Total Knee Arthroplasty in a Patient With Hemophilic Arthropathy and High-Titer Inhibitors : A Cost Analysis

A patient with hemophilia A, who developed factor VIII inhibitors and initially had funding for his total knee arthroplasty declined, is discussed. A total of £1 542 000 (US $2 474 603) was spent on medical treatment for recurrent hemarthroses over a 4-year period, while funding was sought. In comparison, the total cost for his knee arthroplasty was £542 858 (US $871 084) including perioperative recombinant clotting factors. Postoperatively, with 1-year follow-up, no further hemoarthroses have occurred; his analgesic requirement is significantly reduced; he has a much improved level of function; and treatment costs are significantly reduced, leading to a substantial overall saving. Our findings suggest that surgical treatment is beneficial and cost-effective for patients with hemophilia with inhibitors. Hospitals should not deny operative treatment based on cost alone.     

Molecular mechanisms underlying hemophilia A phenotype in seven females

Summary.  Background:  Hemophilia A (HA) in females is a rare observation. Here we describe various genetic mechanisms that result in phenotypic expression of HA in seven females. Methods:  The F8 gene was examined in all patients and relatives by direct sequencing. Multiplex ligation-dependent probe amplification (MLPA) was performed for large deletion screening. X chromosome inactivation was studied by PCR analysis of a polymorphic CAG repeat in the first exon of the human androgen receptor (HUMARA) gene. Results:  In two females sequencing of the F8 gene revealed homozygous missense mutations (Arg593Cys and Tyr1680Phe) as a consequence of consanguineous marriage. The third case was due to compound heterozygosity comprising the missense mutation Leu412Phe inherited from the carrier mother, together with a de novo large deletion spanning exon 9–22, probably originating from the germ cells of the healthy father. Three further cases shared a common mechanism representing heterozygous mutations in the F8 gene (Arg1781His, Arg327His, small deletion in exon 10) combined with non-random inactivation of the X chromosome. The final case describes a coincidental inheritance of HA and Coffin–Lowry syndrome in the same family. The HA phenotype results from a heterozygous small deletion affecting the F8 gene (c.6872 del CT leading to Thr2272 fs ) and a complete inactivation of the maternal X chromosome, which segregates with Coffin–Lowry syndrome in the two brothers of the proposita. Conclusions:  In conclusion, molecular genetic analysis represents an essentially valuable tool in elucidating the nature of the molecular mechanisms underlying the HA phenotype in females.     

Calcifying splenic hematoma in a hemophilic newborn

A 7-day-old hemophilic newborn presented several hemorrhagic manifestations, notably, a large cephalohematoma, intracranial hemorrhage and a splenic hematoma. This was clearly identified on X-rays and at 4 weeks of age showed gross ring-like calcification. Involvement of the spleen in hemophilia is rare, at all ages. Also uncommon are hemorrhagic manifestations of hemophilia during the neonatal period. Calcified splenic hematomas in hemophilic patients have apparently never been described.     

Study on graded therapy of hemophilic arthritis by integrative traditional Chinese and Western medicine

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 stageⅠ,based on the principle of RICE(rest,ice,compression and elevation),1.8g of Xuefuda(血府达)was medicated orally once per day,intravenous dripping of 250mL of hemostasis mixture twice a day and 1.2g of clindamycin per day were also given for hemostasis and anti-inflammation.For stageⅡ-Ⅲ,Kangyanling(抗炎灵)was additionally administered via intra-articular cavity injection twice a week,2mL every time,for 5-6 times in total.For stageⅣ,the drug for intra-articular cavity injection was replaced with 25mg of sodium hyaluronate and the frequency of injection reduced to every two weeks,for 5-6 times in total.Coagulation factorsⅢandⅣas 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%)un-remitted,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 stageⅢandⅣrespectively,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.     

Sustained Expression of Therapeutic Level of Factor IX in Hemophilia B Dogs by AAV-Mediated Gene Therapy in Liver

We demonstrate that a single intraportal vein injection of a recombinant adeno-associated virus (rAAV) vector encoding canine factor IX (cFIX) cDNA under the control of a liver-specific enhancer/promoter leads to a long-term correction of the bleeding disorder in hemophilia B dogs. Stable expression of the therapeutic level of cFIX (5% of normal level) was detected in the plasma of a dog injected with an AAV vector at a dose of 4.6 × 10¹² particles/kg for over 7 months. Both whole-blood clotting time (WBCT) and activated partial thromboplastin time (aPTT) of the treated dogs have been greatly decreased since the treatment. No anti-canine factor IX antibodies have been detected in the treated animals. Importantly, no bleeding has been observed in the dog that expresses a therapeutic level of cFIX for 7 months following vector administration. Moreover, no persistent significant hepatic enzyme abnormalities were detected in the treated dogs. Thus, a single intraportal injection of a rAAV vector expressing cFIX successfully corrected the bleeding disorder of hemophilia B dogs, supporting the feasibility of using AAV-based vectors for liver-targeted gene therapy of genetic diseases.     

Ablation of hemophilic FVIII inhibitors with FVIII priming, cyclophosphamide immune suppression, and rapid tapering of FVIII immune tolerance

The efficacy and toxicity of factor VIII (FVIII) priming, cyclophosphamide immune suppression, and rapid tapering of concurrent FVIII immune tolerance for subjects with hemophilic inhibitors were evaluated. Four subjects with hemophilic inhibitors were studied. Before treatment, inhibitors were present for a median of 8 months (mean 13 +/- 14.0 months). The median FVIII inhibitor titer was 16 BU/mL (mean 27.2 +/- 29.2 BU/mL). Following FVIII priming (80.0 +/- 70.2 U/kg), subjects received cyclophosphamide 1,418 +/- 636 mg/M2 i.v. q3 weeks for 4.4 +/- 1.7 courses. Subjects concurrently received a low (6 U/kg/day), moderate (30 U/kg/day), or high (100 U/kg/day) dose of FVIII followed by a rapid taper as the inhibitor titer decreased or resolved. During treatment, the inhibitor titer initially increased but then rapidly declined. Inhibitors resolved in 3.9 +/- 2.9 months. One inhibitor recurred at 2.8 years, but it was successfully re-treated. Effectiveness did not depend on the FVIII dose. Toxicity was minimal. Cyclophosphamide (1,400 mg/M2) administered after a priming dose of FVIII (80 U/kg) i.v. q3 weeks for 2-6 cycles with a rapid taper of concurrently administered daily FVIII as the inhibitor titer falls is an effective approach to hemophilic inhibitor ablation.     

轻型血友病假性肿瘤并股神经损伤(附1例报告)

为了探讨血友病假性肿瘤(hemophilic pseudotumor)的诊断与治疗，对临床误诊并手术治疗的1例血友病假性肿瘤患者进行临床观察与分析。结果表明：通过病史及家族史的补充询问、实验室检查结合影像学结果确诊为①血友病A(轻型)；②血友病假性肿瘤并股神经损伤。手术后通过积极的凝血因子补充，伤口愈合良好。结论：详细询问病史、重视实验室检查结果可减少血友病假性肿瘤误诊和误治；重视术前准备可减少术中出血危险性，并能促进术后伤口的早期愈合。