Platelet Rich Plasma for Chronic Synovitis Treatment in Patients with Haemophilia.

INTRODUCTION: Haemophilic synovitis is caused by chronic accumulation of blood in the joint. Conservative treatment is insufficient to solve this pathology. Platelet-rich plasma (PRP) has a high concentration of growth factors (GFs) that play a key role in regulation and stimulation of healing processes. The aim of this study was to describe the effect of PRP injection in chronic synovitis of the joints in patients with haemophilia (PWH). PATIENTS AND METHODS: Nineteen patients with 28 joints were treated at our centre in Buenos Aires, Argentina between December 2014 and December 2015. Eighteen were Haemophilia type A (17 severe, one mild) and one was type B severe. Mean age was 26 years old. Chronic synovitis was present in two ankles, seven elbows and 19 knee joints. All affected joints were evaluated for range of motion (ROM), perimeter, Haemophilia Joint Health Score (HJHS), number of bleedings episodes and Visual Analogue Scale (VAS). Evaluations were before treatment and 3 and 6 months after treatment. RESULTS: A mean volume of 4 mL of PRP was injected into the joint cavity. The statistical analysis before and after treatments revealed a statistically significant (P < 0.001) decrease in the HJHS score. Decrease in joint bleeding episodes was also statistically significant (P < 0.001). All patients reported pain relief and VAS scores were statistically significant (P < 0.001). Joint perimeter also showed a statistically significant difference (P < 0.001). No complications were observed in any of the patients, either during blood collection or during PRP injection, even for inhibitor patients. CONCLUSION: Platelet-rich plasma is a useful, safe, and inexpensive treatment for chronic haemophilic synovitis.

Safety and effectiveness of room temperature stable recombinant factor VIIa in patients with haemophilia A or B and inhibitors: Results of a multinational, prospective, observational study.

INTRODUCTION: A room temperature stable formulation of recombinant activated factor VII (NovoSeven® ), allowing convenient storage and therefore improved treatment access, has been developed. Bioequivalence to the previous NovoSeven® was demonstrated in healthy humans, leading to European approval (2008). Although no confirmed cases of neutralising antibodies to rFVIIa in patients with haemophilia A or B have been observed with the original formulation, changes in formulation or storage condition may alter immunogenicity. AIM: SMART-7™ was designed to investigate the safety of NovoSeven® in a real-world setting in patients with haemophilia A or B with inhibitors. METHODS: Study medication was not provided by the sponsor, and treatment was at the discretion of the treating physician, in accordance with the local label. Patient baseline information was collected at enrolment. Information on safety, drug exposure and bleeding episodes was collected and FVII antibody screening was encouraged at baseline and performed at the investigator's discretion. RESULTS: Fifty-one patients were enrolled and 31 completed the study. Forty-one adverse events (AEs) were reported in 23 patients; 25 AEs in 14 patients were serious. No thromboembolic events were observed. Although four cases of reduced therapeutic response were reported, FVII antibody screening was negative. Forty-eight patients experienced 618 bleeding episodes and 93.4% of 609 evaluated bleeds were stopped by treatment. Of the 538 bleeding episodes treated with NovoSeven® monotherapy, 94.2% stopped by end of treatment. CONCLUSION: Data collected during the SMART-7™ study revealed no treatment-related safety issues and no FVII-binding antibodies for patients treated with NovoSeven® under real-world conditions.

Is it possible to use autologous adipose graft for wound repair in patients with coagulation disorders?

INTRODUCTION: Wound healing is an intricate process whereby the skin repairs itself after injury according to a specific sequence: haemostasis, inflammation, proliferation and remodelling. Cell therapy has the potential to improve wound healing conditions and can be applied in both acute and chronic wounds. Normal healing requires adequate haemostatic function. Patients with coagulation disorders whose haemostatic function is altered may not heal naturally. AIM: The aim of this study was to show a simple, safe and inexpensive minimally invasive technique for wound repair in patients with coagulation disorders which involves the use of concentrated autologous adipose cells. PATIENTS AND METHOD: Six patients were enrolled in this study at the Foundation of Haemophilia, in Buenos Aires, Argentina. Five patients had severe haemophilia type A and one had severe von Willebrand diseases. The average age was 37.5 years old. One patient had a retractile scar (RS) and five patients had cutaneous fistulas (CF). Suction was used to obtain autologous adipose graft from subcutaneous abdominal tissue. The graft was centrifuged and, the adipose cell concentrate was transferred to a syringe and injected in the edge of the lesion. RESULTS: One adipose suction in each patient was performed. There were no intraoperative or postoperative complications in any of the six patients. CONCLUSIONS: The application of autologous adipose graft is a simple and safe treatment for complicated wound repair in patients with coagulation disorders.

