Episodic replacement of clotting factor concentrates does not prevent bleeding or musculoskeletal damage - the MUSFIH study.

PATIENTS AND METHODS: A longitudinal study was carried out in 255 children from 10 centres in nine developing countries over 5 years to assess the musculoskeletal outcome of children on episodic factor replacement. Outcome was documented by assessment of the annual joint bleeding rate (AJBR), WFH clinical and Pettersson radiological joint scores as well as the FISH score for activities. Of the 203 patients for whom data was available at the end of 5 years, 164 who had received only episodic treatment are included in this report. RESULTS: The median age at the beginning of the study was 10 years (IQR 7-12). The median clotting factor concentrate (CFC) usage was 662 IU kg-1 year-1 (IQ range: 280-1437). The median AJBR was 10 (IQ range: 5-17). The median AJBR was higher in the older children with the median being 5 for the 5 year old child, while it was 9 for the 10 year old and 11 for children older than 15. Given the episodic nature of the replacement therapy, those with a higher AJBR used significantly greater annual CFC doses (P < 0.001); The median change in WFH clinical score and Pettersson radiological score over the 5 years was 0.4/year for each, while the FISH deteriorated at a rate of 0.2/year with poor correlation of these changes with CFC dose. WFH and FISH scores were significantly worse in those with an AJBR of >3 per year (P = 0.001). The change in the Pettersson score was significantly more in those with an AJBR of >5 per year (P = 0.020). Significant changes in FISH scores were only noted after 10 years of age. CONCLUSION: Episodic CFC replacement over a large range of doses does not alter the natural course of bleeding in haemophilia or the musculoskeletal deterioration and should not be recommended as a long term option for treatment. Prophylaxis is the only way to preserve musculoskeletal function in haemophilia.

Musculoskeletal evaluation in severe haemophilia A patients from Latin America.

There is a paucity of literature on haemophilia treatment in Latin American countries, a region characterized by rapidly improving systems of care, but with substantial disparities in treatment between countries. The aim of this study was to evaluate the musculoskeletal status of haemophilia patients from Latin America and to examine the relationship between musculoskeletal status and treatment practices across countries. The Committee of Latin America on the Therapeutics of Inhibitor Groups conducted a survey of its member country representatives on key aspects of haemophilia treatment in 10 countries. Musculoskeletal status of patients was obtained during routine comprehensive evaluations between March 2009 and March 2011. Eligible patients had severe haemophilia A (factor VIII <1%) without inhibitors (<0.6 BU mL(-1) ) and were ≥5 years of age. Musculoskeletal status was compared between three groups of countries, based primarily on differences in the availability of long-term prophylaxis. Overall, 143 patients (5-66 years of age) were enrolled from nine countries. In countries where long-term prophylaxis had been available for at least 10 years (Group A), patients aged 5-10 years had significantly better mean World Federation of Hemophilia clinical scores, fewer target joints and fewer affected joints than patients from countries where long-term prophylaxis has been available for about 5 years (Group B) or was not available (Group C). In Latin America, the musculoskeletal status of patients with severe haemophilia without inhibitors has improved significantly in association with the provision of long-term prophylaxis. As more countries in Latin America institute this practice, further improvements are anticipated.

Necrosis avascular de cabeza y cuello de fémur en un paciente con sida / Avascular osteonecrosis of femoral head and neck in an AIDS patient

Avascular osteonecrosis (AON) has increased in the last few years in patients infected with the human immunodeficiency virus type-1 (HIV-1). The most commonly affected bone is the femoral head and neck. Frequently these bilateral and clinical findings include moderate to severe pain and functional impotence of the affected joints. The etiology is multifactorial and highly active antiretroviral therapy (HAART) with protease inhibitors (PI) is probably related to its development. In the evolution, a total hip replacement may be needed. We present an hemophilic patient with AIDS, who developed a bilateral AON of the femoral head and neck during HAART.(AU)

