Prevalence of autoantibodies directed against prothrombin in unprovoked venous thromboembolism.

The anti-phospholipid syndrome (APS) is defined by the laboratory detection of at least one of three anti-phospholipid autoantibodies (lupus anticoagulant, or anti-cardiolipin or anti-ß2-glycoprotein I antibodies) in the clinical setting of thrombosis or pregnancy morbidity in a patient. Recognising APS and administering appropriate secondary thromboprophylaxis is important to reduce risk of recurrent thrombosis and/or pregnancy morbidity. In some instances, patients having clinical manifestations highly suggestive of APS are persistently negative for these antibodies but instead have other autoantibodies. Autoantibodies directed against prothrombin (PT) have been associated with increased thrombotic risk and comprise anti-prothrombin (aPT) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies. Detection of aPT and aPS/PT may help stratify patients for more effective treatment, however, their prevalence among patients with unprovoked venous thromboembolism (VTE) is unknown and determination of their frequencies is the objective of this study. Sera from 148 patients with unprovoked VTE were analysed. Autoantibodies directed against PT collectively, aPT and aPS/PT were present in 24.3%, 14.9% and 13.5%, respectively. Prevalence of these autoantibodies in unprovoked VTE is much lower compared to cohorts comprising mainly patients with systemic autoimmune disorders. Detection of these autoantibodies in unprovoked VTE has potential therapeutic implications for patients including the duration of anticoagulation and administration, or otherwise, of direct oral anticoagulants. Data from this study will assist in the design of future clinical studies to estimate risk of recurrent VTE and to determine optimal management.

Prevalence and causes of preoperative anaemia in elective major surgery patients.

BACKGROUND: Preoperative anaemia is associated with increased morbidity and mortality in surgical patients. Recent national patient blood management guideline recommended screening surgical patients for anaemia, particularly iron deficiency anaemia, without reference to the prevalence of anaemia or iron deficiency anaemia in this patient population. AIMS: To establish the prevalence and cause of preoperative anaemia in elective major surgery patients. METHODS: Patients attending the anaesthetic pre-admission clinics from 1 July 2013 to 30 June 2014 prior to their major elective surgery in our institution were screened for anaemia and iron deficiency by measuring full blood count, iron studies and C-reactive protein. Patients who were anaemic were either further assessed in the haematology clinic or had their medical records reviewed to ascertain the cause of the anaemia. RESULTS: Of 1494 patients, 208 (13.9%) were anaemic, with a male predominance (70.7%); 57 (27.4%) of them had iron deficiency anaemia. Other common causes of anaemia include underlying malignancy (18.3%), end-stage renal failure (11.5%) and other chronic diseases (7.2%). In 53 patients (25.5%), the cause was unknown. Anaemia was most commonly found in patients scheduled for gastrointestinal surgery. CONCLUSION: Preoperative anaemia affects 13.9% of patients undergoing elective major surgery. The most common causes are iron deficiency and chronic diseases. The cause was unexplained in 25.5% of patients with anaemia. The prevalence of anaemia in different surgical specialties may have implications on the approach to screening, particularly in resource-limited areas.

Dose-adjusted arsenic trioxide for acute promyelocytic leukaemia in chronic renal failure.

OBJECTIVE: To determine the potential for arsenic trioxide (ATO) to be safely and effectively incorporated into induction therapy of newly diagnosed acute promyelocytic leukaemia (APL) in patients with severe chronic renal failure (CRF) by reduction of the ATO dosage to compensate for reduced renal elimination of arsenic in CRF. PATIENTS AND METHODS: Two of the four CRF patients with APL in the study were dialysis-dependent, and two had eGFRs of 18 and 19 mL/min/1.73 m(2) . ATO dosage schedules were adjusted to obtain comparable whole-blood arsenic levels to those in APL patients with normal renal function who achieved molecular remission (MR) while receiving 10 mg ATO daily for 28 d. RESULTS: Average ATO administered per day in CRF patients ranged from 36 to 50% of the ATO administered to APL patients with normal renal function. No clinically significant cardiac, hepatic or other toxicities were detected. RT-PCR-negative MR was achieved after one treatment course in two patients and after two courses in the others. Relapse-free survival is 155, 60, 43 and 5 months. CONCLUSION: The observations in this pilot study have demonstrated whole-blood arsenic levels can provide a guide to adjustments of ATO dosage schedules that permit safe and effective therapeutic outcomes in APL patients with severely compromised renal function.

