L. A. Parapia

The rare coagulation disorders – review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation

Summary.  The rare coagulation disorders are heritable abnormalities of haemostasis that may present significant difficulties in diagnosis and management. This review summarizes the current literature for disorders of fibrinogen, and deficiencies of prothrombin, factor V, FV + VIII, FVII, FX, the combined vitamin K‐dependent factors, FXI and FXIII. Based on both collective clinical experience and the literature, guidelines for management of bleeding complications are suggested with specific advice for surgery, spontaneous bleeding, management of pregnancy and the neonate. We have chosen to include a section on Ehlers‐Danlos Syndrome because haematologists may be consulted about bleeding manifestations in such patients.

A review of inherited platelet disorders with guidelines for their management on behalf of the UKHCDO

The inherited platelet disorders are an uncommon cause of symptomatic bleeding. They may be difficult to diagnose (and are likely to be under‐diagnosed) and pose problems in management. This review discusses the inherited platelet disorders summarising the current state of the art with respect to investigation and diagnosis and suggests how to manage bleeding manifestations with particular attention to surgical interventions and the management of pregnancy.

Waldenström macroglobulinemia. Development of diagnostic criteria and identification of prognostic factors.

To establish whether a combination of morphologic and immunophenotypic criteria could be developed to more precisely define Waldenström macroglobulinemia (WM) and prognostic factors, we retrospectively assessed the clinical and laboratory features of 111 cases of WM. Bone marrow infiltration by small lymphocytes was documented in each case; and diffuse, interstitial, nodular, and paratrabecular patterns of infiltration were documented in 58%, 32%, 6%, and 4% of cases, respectively. Ninety percent were characterized by a surface immunoglobulin-positive, CD19+CD20+CD5-CD10-CD23- immunophenotype. The median overall survival from diagnosis was 60 months; univariate analysis revealed the following adverse prognostic factors: older than 60 years, performance status more than 1, platelet count less than 100 x 10(3)/microL (< 100 x 10(9)/L), pancytopenia, and diffuse bone marrow infiltration. Associated median survival was 40, 38, 46, 28, and 59 months, respectively. Multivariate analysis revealed age, performance status, and platelet count as prognostically significant, but stratification of patients according to the International Prognostic Index had limited value. We suggest defining WM by the following criteria: IgM monoclonal gammopathy; bone marrow infiltration by small lymphocytes, plasmacytoid cells, and plasma cells in a diffuse, interstitial, or nodular pattern; and a surface immunoglobulin-positive, CD19+CD20+CD5-CD10-CD23- immunophenotype.

Transient and persistent expansions of large granular lymphocytes (LGL) and NK‐associated (NKa) cells: the Yorkshire Leukaemia Group study

Summary. A survey of 870 different adult blood samples (primarily from patients with non‐haematological disorders) found that 269 (31%) had increased proportions (>25%) and/or absolute numbers (>1.0 × 109/l) of morphologically‐defined large granular lymphocytes (LGL), and/or pheno‐typically‐defined NK‐associated (NKa) cells. Of these, 112 were re‐analysed at least 6 months after initial presentation and were classified as‘persistent’(92/112) or ‘transient’(20/112) according to whether or not the original abnormality was still present. Lymphocyte counts in most patients with persistent abnormalities were within normal limits (18/92) or slightly increased (68/92), with only six having a lymphocytosis exceeding 10.0 × 109/l. With the exception of five persistent LGL expansions in which the granular lymphocytes did not express NKa determinants (designated LGL+NKa‐), the remaining 87 cases could be phenotypically grouped according to their primary abnormality as CD8+NKa+ (n = 33), CD4+ NKa+ (n=14), CD8dim+NKa+ (n=7) or CD8−NKa+ (n=33). TCR genotypic studies in 58 patients showed that the 16 patients with rearranged TCR components were restricted to the CD8+NKa+ group and that, in most of these, the CD8+ fraction showed abnormal relative CD16/CD56 expression. Persistent neutropenia (n=15) also appeared to be associated with primary abnormalities of CD8+NKa+ cells (12/15). with 10 of these additionally showing rearranged TCR genes. In contrast, persistently increased CD8dim+NKa+ and CD8–NKa+ components did not appear to phenotypically differ from their corresponding ‘counterparts’in normal bloods or in patients with transient LGL/NKa+ abnormalities. This survey has therefore established that persistent LGL/NKa+ abnormalities are considerably more common than suggested in published work, that a high proportion of patients with expanded CD8+NKa+ components, with quite diverse clinical histories, show evidence of clonal lymphoid populations, and that the clonal nature of such disorders appears to be associated with abnormal NKa phenotypic patterns.

