Alhossain Khalafallah

Iron Deficiency Anaemia in Pregnancy and Postpartum: Pathophysiology and Effect of Oral versus Intravenous Iron Therapy

Nutritional iron-deficiency anaemia (IDA) is the most common disorder in the world, affecting more than two billion people. The World Health Organizations global database on anaemia has estimated a prevalence of 14% based on a regression-based analysis. Recent data show that the prevalence of IDA in pregnant women in industrialized countries is 17.4% while the incidence of IDA in developing countries increases significantly up to 56%. Although oral iron supplementation is widely used for the treatment of IDA, not all patients respond adequately to oral iron therapy. This is due to several factors including the side effects of oral iron which lead to poor compliance and lack of efficacy. The side effects, predominantly gastrointestinal discomfort, occur in a large cohort of patients taking oral iron preparations. Previously, the use of intravenous iron had been associated with undesirable and sometimes serious side effects and therefore was underutilised. However, in recent years, new type II and III iron complexes have been developed, which offer better compliance and toleration as well as high efficacy with a good safety profile. In summary, intravenous iron can be used safely for a rapid repletion of iron stores and correction of anaemia during and after pregnancy.

A prospective randomized, controlled trial of intravenous versus oral iron for moderate iron deficiency anaemia of pregnancy.

Abstract.  Khalafallah A, Dennis A, Bates J, Bates G, Robertson IK, Smith L, Ball MJ, Seaton D, Brain T, Rasko JEJ Launceston General Hospital (LGH), Australia; University of Tasmania, Australia; and Centenary Institute, University of Sydney, NSW, Australia) A prospective randomized, controlled trial of intravenous versus oral iron for moderate iron deficiency anaemia of pregnancy. J Intern Med 2010; 268: 286–295.

Three-year follow-up of a randomised clinical trial of intravenous versus oral iron for anaemia in pregnancy

Background To date, there are no data available concerning the impact of iron therapy on the long-term well-being and health-related quality of life (HRQoL) in pregnancy. Objective To assess the long-term effect of iron therapy on HRQoL in pregnancy. Design This is a follow-up study conducted between January 2010 and January 2011 of an earlier randomised open-label clinical trial of intravenous and oral iron versus oral iron for pregnancy-related iron deficiency anaemia. We used a modified version of the SF-36 questionnaire together with the original prospective HRQoL data collected during and after pregnancy. Participants and interventions Of the original evaluable 183 pregnant Caucasian women randomised to receive oral iron or a single intravenous iron polymaltose infusion followed by oral iron maintenance, 126 women completed the follow-up HRQoL study. Methods The participants were followed up 4 weeks after treatment, predelivery and postdelivery for a median period of 32 months (range, 26–42) with a well-being and HRQoL questionnaire using a modified SF-36 QoL-survey and child growth charts as set by the Australasian Paediatric Endocrine Group (APEG). Results Patients who received intravenous iron demonstrated significantly higher haemoglobin and serum ferritin levels (p<0.001). There were strong associations between iron status and a number of the HRQoL parameters, with improved general health (p<0.001), improved vitality (physical energy) (p<0.001), less psychological downheartedness (p=0.005), less clinical depression (p=0.003) and overall improved mental health (p<0.001). The duration of breastfeeding was longer (p=0.046) in the intravenous iron group. The babies born in both groups recorded similarly on APEG growth chart assessments. Conclusions Our data suggest that HRQoL is improved until after pregnancy in anaemic pregnant women by repletion of their iron stores during pregnancy. About 80% of the intravenous iron group showed a maintained normal ferritin until delivery with long-term benefits. Further studies to confirm these findings are warranted.

Intravenous ferric carboxymaltose versus standard care in the management of postoperative anaemia: a prospective, open-label, randomised controlled trial

