Kevin Ryan

Novel insights into the clinical phenotype and pathophysiology underlying low VWF levels

Critical clinical questions remain unanswered regarding diagnosis and management of patients with low von Willebrand factor (VWF) levels (30-50 IU/dL). To address these questions, the Low VWF Ireland Cohort (LoVIC) study investigated 126 patients registered with low VWF levels. Despite marginally reduced plasma VWF levels, International Society of Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH BAT) confirmed significant bleeding phenotypes in the majority of LoVIC patients. Importantly, bleeding tendency did not correlate with plasma VWF levels within the 30 to 50 IU/dL range. Furthermore, bleeding phenotypes could not be explained by concurrent hemostatic defects. Plasma factor VIII to VWF antigen (VWF:Ag) ratios were significantly increased in LoVIC patients compared with controls (P < .0001). In contrast, VWF propeptide to VWF:Ag ratios >3 were observed in only 6% of the LoVIC cohort. Furthermore, platelet-VWF collagen binding activity levels were both significantly reduced compared with controls (P < .05). In response to 1-desamino-8-D-arginine vasopressin (DDAVP), peak VWF:Ag levels exceeded 100 IU/dL in 88% of patients and was sustained >100 IU/dL after 4 hours in 72% of subjects. In conclusion, our novel data suggest that low VWF levels can be associated with significant bleeding and are predominantly due to reductions in VWF synthesis and/or constitutive secretion. Although enhanced VWF clearance may contribute to the pathophysiology in some individuals, the absolute reduction in VWF plasma half-life is usually mild and not sufficient to significantly impact upon the duration of DDAVP-induced VWF response. This trial was registered at www.clinicaltrials.gov as #NCT03167320.

Lenalidomide as a novel treatment for refractory acquired von Willebrand syndrome associated with monoclonal gammopathy

Essentials Treatment options are limited for refractory bleeding in acquired von Willebrand Syndrome (AVWS). Lenalidomide therapy was studied in two patients with AVWS due to monoclonal gammopathy (MG). Lenalidomide increased von Willebrand factor (VWF), lowered VWF clearance and resolved bleeding. Lenalidomide is a potential treatment option for refractory bleeding in AVWS secondary to MG.

Out of Sight, out of Mind? An Audit Which Proposes a Follow-Up and Management Pathway for Inferior Vena Cava Filters

Insertion of an IVC filter can be a safe and effective way to avoid PE in thrombosis patients who cannot be anticoagulated. If temporary filters are not promptly removed they can become difficult to remove, causing avoidable complications and often requiring lifelong warfarin. In this study, two sequential audits of retrieval of temporary IVC filters were conducted before and after the implementation of a coordinated management strategy for IVC filter follow-up. 33 filter placements were examined over a 15-month period (Group A). Following implementation of the strategy a comparable 15-month period in which 33 IVC filters were placed was audited (Group B). Following implementation, failed retrievals dropped from 15% to 9%. The number successfully retrieved did not change at 45%. The number made permanent from the outset following expert discussion increased from 12% to 39%. The number of filters with no attempted retrieval and no consultation about retrieval decreased from 27% to 9% (these patients were lost to follow-up with multiple contact attempts made). In Group B 100% of placed IVC filters were followed up appropriately. The proposed model is an easily implemented plan to avoid patient morbidity caused by temporary IVC filters made unintentionally permanent by loss to follow-up.

Retrievable Inferior vena cava filters in pregnancy: Risk versus benefit?