La osteonecrosis avascular (ONA) es una complicación que se describe con frecuencia creciente en pacientes infectados por el virus de la inmunodeficiencia humana tipo-1 (HIV-1). En su localización más común compromete la cabeza y cuello del fémur con dolor e impotencia funcional, en una o ambas caderas. Su etiología es multifactorial y la terapia antirretroviral de alta eficacia (HAART) con inhibidoresde proteasa (IP) puede estar relacionada con la patogenia. En su evolución puede requerir el reemplazo total de la cadera con la colocación de una prótesis. Se presenta un paciente hemofílico, HIV-1 seropositivo, quedesarrolló una ONA bilateral de cabeza y cuello de fémur mientras se encontraba bajo HAART.(AU)

Necrosis avascular de cabeza y cuello de fémur en un paciente con sida / Avascular osteonecrosis of femoral head and neck in an AIDS patient

Avascular osteonecrosis (AON) has increased in the last few years in patients infected with the human immunodeficiency virus type-1 (HIV-1). The most commonly affected bone is the femoral head and neck. Frequently these bilateral and clinical findings include moderate to severe pain and functional impotence of the affected joints. The etiology is multifactorial and highly active antiretroviral therapy (HAART) with protease inhibitors (PI) is probably related to its development. In the evolution, a total hip replacement may be needed. We present an hemophilic patient with AIDS, who developed a bilateral AON of the femoral head and neck during HAART.

La osteonecrosis avascular (ONA) es una complicación que se describe con frecuencia creciente en pacientes infectados por el virus de la inmunodeficiencia humana tipo-1 (HIV-1). En su localización más común compromete la cabeza y cuello del fémur con dolor e impotencia funcional, en una o ambas caderas. Su etiología es multifactorial y la terapia antirretroviral de alta eficacia (HAART) con inhibidoresde proteasa (IP) puede estar relacionada con la patogenia. En su evolución puede requerir el reemplazo total de la cadera con la colocación de una prótesis. Se presenta un paciente hemofílico, HIV-1 seropositivo, quedesarrolló una ONA bilateral de cabeza y cuello de fémur mientras se encontraba bajo HAART.

HCV recovery from peripheral blood mononuclear cell culture supernatants derived from HCV-HIV co-infected haemophilic patients with undetectable HCV viraemia.

Hepatitis C viraemia, in 38 human immunodeficiency virus positive (HIV+)/hepatitis C virus positive (HCV+) patients, was determined in haemophilic patients during the 4 years since initiation of highly active antiretroviral therapy (HAART). Six of 38 patients had persistently HCV-negative viraemia for more than 2 years. No correlation between HCV-negative viraemia and CD4+ T-cell counts, HIV viral load, age, type or severity of haemophilia could be established. Reduced levels of HIV viral load and the immune reconstitution that follows the initiation of HAART were not enough to explain the disappearance of HCV from plasma. Individuals who cleared plasma HCV had significantly higher CD8+ T-cell counts (P=0.0013) (mean +/- SE: 1153 +/- 117.8 cells microL(-1)) than those with HCV-positive viraemia (819.1 +/- 40.72 cells microL(-1)). Because HCV could maintain a low replication level in peripheral blood mononuclear cells (PBMC), we cultured PBMC of five of six patients with undetectable HCV viraemia. We found four of five HCV RNA-positive cultures. The presence of HCV RNA in our cultures proved that these cells may be an important viral reservoir that could contribute to HCV recurrence in plasma even after long periods of negative viraemia. In summary, our results indicate that in spite of prolonged HCV-negative plasma viraemia, HCV patients that are co-infected with HIV may harbour replication-competent HCV in their PBMC. Therefore, true clearance of HCV infection is difficult to achieve in these patients.

Prophylaxis in developed and in emerging countries.

The significant progress made in recent years in the safety and efficacy of both plasma-derived and recombinant factor concentrates has allowed treatment programmes to be developed that go beyond the simply curative or the treatment of the consequences of the disease (episodic or on-demand treatment), enabling the criteria of preventative medicine to be applied to congenital bleeding disorders. The aim of these programmes is to achieve constant, minimum levels of factor in patients above 1 or 2%, thereby converting severe haemophilia into moderate haemophilia.