BACKGROUND Despite increasing efforts in perioperative management, postoperative iron deficiency anaemia persists, and few data are available about the management of this condition. In this study, we aimed to determine whether giving postoperative intravenous iron (in the form of ferric carboxymaltose) improved iron stores, haemoglobin concentrations, and outcomes following surgery. METHODS We did a prospective, open-label, randomised, controlled study of patients at two centres (a general hospital and a private health-care centre) in Tasmania, Australia, undergoing elective surgery with functional iron deficiency anaemia (haemoglobin 70-120 g/L and ferritin ≤100 μg/L or iron saturation ≤20%), measured at day 1 postoperatively. Consecutive routine elective surgical patients who were having major orthopaedic surgery, abdominal, and genitourinary surgery, and other surgeries were recruited. Via computer-generated randomisation, patients were randomly assigned (1:1) to either a single dose of intravenous 1000 mg ferric carboxymaltose (intervention group) or standard care, consisting of observation (control group). The primary endpoints were changes in haemoglobin concentrations and iron stores at 4 weeks postoperatively, and the number of transfused units of blood required postoperatively until discharge. Analyses were done on an intention-to-treat basis. This trial is registered with the Australian New Zealand Clinical Trials Registry and the WHO International Clinical Trials Registry platform (number ACTRN12614001261606). FINDINGS Between Dec 17, 2014, and May 7, 2015, we recruited 201 eligible patients, assigning 103 to intravenous ferric carboxymaltose and 98 to standard care only. Baseline mean haemoglobin was 105·5 g/L (SD 13·8) in the standard care group versus 106·2 g/L (11·9) in the ferric carboxymaltose group, improving at 4 weeks to 121·5 g/L (SD 14·5) in the standard group and 130·1 g/L (11·3) in the ferric carboxymaltose group (mean difference of 7·84 g/L, 95% CI 3·79-11·9; p<0·0001 in favour of the ferric carboxymaltose group). Significant improvements in serum iron (5·36 μmol/L, 95% CI 3·62-7·09; p<0·0001), iron saturation (11·40%, 95% CI 8·33-14·50; p<0·0001), and serum ferritin concentrations (468 μg/L, 95% CI 355-582; p<0·0001) were also noted in the ferric carboxymaltose group at 4 weeks compared with standard care, although no differences were noted in transferrin concentrations (0·06 g/L, 95% CI -0·97 to 1·09; p=0·62). Fewer transfused blood units were given in the ferric carboxymaltose group (to one of 103 patients [<1%]) than in the standard care group (to five of 98 patients [5%]; incidence rate ratio 0·10; 95% CI 0·01-0·85; p=0·035). No adverse events were observed with ferric carboxymaltose treatment. INTERPRETATION Postoperative intravenous ferric carboxymaltose is a feasible and pragmatic management approach in surgical patients with functional iron deficiency anaemia. Our study suggests that patient blood management guidelines should be updated, incorporating the use of postoperative intravenous iron infusion to optimise patient outcomes. Further trials to assess our approach are warranted. FUNDING Launceston General Hospital, Launceston, TAS, Australia, in affiliation with the University of Tasmania, TAS, Australia.

D-Dimer levels at different stages of pregnancy in Australian women: a single centre study using two different immunoturbidimetric assays.

BACKGROUND To date there is minimal data available on D-Dimer levels at different stages of pregnancy. PATIENTS AND METHODS We prospectively measured D-Dimer levels in 632 consecutive pregnant women from March 2007 to January 2009. The median age of the participants was 31 years (range; 18-42) with a median weight of 78 kilograms (range; 46-137). All subjects were investigated during each trimester with two different immunoturbidimetric assays; D-Dimer PLUS and INNOVANCE D-Dimer. D-Dimer levels were determined using a Sysmex® CA 1500 analyser. RESULTS Our data demonstrate that D-Dimer levels in pregnancy show different patterns of rise within the first trimester, depending on the assay used; D-Dimer PLUS=0.88 (SD: mean ratio), INNOVANCE D-Dimer=0.72 (SD: mean ratio). Furthermore, the rise in mean results was greater for the INNOVANCE D-Dimer assay compared to the D-Dimer PLUS assay as shown by the ratio of third to first trimester results of 3.68 and 1.96 respectively. Both D-Dimer assays demonstrated moderate levels of intra-subject variability, with overall mean CVs of 16.5% (D-Dimer PLUS) and 16.9% (INNOVANCE D-Dimer). Furthermore, we studied the association between D-Dimer levels and occurrence of diseases of pregnancy. For both assays, there was no consistently interpretable evidence of an association between raised mean D-Dimer levels or rising D-Dimer levels and any of the diseases or conditions associated with pregnancy. CONCLUSION Our data suggest that the INNOVANCE D-Dimer assay increases significantly with the advancement of pregnancy, and is more sensitive than D-Dimer PLUS assay in the pregnant population.