Management of very high risk pregnancy with secondary anti-phospholipid syndrome and triple positivity to the anti-phospholipid antibodies.

There is a significantly increased risk of pregnancy complications in women with anti-phospholipid syndrome (APS). The risk is further heightened in those with previous arterial or venous thromboembolism and so-called 'triple positivity' for anti-phospholipid antibodies (i.e., when lupus anticoagulant, and anti-cardiolipin (aCL) and anti-ß2 glycoprotein-I (anti-ß2Gp-I) antibodies are all detected). Management of these cases is extremely difficult and little is available in the medical literature to guide therapy. This report describes the use of regular plasma exchanges (PEx) to bring about a successful pregnancy outcome in a woman with secondary APS and previous recurrent miscarriages. The patient was also anticoagulated with enoxaparin and administered aspirin, prednisolone, azathioprine and hydroxychloroquine. Through regular PEx and immunomodulation therapy, levels of aCL and anti-ß2Gp-I antibodies were monitored and documented to fall as pregnancy progressed. Although the outcome in this case was successful, further experience is required before this regimen can be accepted as the standard of care for these patients at very high risk of pregnancy loss.

Should adult patients be routinely tested for heritable thrombophilia after an episode of venous thromboembolism?

The clinical usefulness of laboratory testing of adult patients with venous thromboembolism (VTE) for heritable thrombophilia needs to be critically evaluated. At present, some clinicians use testing to identify patients at higher risk of recurrence (who may benefit from an extended period of anticoagulation beyond the usual 3-6 months) and their relatives at risk of a first VTE episode. As prevalence of heritable thrombophilia is related to age and ethnic origin, the pretest probability of detecting heritable thrombophilia may be low in unselected populations. Interpretation of laboratory results may not be straightforward. Apparent deficiencies of a natural anticoagulant may be due to acute thrombosis and "consumption", concomitant therapy with heparin and/or warfarin and other clinical factors. The predictive value of recurrent VTE conferred by the most common types of heritable thrombophilia (factor V Leiden and the G20210A prothrombin mutation) is limited. Risk of recurrence associated with deficiencies of a natural anticoagulant is less certain due to their rarity. Clinical risk factors (eg, the presence or otherwise of provoking factor(s) and whether or not the risk factor for VTE is reversible or permanent) appear to be the most important predictors of VTE recurrence. Duration of anticoagulation should be determined by clinical risk factors rather than the presence, or otherwise, of heritable thrombophilia. The benefit of identifying relatives who are carriers of thrombophilia is uncertain, as VTE is a multifactorial disease resulting from the interaction of various risk factors, some well recognised and others as yet unknown.

Low prevalence of antiannexin A5 antibodies in unprovoked venous thrombosis.

INTRODUCTION: The antiphospholipid syndrome (APS) is characterized by thrombosis or pregnancy morbidity, and the detection in the blood of at least one of three antiphospholipid antibodies (lupus anticoagulant, or anticardiolipin or anti-ß2 -glycoprotein I antibodies). Diagnosing APS is important so that secondary prophylaxis may be administered to reduce risk of recurrent thrombosis and/or pregnancy morbidity. In addition to APS-defining antibodies, there may be additional autoantibodies that have a role in thrombosis and/or pregnancy morbidity. Furthermore, some patients have clinical manifestations highly suggestive of APS but are persistently negative for the APS-defining antibodies ("seronegative APS") and instead, have other autoantibodies. Antiannexin A5 (aANXA5) autoantibodies have been associated with increased risk of thrombosis and pregnancy morbidity; levels are also reportedly higher in patients with venous thrombosis compared with healthy controls. The prevalence of aANXA5 among patients with unprovoked venous thrombosis is not well-documented and determination of the frequency of aANXA5 is the objective of this study. METHODS: We analysed sera from 148 patients with unprovoked venous thrombosis who had undergone routine laboratory testing for the present APS-defining antibodies. RESULTS: aANXA5 IgG and IgM were present in 6% and 1%, respectively. CONCLUSION: Prevalence of these antibodies in unprovoked venous thrombosis is comparable with frequencies reported in healthy individuals and is far lower than the prevalence in women with pregnancy morbidity. This may indicate lack of association with venous thrombosis, however, adequately powered case-control studies will be required to resolve this and prevalence data from this study will assist in the design of such studies.