Treatment of subchondral cysts in patients with haemophilia.

INTRODUCTION: The haemophilic arthropathy is a disabling disease that causes chronic pain and functional limitation, due to recurrent intra-articular bleeding, with impaired quality of life. OBJECTIVE: The aim of this work is to present our 24-year experience in the treatment of subchondral cysts filled with hydroxyapatite coralline in patients with haemophilia. PATIENTS AND METHOD: Thirty-seven male patients with forty-nine cystic lesions were treated and evaluated between 1990 and 2014. Thirty four patients were haemophilia type A, three were haemophilia type B, two patients had inhibitors to factor VIII. The average age was 23.6 years. The average follow-up was 10 years. The lesions were located: twenty-four in the tibia (49%), six in the talus (12.2%), seven in the ulna (14.4%), five in the humerus (10.2%), five in the femur (10.2%) and two in the distal radius (4%). In all patients' radiographs, Computed Tomography and Magnetic Resonance Imaging were performed before surgery. The lesions were treated when the injury was greater than 15% of the joint area, and when the joint area was greater than 1 cm of diameter. Surgical technique consisted of aspirating the cyst contents and refilling it with hydroxyapatite coralline. RESULTS: In forty-eight cysts, restitution of bone structure was achieved by impaction of hydroxyapatite coralline. The average time of bone restoration was 10 months. Only one patient required a second intervention. CONCLUSION: The treatment of subchondral cyst in PWH by aspiration and filling with hydroxyapatite coralline allows bone restoration and delays deterioration of the joint treated.

Epidemiology of fractures in patients with haemophilia.

INTRODUCTION: Haemophilia is an X-chromosome linked inherited bleeding disorder characterised by an anomaly synthesis of coagulation factor VIII (Haemophilia A) or factor IX (Haemophilia B). There is very little information on the magnitude and management of fractures in PWH in the literature regards the advance on replacement therapy. The purpose of this paper is to present our 28 years experience treating PWH who suffered fractures and evaluate the impact of access to treatment. MATERIALS AND METHODS: In the period 1986-2013, 151 fractures in 141 PWH were treated, 125 patients type A (88.7%), 12 type B (8.5%) and 4 (2.8%) with von Willebrand's disease. For the sake of analysis we divided the fractures in five groups: 1986-1990: 25, 1991-1995: 35, 1996-2001: 33, 2002-2007: 31, and 2008-2013: 27; and classified the fractures in lower limb (LL) and upper limb (UL). We also considered the age at which the fractures occurred. RESULTS: However the incidence of presentation of the fractures of the upper limb and lower limb changed through the years, being more frequent in the LL in the first period analysed (76% LL vs. 24% UL) and in the UL in the latter one (63% UL vs. 37% LL), the difference was statically significant (p=0.0168). In the relation with the age, the 1986-1990 cohort vs. 2008-2013 cohort reached statistical significance (p: 0.035). Regarding treatment, 121 fractures were treated in a non invasive way, the others 30 fractures, were treated with internal fixation. The patient treated with internal fixation had less mal-alignment, and delay consolidation. DISCUSSION: This is the largest series of fractures in PWH published. We show a higher incidence of LL fractures in the first period analysed (1986-1990), over time, the ratio LL/UL changed as UL fractures became more frequent. This change is due to the access of the treatment and specifically to the prophylaxis. CONCLUSION: Fractures in PWH have changed their pattern, becoming more common in the UL than in the LL, lowering the age at which they occur and being less frequent. We believe that the advent of new and accessibly treatments, decreased the development of orthopaedic complications and favours the improvement in quality of life of PWH.

