The incidence of raised procoagulant factors and hyperhomocysteinaemia in Chinese patients with chronic venous insufficiency.

BACKGROUND: For reasons that are poorly understood, there appear to be differences in the prevalence of chronic venous insufficiency (CVI) and venous thromboembolism between Caucasians and Asians. OBJECTIVES: To compare levels of procoagulant factors and homocysteine (Hcy) in Hong Kong (HK) Chinese and United Kingdom (UK) Caucasian populations of patients with CVI (patients of CEAP clinical stages C4 - C6). METHODS: HK Chinese and UK Caucasian patients with CEAP clinical grade 4-6 venous disease were enrolled. Patients with conditions known to be associated with thrombophilia (TP) were excluded. UK and HK patients were matched by gender, age (within 5 years) and by CEAP clinical grade. All subjects underwent clinical examination, venous duplex ultrasound, and measurement of Hcy and factors (F) VIII, IX and XI. RESULTS: 63 Patients were enrolled in each group: Mean age 64y (HK group); 67y (UK group). 37% were female; 19% had active venous ulceration. One-third of patients in each group had deep venous reflux. High Hcy, FIX and FXI were significantly more common in the UK group. Multiple TP was more common in the UK group: raised levels of >or=2 factors in 26 vs. 14 patients (P = 0.022, chi(2)). Median Hcy (14.3 vs. 10.8 micromol/L; P < 0.0005, Wilcoxon signed rank [WSR]), FIX (131 vs. 115%; P = 0.048), and FXI (114 vs. 97%; P = 0.002) were significantly higher in the UK group. There was no significant difference in FVIII levels. CONCLUSIONS: Raised procoagulant factors were more common in Caucasians compared with Chinese patients with CVI in this study. As with the inherited thrombophilias, the pattern of raised procoagulant factors in Chinese patients appears to differ from that in Caucasians.

A randomised study comparing peripheral blood progenitor mobilisation using intermediate-dose cyclophosphamide plus lenograstim with lenograstim alone.

We conducted a prospective randomised study to compare the efficiency of out-patient progenitor cell mobilisation using either intermediate-dose cyclophosphamide (2 g/m(2)) and lenograstim at 5 micrograms/kg (Cyclo-G-CSF group, n=39) or lenograstim alone at 10 micrograms/kg (G-CSF group, n=40). The end points were to compare the impact of the two regimens on mobilisation efficiency, morbidity, time spent in hospital, the number of apheresis procedures required and engraftment kinetics. Successful mobilisation was achieved in 28/40 (70%) in the G-CSF group vs 22/39 (56.4%) for Cyclo-G-CSF (P=0.21). The median number of CD34+ cells mobilised was 2.3 x 10(6)/kg and 2.2 x 10(6)/kg for G-CSF and cyclo-G-CSF arms following a median of two apheresis procedures. Nausea and vomiting and total time spent in the hospital during mobilisation were significantly greater after Cyclo-G-CSF (P<0.05). Rapid neutrophil and platelet engraftment was achieved in all transplanted patients in both groups. In conclusion, G-CSF at 10 micrograms/kg was as efficient at mobilising progenitor cells as a combination of cyclophosphamide and G-CSF with reduced hospitalisation and side effects and prompt engraftment. When aggressive in-patient cytoreductive regimens are not required to both control disease and generate progenitor cells, the use of G-CSF alone appears preferable to combination with intermediate-dose cyclophosphamide.

Enterovirus infections following T-cell depleted allogeneic transplants in adults.

Anecdotally, enteroviruses have been reported to cause serious complications post BMT, but the exact impact of these viruses in the post transplant period has not been reported. We prospectively evaluated stool, urine and throat samples for enteroviruses by viral culture together with relevant body fluids by RT-PCR in 64 allograft recipients receiving grafts T-cell depleted by Campath-1H, following both conventional and reduced-intensity conditioning. Seven patients (10.4%) developed nine episodes of enterovirus infections at a median of 146 days post transplant. Four episodes were associated with symptomatic illnesses, which could be attributable to enteroviruses. There was no mortality directly related to enteroviruses. There was no correlation between dose and mode of Campath-1H use, lymphocyte recovery, IgG and IgA levels and enterovirus isolation. Although enteroviruses tended to be more frequent in TBI-based conventional conditioning recipients, the only significant risk factor for enterovirus infection was unrelated donor graft. The low incidence of the severe enterovirus infections could have been related to a low lymphocyte count in this cohort in the absence of GVHD, particularly CD4+ count, which has been implicated in tissue damage in experimental animals. Further studies are needed to define its impact in different allograft settings.

