International Society For Thrombosis And Haemostasis Research Articles

Modern Treatment of Pulmonary Embolism (USCDT vs MT): Results From a Real-World, Big Data Analysis (REAL-PE)

BackgroundAdvanced therapies are increasingly utilized to treat pulmonary embolism (PE). A unique data platform allows access to electronic health record data for comparison of the safety of PE therapies. MethodsAll data from Truveta (Truveta, Inc) were analyzed (16 systems, 83,612,413 patients, 535,567 with PE). All patients treated with ultrasound-assisted catheter-directed thrombolysis (USCDT) (Boston Scientific) or mechanical thrombectomy (MT) (Inari Medical) for PE were identified. The primary analysis was based on index procedures performed from January 2009 to May 2023, and contemporary analysis on those performed from January 2018 to May 2023. Bleeding was assessed via direct laboratory analysis and transfusion administration documentation. International Society for Thrombosis and Hemostasis (ISTH) and Bleeding Academic Research Consortium (BARC) 3b definitions were recreated. Multiple logistic regression analysis of major bleeding was performed. In-hospital death and median length of stay were measured. ResultsFor the primary analysis, 2259 patients (N = 1577 USCDT, N = 682 MT) and for the contemporary analysis 1798 patients (N = 1137 USCDT, N = 661 MT) met the criteria. Incidence of hemoglobin reduction (>2 and >5 g/dL) and transfusions received were significantly higher among MT-treated patients in both analyses, as was ISTH and BARC 3b major bleeding (primary: ISTH MT 17.3% vs USCDT 12.4% P = .002; BARC 3b MT 15.4% vs USCDT 11.8% P = .019) (contemporary: ISTH MT 17.2% vs USCDT 11.0% P = .0002; BARC 3b MT 15.4% vs USCDT 10.6% P = .002). Regression analysis demonstrated that MT is associated with major bleeding. Median length of stay, all-cause 30-day readmission and in-hospital mortality were similar between groups. Intracranial hemorrhage was more common with MT. ConclusionsMajor bleeding derived from direct laboratory and transfusion data occurred more frequently with MT vs USCDT. Intracranial hemorrhage was more common among MT-treated patients. In the absence of randomized data, these results provide guidance regarding the bleeding risk and safety of strategies for advanced PE therapy.

Improving the Effectiveness of Anticoagulant Therapy: The Promise of Factor XI Inhibition

This continuing medical education-accredited symposium, held at the 2023 International Society for Thrombosis and Haemostasis (ISTH) congress in Montréal, Canada, focused on current unmet needs in anticoagulation, especially in the atrial fibrillation (AF) population, and reflected on the promise of the emerging class of Factor XI inhibitors for stroke prevention (SPAF) in susceptible patients. The faculty agreed that, although direct oral anticoagulants (DOAC) have represented a major advance compared with vitamin K antagonists, their utilisation remains suboptimal, often due to the prevailing fear of bleeding in many types of patients. Older age alone can be a reason for withholding anticoagulation, due to the risk and implications of bleeding. Frailty and comorbidities, such as chronic kidney disease (CKD), which can adversely affect the bioavailability of DOACs, are also deterrents to optimal anticoagulant use. Clinicians may try to avoid or mitigate bleeding by inappropriately prescribing low doses of DOACs, an off-label practice that has been found to fail to protect patients from thrombotic risk, without attenuating the risk of bleeding. In addition, the potential for drug-drug interactions and poor adherence also limit the optimal use of DOACs in real-world clinical practice. A recent patient survey focusing on the topic of ‘minor bleeding’, often referred to by clinicians as ‘nuisance bleeding’, and typically not well captured in clinical trials, revealed the far-reaching impact of ongoing problems with bleeding on quality of life, and the possibility that these experiences may deter patients from adherence to their prescribed anticoagulant regimen. Factor XI represents a promising new target for anticoagulation, which may minimise the risk of bleeding by pharmacologically ‘uncoupling’ the clotting pathway, leading to pathological thrombosis from the cascade largely responsible for physiological haemostasis. Phase II research with investigational Factor XI inhibitors has established their antithrombotic and safety potential, and some of these agents may also avoid other practical drawbacks of DOACs. Phase III evaluation of Factor XI inhibition is ongoing in a number of clinical settings.

Managing argatroban in heparin-induced thrombocytopenia: Aretrospective analysis of 729 treatment days in 32 patients with confirmed heparin-induced thrombocytopenia.