Haemophilia pseudotumours in patients with inhibitors.

Development of inhibitors against factor VIII (FVIII) or FIX is the most serious complication of replacement therapy in patients with haemophilia. Haemophilic pseudotumours in a patient with inhibitors can lead to devastating consequences. The aim of this study is to show our experience in the treatment of 10 pseudotumours in 7 patients with inhibitors who were treated by the same multidisciplinary team in the period between January 2000 and March 2013. Seven severe haemophilia A patients were treated at the Haemophilia Foundation in Buenos Aires, Argentina, for 10 pseudotumours. Eight were bone pseudotumours and two soft tissue. All patients underwent imaging studies at baseline to assess the size and content of the lesion. The patients received Buenos Aires protocol as conservative treatment of their pseudotumours for 6 weeks, after which they were evaluated. Only one patient responded to conservative treatment. Surgery was performed on the others six patients, since their pseudotumours did not shrink to less than half their original size. Any bleeding in the musculoskeletal system must be treated promptly in order to prevent pseudotumours. When pseudotumours do appear in inhibitor patients, they can be surgically removed when patients received proper haemostatic coverage, improving the quality of life of these patients.

Phenotype-genotype correlations in hemophilia A carriers are consistent with the binary role of the phase between F8 and X-chromosome inactivation.

BACKGROUND: The recessive X-linked disorder hemophilia A (HA) is rarely expressed in female carriers, most of whom express about half of normal factor VIII activity ( FVIII: C). OBJECTIVE: To propose an integrative assessment model for the binary role of the phase between the mutated F8 and the active X-chromosome (Xa) in FVIII: C in HA carriers. METHODS: We studied 67 females at risk of severe HA, comprising five symptomatic females ( FVIII: C < 1.5 IU dL(-1) ) and 14 controls. A correlation study between FVIII: C (observed vs. expected) and X-chromosome inactivation (XCI) patterns (XIPs; androgen receptor gene [AR] system) in blood leukocyte DNA was performed in carriers, by comparison of a model correlating FVIII: C and XIP with arbitrary models devoid of biological significance, and with FVIII: C levels in non-carriers (mean model) as a proxy from background data dispersion not influenced by XIP. RESULTS: We provide proof-of-concept example from a family presenting with extremely skewed XIPs in which the severe HA phenotype appeared in a heterozygous carrier of a crossover between AR and F8 loci that phased the mutated F8 with the maternally inherited Xa. Furthermore, four cases of severe HA affected women who had a combination of a heterozygous F8 mutation and extremely skewed XIPs in leukocytes or oral mucosa are presented. Correlation analyses between FVIII: C levels and XIPs in carriers (n = 38) but not in non-carriers (n = 20) showed highly significant differences between the proposed correlation model and models without biological significance. The data support a binary influence of XCI, either increasing or decreasing the FVIII: C, subject to the underlying phase set between the F8 mutation and XCI. CONCLUSIONS: Our evidence suggests that the phase between XCI and mutated F8 acts as a molecular switch conditioning FVIII: C levels and HA expression in carriers.

Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: a comprehensive Argentine study of inhibitor risks.

Inhibitor development against exogenous factor VIII is a severe impairment of replacement therapy affecting 18% of Argentine patients with severe haemophilia A (HA). To study the molecular predisposition for inhibitor development, we genotyped 260 HA patients with and without inhibitors, countrywide. The inhibitor-positive population (19 transients, 15 low responders, LR and 70 high responders, HR) of 104 severe-HA patients showed 59 Inv22 (intron 22 inversions), 18 small ins/del-frameshifts, 12 gross deletions, 12 nonsense, one splicing defect and two missense, p.Arg531Pro and p.Leu575Pro, both LR and thought to impair FVIII A2 domain secondary structure. In addition, a patient with mild HA and HR showed the missense p.Glu1704Lys associated with two neutral intronic substitutions potentially affecting the A3 domain. A case/control study (84/143) permitted estimation of F8 genotype-specific inhibitor risks [OR; prevalence (CI)] in severe-HA patients classifying a high-risk group including multi-exon deletions [3.66; 55% (19-100)], Inv22 [1.8; 24% (19-100)] and nonsense in FVIII-LCh [1.2; 21% (7-59)]; an average risk group including single-exon deletions, indel frameshifts and nonsense-HCh; and a low-risk group represented by missense defects [0.14; 3% (0.6-11)]. Analysis of inhibitor concordance/discordance in related patients indicated additional genetic factors other than F8 genotype for inhibitor formation. No significant inhibitor-predisposing factors related to FVIII product exposure were found in age- and F8 genotype-stratified populations of severe-HA patients. In conclusion, the Argentine HA patient series presents similar global and mutation-specific inhibitor risks than the HA database and other published series. This case-specific information will help in designing fitted therapies and follow-up protocols in Argentina.