Chemical synoviorthesis with rifampicin in haemophilia.

Rifampicin is an antibiotic that has been currently used for the treatment of noninfectious articular lesions with satisfactory results. The first experience was performed with patients who presented rheumatoid arthritis, and later with haemophilic patients. The clinical experience of three haemophilia centres which used rifampicin for the treatment of chronic haemophilic synovitis is presented here. The protocols were different. It was observed that rifampicin is more effective when it is used in small joints (elbows and ankles), than when used in bigger ones (knees), and that a high number of injections predicts failure. Mention is also made of experimental studies in animals where it was shown that the healing pattern of rifampicin is similar to that of NSAIDs.

[Cerebrospinal fluid viral load in HIV-1 positive hemophilic patients treated with HAART]. / Carga viral en líquido cefalorraquídeo de pacientes hemofilicos HIV-1 positivos bajo tratamiento con HAART.

As HIV seropositive patients with undetectable CSF viral load have a lower likelihood of developing neurologic disease, the determination of CSF viral load levels may be useful to evaluate the efficacy of HAART. We compared plasma viral load levels with HIV-1 RNA CSF levels in 18 hemophilic patients without neurocognitive involvement under HAART. We detected a significant correlation between plasma viral load levels and CSF viral load levels. Fourteen patients with undetectable plasma viral load had undetectable RNA HIV-1 CSF levels as well. Four patients with detectable plasma viral load had detectable HIV-RNA in CSF, but the latter were significantly lower. Viral load is usually lower in non-blood fluids and HAART decreases the viral load in CSF as well as in blood.

Carga viral en líquido cefalorraquídeo de pacientes hemofilicos HIV-1 positivos bajo tratamiento con HAART. / [Cerebrospinal fluid viral load in HIV-1 positive hemophilic patients treated with HAART]

As HIV seropositive patients with undetectable CSF viral load have a lower likelihood of developing neurologic disease, the determination of CSF viral load levels may be useful to evaluate the efficacy of HAART. We compared plasma viral load levels with HIV-1 RNA CSF levels in 18 hemophilic patients without neurocognitive involvement under HAART. We detected a significant correlation between plasma viral load levels and CSF viral load levels. Fourteen patients with undetectable plasma viral load had undetectable RNA HIV-1 CSF levels as well. Four patients with detectable plasma viral load had detectable HIV-RNA in CSF, but the latter were significantly lower. Viral load is usually lower in non-blood fluids and HAART decreases the viral load in CSF as well as in blood.

Extensor supracondylar femoral osteotomy as treatment for flexed haemophilic knee.

The experience with extensor supracondylar femoral osteotomy as treatment for the flexed haemophilic knee is presented with the description of 19 patients treated during a 30-year period (1968-98). The average age of the patients was 16 (8-35 years), and the average age follow-up was 13 years (3-30 years). Six patients had flexion fixed deformity while the rest presented 40 degrees average range of motion (10-75 degrees). In 13 patients a single osteotomy without internal fixation was performed, in one an osteosynthesis with a condylar plate and in five stabilization was achieved by means of Blount staples. Previous surgery was performed in two patients with patello-femoral ankylosis. The osteotomy site was consolidated in every patient and the deformity was corrected. Two bleeding complications were observed: one haemarthrosis and one psoas haematoma. Flexion relapsed in one patient who underwent another procedure after 12 years. One patient presented with a peroneal nerve paralysis; another one a genu recurvartum; which required flexor osteotomy. The extensor supracondylar femoral osteotomy is a procedure that aligns the limb with scarce modification of articular mobility.

Haemophilic synovitis: is rifampicin an alternative?

