyogenic arthritis were excluded through examinations of iconography, joint cavity fluid puncturing, erythrocyte sedimentation rate and tuberculo-antibody.

General Materials

The 40 enrolled subjects were inpatients hospitalized from January to December 2006.The individuals came from various places in China, all males, with a median age of 14.1 years(4-35 years old).For the study, 31 patients belonged to type A, with a mean value of coagulation factor Ⅷ activity(FⅧ:C)of 2.83%; 9 belonged to type B, with mean value of FⅨ:C of 4.16%; 12(30.0%)were severe cases, 23(57.5%)moderate cases and 5(12.5%)mild cases, and no sub-clinical case was found.

The affected joints were knees in 31 patients(77.5%), ankles in 6(15.0%)and elbows in 3(7.5%).By Palma-Cotler grading of MRI, the median age, the duration of target arthritis and frequency of attacks within a half year in the 5 patients of grade I were 6.13 years,0.58 years and 1.8 times; in the 14 patients of grade II were 8.86 years,4.27 years and 3.22 times; in the 14 of grade Ⅲ the numbers were 16.89 years, 7.69 years and 5.29 times; in 7 of grade Ⅳ the figures were 26.75years, 15.87 years and 6 times.Joint puncturing was performed in 40 patients 215 times; except 3 patients with hematocele punctured the first time, all the 212 times were dry suction.

Pathological examination on biopsy of synovial membrane showed violet red or pale red tissue, with a rough surface visible to the naked eye.Under light microscopy, the synovial tissue with apparent hyperplasia epithelium formed a papillary structure uneven in size.The cells were arranged strata with abundant plasma, and contained lots of black pigmentation granules.The nuclei were oval-shaped and uniform in size, and the chromatin in nuclei was fine grainy without obvious abnormality.Vascular proliferation could be seen in villus stroma accompanied with significant inflammatory cell infiltration.

Figure1.Pathological Figure of a Synovial Biopsy of the Left Knee Joint in a Case Diagnosed as Pigmentary Villus Nodular Synovitis

Testing Drugs

Xuefuda(血府达)was a self-formulated Chinese medical preparation made by the authors' hospital for anti-inflammation and subsiding tumidness to prevent bone damage.The product consisted of thorowax root, Chinese angelica root, achyranthes root, red sage root, notoginseng, bitter orange and red peony root; dosage form of the preparation was 0.3 g per pill.Clindamycin was the product of Baiyunshan Tianxin Pharmaceutical Co.Ltd.Guangdong Province, batch No.H20063575.Kangyanling(抗炎灵)was self-prepared using triamcinolone acetonide plus methotrexate, the product of Xianju Pharmaceutical Co.Ltd., Zhejiang Province, batch No.H20033525 and product of Shanghai Hualian Pharmaceutic, Fartory, batch No.H31021683, respectively.The hemostasis mixture,which combines etamsylate and aminomethylbenzole acid, was produced by Hubei Tianyao Pharmaceutic Co.Ltd., batch No.H42020039 and Shandong Sishui Xi'erkang Pharmaceutic Co.Ltd., batch No.H37022163.

Treatment

The graded treatment of ICWM was applied with no assistance from coagulation factorsⅧ, Ⅸ and plasma, according to the grade of arthritis and condition of joint cavity puncture in patients.For patients of stage I, RICE treatment(rest, ice, compression, and elevation)of the affected limbs was applied in combination with small oral doses of Xuefuda at two pills three times a day; intravenous dripping of hemostasis mixture 250 mL, twice a day; as well as 1.2 g of clindamycin per day.The course of therapy was 3 weeks.For patients of stages Ⅱ-Ⅲ, besides the above-mentioned treatment, intra articular injection of 2 mL Kangyanling was given twice a week for 6 times in total; For patients of stage IV, the same regimen in stage I was used, but with 25 mg of sodium hyaluronate intra-articular injection every two weeks for 6 times in total.

The intra-articular injection should be conducted aseptically in a therapeutic room with sterilized air and punctured into the joint cavity with a No.7 needle.The joint fluid was sucked first for microscopic examination, the drug was injected, and the operation was finished with disinfection and compression.

Evaluation of Therapeutic Effect

Evaluation on short-term effects was carried out by comparing the degree of joint swelling(DJS), joint pain(DJP)and joint tenderness(DJT)before and after treatment; the longterm effect was followed-up a half-year later.

DJS was expressed by the joint perimeter in centimeter, which was measured on the middle line level of the patella/olecranon for the knee/elbow joint and on the level beneath the medial and lateral malleolus for the ankle joint.

DJP and DJT were evaluated by six-grade scoring on dictation, with degrees of none,mild, moderate, severe, extreme and uttermost scored from 0-6 in that order.

The therapeutic efficacy was evaluated according the above outcomes in 3 grades: complete remission(CR)was defined as the DJS of the affected joint equal to that of the normal joint on the opposite side, with scores of DJP and DJT reduced to zero; partial remission(PR)was markedly reduced.

DJS, DJP and DJT; while no remission(NR)meant no change in DJS, DJP and DJT.

