M. Greaves

Thrombophilia in pregnancy: a systematic review

Growing evidence suggests that thrombophilia is associated with venous thromboembolism (VTE) and adverse pregnancy outcomes. However, methodological limitations have made it difficult to obtain a clear overview of the overall risks. We conducted a systematic review to determine the risk of VTE and adverse pregnancy outcomes associated with thrombophilia in pregnancy. The effectiveness of prophylactic interventions during pregnancy was also evaluated. Major electronic databases were searched, relevant data abstracted and study quality assessed by two independent reviewers. Odds ratios (ORs) stratified by thrombophilia type were calculated for each outcome. A total of 79 studies were included in our review. The risks for individual thrombophilic defects were determined for VTE (ORs, 0·74–34·40); early pregnancy loss (ORs, 1·40–6·25); late pregnancy loss (ORs, 1·31–20·09); pre‐eclampsia (ORs, 1·37–3·49); placental abruption (ORs, 1·42–7·71) and intrauterine growth restriction (ORs, 1·24–2·92). Low‐dose aspirin plus heparin was the most effective in preventing pregnancy loss in thrombophilic women (OR, 1·62). Our findings confirm that women with thrombophilia are at risk of developing VTE and complications in pregnancy. However, despite the increase in relative risk, the absolute risk of VTE and adverse outcomes remains low. There is also a lack of controlled trials of antithrombotic intervention to prevent pregnancy complications. Thus, at present, universal screening for thrombophilia in pregnancy cannot be justified clinically.

Guidelines on the investigation and management of antiphospholipid syndrome

This guidance updates and replaces the previous guideline on the investigation and management of antiphospholipid syndrome (APS) published in 2000 (Greaves et al, 2000), though where there have not been changes we refer back to them when appropriate. The guidance is updated with reference to relevant publications since 2000. Publications known to the writing group were supplemented with additional papers identified by searching PubMed for publications in the last 11 years using the key words: lupus anticoagulant, anticardiolipin, antiphospholipid, b2–glycoprotein I, antiprothrombin and limits (clinical trial, randomized control trial, meta-analysis, humans, core clinical journals, English language). The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. The guideline was then reviewed by a sounding board of approximately 50 UK haematologists, the Royal College of Obstetricians and Gynaecologists (RCOG), and the British Committee for Standards in Haematology (BCSH) Committee and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found at http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMEN DATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with antiphospholipid syndrome though individual patient circumstances may dictate an alternative approach.

Clinical guidelines for testing for heritable thrombophilia

Trevor Baglin, Elaine Gray, Mike Greaves, Beverley J. Hunt, David Keeling, Sam Machin, Ian Mackie, Mike Makris, Tim Nokes, David Perry, R. C. Tait, Isobel Walker and Henry Watson Addenbrooke’s Hospital, Cambridge, NIBSC, South Mimms, University of Aberdeen, Aberdeen, Guy’s and St Thomas’, London, Churchill Hospital, Oxford, University College Hospital, London, Royal Hallamshire Hospital, Sheffield, Derriford Hospital, Plymouth, Glasgow Royal Infirmary, Glasgow and Aberdeen Royal Infirmary, UK

Guidelines on the assessment of bleeding risk prior to surgery or invasive procedures

Unselected coagulation testing is widely practiced in the process of assessing bleeding risk prior to surgery. This may delay surgery inappropriately and cause unnecessary concern in patients who are found to have ‘abnormal’ tests. In addition it is associated with a significant cost. This systematic review was performed to determine whether patient bleeding history and unselected coagulation testing predict abnormal perioperative bleeding. A literature search of Medline between 1966 and 2005 was performed to identify appropriate studies. Studies that contained enough data to allow the calculation of the predictive value and likelihood ratios of tests for perioperative bleeding were included. Nine observational studies (three prospective) were identified. The positive predictive value (0·03–0·22) and likelihood ratio (0·94–5·1) for coagulation tests indicate that they are poor predictors of bleeding. Patients undergoing surgery should have a bleeding history taken. This should include detail of previous surgery and trauma, a family history, and detail of anti‐thrombotic medication. Patients with a negative bleeding history do not require routine coagulation screening prior to surgery.

Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study

Combined oral contraceptives, oral hormone replacement therapy and thrombophilias are recognised risk factors for venous thromboembolism in women. The objective of this study was to assess the risk of thromboembolism among women with thrombophilia who are taking oral contraceptives or hormone replacement therapy, conducting a systematic review and metaanalysis. Of 201 studies identified, only nine met the inclusion criteria. Seven studies included pre-menopausal women on oral contraceptives and two studies included peri-menopausal women on hormone replacement therapy. For oral contraceptive use, significant associations of the risk of venous thromboembolism were found in women with factor V Leiden (OR 15.62; 95%CI 8.66 to 28.15); deficiencies of antithrombin (OR 12.60; 95%CI 1.37 to 115.79), protein C (OR 6.33; 95%CI 1.68 to 23.87), or protein S (OR 4.88; 95%CI 1.39 to 17.10), elevated levels of factor VIIIc (OR 8.80; 95%CI 4.13 to 18.75); and factor V Leiden and prothrombin G20210A (OR 7.85; 95%CI 1.65 to 37.41). For hormone replacement therapy, a significant association was found in women with factor V Leiden (OR 13.16; 95%CI 4.28 to 40.47). Although limited by the small number of studies, the findings of this study support the presence of interaction between thrombophilia and venous thromboembolism among women taking oral contraceptives. However, further studies are required to establish with greater confidence the associations of these, and other, thrombophilias with venous thromboembolism among hormone users.