Assessment of whole body MRI and sestamibi technetium-99m bone marrow scan in prediction of multiple myeloma disease progression and outcome: a prospective comparative study

Objectives This study aims primarily to determine whether whole body MRI (WB-MRI) and Sestamibi Technetium-99m-bone marrow (MIBI) scans in the same patients produce the same estimate of disease load and location, and secondly, to study possible association between the bone disease detected by these scans and the effect on disease outcome and survival. Bone disease occurs in about 90% of multiple myeloma (MM) patients. There are no data comparing the new diagnostic modalities with WB-MRI and MIBI in MM. Design A prospective comparative study between WB-MRI and MIBI scans in assessing bone disease and outcome of MM. Participants and methods Sixty-two consecutive patients with confirmed MM underwent simultaneous WB-MRI (both axial T1 and turbo spin echo short tau inversion recovery (STIR)) and MIBI scans at a single institution from January 2010 to January 2011, and their survival status was determined in January 2012. The median age was 62 years (range 37–88) with a male-to-female ratio of 33 : 29. Results In vertebrae and long bones, MRI scan detected more disease compared with MIBI scan (p<0.001) but there was less difference in the skull (p=0.09). In the ribcage, the MIBI scan detected more lytic lesions of the ribs compared with MRI scan (p<0.001). Thirteen of the 62 patients died during the 24-month follow-up. Increased disease detected in all bones by both scans was associated with increased mortality risk (MIBI p=0.001; MRI-STIR p=0.044; but not MRI-T1 p=0.44). In all combined bone groups, the mean MIBI scan results provided a better prediction of mortality than MRI scan over the follow-up period (MRI-T1 vs MIBI p=0.019; MRI-STIR vs MIBI p=0.047). Conclusions Although WB-MRI detected more MM bone disease, MIBI scan predicted overall disease outcome and mortality better than MRI scan. Further studies to define optimum use of these imaging techniques are warranted. Trial registration number The study was registered prospectively in the Australian and New Zealand Clinical Trials Registry at http://www.ANZCTR.org.au under No: ACTRN12609000761268.

Successful Treatment with Thrombopoietin Receptor Agonist in Avoiding Splenectomy for Patients with Chronic Refractory Immune Thrombocytopenia

Background Chronic immune thrombocytopenia (ITP) is a condition associated with significant morbidity; however the management options are often unsatisfactory with a portion of patients exhibiting a refractory-relapsing disease path despite various lines of treatment including splenectomy. As a thrombopoietin receptor agonist, eltrombopag (GlaxoSmithKline, Australia) provides a novel treatment option for patients with refractory disease. We describe the outcomes of four patients with chronic ITP, who were treated with eltrombopag as a single agent. Methods Four Caucasian patients with chronic refractory ITP (2 males; 2 females) were enrolled in this study with a mean age of 48 years (range, 39–59). All patients were non-splenectomised and were refractory to several lines of treatment including steroids, intravenous immunoglobulin, vincristine, and azathioprine, one patient has also received rituximab (a monoclonal antibody that binds the CD20 antigen expressed by B-lymphocytes). All patients were treated with oral eltrombopag (50–75 mg) for a median period of 12 months (range, 9–16). Results After a median follow up of 20 months (range, 11–34), platelet counts recovered to normal levels in two patients. One recovered a normal platelet count after 13 months, the other 34 months of completion of treatment with eltrombopag. No additional immune suppressive therapy was required. The other two patients also discontinued eltrombopag at 27 and 11 months after achievement of satisfactory platelet counts above 30/nL without any bleeding complications. Other forms of immune therapy were also ceased in these two cases. None of the four patients required splenectomy. Conclusion The clinical outcomes in this small cohort of patients suggests that eltrombopag may have a role to play in the long term control of chronic ITP whilst avoiding splenectomy and long term immunosuppressive therapy. The beneficial outcomes in our patients led to a sustained elevation in platelets with no adverse effects noted when used for relatively longer periods than previously reported. It is worth noting that spontaneous remission does occur with ITP and is the most likely cause for the favourable outcome with eltrombopag therapy. However, if eltrombopag is able to reduce the need for splenectomy in patients with chronic ITP then a distinct quality of care outcome can be achieved by avoiding the recognised short- and long-term complications of splenectomy. Randomised controlled trials with long-term follow up are warranted.

Glycosylated haemoglobin for screening and diagnosis of gestational diabetes mellitus

Objectives The oral glucose tolerance test (OGTT) is a cumbersome test that is time consuming, labour intensive and often poorly tolerated by pregnant women. To date, glycosylated haemoglobin (HbA1c) is the most accepted measure of chronic glycaemia outside of pregnancy. HbA1c is an uncomplicated test, less time consuming, does not require any specific patient preparation and is considered straightforward compared with the OGTT. Therefore, we prospectively tested the utility of the HbA1c when used as a screening tool in pregnancy for gestational diabetes mellitus (GDM). Settings Primary health care. Single tertiary referral centre, Tasmania, Australia. Participants A direct comparison between HbA1c levels and the OGTT results in pregnant women, tested concurrently at the 24–28 gestational week, was undertaken. A full profile of 480 pregnant women during the period from September 2012 to July 2014 was completed. Median and mean age of participants was 29 years (range 18–47 years). Interventions A simultaneous prospective assessment of HbA1c versus standard OGTT in a cohort of consecutive pregnant women presenting to our institute was performed. Results The number of women who had GDM according to OGTT criteria was 57, representing 11.9% of the evaluated 480 pregnant women. Using a cut-off value for HbA1c at 5.1% (32 mmol/mol) for detecting GDM showed sensitivity of 61% and specificity of 68% with negative predictive value (NPV) of 93%, versus sensitivity of 27% and specificity of 95% with NPV of 91% when using HbA1c cut-off value of 5.4% (36 mmol/mol). Conclusions Our results suggest that pregnant women with an HbA1c of≥5.4% (36 mmol/mol) should proceed with an OGTT. This may result in a significant reduction in the burden of testing on both patients and testing facility staff and resources. Further investigations are required to integrate and optimise the HbA1c as a single, non-fasting, screening tool for GDM. Trial registration number ACTRN12611000739910.

