Barry Kevane

Adjustment of therapeutic LMWH to achieve specific target anti-FXa activity does not affect outcomes in pregnant patients with venous thromboembolism

Venous thromboembolism (VTE) remains a leading cause of maternal morbidity and mortality in the developed world. Low molecular weight heparins (LMWH) are routinely used to provide therapeutic anticoagulation during pregnancy for women with VTE, with measurement of plasma anti-FXa activity used to guide dosing in certain patient groups. There is limited evidence to support the use of anti-FXa monitoring in pregnant patients. This study seeks to ascertain whether anti-FXa monitoring of pregnant patients with VTE influences patient outcomes. We performed a single-centre case series including two consecutive groups of pregnant patients treated with LMWH for VTE sustained in the index pregnancy with and without monitoring of anti-FXa levels. 35,394 patients delivered during the study period in a large urban stand-alone maternity hospital, with 26 cases of VTE eligible for inclusion. There was no significant difference between the two groups in any clinical outcome; including maternal blood loss at delivery, recurrent thromboembolic events or rates of planned delivery. These data provide clinical evidence to support current international guideline recommendations that measurement of plasma anti-FXa activity in the majority of patients receiving therapeutic-intensity antenatal LMWH is not warranted.

Plasma Thrombin Generation and Sensitivity to Activated Protein C Among Patients With Myeloma and Monoclonal Gammopathy of Undetermined Significance

The etiology of the prothrombotic state in myeloma has yet to be definitively characterized. Similarly, while recent evidence suggests that patients with monoclonal gammopathy of undetermined significance (MGUS) may also be at increased risk of thrombosis, the magnitude and the etiology of this risk have also yet to be defined. The present study aims to characterize patterns of plasma thrombin generation and sensitivity to the anticoagulant activity of activated protein C (APC) at the time of initial diagnosis of myeloma and in response to therapy in comparison to that observed among patients with MGUS and matched, healthy volunteers. Patients presenting with newly diagnosed/newly relapsed myeloma (n = 8), MGUS (n = 8), and matched healthy volunteers (n = 8) were recruited. Plasma thrombin generation was determined by calibrated automated thrombography. Peak thrombin generation was significantly higher in patients with myeloma (383.4 ± 33.4 nmol/L) and MGUS (353.4 ± 16.5 nmol/L) compared to healthy volunteers (276.7 ± 20.8 nmol/L; P < .05). In the presence of APC, endogenous thrombin potential was significantly lower in control plasma (228.6 ± 44.5 nmol/L × min) than in either myeloma (866.2 ± 241.3 nmol/L × min, P = .01) or MGUS plasma (627 ± 91.5 nmol/L × min, P = .003). Within the myeloma cohort, peak thrombin generation was significantly higher at diagnosis (353.2 ± 15.9 nmol/L) than following completion of the third cycle of therapy (282.1 ± 15.2 nmol/L; P < .005). Moreover, sensitivity to APC increased progressively with each cycle of chemotherapy. Further study of the etiology and evolving patterns of hypercoagulability among patients with these conditions is warranted and may have future implications for thromboprophylaxis strategies.

Haemorrhagic and thrombotic complications in pregnant women with acquired and congenital cardiac disease

Abstract Background: Pregnant patients with cardiac disease have significantly higher predicted maternal morbidity and mortality compared to the general obstetric population. Published guidelines on optimal management of these patients recommend multidisciplinary care provision. There are few published data on the incidence of haematological complications in pregnant women with cardiac disease, although the data that does exist suggests a relatively high rate of bleeding and thrombotic events. Aims: To determine the outcomes in terms of haematological morbidity occurring within a cohort of pregnant women with cardiac disease in the setting of multidisciplinary care provision. Methods: Patients were identified from a database compiled by the obstetric cardiology service listing all cardiac patients managed in the Rotunda maternity hospital during the period from 2004 to 2011. Data were obtained from the medical and obstetric case notes relating to details of perinatal care and the occurrence of antenatal and postnatal complications. Results: During the 8-year review period, 451 women with cardiac disease were assessed. Fifty-nine were determined to have moderate to high-risk disease. Each received consultant-delivered multidisciplinary care, where written management strategies were agreed by collaborating senior colleagues either preconceptually or in early pregnancy. No venous thromboembolic events occurred and a modest rate of post-partum haemorrhage (approximately 5%) was recorded. There were no maternal deaths. Conclusion: The relatively favourable outcomes observed within our institution highlight the importance of a multidisciplinary approach to the management of pregnant women with cardiac disease, particularly in scenarios where limited published evidence exists to guide management.

Effect of platelet-derived β-thromboglobulins on coagulation

BACKGROUND β-thromboglobulins are derived from the cleavage of the CXC chemokine platelet basic protein and are released in high concentrations by activated platelets. Platelet-derived β-thromboglobulins (βTG) share 70% homology with platelet factor 4 (PF4), another CXC chemokine released by activated platelets. PF4 modulates coagulation by inhibiting heparin-antithrombin interactions, promoting protein C activation, and attenuating the activity of activated protein C. In contrast, the effect of βTG on coagulation is unknown. AIM/METHODS Clotting times, thrombin generation, chromogenic clotting factor assays, and surface plasmon resonance (SPR) were used to assess the effect of purified βTG on coagulation. RESULTS In normal pooled plasma, βTG shortened the lagtime and time to peak thrombin generation of tissue factor (TF)-dependent and TF-independent thrombin generation. In factor VIII and factor IX-deficient plasmas, βTG induced thrombin generation in the absence of a TF stimulus and in the presence of anti-TF and factor VIIa inhibitory antibodies. The procoagulant effect was not observed when thrombin generation was independent of factor X activation (supplementation of factor X-deficient plasma with factor Xa). Cleavage of a factor Xa-specific chromogenic substrate was observed when βTG was incubated with factor X, suggesting a direct interaction between βTG and factor X. Using SPR, βTG were found to bind to immobilised factor X in a dose dependent manner. CONCLUSION βTG modulate coagulation in vitro via an interaction with factor X.