Screening for thrombophilia in high-risk situations: a meta-analysis and cost-effectiveness analysis

Laboratory testing for the identification of heritable thrombophilia in high‐risk patient groups have become common practice; however, indiscriminate testing of all patients is unjustified. The objective of this study was to evaluate the cost‐effectiveness of universal and selective history‐based thrombophilia screening relative to no screening, from the perspective of the UK National Health Service, in women prior to prescribing combined oral contraceptives and hormone replacement therapy, women during pregnancy and patients prior to major orthopaedic surgery. A decision analysis model was developed, and data from meta‐analysis, the literature and two Delphi studies were incorporated in the model. Incremental cost‐effectiveness ratios (ICERs) for screening compared with no screening was calculated for each patient group. Of all the patient groups evaluated, universal screening of women prior to prescribing hormone replacement therapy was the most cost‐effective (ICER £6824). In contrast, universal screening of women prior to prescribing combined oral contraceptives was the least cost‐effective strategy (ICER £202 402). Selective thrombophilia screening based on previous personal and/or family history of venous thromboembolism was more cost‐effective than universal screening in all the patient groups evaluated.

Expression of interleukin‐1β and tumour necrosis factor‐α in plasma cells from patients with multiple myeloma

Interleukin‐1β (IL‐1β) and tumour necrosis factor‐α (TNF‐α) are potent bone resorbing cytokines that may contribute to the development of the osteolytic bone disease observed in patients with multiple myeloma (MM). Although these factors have been identified in cultures of bone marrow mononuclear cells isolated from patients, the identity of the cells responsible for producing IL‐1β and TNFα remains unclear. Using a sensitive dual‐colour fluorescence in situ hybridization (FISH) technique and a two‐colour immunofluorescence method we have investigated the expression of the mRNA and protein, for IL‐1β and TNFα, by individual bone marrow plasma cells from patients with MM and monoclonal gammopathy of undetermined significance (MGUS). The mRNA for IL‐1β and TNFα was identified in all cells expressing the immunoglobulin light chain from all patients with MM and MGUS. However, the IL‐1β protein could not be detected in cytoplasmic light chain positive cells in any of the patients examined. In contrast, the TNFα protein was detected in clonal plasma cells from patients with both MM and MGUS. Interestingly, the IL‐1β and TNFα mRNA and proteins were readily detected within a small proportion of the non‐plasma cells from patients with both MM and MGUS. These data suggest that myeloma cells in vivo are able to produce TNFα but not IL‐1β. In addition, a small proportion of accessory cells are likely to be able to contribute to the production of both IL‐1β and TNFα.

Platelet activation is increased in peripheral arterial disease

OBJECTIVE Platelet activation was assessed in patients with peripheral arterial disease compared with healthy control subjects. METHODS This prospective comparative study included 100 subjects: 40 consecutive patients with intermittent claudication, 20 consecutive patients with critical ischemia and tissue loss, and 40 healthy control subjects. Whole blood flow cytometric analysis was performed to determine resting and stimulated platelet P-selectin expression and resting and stimulated platelet fibrinogen binding. Results are presented as platelet percentage and also as mean fluorescence intensity. RESULTS P-selectin expression was significantly increased in patients with intermittent claudication (median, 0.85%; range, 0.31%-4.77%; P =.023) and critical ischemia (median, 1.11%; range, 0.2%-3.26%; P =.028) compared with control subjects (median, 0.59%; range, 0.16%-4.58%). The percentage of platelets binding fibrinogen was also significantly higher in patients with intermittent claudication (median, 2.89%; range, 1.08%-9.59%; P <.001) compared with control subjects (median, 1.57%; range, 0.17%-10.7%). There was no significant difference in percentage of platelet fibrinogen binding between control subjects and patients with critical ischemia. Fibrinogen binding by stimulated platelets was significantly diminished in patients with critical limb ischemia compared with control subjects (67.2% vs 77.9%; P =.006). CONCLUSIONS Platelet activation is increased in patients with peripheral arterial disease, suggesting an underlying prothrombotic state. Platelets from patients with critical limb ischemia are less responsive to in vitro stimulation.

Lupus anticoagulant testing: improvements in performance in a UK NEQAS proficiency testing exercise after dissemination of national guidelines on laboratory methods

Summary. Laboratory screening for lupus anticoagulant (LA) has been shown to be suboptimal in several studies. Guidelines have recently been published by an expert group for the British Committee for Standards in Haematology, in an attempt to standardize and improve screening procedures. The value of using screening tests conforming with these guidelines was investigated in a United Kingdom National External Quality Assessment Scheme (UK NEQAS) proficiency testing exercise. The correct diagnosis was achieved by 97% of laboratories for a LA‐negative sample. However, 18·3% of centres reported a false‐negative result for a sample from a LA‐positive subject. A significantly higher proportion of centres that used methods conforming with the published guidelines achieved the correct diagnosis for this sample (P < 0·002, chi‐square test). A wide variety of screening tests were used by laboratories in this study. Within‐method agreement could be improved by the use of a common normal pooled plasma to determine ratios. However, between‐method agreement was not improved by this procedure. We conclude that adoption of methods compliant with national guidelines may improve the diagnosis of LA. There is a need, however, for reference and standardization materials to ensure further improvement in the accuracy of LA methods.

Can we predict bleeding

The prior identification of subjects who are likely to bleed excessively when subjected to operative surgery and other invasive procedures is desirable. Frequently, reliance is placed on laboratory-based screening tests of blood coagulation for this purpose. However, published evidence does not support this approach as the tests are not fit for purpose, and their sensitivity and specificity are low. Some more global assays may have use in the diagnostic workup in subjects with hemorrhage, but none has been established to date as an efficient method for prediction of bleeding in unselected populations. There is renewed interest in the use of the clinical history for the prediction of bleeding. Recent reports suggest that when a structured questionnaire is employed to derive a bleeding score, the positive predictive value of the approach for the detection of bleeding disorders is high.