Elective orthopaedic surgery for haemophilia patients with inhibitors: single centre experience of 40 procedures and review of the literature.

With the introduction of safe and effective factor VIII/IX-bypassing agents--recombinant activated factor VII (rFVIIa) and plasma-derived activated prothrombin complex concentrates (pd-APCC)--elective orthopaedic surgery (EOS) is a viable option for haemophilia patients with inhibitors. We report a series of patients with haemophilia and inhibitors undergoing EOS between 1997 and 2008 using bypassing agents to provide haemostatic cover. All inhibitor patients undergoing EOS and receiving rFVIIa, plasma-derived prothrombin complex concentrates (pd-PCC) or pd-APCC as haemostatic cover were included. Patients were operated on by the same surgeon and were managed by the same haemophilia treatment centre. Forty procedures (25 minor and 15 major) were conducted in 18 patients. Twenty-one minor cases were covered using rFVIIa, three with pd-PCC, and one with pd-APCC; all major cases were covered using rFVIIa. Bleeding was no greater than expected compared with a non-haemophilic population in all 25 minor procedures. In the major procedure group, there was no excessive bleeding in 40% of cases (6/15) and bleeding completely stopped in response to rFVIIa. For the remaining nine cases, bleeding response to rFVIIa was described as 'markedly decreased' or 'decreased' in 4/15 cases and 'unchanged' in 5/15 cases. Overall, efficacy of rFVIIa, based on final patient outcome, was 85%. One death occurred as a result of sepsis secondary to necrotizing fasciitis. Good control of haemostasis can be achieved with bypassing agents in haemophilia patients with inhibitors undergoing minor EOS; rFVIIa was used as an effective bypassing agent, enabling EOS in patients undergoing minor and major procedures.

Guillain-Barre syndrome following 2-chlorodeoxyadenosine treatment for Hairy Cell Leukemia.

A 68-year-old man, with Hairy Cell Leukemia developed a Guillain-Barré syndrome (G-B), 32 days after a single course of 2-Chlorodeoxyadenosine (CDA) at 0,14 mg/k/d, for five days in a two-hour-i.v. infusion and following a febrile neutropenia episode. In order to clarify whether this G-B case was related to an infection or to CDA neurotoxicity, we screened for infection-related autoimmune G-B and for antibodies (abs.) against gangliosides of peripheral nerves. Blood and urinary cultures were negative as well as serum anti-virus abs. However, serum anti-ganglioside abs. were positive for anti-asialo GM1 and anti-Gd1b. This latter finding was consistent with an autoimmune mechanism, not described until now as CDA neurotoxicity. In the present case, we do not have enough evidence to link CDA administration to the G-B syndrome. We think that it is necessary to exclude other causes of neurotoxicity before considering CDA adverse effect.

[DIAGNOSIS AND TREATMENT OF CYCLOSPORA CAYETANENSISINFECTION IN PAEDIATRIC PATIENTS] / Diagnóstico y Tratamiento de Infecciónpor Cyclospora Cayetanensis en pacientes pediátricos.

The study was made to determine the clinical profile and laboratory of 10 paediatric patients whose diagnosis of cyclosporiosis was established by identifying the parasite in fecal matter, through a smear with modified Zehl-Nielsen and incubation in dichromate of potassium. We obtained clinical data form these patients correlating them with absorption tests (digestive activity, sugar reducers and fats in feces.)After treatment with trimethroprim-sulfamethoxazole and nitazoxanide patients were controlled by laboratory exams to determine the existence of the parasite and its viability.