Human metapneumovirus in a haematopoietic stem cell transplant recipient with fatal lower respiratory tract disease.

Respiratory viruses are increasingly recognized as a cause of pneumonitis following haematopoietic stem cell transplantation (HSCT). However, frequently, no pathogen is identified in cases of suspected viral pneumonia. Recently, a previously undescribed paramyxovirus, designated 'human metapneumovirus' (hMPV), was isolated from children with respiratory illness. We have detected hMPV as the sole pathogen in the nasopharyngeal aspirate of an HSCT recipient who succumbed to progressive respiratory failure following an upper respiratory prodrome. This report highlights the importance of further studies to elucidate the role of hMPV in causing respiratory illnesses in the HSCT population.

Outpatient management of DVT using low molecular weight heparin and a hospital outreach service.

In recent years there have been several studies comparing the efficacy and safety of low molecular weight (LMW) and unfractionated heparin for the treatment of deep venous thrombosis (DVT), showing them in the clinical trial setting to be equal in these regards. LMWH has the advantage of once daily subcutaneous injection and daily monitoring of levels is not usually required. This has led many centres to develop outpatient treatment strategies for these patients but evidence for the safety of this approach is scarce. In 1997 we developed a hospital outreach service for the treatment of patients with DVT and, in a retrospective study, have compared the outcome in 172 patients treated at home with 172 age, sex and thrombotic risk factor matched inpatients treated at our institution with unfractionated heparin. Five patients in the home treatment group suffered a haemorrhagic event, compared with six patients in the hospital group. One patient in the home treatment group had a recurrent DVT within the first 3 months of treatment; in the hospital-treated group, six patients had recurrent DVTs and nine developed pulmonary emboli. At 3 months, there were three deaths in the home treatment group, compared with five deaths in the hospital group. There was no difference in re-admission rate at 3 months: 23 in the home treatment group, 24 in the hospital-treated group. Average length of hospital stay for the home-treatment group was 2.1 days and 12 days for the hospital group. Warfarin control was found to be significantly better in those patients treated at home, and only 18% of patients treated in hospital received heparin according to hospital guidelines. In conclusion, outpatient management of patients with DVT using LMWH is as safe as hospitalization and continuous infusion of unfractionated heparin. The complication rate was lower in the home treatment group and, in particular, the incidence of recurrent thrombosis was significantly less in the home treatment group. In addition, warfarin control was better when managed by specialist nurses. Patients expressed a preference for home treatment.

Central retinal vein occlusion and thrombophilia.

Central retinal vein occlusion is one of the commonest vascular diseases of the eye. The pathogenesis is multifactorial with both local factors and systemic diseases being aetiologically important. Many thrombophilic conditions have recently been identified and studies looking at their potential role in CRVO have been undertaken. The aim of this review is to critically appraise these studies as to date many have given conflicting results, making it far from clear what role thrombophilic conditions play in CRVO. It appears that hyperhomocysteinaemia and antiphospholipid syndrome are causes of CRVO and there is evidence that disorders causing hypofibrinolysis may also be important. The common hereditary thrombophilic conditions however do not appear to be strong risk factors but larger studies are needed for a definitive answer.

Respiratory virus infections in adult T cell-depleted transplant recipients: the role of cellular immunity.

BACKGROUND: Little is known about the role of cellular immunity in respiratory virus infections after bone marrow transplantation. METHODS: Forty allograft recipients T-cell depleted with Campath antibodies were evaluated for respiratory virus infections in an active surveillance program with early initiation of antiviral therapy. RESULTS: Eighteen episodes of respiratory virus infection were detected in nine patients (22%) at a median of 95 days, with lower respiratory involvement in 44%. Fourteen episodes were treated with antiviral therapy for 7 to 46 days, with 11% mortality. Respiratory virus infections were more common in patients receiving Campath 100 mg in vivo, but delayed CD4+ recovery was the most significant risk factor. CONCLUSIONS: Respiratory virus infections are common and often recurrent in patients with severe CD4+ T lymphopenia. However, the mortality was low, which may have been due to early institution of antiviral treatment or reduced inflammatory damage to the lungs due to severe lymphopenia.

Role for CCG-trinucleotide repeats in the pathogenesis of chronic lymphocytic leukemia.