OBJECTIVE Venous thromboembolism remains one of the leading causes of maternal mortality in the developed world. Retrievable inferior vena cava (IVC) filters have a role in the prevention of lethal pulmonary emboli when anticoagulation is contraindicated or has failed [1]. It is unclear whether or not the physiological changes in pregnancy influence efficacy and complications of these devices. The decision to place an IVC filter in pregnancy is complex and there is limited information in terms of benefit and risk to the mother. The objective of this study was to determine the efficacy and safety of these devices in pregnancy and to compare these with rates reported in the general population. STUDY DESIGN The aim of this study was report three recent cases of retrievable IVC filter use in pregnant women in our department and to perform a systematic review of the literature to identify published cases of filters in pregnancy. The efficacy and complication rates of these devices in pregnancy were estimated and compared to rates reported in the general population in a recent review [2]. Fishers exact test was used for statistical analysis. RESULTS In addition to our three cases, 16 publications were identified with retrievable IVC filter use in 40 pregnant women resulting in a total of 43 cases. There was no pulmonary embolus in the pregnant group (0/43) compared to 57/6291 (0.9%) in the general population. Thrombosis of the filter (2.3% vs. 0.9%, p = 0.33) and perforation of the IVC (7.0% vs 4.4%, p = 0.44) were more common in pregnancy compared to the general population but the difference was not statistically significant. Failure to retrieve the filter is more likely to occur in pregnancy (26% vs. 11%, p = 0.006) but this did not correlate with the type of device (p = 0.61), duration of insertion (p = 0.58) or mode of delivery (p = 0.37). CONCLUSION Data for retrievable IVC filters in pregnancy is limited and there may be a publication bias towards complicated cases. This study shows that the filter appears to protect against PE in pregnancy but the numbers are small. Complications such as filter thrombosis and IVC penetration appear to be higher in pregnancy but this difference is not statistically significant. It is not possible to retrieve the device in one out of every four pregnant women. This has implications in terms of long term risk of lower limb thrombosis and post thrombotic syndrome. The decision to use an IVC filter in pregnancy needs careful consideration by a multidisciplinary team. The benefit and risk assessment should be individualised and clearly outlined to the patient.

417. The impact of a tailored checklist on the quality of peripartum care delivered to women with inherited bleeding disorders.

Introduction Women with inherited bleeding disorders (IBD) can be at increased risk of bleeding peripartum and/or their babies are at risk of fetal or neonatal haemorrhage. The care they require is specific to the type of bleeding disorder they have and the plan for delivery requires multidisciplinary input. The World Health Organisation (WHO) has recommended new safety checklists as part of a drive to reduce medical errors and make healthcare safer. Communication is essential for optimal care. Developing an easy to follow bleeding disorder checklist draws the specialists information together and enables all healthcare professionals to quickly identify the care they must provide. Objectives The aim of the study was to identify any errors in care, to develop and implement a tailored bleeding disorder checklist, and to assess the impact of this on quality of care. Methods Fifty women with (or carriers of) an IBD were identified from a Maternal medicine service database and charts were reviewed. Quality of care indicators were assessed by chart review before and after the introduction of the checklist into clinical practice. Results When standards of care were compared before and after the introduction of the checklist: Haemostatic support was recommended for 19% of the group peripartum and given to 100%, compared to 29% and 100%. Maternal precautions were recommended in 42% and adopted in 78% compared to 43% and 100%. Fetal precautions were recommended in 86% and implemented in 94% compared to 89% and 100%. Cord bloods were advised in 58% and taken in 55% compared to 54% and 93%. Discussion Deficiencies in care were identified in this high risk group of women despite multidisciplinary peripartum planning of care. The development of a simple checklist that could be modified to meet the specific individuals needs resulted in improved quality and safety of care.

Management of combined factor V and factor VIII deficiency in pregnancy

Helen Fogarty, Mairead M. Doyle, Raechel Campbell, Catriona Keenan, Barry White, Kevin Ryan, James S. O’Donnell, John Slevin, Denis O’Keeffe, Niamh M. O’Connell and Michelle Lavin National Coagulation Centre, St. James’s Hospital, Dublin, Ireland; Irish Centre for Vascular Biology, Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Obstetrics, University Maternity Hospital, Limerick, Ireland; Department of Haematology, University Hospital Limerick, Limerick, Ireland

A role for intravenous immunoglobulin in the treatment of Acquired Von Willebrand Syndrome associated with IgM gammopathy.