Pitfalls in the assessment of disseminated intravascular coagulation in patients on dabigatran.

Dabigatran is an orally administrated anticoagulant that directly inhibits thrombin. However, the drug can affect routine coagulation tests such as prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time (TT), as well as haemostasis assays, (e.g., clot-based coagulation factor assays). There are limited data on the effect of dabigatran on some fibrinogen measurements and on D-dimer assays, both important components in the laboratory assessment of disseminated intravascular coagulation (DIC). The objectives of this study were: (1) to determine the effects of various concentrations of dabigatran on fibrinogen and D-Dimer assays; and (2) to compare the von Clauss method of fibrinogen measurement using two reagents with differing thrombin concentrations (35 UNIH/mL and 100 UNIH/mL) and PT-derived fibrinogen measurement in the presence of the drug. Aliquots of pooled normal plasma were spiked with different concentrations of dabigatran to reflect in vivo on-therapy levels as well as levels observed in cases of massive accumulation of the drug. Of the routine coagulation assays, in ascending order of sensitivity to dabigatran were PT, APTT and TT. The von Clauss method of measuring fibrinogen using a reagent with low thrombin concentration was affected even at drug levels corresponding to in vivo trough concentrations, whereas the reagent with higher thrombin concentration was only affected at drug levels that were above observed peak concentrations in patients taking 150 mg of the drug twice daily. PT-derived fibrinogen was affected at approximately in vivo peak drug concentrations. The D-dimer assay was affected only at drug concentrations well above peak drug levels. Attempts at in vitro neutralisation of the drug with DOAC-Stop resulted in 'correction' of some of these measurements depending on drug concentration. Like the routine coagulation assays, there is a dabigatran concentration dependent effect on the accuracy of fibrinogen and D-dimer assays. Falsely low fibrinogen results due to dabigatran may confound the assessment of DIC and diagnostic laboratories need to evaluate the performance of their own reagents.

Deep vein thrombosis--risks and diagnosis.

BACKGROUND: Venous thromboembolism, comprising deep vein thrombosis (DVT) and pulmonary embolism, is common in Australia and is associated with high morbidity. OBJECTIVE: This article provides a summary of the risk factors for DVT of the lower limb and discusses the diagnosis of the condition using a diagnostic algorithm incorporating clinical assessment, D-dimer testing and imaging studies. It also briefly reviews the clinical significance of isolated distal lower limb DVT and superficial vein thrombosis. DISCUSSION: Many conditions in the lower limb mimic DVT. Diagnosing DVT on clinical grounds without objective testing is unreliable. Patients incorrectly diagnosed as having DVT may be subjected to unnecessary anticoagulation and its associated risks of bleeding. In contrast, there is a risk of thrombus extension and embolisation when DVT is missed or inappropriately treated.

Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review.

