Robert Bird

Review article: Coagulation cascade and therapeutics update: Relevance to nephrology. Part 1: Overview of coagulation, thrombophilias and history of anticoagulants

Coagulation involves the regulated sequence of proteolytic activation of a series of zymogens to achieve appropriate and timely haemostasis in an injured vessel, in an environment that overwhelmingly favours an anticoagulant state. In the non‐pathological state, the inciting event involves exposure of circulating factor VII/VIIa to extravascularly expressed tissue factor, which brings into motion the series of steps which results in amplification of the initial stimulus, culminating in the conversion of fibrinogen to fibrin and clot formation. The precisely synchronized cascade of events is counter‐balanced by a system of anticoagulant mechanisms, which serve to ensure that the haemostatic effect is regulated and does not extend inappropriately. Conversely, in pathological states, these events can escape normal control mechanisms, due to either inherited or acquired defects, which lead to thrombosis. Current anticoagulant therapy, although based on medications that have been in existence for upwards of 80 years, is moving towards targeted therapy for specific coagulation factors and events in the coagulation cascade, based on the current knowledge of the main triggers and key events within the series of reactions that culminates in haemostasis. It remains to be seen whether these newer medications will become first‐line therapies for thrombosis in the coming decade. This review aims to elucidate the main events within the coagulation cascade as it is currently understood to operate in vivo, with a brief discussion focusing on hypercoagulable states, and also a short review of the history of anticoagulants as they relate to this model.

Clinical utility of serum soluble transferrin receptor levels and comparison with bone marrow iron stores as an index for iron‐deficient erythropoiesis in a heterogeneous group of patients

Aim: To evaluate the correlation between raised soluble transferrin receptor (sTfR) and stainable marrow iron, and to define the utility of sTfR in discriminating between the presence or absence of iron‐deficient erythropoiesis in patients with anaemia of chronic disease. Methods: Seventy‐six consecutive adult patients without accelerated erythropoiesis who had undergone bone marrow (BM) aspiration/trephine for various clinical reasons during 2003–2006 were studied. All patients had serum iron studies (iron, transferrin and ferritin) and sTfR performed within 1 week of BM aspiration/trephine. These 76 patients were assigned to three groups based on the iron status of the BM and sTfR level: patients with normal sTfR and normal BM iron stores (n = 49), patients with an elevated sTfR and normal BM iron stores (n = 13) and patients reduced or absent BM iron stores (n = 14). Means (95% confidence interval) for mean corpuscular volume (MCV), mean corpuscular haemoglobin concentration (MCHC), red blood cell haemoglobin (RBC Hb) content and median (5th and 95th percentiles) for haemoglobin were then calculated. Results: All patients with absent BM iron stores had an elevated sTfR level. Patients with normal BM iron stores and elevated sTfR levels had significantly lower Hb, MCV, MCHC and RBC Hb content than patients with normal BM iron stores and normal sTfR levels. Conclusion: sTfR is the most sensitive serum biochemical marker for the identification of iron‐deficient erythropoiesis. Normal BM iron stores can coexist with elevated sTfR and decreased MCV and MCHC. sTfR levels correlate better than BM iron stores with decreased MCV and MCHC. Therefore, sTfR is a useful marker of iron‐deficient erythropoiesis, due to both absent iron stores, and restricted iron supply due to anaemia of chronic disease. As a single investigation, however, sTfR does not discriminate between these two causes of iron‐deficient erythropoiesis.

Consensus guidelines on anti-beta 2 glycoprotein I testing and reporting

Consensus guidelines on anti-beta 2 glycoprotein I (anti-beta2GPI) testing have been developed to help minimise laboratory variation in the performance and reporting of assays for these antibodies. These guidelines include minimum and optional recommendations for the following aspects of anti-beta2GPI testing and reporting: (1) isotype of anti-beta2GPI tested; (2) specimen type; (3) controls and assay precision; (4) calibrators; (5) patient samples; (6) rheumatoid factors and IgM anti-beta2GPI testing; (7) reporting of results; (8) cutoff values; and (9) interpretative comments. Issues related to inter-kit/assay standardisation and the manufacturing process of commercial anti-beta2GPI kits/assays have not been addressed in the current guidelines.

Diagnostic and prognostic utility of the serum free light chain assay in patients with AL amyloidosis

Background: Organ dysfunction in AL amyloidosis is related to the production and deposition of amyloidogenic monoclonal light chains. These pathological light chains can now be quantified using the recently developed serum free light chain assay.

Can Thromboelastography performed on kaolin-activated citrated samples from critically ill patients provide stable and consistent parameters?