Trepanning or trephines: a history of bone marrow biopsy.

Trepanning of bone is the oldest known procedure carried out by man and yet it is only in the last 100 years that we have made use of the technique to diagnose and treat haematological disorders. These advances have been made possible by improvements in instruments, techniques, anaesthesia, laboratory processing and the expertise of haematologists to report the specimens. With the advent of immunological markers and molecular biology, the need for quality bone marrow specimens, if anything, has increased. It will be many years before the bone marrow aspiration/trephine procedure is relegated to the annals of history.

A distinct large granular lymphocyte (LGL)/NK-associated (NKa) abnormality characterized by membrane CD4 and CD8 coexpression

Summary. In a study of 870 individual patients with either lymphocytosis (excluding known lymphoproliferative disease), increased proportions of blood lymphocytes with granular morphology (LGL), or neutropenia, 14 cases were found with abnormally increased CD3+CD4+CD8+ components. Eleven of these were further investigated and 10 shown in follow‐up studies to be persistent in nature. Morphological assessments revealed increased LGL in 9/11 cases, and in seven of these > 50% lymphocytes had discernable cytoplasmic granulation. Immunophenotypic studies indicated that CD8 expression by CD4+ lymphocytes in these patients was of low density (CD8dim+), and that both the CD4+CD8− and CD4+CD8dim+ fractions in each patient was characterized by a CD11b+ CD16−CD56+CD57+ composite NK‐associated (NKa) phenotype (in contrast to normal CD4+ CD8− blood lymphocytes and CD4+CD8+ thymocytes which were consistently CD11b−CD16−CD56−CD57−). TCR genotypic studies revealed rearranged components (β plus 7. or β alone) in 5/11 cases, but there were no obvious relationships between TCR configuration (including rearranged band densities) and immunophenotypes, absolute lymphocyte or neutrophil numbers, the proportions of blood LGL, or the proportions of CD4+ cells coexpressing CD8. The occurrence of identical NKa phenotypic profiles in both germline and rearranged TCR cases does, however, suggest the possiblity of an evolutionary process from a non‐clonal expansion to a clonal state. Serum studies, including soluble CD4. CD8 and IL2‐R concentrations and autoantibody investigations, of representative germline and rearranged TCR cases failed to indicate any consistent abnormalities, but there was some suggestion for the existence of a chronic reactive process in some of the patients with germline TCR. These findings suggest that expanded LGL/NKa+ components with phenotypic evidence of CD4/CD8 coexpression should be regarded as a distinct diagnostic category and that persistent CD4+CD8+ abnormalities with germline TCR should be monitored for possible clonal transition.