The 2 most common genetic polymorphisms that predispose to a first episode of venous thromboembolism (VTE) are factor V Leiden (FVL) and prothrombin G20210A. However, the effect of these polymorphisms on the risk of recurrent VTE is unclear. We performed a meta-analysis to obtain best estimates of the relative risk of recurrent VTE associated with these genetic polymorphisms. Electronic and manual searches were used to identify cohort studies of patients with a first episode of VTE that reported the incidence of objectively confirmed recurrence following discontinuation of anticoagulation among those with or without heterozygous FVL or prothrombin G20210A polymorphism. Thirteen reports fulfilled our criteria for inclusion. Pooled results from 10 studies involving 3104 patients with first-ever VTE revealed that FVL was present in 21.4% of patients (95% confidence interval [CI], 20%-23%) and associated with an increased odds of recurrent VTE of 1.41 (95% CI, 1.14-1.75; P = .08 for heterogeneity). Pooled results from 9 studies involving 2903 patients with first-ever VTE revealed that prothrombin G20210A was present in 9.7% of patients (95% CI, 9%-11%) and associated with an increased odds of recurrent VTE of 1.72 (95% CI, 1.27-2.31; P = .19). The estimated population-attributable risk of recurrence for FVL was 9.0% (95% CI, 4.5%-13.2%) and for prothrombin G20210A was 6.7% (95% CI, 3.4%-9.9%). Heterozygous FVL and prothrombin G20210A are each associated with a significantly increased risk of recurrent VTE after a first event, but the magnitude of the increase in risk is modest and by itself is unlikely to merit extended-duration anticoagulation. These data call into question the cost-effectiveness of routine testing for these common inherited thrombophilic polymorphisms among patients with a first episode of VTE.

Prevention of coronary heart disease with aspirin and clopidogrel: efficacy, safety, costs and cost-effectiveness.

Atherothrombotic coronary artery disease is the single most common cause of death worldwide and a growing public health problem. Platelets play a central role in the pathogenesis of atherothrombosis and are therefore commonly targeted by one or more antiplatelet drugs as part of primary and secondary atherothrombosis prevention strategies. Aspirin reduces the risk of serious vascular events (myocardial infarction, stroke or cardiovascular death) by approximately 20% in a broad range of high-risk patients and remains the first-line antiplatelet drug because of its relative safety, low cost and cost-effectiveness. Compared with aspirin alone, clopidogrel reduces the risk of serious vascular events by approximately 10% and the combination of aspirin and clopidogrel reduces the risk by approximately 20% in patients with non-ST-segment elevation acute coronary syndrome. Clopidogrel has a similar safety profile to aspirin but clopidogrel tablets are substantially more expensive. However, the incremental cost-effectiveness ratio of clopidogrel compared with aspirin is favourable, particularly in high-risk patients and is intermediate compared with a range of other effective therapeutic strategies for the treatment of coronary heart disease. Clopidogrel should be considered as a replacement for aspirin in patients who are allergic to aspirin, cannot tolerate aspirin, have experienced a recurrent atherothrombotic vascular event whilst taking aspirin and are at very high absolute risk of a serious vascular event (e.g., > 20%/year). The combination of clopidogrel and aspirin should be considered in patients with non-ST-segment elevation acute coronary syndrome or undergoing percutaneous coronary intervention.

The incidence of venous thromboembolism: a prospective, community-based study in Perth, Western Australia.

OBJECTIVE: To determine the incidence of venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), in a well defined urban community broadly representative of the Australian population in terms of age, sex and ethnic distribution. DESIGN, SETTING AND PARTICIPANTS: A prospective, community-based study conducted over a 13-month period from 1 October 2003 to 31 October 2004. People in a population of 151 923 permanent residents of north-eastern metropolitan Perth, Western Australia, who developed VTE during the study period were identified prospectively and retrospectively through multiple overlapping sources. MAIN OUTCOME MEASURE: Number of cases of symptomatic, objectively verified DVT and PE. RESULTS: 137 patients had 140 VTE events (87 DVT and 53 PE). The crude annual incidence per 1000 residents was 0.83 (95% CI, 0.69-0.97) for VTE, 0.52 (95% CI, 0.41-0.63) for DVT, and 0.31 (95% CI, 0.22-0.40) for PE. The annual incidence per 1000 residents after age adjustment to the World Health Organization World Standard Population was 0.57 (95% CI, 0.47-0.67) for VTE, 0.35 (95% CI, 0.26-0.44) for DVT, and 0.21 (95% CI, 0.14-0.28) for PE. CONCLUSION: If the crude annual incidence of VTE in this area of metropolitan Perth is externally valid, then VTE affects about 17 000 Australians annually. Future studies of trends in VTE incidence will be needed to measure the effectiveness of VTE prevention strategies.