Adverse Reaction and Complication of Puncturing

Observation was carried out for possible general adverse reactions by examining functions of the liver and kidney, electrolytes, ECG, and routine tests on blood and urine before and after treatment.Complications of puncturing such as infection, fresh bleeding and aggravated pain were observed as well.

Statistical Analysis

Statistical analysis was carried out by adopting SPSS 11.0 Software; the t-test, χ2test and rank-sum test were also used.

RESULTS

Therapeutic Effect

Results of the 40 patients with hemophilic arthritis after being treated with graded therapy of ICWM for 3 weeks and without auxiliary treatment of coagulation factors and plasma showed that CR was obtained in 33 patients(82.5%), PR in 5(12.5%)and NR in 2(5.0%), with the short-term effective rate at 95.0%.The treatment showed the best efficacy on patients of stage Ⅰ and Ⅱ, favorable on patients of stage Ⅲ, but poor on those of stage Ⅳ(Table 1).

Table1　Therapeutic Effect on Patients of Various Stages(Case)

Table2　Changes in Scores of Affected Joints in Patients of Various Stages(Score, ±s)

Notes: ∗P＜0.05, ∗∗P＜0.01, compared with BT; BT: before treatment; AT: after treatment

The changes before and after treatment of DJS, DJP and DJT are listed in detail in Table 2.

Adverse Reaction and Complications of Puncturing

No complications from puncturing such as infection, fresh bleeding and aggravation of pain were found in the 215 times used for the 40 patients.No adverse reaction was also found in the whole course of treatment, with checks of liver and kidney function, electrolytes, blood glucose and routine test on blood and urine all showing normal results.

Outcomes of Follow-up Study

The 6-month follow-up in the 40 patients showed that relapse occurred in 6 patients, 2 of stage Ⅲ and 4 of stage Ⅳ; continuous remission was observed in 34 patients(85.0%),indicating favorable long-term efficacy of the treatment.

DISCUSSION

The pathogenesis of hemophilic arthritis is still unclear at present, although the existence of hematocele in the joint cavity is commonly considered as one of the important predesposing factors.The synovial cells would highly proliferate and become hyperplasia, with markedly accretionary, dilated, congestive and villiform capillaries.This would aggravate bleeding, form a vicious circle and inhibit the glucoprotein synthesis function of chondrocytes to cause the disintegration of extra-chondrocyte stroma and destroy the cartilage and lead to panarthritis.Moreover, the same pathogenetic process could also result from the release of the lysosomal enzyme induced by inflammatory cell infiltration and accelerate the formation of panarthritis[8-11].

Many approaches could be used for the treatment of hemophilic arthritis, but none is satisfactory, with the options having their respective strong points and shortcomings.An effective rate of80% could be reached by surgical resection of the synovial membrane, but the application is limited due to its high expense for supplementing many coagulation factors in the peri-operative stage and the effect on joint function from the coagulation factor antibody produced.The removal of synovial membrane by chemical agents is rarely used for its poor efficacy, severe pain after medication and effect on joint function.At present, the commonly used method is radionuclide synovial resection.However, although the technique's effective rate is about 80%, there is concern for its underlying risks of carcinogenesis, mal-development in children, local necrosis of injection, aggravation of bleeding and recurrence.

Since the nature of the disease was considered to be a low-toxic synovitis with cartilage and sclerotin destruction, viewing the lack of good treatments, the authors created a therapeutic principle of anti-sepsis, anti-inflammation, preventing and treating sclerotin destruction for the treatment of hemophilic arthritis, the graded therapy of ICWM mainly with the intra-articular injection of Kangyanling and sodium hyaluronate, and assistance from small doses of Xuefuda and clindamycin.The Kangyanling used in this protocol has functions of anti-inflammation; anti-allergy; inhibiting inflammatory cells, including lymphocytes, monocytes and macrophages, and the inflammatory media; lowering the permeability of capillaries; reducing congestion; hemostasis and subsiding the swelling.The sod.ium hyaluronate could act on the synovial cells to promote the synthesis and metabolism of hyaluronic acid to prevent the destruction of cartilage and sclerotin and moisten the joint to enhance the scope of joint motion.Clindamycin is an antibiotic that displays high concentration in the joint and is effective on both aerobic and anaerobic, Gram's positive and negative, coccus and bacillus bacteria.Xuefuda is a pure Chinese medicinal preparation with actions of activating blood circulation to remove stasis, anti-inflammation, subsiding swelling, arresting pain,improving microcirculation, and promote the repair of tissues and bones, but it could only be used in small dosages after hemorrhage is controlled due to the coagulation dysfunction in hemophilic patients.

A favorable clinical effect was shown in this study.The short-term effective rate reached 95.0% and the long-term effective rate 85.0%.The approach was more effective on patients in early stages; no obvious adverse reactions or complications from articular puncturing were found.

In sum, the clinical observation illustrated that the graded therapy of ICWM on hemophilic arthritis was highly effective, low-cost, simple in operation, safe and without adverse reactions, providing a new path and thinking for prevention and treatment of it.[原载于Chin J Integr Med, 2007, 13(4):301-305]

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