Early Application of High Cut-Off Haemodialysis for de-Novo Myeloma Nephropathy is Associated with Long-Term Dialysis-Independency and Renal Recovery.

Background Multiple myeloma (MM) is a haematological malignancy associated with kidney injury resulting from cast nephropathy, which can be caused by monoclonal free light chains (FLC). It has been demonstrated that early reduction of FLC can lead to a higher proportion of patients recovering renal function with a better outcome, especially if high cut-off haemodialysis (HCO-HD) combined with chemotherapy is used. Patients and Methods In this study, four cases with MM nephropathy were treated with HCO-HD and chemotherapy at a single institution during the period from August 2009 to August 2011. All of the patients presented with acute renal failure and high serum FLC. All patients underwent a bone marrow biopsy to confirm the diagnosis of MM, according to the WHO criteria. Three patients had de novo MM and one patient had relapsed light chain myeloma disease. All patients underwent HCO-HD concomitantly with specific myeloma therapy once the diagnosis or relapse of MM was established. Results After a medial follow up of 26 months, (range, 13–36) our data showed that all patients had a significant decrease in serum FLC through HCO-HD, proving the effectiveness of HCO-HD in managing MM. De-novo MM patients restored their renal function and achieved low-level FLC early in the treatment and became dialysis-independent. One patient with relapsed myeloma remained dialysis-dependent. Conclusion In summary, our study suggests that in myeloma nephropathy associated with light-chain MM, HCO-HD should be initiated as early as possible. At the same time a specific MM treatment should be initiated to gain control of the disease and salvage the kidneys in order to achieve dialysis-independency. Further randomized trials to confirm our results are warranted.

Impaired control of the tissue factor pathway of blood coagulation in systemic lupus erythematosus

Thrombosis is a frequent manifestation in patients with systemic lupus erythematosus (SLE), although precise mechanisms remain unclear. This study investigated whether the major physiological trigger of blood coagulation, the tissue factor (TF) pathway, was altered in SLE patients. Furthermore, we investigated potential associations between the TF pathway, the presence of antiphospholipid (APL) antibodies and other abnormalities present in SLE. A total of 101 participants (40 SLE patients and 61 age- and sex-matched controls) were recruited from Tasmania, Australia. Markers of the TF pathway, hypercoagulability, inflammation and endothelial cell damage were measured in plasma. Serum levels of APL antibodies (anti-cardiolipin antibodies [ACL], lupus anticoagulants [LAC], anti-beta2-glycoprotein-1 [anti-β2GP1] and anti-prothrombin antibodies) were also determined. Despite similar TF and TF pathway inhibitor (TFPI) total antigen levels, SLE patients had significantly increased levels of TFPI free antigen (patients vs controls; mean ± SD) (11.6 ± 0.9 ng/mL vs 6.4 ± 0.4 ng/mL; p < 0.001) but significantly reduced TFPI activity (0.66 ± 0.07 U/mL vs 1.22 ± 0.03 U/mL; p < 0.001), compared with healthy controls. Anti-TFPI activity, designated as the ability of isolated IgG fractions to inhibit TFPI activity in normal plasma, was detected in 19/40 (47.5%) of SLE patients and 3/40 (7.5%) of healthy controls. The significant reduction in TFPI activity in SLE patients reflects impaired functional control of the TF pathway. Moreover, SLE patients with a history of thrombosis demonstrated higher levels of TFPI activity compared with patients without a previous thrombotic event (0.97 ± 0.07 U/mL vs 0.53 ± 0.14 U/mL; p = 0.0026). Changes to the TF pathway were not associated with manifestations of SLE such as inflammation or endothelial cell damage. The results from this study suggest hypercoagulability in SLE may (in part) be due to reduced TFPI activity, a mechanism that appears to be independent of other abnormalities in SLE.