Managing argatroban in heparin-induced thrombocytopenia: Aretrospective analysis of 729 treatment days in 32 patients with confirmed heparin-induced thrombocytopenia.

Evaluation of definitions for oral anticoagulant-associated major bleeding: A population-based cohort study

IntroductionMajor bleeding is the most serious complication of oral anticoagulants (OACs). While consensus criteria to define major bleeding have been established by the International Society for Thrombosis and Haemostasis (ISTH), Bleeding Academic Research Consortium (BARC) and Thrombolysis in Myocardial Infarction (TIMI), significant variability exists across these definitions. We sought to evaluate the agreement of cases identified by the three definitions and to assess their effect on mortality and OAC resumption. MethodsWe used a dataset of individuals ≥66 years in Ontario, Canada presenting with OAC-related bleeding from 2010 to 2015. For case agreement, we calculated Cohen's κ between the three major bleeding definitions. We used multivariate regression to determine differences in mortality and OAC resumption among ISTH, BARC and TIMI-defined major bleeds. ResultsAmong 2002 cases of OAC-related bleeding, agreement in case identification between ISTH and BARC was substantial (Cohen's κ = 0.69); however, agreement between TIMI and other definitions were poor. Using 30-day mortality of clinically relevant non-major bleeds as comparator, ISTH-, BARC- and TIMI-defined major bleeds conferred 3.3-, 3.2- and 5.9-fold increased risk. Among survivors, 50% with ISTH- and BARC-defined major bleeds resumed OACs at 180 days, compared to 31% of TIMI-associated cases. ConclusionMajor bleeds identified by ISTH and BARC criteria showed good agreement and similar prognostic utility, whereas TIMI criteria identified patients at greater clinical risk. Our results highlight the need to revise major bleeding definitions based on criteria that are independently predictive of clinically relevant morbidity and mortality to more effectively reflect the risk associated with major bleeding and appropriately influence anticoagulant therapy decisions.

Obituary: Samuel J. Machin MB ChB FRCP FRCPath, 26 March 1949 – 2 October 2021

On Saturday 2 October, we were saddened to learn of the death of Professor Samuel (Sam) Machin after a short, final illness. Sam was a larger than life character who had a certain vision about how haematology should be and strived to achieve modernization. Through his distinguished career, he was involved with many of the National and International societies and committees involved in haematology and standardization. Sam studied medicine at Sheffield University from 1966 to 1971. He received his haematology training at Manchester Royal Infirmary before taking a Senior Registrar post at the Middlesex Hospital Medical School. In 1979, he joined Jos Vermylen and others at the Department of Vascular and Haemostasis Research, KU, Leuven. It was here where he commenced his career in haemostasis and thrombosis, researching on platelets, prostacyclin and haemolytic uraemic syndrome. Returning to London, he was appointed Consultant Haematologist (the youngest at the time to achieve that post in the UK) and worked with Professor Jimmie Stewart. Sam’s career progressed with his achievements leading to his appointment as Professor of Haematology at The Middlesex and later University College London (UCL). A large number of scientists and junior doctors received expert training in the Department, many obtaining MD and/or PhD. Almost without exception, trainees whom Sam mentored and supported have gone on to become consultants, professors, heads of department and divisions in hospitals, universities, the National Blood Service and industry. He took an active role in organizing the UCL Haemostasis Training Course, which helped haematologists from many parts of the world to obtain Fellowship of the Royal College of Pathologists. In 1981, Sam founded what was to become the Haemostasis Research Unit at UCL and directed research in many aspects of haemostasis and thrombosis. His primary areas were platelet function, thrombotic thrombocytopaenia, antiphospholipid syndrome and the prothrombotic effects of combined oral contraceptives. He was also interested in laboratory automation and set up an analyser and reagent evaluations unit that studied most new haematology and coagulation systems. He understood the need to communicate and encouraged staff to present their data at conferences, and he co-authored over 400 peer-reviewed publications. Sam worked tirelessly in supporting the interests of many societies and organizations. He was President of the British Society for Haemostasis and Thrombosis (2001-03) and British Society for Haematology (2005-07), serving as treasurer from 1994 to 2000. He chaired the British Committee for Standardisation in Haematology, UK NEQAS Haematology Steering Committee (2006-11) and the International Council for Standardization in Haematology (2007-20). He was Treasurer of the International Society for Thrombosis and Haemostasis (ISTH) for the 2003 congress in Birmingham and Vice Chairman of the ISTH Scientific Standards Committee. In 2007, Sam led the reorganization and modernization of the International Council for Standardization in Haematology and remained as Chair of this body until 2020. His enthusiasm and energy resulted in the publication of more than 30 peer-review publications on standardization in haematology, including many guidance and recommendation documents. He was a supporter of laboratory haematology as a discipline. He encouraged the late Berend Houwen to develop further meetings on “Technical Innovations in Laboratory Hematology,” which later led to the formation of the International Society for Laboratory Hematology, of which Sam became a board member. He served on the Editorial Board of this journal (International Journal of Laboratory Hematology) and remained an active reviewer (even saying just 2 weeks prior to his death that he would like to receive more manuscripts). Sam enjoyed playing and watching sport, being passionate about cricket, hockey and rugby league. A kind and generous man, although sometimes controversial because he liked to speak his mind. He had a way of cutting through bureaucracy, side stepping obstacles and getting things done. He is survived by his wife Jean, son Robert and daughters Clare and Rowena as well as 5 grandchildren.