Early onset preeclampsia is associated with an elevated mean platelet volume (MPV) and a greater rise in MPV from time of booking compared with pregnant controls: results of the CAPE study

Abstract Objective: To characterise Mean platelet volume (MPV) in patients with early onset preeclampsia (EOPE) and unaffected controls from time of first antenatal visit until the postpartum. Materials and methods: Retrospective secondary analysis of an observational study in an Irish tertiary referral centre with 9000 deliveries annually. The MPV of 27 women with EOPE was compared to 19 unaffected controls. The inclusion criteria for the disease state was the development of EOPE defined by the National Institute for Health and Care Excellence (NICE) guideline, as new onset hypertension presenting after 20 weeks and prior to 34 weeks with significant proteinuria. Between October 2013 and July 2015 we recruited 27 women with EOPE and 19 pregnant controls. Statistical analysis was performed using paired T-test of Mann-Whitney test where appropriate and a P-value <0.05 was deemed significant. Results: At time of diagnosis and late in the third trimester MPV was significantly increased to 9.0 (±0.3) fL in cases of EOPE in comparison to 8.5 (±0.6) fL in normotensive controls (P<0.05). There was no significant difference during the first trimester or postpartum when comparing the MPV in EOPE to controls. Conclusion: Despite an increased MPV at time of diagnosis of EOPE this study did not demonstrate a potential use for increased MPV as a first trimester screening tool.

Dual endothelin-1 receptor antagonism attenuates platelet-mediated derangements of blood coagulation in Eisenmenger syndrome

Essentials Eisenmenger syndrome is characterised by thrombotic and hemorrhagic risks of unclear aetiology. Calibrated automated thrombography was used to assess these coagulation derangements. Platelet activity supported abnormalities in procoagulant and anticoagulant pathway function. Endothelin‐1 antagonism appeared to ameliorate these derangements.

Elevated plasma TFPI activity causes attenuated TF-dependent thrombin generation in early onset preeclampsia

Early onset preeclampsia (EOP) is a pregnancy-specific proinflammatory disorder that is characterised by competing thrombotic and bleeding risks. It was the aim of this study to characterise thrombin generation, a major determinant of thrombotic and bleeding risk, in order to better understand the haemostatic balance in patients with EOP. Patients with EOP were recruited at the Rotunda Hospital, Dublin. Twenty-six cases of EOP were recruited over a 21-month period, out of 15,299 deliveries at the Rotunda. Blood samples were collected into sodium citrate plus corn trypsin inhibitor anticoagulated vacutainers, platelet-poor plasma was prepared, and calibrated automated thrombography was used to assess thrombin generation. Results were compared to age and sex-matched non-pregnant controls (n=13) and age- and gestation-matched pregnant controls (n=20). The rate and extent of thrombin generation triggered by low-dose tissue factor (TF) was significantly reduced in patients with EOP compared to pregnant controls, most significantly in cases of severe EOP. EOP patients displayed a trend towards an increased response to endogenous activated protein C and thrombomodulin relative to pregnant controls. Plasma tissue factor pathway inhibitor (TFPI) activity was increased in EOP patients. Inhibition of TFPI abolished the attenuation of thrombin generation stimulated by low-dose TF. In conclusion, patients with EOP are characterised by an attenuated coagulation response characterised by reduced thrombin generation stimulated by low-dose TF and elevated plasma TFPI activity. These changes in coagulation may modulate thrombotic risk and bleeding risk in patients with EOP.

Endothelial barrier protective properties of low molecular weight heparin: A novel potential tool in the prevention of cancer metastasis?

Essentials Inhibition of tumor cell trans‐endothelial migration inhibits metastasis formation. Low molecular weight heparin (LMWH)‐mediated endothelial barrier protection was investigated. LMWH enhanced endothelial barrier activity and attenuated tumor cell transmigration. The cytoprotective activity of LMWH did not appear to be dependent on anticoagulant activity.

Screening for Malignancy in Patients With Unprovoked Venous Thromboembolism: A Single-Center Retrospective Case Series:

In this prospective review of cancer screening in unselected patients with unprovoked venous thromboembolism (VTE) presenting to a large teaching hospital in the Republic of Ireland, we aimed to determine the effects of the implementation of the National Institute for Health and Care Excellence screening policy in a “real-world” population. Within our institution, 64 individuals presented with unprovoked VTE during the study period, of whom 47 underwent a screening computed tomography (CT) scan. Two cases of previously undiagnosed cancer were identified. However, in both cases, the clinical history provided by the affected individuals would have prompted a CT scan regardless of the recommendations of the screening policy. The screening CT scans identified 18 incidental lesions within the cohort, which required further diagnostic studies. None of the additional investigations completed to date have detected any lesion of clinical significance. These findings support the view that cancer screening with CT imaging in unselected individuals with unprovoked VTE is not justified or cost-effective.

Antenatal identification of factor VII Padua during a healthy pregnancy: implications for labor and delivery

Abstract We present a case in which a 28-year-old pregnant woman (para 1) was suspected to have inherited factor VII (FVII) deficiency following investigation for recurrent mild easy bruising. However, this was ruled out by identification of a rare FVII variant not associated with an increased bleeding risk. This allowed usual obstetric care to proceed without any restrictions, facilitating an uncomplicated spontaneous vaginal delivery at term.