Chromosome 11q deletions are frequently observed in chronic lymphocytic leukemia (CLL) in association with progressive disease and a poor prognosis. A minimal region of deletion has been assigned to 11q22-q23. Trinucleotide repeats have been associated with anticipation in disease, and evidence of anticipation has been observed in various malignancies including CLL. Loss of heterozygosity at 11q22-23 is common in a wide range of cancers, suggesting this is an unstable area prone to chromosome breakage. The location of 8 CCG-trinucleotide repeats on 11q was determined by Southern blot analysis of a 40-Mb YAC and PAC contig spanning 11q22-qter. Deletion breakpoints in CLL are found to co-localize at specific sites on 11q where CCG repeats are located. In addition, a CCG repeat has been identified within the minimal region of deletion. Specific alleles of this repeat are associated with worse prognosis. Folate-sensitive fragile sites are regions of late replication and are characterized by CCG repeats. The mechanism for chromosome deletion at 11q could be explained by a delay in replication. Described here is an association between CCG repeats and chromosome loss suggesting that in vivo "fragile sites" exist on 11q and that the instability of CCG repeats may play an important role in the pathogenesis of CLL.

Pre-emptive oral ribavirin therapy of paramyxovirus infections after haematopoietic stem cell transplantation: a pilot study.

Infections with the paramyxoviruses, respiratory syncytial virus (RSV) and parainfluenza virus (PIV) can result in serious morbidity and mortality after haemopoietic stem cell transplant (HSCT). Once pneumonia develops, the outcome of these infections is often poor despite anti-viral therapy. Aerosolised ribavirin has been evaluated as pre-emptive therapy for post-transplant RSV infections with some success. Due to the financial and logistic burden involved with the use of aerosolised ribavirin, we explored the efficacy and toxicity of oral ribavirin for pre-emptive therapy of post-transplant RSV and PIV infections in a dose escalating schedule (15-60 mg/kg/day). Five episodes each of RSV and PIV were treated in seven patients. Five patients were receiving treatment for GVHD and two acquired the infection in the pre-engraftment period. All the episodes of RSV infection improved with oral ribavirin with dose escalation to 30-45 mg/kg in three of them. On the other hand, only two of the five PIV infections improved with oral ribavirin. Of the three non-responders, two infections were acquired in the pre-engraftment period with one death from PIV pneumonia. Reversible anaemia was the only side-effect noted in patients treated for over 2 weeks. Thus, the use of oral ribavirin was well tolerated in the post-transplant period with no untoward toxicities. There was a trend towards better response in RSV infections, which needs to be further explored in controlled studies.

Cidofovir as primary pre-emptive therapy for post-transplant cytomegalovirus infections.

Pre-emptive antiviral therapy for CMV infection following allogeneic stem cell transplantation is an effective strategy for preventing CMV disease. This entails the logistic difficulty of daily intravenous therapy with ganciclovir or foscarnet to clinically asymptomatic patients. Cidofovir (CDV) is effective against CMV in vitro and has the practical advantage of weekly administration. However, there are limited data on the pre-emptive use of CDV in CMV infections. We carried out a pilot study exploring the efficacy and toxicity of CDV as primary pre-emptive therapy for CMV infections monitored by PCR-based assays. CDV was used at 5 mg/kg with probenecid and hydration, weekly for a maximum of 4 weeks, followed by fortnightly maintenance treatment. Four patients were treated with CDV and two of them responded. Both the non-responders developed CMV disease. There was no renal toxicity noted in any of the patients, but three patients had severe vomiting and one developed uveitis, which precluded maintenance treatment in the two responders. Following failure of CDV, foscarnet was effective in controlling the CMV infection in both patients, although the infection recurred in both. Thus, larger randomised studies are required before CDV can be recommended as a primary pre-emptive therapy for post-transplant CMV infections.

Philadelphia-positive T-ALL in a patient with follicular lymphoma.

Follicular lymphoma is a B cell malignancy prone to transformation into a large cell diffuse histology. This progression may be multi-clonal as determined by IgH rearrangement. Similar multi-clonal occurrences have been described in immunocompromised patients. However, the lymphoma cells remain predominantly of B cell type. Rarely, composite lymphomas with diffuse T cell histology have been reported arising from follicular lymphoma. The development of T cell leukaemia in a patient with a pre-existing B cell malignancy is an extremely rare event. The occurrence of T cell acute lymphoblastic leukaemia (T-ALL) following follicular lymphoma (FL) has not previously been reported. We report a case of Philadelphia positive (Ph+) T cell ALL developing in a patient who previously had FL which may give some insight into the cell of origin and the defects responsible for malignant transformation of the lymphocytes.

Adenovirus infections following haematopoietic cell transplantation: is there a role for adoptive immunotherapy?

Adenovirus has been recognised as an important pathogen in BMT recipients, especially in patients with GVHD and those receiving T cell-depleted allografts. We report adenovirus infections from an ongoing surveillance study in four patients after a non-myeloablative transplant and their improved outcome following withdrawal of immunosuppression in two patients and donor lymphocyte infusion for relapsed disease in the others. We discuss the control of adenovirus infections following immune manipulations and the feasibility of adoptive immunotherapy for post-transplant adenovirus infections.