Bleeding in Patients with Clinically Severe Von Willebrand Disease: Interim Analysis of Athn 9: A Natural History Study for People with Severe Von Willebrand Disease (VWD)

Background:Von Willebrand Disease (VWD) is the most common inherited bleeding disorder, occurring in ~0.1% of the population. VWD results from either a quantitative (Type 1 or 3) or qualitative (Type 2) defect in von Willebrand Factor (VWF), a multimeric plasma protein involved in platelet adhesion and aggregation at the vascular injury site. Accurate diagnosis of VWD is complex due to pre-analytical variables, a wide coefficient of variation in testing, and incomplete penetrance. Though individuals with mild VWD and bleeding symptoms are common, less is known regarding persons with VWD and a clinically severe bleeding phenotype.Aims:To characterize the bleeding phenotype and safety of treatment regimens in participants with clinically severe VWD in the United States (US).Study Design and Methods:ATHN 9 is sponsored by the American Thrombosis and Hemostasis Network (ATHN) and is being conducted at 25 ATHN-affiliated sites across the US. Participants are identified by the site investigators with a projected goal to enroll 130 individuals. Patients with severe VWD defined as type 3 VWD, or a VWF:RCo, VWF:GPIbM or VWF:Ag ≤ 30%, or persons with “clinically severe VWD” defined by VWF:RCo, VWF:GPIbM or VWF:Ag ≤ 40% and requiring recurrent use of factor concentrates and prior enrollment in the ATHNdataset national surveillance data collection project are included. Participants with platelet-type or acquired VWD are excluded. Laboratory assessments including a standardized diagnostic battery, VWF genetic analysis (Next-gen sequencing), and inhibitor testing, performed by a central laboratory. Bleeding tendency is assessed by International Society for Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool (BAT) (abnormal BS is ≥4 in adult males, ≥6 in adult females and ≥3 in children) and the Pictorial Bleeding Assessment Chart (PBAC; heavy menstrual blood loss ≥100) if applicable.Results:Initial data on 81 participants was analyzed. Given that the enrollment occurred during the pandemic, the completion of data varied as follows: Baseline Demographics Forms 81 completed, Baseline History Forms 73 completed, and VWD Diagnostic Testing Results Forms 38 completed. Most were adult (53%), female (58%), Caucasian (82%) and non-Hispanic (82%). Approximately half (38/81, 47%) have undergone central lab diagnostic testing (Table 1) while the remaining had previous diagnostic studies. About half of the patients had Type 1, a quarter have Type 3, and the remaining had Type 2 VWD or unknown. The majority of patients (91%) had VWF:GPIbM activity <30IU/dL and (61%) had a VWF:Ag <30IU/dL. One participant had an inhibitor (1/22, 4%) to VWF. Of the participants with a baseline history form submission (73 in total), more than half (42/73, 57%) had undergone surgery, the most common being nasal cautery (11/42, 26.2%) and dental extraction (11/42, 26.2%); complicated by bleeding most commonly during or following dental extraction (2/11, 18.2%) and endoscopy/colonoscopy (2/4, 50%). Few participants (6/73, 8%) reported the presence of a target joint at enrollment, ankle being most common. The bleeding phenotype was variable with a mean ISTH BAT score of 10 (range 0-39) with the first bleeding event commonly occurring prior to age 10 years (51%), with 20% occurring prior to age 12 months (20%). The PBAC was performed on 6 of the 47 female participants in reference to their last period and was abnormal(mean 247; range 0-754). The majority (70 participants, 96%) utilized factor concentrates for prophylaxis or on-demand treatment; 27 participants (39%) were on continuous prophylaxis, while 8 (11%) were on event-based while less (10%) were on heavy menstrual bleeding (HMB) prophylaxis, and the remainder (40%) received episodic treatment. Participants used plasma derived VWF concentrate most commonly (64.3%) with the remainder using recombinant VWF or DDAVP/antifibrinolytics.Discussion: Initial evaluation of 81 participants with clinically severe VWD were diagnostically determined to be type 1 VWD with a majority having a bleeding phenotype (mean (ISTH BAT 10) and HMB (mean PBAC 247). In contrast to patients with mild disease where antifibrinolytics and desmopressin are frequently used, factor replacement was the most common treatment modality. Future analysis will focus on response to factor replacement therapy, genotype-phenotype correlation and quality of life. DisclosuresWeyand: Novo Nordisk: Research Funding; Genentech: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy. Friedman: Siemens: Consultancy; Bayer: Consultancy; Alexion: Speakers Bureau; Genentech: Consultancy; Instrumentation Laboratories: Consultancy; Sanofi: Consultancy. Haley: American Thrombosis and Hemostasis Network: Research Funding. He: ATHN: Ended employment in the past 24 months. Roberts: Takeda; Speakers Bureau: Novo Nordisk, Octapharma, Sanofi, Takeda.: Research Funding; Genentech, Novo Nordisk, Octapharma, Pfizer, Sanofi, Takeda, uniQure: Consultancy. Wynn: Sanofi: Research Funding; Takeda: Research Funding; Genentech: Research Funding. Sidonio: Sanofi, Takeda, Octapharma, Bayer, Biomain, Grifols, Kedrion, Genentech. Catalyst, Guardian Therapeutics, Novo Nordisk, Hema Biologics, Uniqure.: Consultancy, Honoraria. OffLabel Disclosure:Vonvendi (recombinant VWF) does not have a product indication for prophylaxis