Thromboelastography (TEG®) is a potentially useful tool but analysis within 4‐6 min of collection imposes limitations on its use and access. The use of citrate blood tubes potentially increases the time frame for processing specimens. There is, however, limited research on the stability of citrate specimens, timing of processing and the accuracy of TEG® results. The purpose of this study was to examine the effects of early and delayed processing on TEG® parameters using kaolin‐activated citrated blood samples in the intensive care population. TEG® analysis was performed on 61 patients. Blood was collected into two 3.2% sodium citrate (0.105 m) tubes. Kaolin‐activated samples were analysed at 15, 30 and 120 min postcollection. TEG® parameters analysed included reaction time (R), clot formation time (K), alpha angle (α), maximum amplitude, LY30, the coagulation index, time to maximum rate of thrombus generation, maximum rate of thrombus generation and total thrombus generation. Sixty‐one critically ill patients were included. The results of the anova showed that time from collection was significantly associated with the TEG® results (P < 0.05). On comparison of individual outcome variables, this difference in most cases was due to changes over time from 30 to 120 min. Furthermore, progressive changes in TEG® parameters such as decreasing R were suggestive of a trend toward hypercoagulability of the specimens. Processing of kaolin‐activated citrate TEG® specimens can begin as early as 15 min postvenipuncture. However, delaying processing by more than 30 min leads to a significant change in results.

WT1 expression as a marker of minimal residual disease predicts outcome in acute myeloid leukemia when measured post-consolidation

WT1 levels may be a useful predictor of leukemia free survival (LFS) following treatment of acute myeloid leukemia (AML). We report a retrospective study in which levels of WT1 expression from patients with de novo AML were measured from bone marrow and peripheral blood at diagnosis, post-induction, post-consolidation and relapse. We demonstrate that higher levels of WT1 in peripheral blood at diagnosis are associated with poorer LFS independent of age and cytogenetic risk-group (n=85, p=0.028). When measured at post-consolidation, the presence of detectable WT1 is associated with poorer LFS in univariate analysis of both peripheral blood (p=0.024) and bone marrow (p=0.019). In a multivariate analysis including age and cytogenetic risk, the association remained significant for bone marrow (p=0.016) with a trend observed for peripheral blood (p=0.06). These findings have formed the basis for ongoing research.

Use of rFVIIa for critical bleeding in cardiac surgery: dose variation and patient outcomes

Background and Objectives  Recombinant activated factor VIIa (rFVIIa) is increasingly being used in non‐haemophiliac patients for the treatment of severe bleeding refractory to standard interventions. Optimal dosing regimens remain debated in cardiac surgery. Therefore, this study investigated the use of different rFVIIa dosing practices on response to bleeding and patient outcomes in cardiac surgery patients using data from the Haemostasis Registry.

The oral iron chelator deferasirox inhibits NF‐κB mediated gene expression without impacting on proximal activation: implications for myelodysplasia and aplastic anaemia

The myelodysplastic syndromes (MDS) are a group of disorders characterized by ineffective haematopoiesis, bone marrow dysplasia and cytopenias. Failure of red cell production often results in transfusion dependency with subsequent iron loading requiring iron chelation in lower risk patients. Consistent with previous reports, we have observed haematopoietic improvement in a cohort of patients treated with the oral iron chelator deferasirox (DFX). It has been postulated that MDS patients have a pro‐inflammatory bone marrow environment with increased numbers of activated T cells producing elevated levels of tumour necrosis factor (TNF), which is detrimental to normal haematopoiesis. We demonstrate that DFX inhibits nuclear factor (NF)‐κB dependent transcription without affecting its proximal activation, resulting in reduced TNF production from T cells stimulated in vitro. These results suggest that the haematopoietic improvement observed in DFX‐treated patients may reflect an anti‐inflammatory effect, mediated through inhibition of the transcription factor NF‐κB and support the therapeutic targeting of this pathway, which is aberrantly activated in a large proportion of haematological malignancies.

A study of atypical APTT derivative curves on the ACL TOP coagulation analyser

Introduction:  The graphical representation of clotting data can provide useful information. A novel feature of the ACL TOP software allows display of clot reaction curves with superimposed first and second derivative curves. We noted atypical derivative plots associated with normal ‘S’‐shaped clot reaction curves in some abnormal activated partial thromboplastin time (APTT).

When should iron chelation therapy be considered in patients with myelodysplasia and other bone marrow failure syndromes with iron overload

Despite the absence of a robust evidence base, there is growing consensus that effective treatment of iron overload leads to decreased morbidity and premature mortality in patients with good prognosis myelodysplastic syndromes (MDSs). Furthermore, new treatment modalities, including disease‐modifying therapies (lenalidamide and azacytidine) and reduced intensity conditioning therapies for allogeneic blood stem cell transplants, are offering the prospect of longer survival for patients with traditionally less favourable prognosis MDS, who might also benefit from iron chelation. This article proposes assessment of patients with MDS and related bone marrow failure syndromes to determine suitability for iron chelation. Iron chelation therapy options and monitoring are discussed.