Rifampicin synoviorthesis has been empirically used for the treatment of haemophilic synovitis for some time. This paper reports on the experience of three Latin American centers with this treatment and compares it with radioactive synoviorthesis results. Chemical synoviorthesis with rifampicin is best indicated in younger patients (< 15 years) and small joint (ankles and elbows).

Increased CD4-positive monocytes in HIV-infected haemophilic patients.

The monocyte-macrophage system is known to play a central role in HIV infection, and expression of CD4 on the surface of monocytes/macrophages is important, since this molecule is a key factor for the entrance of HIV into susceptible cells. In this paper we evaluated the expression of CD4 in monocytes of haemophilic patients (He) who had been infected with HIV (HIV + He) through transfusion of contaminated plasma concentrates. Thirty seropositive patients (HIV + He), 10 seronegative He patients (HIV-He) and 20 voluntary normal blood donors were studied. Phenotypic evaluation of monocytes was performed by flow cytometry of peripheral blood stained with anti-CD45, -CD3, -CD4 and -CD14 monoclonal antibodies. The percentage of CD4 monocytes was increased in all HIV+ patients groups, but it was highest in those belonging to Groups III and IV A of the CDC classification. Furthermore, the median of fluorescence intensity of CD4+ monocytes from individual patients was shifted to the right, indicating expression of increased numbers of CD4 molecules on the cell membrane of monocytes. This could in turn favour HIV infection and viral persistence, facilitating in vivo dissemination of the virus.

Hepatitis C (HCV) genotype and viral titer distribution among Argentinean hemophilic patients in the presence or absence of human immunodeficiency virus (HIV) co-infection.

Hepatitis C (HCV) infection is frequent among hemophilic patients treated with non-inactivated factor-concentrates. Both HCV genotype and viral load have been suggested to be important prognostic markers of disease progression and treatment outcome. In addition, co-infection with the human immunodeficiency virus (HIV) has been associated with increased level of HCV replication and higher risk of developing liver failure. Thus, HCV genotype, viral load, and HIV co-infection are important factors in HCV infection. Using restriction fragment length polymorphism analysis (RFLP) and the branched-DNA (bDNA) assay, we retrospectively investigated the HCV genotypes and viral loads present in 59 Argentinean hemophiliacs, in the presence or absence of HIV infection. HCV genotype 1 was the predominant viral variant detected among HIV-negative (HIV-) (76%) and HIV-positive (HIV+) (82.5%) patients, followed by genotypes 3 (10.4%), 2 (2%) and a small proportion of multiply co-infected patients including genotypes 4 and 5 (6.25%). HIV+ patients had higher plasma HCV RNA levels than HIV- patients (88.4 +/- 16.5 x 10(5) Eq/ml vs. 24.7 +/- 10(5) Eq/ml) (P < 0.001); however, no correlation between HCV replication and level of immune suppression, evaluated by CD4+ T-cell measurement, was observed among HIV+ patients (r = 0.017). Abnormal and higher ALT levels were more frequently detected among HIV+ (93%; 123.6 +/- 15.7 U/liter) than HIV- (41%; 70.2 +/- 24.2 U/liter) patients (P < 0.001; P < 0.05). Although we were able to confirm previous reports suggesting the existence of increased HCV replication in HIV/HCV co-infected hemophiliacs, our data did not support the conclusion that HIV-induced immune suppression is directly responsible for this phenomena. It is possible that other factors induced by HIV are responsible for the increased levels in HCV replication observed.

PIP: Hepatitis C virus (HCV) infection is widespread among hemophiliacs treated with non-inactivated factor concentrates. The HCV genotypes and viral loads present in 59 hemophiliacs from Argentina were investigated through use of restriction fragment length polymorphism analysis and the branched DNA assay. 30 subjects were also infected with HIV. In both HIV-positive and HIV-negative hemophiliacs, HCV genotype 1 was the predominant viral variant (82.5% and 76%, respectively), followed by genotypes 3 and 2. HIV-positive hemophiliacs had significantly higher mean HCV viral loads than HIV-negative hemophiliacs; however, there was no association between HCV replication and the level of immune suppression as evaluated by CD4 T-cell measurement. Although HCV replication was increased in individuals co-infected with HCV and HIV, the data did not support the hypothesis that HIV-induced immune suppression is directly responsible for this finding. A study currently underway is investigating a possible correlation between infecting HCV genotype or pre-existing viral load and the severity of disease as assessed by liver histology or treatment outcome.