Bleeding in Patients with Clinically Severe Von Willebrand Disease: Preliminary Results of Athn 9, a Natural History Study of the Safety, Effectiveness, and Practice of Treatment for People with Severe Von Willebrand Disease (VWD)

Bleeding in Patients with Clinically Severe Von Willebrand Disease: Preliminary Results of Athn 9, a Natural History Study of the Safety, Effectiveness, and Practice of Treatment for People with Severe Von Willebrand Disease (VWD)

Reliability and Feasibility of the Self-Administered ISTH-Bleeding Assessment Tool.

Introduction Standardized bleeding assessment tools (BATs), such as the International Society for Thrombosis and Hemostasis (ISTH)-BAT, are screening instruments used during the diagnostic workup of suspected bleeding disorders. A self-administered ISTH-BAT (self-BAT) would enhance screening and save time during an outpatient clinic visit. Aim This study was aimed to investigate the reliability and feasibility of the self-BAT. Methods The electronic self-BAT was created from the ISTH-BAT and paper-version of self-BAT and optimized by patients and physicians. Patients with a (suspected) congenital platelet defect (CPD), who had previously undergone physician-administered ISTH-BAT assessment, were invited to complete the self-BAT. Optimal self-BAT cut-off values to detect a bleeding tendency, as defined by the ISTH-BAT, were evaluated by receiver operator characteristic (ROC) curve analysis to reach a sensitivity ≥95%. Reliability was tested by assessing sensitivity, specificity, and intraclass correlation (ICC). Feasibility was evaluated on comprehension and length of self-BAT. Results Both versions of the BAT were completed by 156 patients. Optimal cut-off values for self-BAT to define a bleeding tendency were found to be identical to those of the ISTH-BAT. Normal/abnormal scores of the ISTH-BAT and self-BAT were agreed in 88.5% (138/156, 95% confidence interval [CI]: 0.83–0.93) of patients. The sensitivity and specificity of the self-BAT to detect a bleeding tendency were 96.9 and 48.1%, respectively. The ICC was 0.73. Self-BAT questions were graded by 96.8% (151/156) as “very easy,” “easy,” and “satisfactory” and questionnaire length as “exactly right” by 91% (142/156) of patients. Conclusion In patients with a (suspected) CPD, the self-BAT is sufficiently reliable and feasible to detect a bleeding tendency, which supports its use as a screening tool.