Respiratory failure during induction chemotherapy for acute myelomonocytic leukaemia (FAB M4Eo) with ara-C and all-trans retinoic acid.

We report two cases of acute myeloid leukaemia FAB classification M4Eo with high white cell counts at presentation, who developed acute respiratory failure with pulmonary infiltrates on chest radiograph soon after commencing conventional cytotoxic chemotherapy plus all-trans retinoic acid (ATRA). We suggest that in patients with M4Eo ATRA should be used with caution, perhaps delaying its commencement until the white cell count is < 10 x 109/l.

Isolation of viruses from stools in stem cell transplant recipients: a prospective surveillance study.

We prospectively examined stool specimens for enteric viruses in 75 stem cell transplant recipients (autologous 48, allogeneic 27) to determine the frequency and significance of these infections. Only six patients (8%) had a positive isolate. Five of these were allograft recipients (18%) compared to one autograft recipient (2%) (P = 0.02). Unrelated donor BMT recipients were at the highest risk for a viral isolate (OR = 10.5). Adenovirus was the commonest isolate (four patients). One patient each had an echovirus, enterovirus and small round structured virus identified. No correlation was found between the severity of gastro-intestinal symptoms and detection of a viral pathogen. There was no correlation with GVHD or CMV status. The only risk factor identified for isolation of an enterovirus was allogeneic BMT from an unrelated donor. There was a negative correlation with PBSC grafts. All the patients infected with an enteric virus had concomitant infection with other pathogens, compared to only 18% of uninfected patients (P = 0.001). The non-relapse mortality of the infected patients was 50% and only 7% in the uninfected patients (P = 0.01, OR = 12.5), although the isolated virus was the direct cause of death in one patient only. This study indicates a low rate of enteric virus isolation in recipients of PBSC grafts, both autologous and allogeneic. However, unrelated donor BMT is associated with a higher risk of enteric virus infection and an adverse outcome. Bone Marrow Transplantation (2000) 25, 277-282.

Trained nurses can obtain satisfactory bone marrow aspirates and trephine biopsies.

AIMS: To assess the feasibility of training nurse practitioners to perform bone marrow aspiration and trephine biopsy, and to compare the quality of these samples with those obtained by medical staff. METHODS: A retrospective audit was undertaken of nurse practitioner and medical staff performance in bone marrow procedures in a busy haematology day unit. RESULTS: Nurse practitioners fared favourably in comparison with medical staff in performing bone marrow trephine biopsies, with mean biopsy lengths of 11 mm and 10.7 mm respectively. However, only 78% of the smears obtained by the nurses were judged technically satisfactory, compared with 91% prepared by doctors. This discrepancy was thought to be due largely to the quality of slide spreading. CONCLUSIONS: With motivated staff and a structured educational and training programme it is possible for nurse practitioners to perform the techniques of bone marrow aspiration and biopsy, and obtain specimens of satisfactory quality, thus improving efficiency of the haematology day unit and increasing quality of patient care.

Fulminant adenovirus hepatitis following unrelated bone marrow transplantation: failure of intravenous ribavirin therapy.

Fulminant hepatic failure due to adenovirus infection is a rare complication following stem cell transplantation. We report this complication in an unrelated bone marrow transplant recipient 30 weeks post-transplant. Treatment with intravenous ribavirin was started within 36 h of admission, but he succumbed to unusually fulminant hepatic failure. Adenovirus type 2 was isolated from stool surveillance samples and from post-mortem liver samples. Adenovirus DNA was detected by PCR in blood and sputum samples at admission and was identified in post-mortem liver tissue by electron microscopy. Implications of the failure of ribavirin therapy are discussed.

The sequential analysis of trisomy 12 in B-cell chronic lymphocytic leukaemia.

In this longitudinal study we evaluated the clinical significance of screening for trisomy 12 by fluorescence in situ hybridization (FISH) and correlated these findings with survival, disease progression and need for treatment. Interphase FISH was performed on 85 patients in 1993/94 and repeated on 41 patients in 1996/97. Over the 4-year period there was no significant change in the percentage of trisomic cells, even in patients with disease progression. Overall survival and requirement for treatment were similar for patients with and without FISH-defined trisomy 12.

Tinzaparin as an antithrombotic: an overview.

Tinzaparin is a low molecular weight heparin which is given subcutaneously once daily without the need for laboratory monitoring. Already established as effective therapy for deep venous thrombosis, in November 1997 it became the first low molecular weight heparin to be licensed for the treatment of pulmonary embolism.