Anti-factor VIII inhibitors and lupus anticoagulants in haemophilia A patients.

In a study of 170 haemophilia A patients, 43 were found to have an inhibitory effect; seven had anti-factor VIII inhibitors (a-fVIII)(A), 18 had lupus anticoagulants (LAs) with a strong (B: 12) or weak (C: 6) time-dependent effect and 18 had no time-dependent LAs (D). The a-fVIII showed a neutralizing effect only against factor VIII and negative diluted Russell viper venom time (dRVVT). The LAs were diagnosed by dRVVT; the Staclot LA agreed with the dRVVT. During the study, three patients changed from an a-fVIII to an LA pattern; they also modified their clinical response. Our prevalence of a-fVIII was low (4%) and we found 21% of LA, with a high (50%) prevalence of time-dependent inhibition. This pattern raises the possibility of the coexistence of LA and a-fVIII, stressing the need to develop specific tests to identify a-fVIII and LA.

Chemical synovectomy vs. radioactive synovectomy for the treatment of chronic haemophilic synovitis: a prospective short-term study.

Between January 1992 and December 1994, a prospective study was performed in two centres comparing chemical synovectomy using repeated weekly injections (range, 1-17) of Rifampicin (Group R) vs. radioactive synovectomy using 1-2 injections of Yttrium-90 (Group Y). The study was performed on 38 joints in a total of 35 haemophilic patients suffering from chronic haemophilic synovitis unresponsive to 3 months of conservative treatment (substitution therapy with the deficient coagulation factor plus a rehabilitation protocol). Group R included 18 patients with an average age of 9 years, with an average follow-up time of 25 months. In Group R, 19 joints were treated: nine knees, four elbows and six ankles. Group Y included 17 patients with an average age of 18 years, with an average follow-up time of 23 months. In Group Y, 19 joints were treated: 14 knees, two elbows and three ankles. The joints were evaluated according to the frequency of bleeding episodes and the Pettersson radiographic score. On the basis of the radiographic scale at the time of the synoviortheses, the joints were categorized as stage I (0 points), stage II (1-2 points), stage III (3-7 points), stage IV (8-10 points) and stage V (11-13 points). The overall results showed that in Group R, bleeding decreased in 12 joints, remained the same in six and worsened in one. In Group Y, bleeding decreased in 11 joints, remained the same in seven and worsened in one. In both Groups, bleeding was controlled best if joints were in stages I and II. In stages III, IV and V, synoviorthesis should not be carried out in haemophilia because it is not effective. Use of radioactive substances in persons under the age of 9 years has been discouraged in the past and therefore only Rifampicin was used in this age group. However, in patients over 9 years of age, this study showed similar decrease of bleeding in both treatment groups. Taking into account the advantages and disadvantages of both agents, we suggest the use of Rifampicin in elbows and ankles but prefer Yttrium-90 for the knees.

[Concurrence of cytochemical and immune patterns of different cell lines in cases of acute leukemia]. / Concurrencia de marcación citoquímica e inmune de diferentes linajes celulares en casos de leucemias agudas.

Mixed, bilineal, biclonal and hybrid leukemias are synonymous, differing from biphenotypical ones. Mixed acute leukemia is defined by the coincidence of 1) two cytochemical markers of different lineage, or 2) one of them with more than one opposite immunological marker, or 3) more than one immunological marker opposite to another immunological lineage. Seven cases of mixed acute leukemia are presented, two of which showed posttreatment switching. It is concluded that mixed acute leukemias are associated with a poor prognosis, and therapeutic criteria are defined.