Evaluation of Definitions for Oral Anticoagulant–Associated Major Bleeding: A Population-Based Cohort Study

Background: Major bleeding is the most serious complication of oral anticoagulation. Consensus criteria to define major bleeding have been established by the International Society for Thrombosis and Haemostasis (ISTH), Bleeding Academic Research Consortium (BARC) and Thrombolysis in Myocardial Infarction (TIMI). Significant variability exists across these definitions, and their agreement for identifying oral anticoagulant (OAC) related major bleeding is unknown. Furthermore, the association between each definition and mortality in cases of OAC bleeding has not been evaluated. We therefore, sought to evaluate the agreement of cases identified as major bleeding by the ISTH, BARC and TIMI definitions, and to assess associated in-hospital (emergency department or inpatient) and 30-day mortality of cases identified by these criteria.Methods: We used an existing dataset of individuals ≥66 years in Ontario, Canada, who presented to one of five tertiary care institutions with OAC related bleeding across three cities from 2010-2015. Detailed clinical data on consecutive episodes of OAC-associated bleeding were linked to population-based databases held at the Institute for Clinical Evaluative Sciences. We calculated Cohen's κ for agreement between the three major bleeding definitions, and used Pearson's χ2 to determine any differences in in-hospital and 30-day mortality for cases defined as major bleeding by ISTH, BARC and TIMI criteria.Results: We included 2,002 cases of OAC related bleeding in the analysis (460 on direct oral anticoagulants, 1,542 on warfarin). ISTH, BARC and TIMI major bleeding definitions were met in 75%, 77% and 29% of cases, respectively. 18% of cases did not meet criteria for major bleeding by any definition. Age, sex, CHA2DS2-VASc and HAS-BLED score, as well as proportion of chronic kidney disease were similar across ISTH-, BARC- and TIMI-defined cases. Over 9 in 10 cases of TIMI-defined major bleeding events involved an intracranial hemorrhage (94.4%), compared to 37% and 36% of cases identified by ISTH or BARC definitions respectively (p<0.001 across three groups). Agreement in case identification between ISTH and BARC was substantial (agreement 89%; Cohen's κ=0.69). On the other hand, agreement between TIMI and both ISTH (agreement 54%; Cohen's κ =0.24) and BARC (agreement 52%; Cohen's κ=0.21) were poor. The association between in-hospital mortality and TIMI-defined major bleeding was higher (29%) than that for ISTH and BARC (17% for both; p<0.001 for TIMI vs. ISTH and TIMI vs. BARC). The association with 30-day mortality showed a similar trend (30%, 18% and 18% for TIMI-, ISTH- and BARC- defined major bleeding events respectively; p<0.001 for TIMI vs. ISTH and TIMI vs. BARC). 6% of cases that were not categorized as major bleeding by ISTH or BARC definitions died within 30 days of hospital presentation, and this was 10% for cases not meeting criteria for TIMI major bleeding (10%, p=0.036 by Pearson's χ2).Conclusions: Among patients with OAC-associated bleeding, major bleeding events identified by ISTH and BARC criteria showed good agreement and similar prognostic utility. Meanwhile, TIMI criteria identified patients with higher clinical risk and subsequent mortality. Patients presenting with OAC-associated bleeding who did not fulfill ISTH or BARC major bleeding criteria had considerable risk of 30-day mortality and was even higher among those not meeting the TIMI criteria. Our findings suggest the need to refine current major bleeding definitions to identify additional patients at risk of death. DisclosuresWells:Bayer: Honoraria; BMS: Honoraria, Research Funding; Sanofi: Honoraria; Janssen: Honoraria. Sholzberg:Amgen: Research Funding; CSL Behring: Research Funding; Octapharma: Research Funding; Shire: Research Funding.

Dilute Russell viper venom time interpretation and clinical correlation: A two-year retrospective institutional review.

The dilute Russell viper venom time (dRVVT) detects lupus anticoagulant (LA). International Society for Thrombosis and Haemostasis (ISTH) guidelines specify positivity criteria, which differ from the assay manufacturer's criteria. Two years of dRVVT testing at our institution were reviewed. For patients with prolonged dRVVT screening times, we evaluated dRVVT results by ISTH and manufacturer's criteria and correlated with the results of other antiphospholipid syndrome (APS) testing (LA-sensitive activated partial thromboplastin time and antiphospholipid antibodies) and with history of thromboembolism and other APS manifestations. Approximately one-fifth of dRVVTs exhibited a prolonged screening time. Among first prolonged dRVVTs, 35% were positive by both ISTH and manufacturer criteria, 44% met neither criteria, and 20% were equivocal (positive by only ISTH or manufacturer). Positivity by ISTH guidelines alone correlated better with other positive APS tests than manufacturer criteria positivity. Positive dRVVTs by both criteria correlated even more strongly with other positive APS assays. We investigated the likelihood of eventual APS diagnosis depending on the testing indication. No patient tested for LA solely for prolonged screening aPTT was subsequently diagnosed with APS. In patients with thrombosis, prolonged dRVVT clotting time not meeting both ISTH and manufacturer criteria was rarely associated with eventual APS diagnosis. We examined the correlation of dRVVT results with other APS testing and clinical outcomes. Interpretation method impacted how dRVVT results related to other APS testing, and, in limited data, to clinical findings. Patients with prolonged dRVVTs meeting only one set of positivity criteria rarely received an APS diagnosis.