1. Li R, Emsley J. The organizing principle of the platelet glycoprotein IbIXV complex. J Thromb Haemost. 2013;11:605-614. 2. Noris P, Perrotta S, Bottega R, et al. Clinical and laboratory features of 103 patients from 42 Italian families with inherited thrombocytopenia derived from the monoallelic Ala156Val mutation of GPIbalpha (Bolzano mutation). Haematologica. 2012;97:82-88. 3. Borhany M, Boijout H, Pellequer JL, et al. Genotype and phenotype relationships in 10 Pakistani unrelated patients with inherited factor VII deficiency. Haemophilia. 2013;19:893-897. 4. Zieger B, Jenny A, Tsakiris DA, et al. A large Swiss family with BernardSoulier syndrome Correlation phenotype and genotype. Hamostaseologie. 2009;29:161-167. 5. Savoia A, Kunishima S, De RD, et al. Spectrum of the mutations in BernardSoulier syndrome. Hum Mutat. 2014;35:1033-1045. 6. Gohda F, Uchiumi H, Handa H, et al. Identification of inherited macrothrombocytopenias based on mean platelet volume among patients diagnosed with idiopathic thrombocytopenia. Thromb Res. 2007;119:741-746. 7. Ali S, Ghosh K, Shetty S. Molecular pathology of BernardSoulier syndrome in Indian patients. Platelets. 2013;24:571-573. 8. Gonzalez-Manchon C, Larrucea S, Pastor AL, et al. Compound heterozygosity of the GPIbalpha gene associated with BernardSoulier syndrome. Thromb Haemost. 2001;86:1385-1391. 9. Kanaji T, Okamura T, Kurolwa M, et al. Molecular and genetic analysis of two patients with BernardSoulier syndrome–identification of new mutations in glycoprotein Ib alpha gene. Thromb Haemost. 1997;77:1055-1061. 10. Rivera CE, Villagra J, Riordan M, Williams S, Lindstrom KJ, Rick ME. Identification of a new mutation in platelet glycoprotein IX (GPIX) in a patient with BernardSoulier syndrome. Br J Haematol. 2001;112:105-108. 11. Kulkarni BP, Nair SB, Vijapurkar M, et al. Molecular pathology of rare bleeding disorders (RBDs) in India: a systematic review. PLoS ONE. 2014;9:e108683. 12. Boeckelmann D, Hengartner H, Greinacher A, et al. Patients with BernardSoulier syndrome and different severity of the bleeding phenotype. Blood Cells Mol Dis. 2017;pii:S1079-9796:30281-30289. 13. Ul Haq MI, Sohaib M, Khan S, Nazir M. BernardSoulier syndrome: a challenge for anesthetist in an emergency surgery. J Anaesthesiol Clin Pharmacol. 2015;31:416-417. 14. Zaffar N, Saleem M, Ahmed SA. Functional platelet defects: a clinicopathological study of 10 cases. J Pak Med Assoc. 1987;37:223-228. 15. Zafar S, Sultana S, Iqbal W, et al. Pregnancy outcome in BernardSoulier syndrome complicated by preeclampsia. J TurkishGerman Gynecol Assoc. 2007;8:324-326.

Significant gynecological bleeding in women with low von Willebrand factor levels

Gynecological bleeding is frequently reported in women with von Willebrand disease (VWD). Low von Willebrand factor (VWF) may be associated with significant bleeding phenotype despite only mild plasma VWF reductions. The contribution of gynecological bleeding to this phenotype has yet to be described. The optimal clinical bleeding assessment tool (BAT) to evaluate bleeding remains unclear. Using a standardized approach to phenotypic assessment, we evaluated gynecological bleeding and directly compared the Condensed Molecular and Clinical Markers for the Diagnosis and Management of type 1 VWD (Condensed MCMDM-1 VWD) and International Society on Thrombosis and Haemostasis (ISTH) BAT scores in 120 women enrolled in the Low von Willebrand in Ireland Cohort study. Heavy menstrual bleeding (HMB) was reported in 89% of female participants; 45.8% developed iron deficiency. Using identical data, Condensed MCMDM-1 VWD menorrhagia domain scores were significantly lower than ISTH BAT scores (2 vs 3; P < .0001), the discrepant results related to 40% of women not seeking medical consultation for HMB, reducing the sensitivity of the Condensed score. For those who reported HMB to physicians, the low VWF diagnosis was not expedited (age at diagnosis 34.2 vs 33.4 years in women failing to present; P = .7). Postpartum hemorrhage (PPH) was self-reported in 63.5% of parous women (n = 74); 21.6% required transfusion, critical care, radiological, or surgical intervention. Our data demonstrate that gynecological bleeding is frequently reported in women with low VWF; despite pregnancy-related increases in plasma VWF levels, these women may experience PPH. Defining the optimal management approach for these patients requires further research. This trial was registered at www.clinicaltrials.gov as #NCT03167320.