Use of recombinant factor VIIa in inherited platelet disorders

We read with interest the recent publication by Almeida et al (2003) and would like to comment on the authors’ observations on the treatment of patients with Glanzmann’s thrombasthenia and Bernard–Soulier syndrome on the basis of our own experience. We have used recombinant factor VIIa (rFVIIa) to treat eight bleeding episodes in three children and one adult with severe disorders of platelet function (Table I). With the exception of a 1-year-old girl with Glanzmann’s thrombasthenia, all patients who had previous moderate to severe bleeding levels required platelet transfusions. We found that two children with Glanzmann’s thrombasthenia responded well to rFVIIa whereas Almeida et al (2003) found variable responses in their Glanzmann’s thrombasthenia patients. Their patient with Bernard–Soulier syndrome also showed variable responses. rFVIIa was ineffective in treating an episode of epistaxis and gum bleeding in one of our patients with Bernard–Soulier syndrome, although the three doses used at that time (60 lg/kg per dose) may have been too low. Our other patient with Bernard–Soulier syndrome has had three severe episodes of menorrhagia. On the first occasion rFVIIa was given within 12 h of the onset of bleeding and resulted in an excellent response; however, in the two other episodes of severe menorrhagia, when rFVIIa was given more than 48 h after the onset of bleeding, the response was either ineffective or bleeding recurred after 24 h. Our experience with this patient would support the observations of Almeida et al (2003) that rFVIIa is less effective in severe bleeding episodes or when there is a delay in administering rFVIIa. Recombinant FVIIa has been shown to be an effective treatment in a number of patients with these disorders and, as pointed out by Almeida et al (2003), there are advantages in using rFVIIa over the more traditional treatment with platelet transfusions. Although, the infection risk associated with platelet transfusion has decreased substantially in recent years, the risk of alloimmunization to platelet antigens remains significant. On the contrary, rFVIIa is a much more expensive form of treatment than platelet transfusion. Platelet function disorders are rare and many types of bleeding can be treated with local measures or antifibrinolytic

Phase II trial of idarubicin in patients with advanced lymphoma

SummaryA phase II trial of idarubicin was performed in 24 patients with advanced lymphoma. The drug was administered in a dose of 10–15 mg/m2 i.v. or 15–70 mg/m2 p.o. (single dose) every 3 weeks. There were four partial responses and four minor responses. All but one of the responders had received prior doxorubicin therapy. The toxicities were myelosuppression, nausea and vomiting, and alopecia. Two patients with compromised cardiac function were observed to have further deterioration in the ejection fraction as measured by gated cardiac scan after idarubicin therapy. Further assessment of the activity of idarubicin against lymphoma is recommended in less heavily pretreated patients. The cardiac toxicity should be carefully monitored in future studies.

Incidence of iron-deficiency anaemia in infants in a prospective study in Jordan.

Abstract: A high prevalence of iron‐deficiency anaemia has been reported in Jordanian infants.A prospective study of infants in downtown Amman examined the relationship between anaemia in pregnancy and iron deficiency in infancy. The iron status of infants born to 107 anaemic (Hb <11 g/dl) and 125 non‐anaemic mothers was reviewed at 3, 6, 9 and 12 months. Indicators to define iron‐deficiency anaemia were Hb <11 g/dl and either plasma ferritin <12 μg/l or zinc protoporphyrin (ZPP) >35 μg/dl whole blood. Haemoglobin electrophoresis excluded haemoglobinopathy. There was 72% iron‐deficiency anaemia throughout the year, significantly higher in infants born to anaemic mothers (81%; n=91) compared with controls (65%; n=112). At 12 months, 72% of the infants tested (n=195) were anaemic. While 57% were identified as iron‐deficient by research criteria of either ferritin or ZPP, only 37% were identified by ferritin alone, 40% by ZPP alone and 29% if both ferritin and ZPP were required to meet criteria. Most infant anaemia was identified as due to iron deficiency, supporting contextual setting as assisting diagnosis: infants in developing countries are recognised as vulnerable to iron deficiency. Using multiple criteria, more cases were identified when either ferritin or ZPP were abnormal than when one alone, or both parameters were required to meet research criteria.

Successful oral chemotherapy with idarubicin in refractory anaemia with excess blasts

6 patients with refractory anaemia with excess blasts (RAEB) were treated with a new oral anthracycline, idarubicin. 3 patients achieved complete remission, and the remaining 3 achieved partial remission. These responses were maintained for 8–60 wk, the longer durations being in the patients who achieved complete remission. Treatment was given on an outpatient basis, and all but 1 patient remained at home for most of the disease course. Unwanted effects were mild. It would thus appear that oral idarubicin is an effective treatment for RAEB, in addition to allowing outpatient management. Larger studies are required for futher evaluation.