An international collaborative study to compare different von Willebrand factor glycoprotein Ib binding activity assays: the COMPASS‐VWF study

Essentials New VWF activity assays are increasingly used but information on their comparability is limited. This is an ISTH SSC-organized study (expert labs, 5 countries) to compare all available assays. VWF activity by six assays correlated well with each other. The new assays show improved characteristics - minor differences are noted. SUMMARY: Background Several new assays have become available to measure von Willebrand factor (VWF) activity. The new assays appear to have improved performance characteristics compared with the old reference standard, ristocetin cofactor activity (VWF:RCo), but information is limited about how they compare with VWF:RCo and each other. Methods The von Willebrand factor Subcommittee of the International Society for Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee (SSC) designed a collaborative study involving expert laboratories from several countries to compare available tests with each other and with VWF:RCo. Eight laboratories from five countries were provided with blinded samples from normal healthy individuals and well-characterized clinical cases. Laboratories measured VWF activity using all tests available to them; data from six laboratories, not affected by thawing during transportation, are included in this study. Results All tests correlated well with VWF:RCo activity (r-values ranged from 0.963 to 0.989). Slightly steeper regression lines for VWF:Ab and VWF:GPIbM were clinically insignificant. The new assays showed improved performance characteristics. Of the commercially available assays, the VWF:GPIbR using the AcuStar system was the most sensitive and could reliably detect VWF activity below 1IUdL-1 . The lower limit of the measuring interval for the VWF:GPIbM and the VWF:GPIbR assays was in the 3-4 and 3-6IUdL-1 range, respectively. Inter-laboratory variation was also improved for most new assays. Conclusion All VWF activity assays correlated well with each other and the VWF:RCo assay. The slight differences in characteristics found in the COMPASS-VWF study will assist the VWF community in interpreting and comparing activity results.

Dilute Russell Viper Venom Time Interpretation and Clinical Correlation: A Two-Year Retrospective Institutional Review

Background:In 2009, the International Society for Thrombosis and Hemostasis (ISTH) issued interpretative guidelines for the performance and interpretation of lupus anticoagulant testing, including the dilute Russell Viper venom test (RVVT). At UCSF, we noted that the manufacturer guidelines approved by the FDA were not equivalent to these ISTH guidelines. As a result, we report RVVT results as positive if both sets of criteria are met, equivocal if only one set of criteria is met, and negative if neither the manufacturer nor the ISTH criteria are met.Study design:We performed a retrospective review of all RVVT testing at UCSF performed between 6/4/2011 and 7/3/2013. Patients who had a RVVT test performed within that time period were included in the study. For patients with a prolonged RVVT screening time, we gathered records of their previous and subsequent antiphospholipid syndrome (APS) testing at UCSF as well as any history of prolonged aPTT. These laboratory data were correlated with any clinical history of clotting, embolism, bleeding, pregnancy morbidity, systemic lupus erythematosus (SLE) and/or death. Clinical history was obtained through review of the UCSF electronic medical record. This study was approved by the UCSF institutional review board (Human Research Protection Program, Committee on Human Research). UCSF uses Precision Biologic (Halifax, Nova Scotia, Canada) LA Check and LA Sure reagents for the RVVT.Findings:21.6% of RVVT tests showed a prolonged clotting time. Of these, 12% met only the ISTH criteria for the diagnosis of LA, 11% met only the manufacturer criteria, 37% were positive by both sets of criteria, and 40% were not positive by either set of criteria. When comparing the manufacturer and ISTH criteria for RVVT positivity, the latter were more predictive of a concomitant positive Staclot LA (Diagnotica Stago, Parsippany, NJ) result (Risk ratio 1.806 (95th CI 1.133-2.877)). When comparing the manufacturer and ISTH criteria for RVVT positivity, the latter was non-significantly associated with a positive aPL immunoassay result (Risk ratio 6.682 (95th CI 0.8965-49.8)). Patients with a positive RVVT result by only ISTH criteria, only manufacturer criteria, or both did not differ in their relative risk for thrombosis, pregnancy morbidity, systemic lupus erythematosus, or death.If prolonged activated partial thromboplastin time was the only reason for testing, none of these patients subsequently were diagnosed with APS.Patients with an initial positive RVVT who were retested according to ISTH recommendations had a significantly increased risk of being diagnosed with APS during our study period (RR 7.827, 95th CI 1.89-32.41) as compared to those patients without an initial positive RVVT. This indicates an RVVT sensitivity of 0.846 and specificity of 0.7 for a diagnosis of APS.Of 26 patients who had a positive RVVT (regardless of Staclot LA result) and had repeat testing, 11 (42%) went on to meet APS criteria. Of 35 patients who had a positive Staclot LA (regardless of RVVT result) and had repeat testing, 13 (37%) went on to meet APS criteria. In contrast, very few patients with only a positive RVVT or only a positive Staclot-LA were diagnosed with APS (2 patients out of 47). Those patients who tested positive on both RVVT and Staclot LA were significantly more likely to have an APS diagnosis than those positive with Staclot LA alone (RR 6.531, 95th CI 1.69-25.25).Conclusion: This observational study should help laboratorians and physicians better interpret the clinical significance of RVVT results. The ISTH guidelines for RVVT interpretation appear to better correlate with Staclot LA positivity. ISTH and manufacturer criteria do not differ in prediction of subsequent thrombosis, pregnancy morbidity, SLE, or death. Whereas the frequently used term "triple-positivity" in antiphospholipid testing implies significant clinical APS risk and is defined by a single positive lupus anticoagulant in the presence of both anticardiolipin and anti-β2-glycoprotein antibodies, we show that those patients with combined positivity for two lupus anticoagulant assays (both RVVT and Staclot LA) have a 6.5-fold higher risk of subsequent APS diagnosis than those with single lupus anticoagulant positivity. DisclosuresWool:Inova Diagnostics: Honoraria.

Comparison of Two Diagnostic Scores of Disseminated Intravascular Coagulation in Pregnant Women Admitted to the ICU.

ObjectiveTo compare the validity of two previously published diagnostic scores of disseminated intravascular coagulation (DIC) in pregnant women admitted to ICU for an acute thrombotic or hemorrhagic complication of delivery and postpartum.MethodsThis was a population based retrospective study of 154 patients admitted to ICU for severe delivery and postpartum complications in a University Hospital. A recently published score (adapted to physiological changes of pregnancy and based on three components: platelet count, prothrombin time difference and fibrinogen) was compared to the International Society for Thrombosis and Hemostasis (ISTH) score (based on four components: platelet count, fibrinogen, prothrombin time, and fibrin related marker). Both scores were calculated at delivery, ICU admission (day 0), day 1 and day 2 during the postpartum ICU stay. The validity of both scores was assessed by comparison with the consensual and blinded analysis of two experts. The sensitivity, specificity, and area under the curve (AUC) of each score were calculated at each time and overall by generalized linear mixed model. The agreement between the two scores was evaluated by the Kappa coefficient.ResultsThe new score had a sensitivity of 0.78, a specificity of 0.97 (p <0.01) and a global AUC of 96% while the ISTH score had a sensitivity of 0.31, a specificity of 0.99 and an AUC of 94% (p <0.01). The Kappa coefficient of correlation between both scores was 0.35. The lower sensitivity of the ISTH score was mainly explained by the lack of fibrinogen and fibrin-related peptides thresholds adapted to the physiological changes of coagulation induced by pregnancy.ConclusionThe new DIC score seem highly discriminant in the subset of patients admitted to the ICU after delivery for an acute specific complication. The ISTH score is not recommended in pregnant women because of its poor sensitivity.

Laboratory Diagnosis of Factor XIII Deficiency in Developing Countries: An Iranian Experience.

Factor XIII (FXIII) deficiency is an extremely rare bleeding disorder with an approximately 12-times higher than the rest of the world. The International Society for Thrombosis and Hemostasis (ISTH) suggested a standard algorithm for precise diagnosis and classification of FXIII deficiency (FXIIID). However, due to lack of investment in proper equipment and procedures in Iran, almost no part of this algorithm can be used to diagnose Iranian patients. Thus, this study proposes a guideline for accurate molecular and laboratory diagnosis of FXIIID based on the available tools. Because this study suggests a simple and reliable algorithm for early diagnosis, it can therefore, reduce the rates of morbidity and mortality of FXIIID patients with this condition.

Pentoxifylline-Induced Thrombocytopenia

Pentoxifylline-induced thrombocytopenia is rare, and information is lacking about its presentation. We describe a 72-year-old Chinese male who developed thrombocytopenia after initiation of pentoxifylline for the treatment of chronic lower limb ischemia due to peripheral artery disease. Venous thromboembolism had been ruled out with an ultrasound. Vascular surgeons had also determined there was no indication for surgical intervention. Four days after initiation of pentoxifylline, he developed thrombocytopenia, and his platelets were 68 × 103/μL. He was not in overt disseminated intravascular coagulation (DIC), based on his International Society for Thrombosis and Hemostasis (ISTH) DIC score of 4. Dengue fever, which is endemic in Singapore, was ruled out. Pseudothrombocytopenia was also excluded with a peripheral blood film. When his platelets continued to fall, pentoxifylline was discontinued on the fifth day of treatment, and platelets normalized 48 hours after discontinuation. Pentoxifylline was a probable cause of thrombocytopenia using the Naranjo Adverse Drug Reaction Probability Scale (score = 7). The patient did not receive further doses of pentoxifylline. Prescribers should be aware of the risk of thrombocytopenia with pentoxifylline therapy and discontinue its use promptly if it is suspected.

Post Operative Thrombosis Among Patients Testing Indeterminate for Lupus Anticoagulant

Background: The presence of the lupus anticoagulant (LA) is an established risk factor for thrombosis especially in the post operative setting. The risk of thrombosis among patients testing indeterminate for lupus anticoagulant is unknown. In our study we aim to estimate the incidence of postoperative thrombosis in this population and determine risk factors.Methods: We studied adult patients undergoing LA testing within 3 months of major surgery at the Cleveland Clinic between 2008 and 2013. The International Society for Thrombosis and Hemostasis (ISTH) defines the following criteria for a positive lupus anticoagulant: 1) a prolonged phospholipid dependent screening test, 2) an inhibitor demonstrated on a mixing study with normal plasma, 3) evidence that the inhibitor is phospholipid dependent, and 4) absence of a coexisting factor inhibitor, direct thrombin inhibitor or heparin. Patients fulfilling some but not all of the ISTH criteria were considered to be LA indeterminate. Patients with previous venous thromboembolism (VTE) and hypercoagulable states were excluded. We collected data on patient demographics, surgery and VTE in the first 30 postoperative days. Patients were divided into different groups based upon the presence of concomitant malignant or rheumatological disease, types of surgery and the utilization of thromboprophylaxis. Associations between categorical variables were determined using Fisher’s exact test. Multivariate logistic regression was performed; variables included age, type of surgery and utilization of pharmacologic thromboprophylaxis.Results: Of 791patients undergoing perioperative lupus anticoagulant testing, 176 were diagnosed LA indeterminate. The median age was 55 years with males comprising 52.3% of the population. Twenty six (14.7%) patients had a concomitant malignancy. Eighteen patients (10.2%) were diagnosed with a rheumatological illness. Seventy four (42.1%) patients underwent cardiac and vascular surgical procedures. General surgery including gastrointestinal surgery accounted for 53 (30.1%) patients. Neurosurgical patients (20) comprised 11.4% of the population studied. Fifteen (8.5%) patients underwent orthopedic surgery and fourteen (8%) patients had urologic procedures. Thirty eight (21.6%,CI 16.1-28.3%) patients developed VTE in the first 30 postoperative days. Of the patients with VTE, 16 (42.1%) had isolated deep vein thrombosis (DVT). Six patients had DVT associated with internal jugular vein (IJV) thrombosis (15.8%). Five patients (13.2%) patients had DVT associated with PE. Two patients (5.2%)had IJV DVT and PE in combination. Thrombosis was also reported at the sites of arteriovenous grafts, portal vein and in the central retinal vein. Twelve (31.5%) clots were related to the presence of indwelling central venous catheters.No significant association between presence of cancer or rheumatological disease and incident thrombosis was identified. Of those tested for beta 2 glycoprotein antibodies and anticardiolipin antibodies, no significant association was observed between presence of post-operative thrombosis and the presence of antibodies. While only 70 patients (39.8%) received any form of pharmacological prophylaxis against VTE, there was significant reduction in the incidence of VTE in patients that received prophylaxis as compared to those that did not. A statistically significant increased odds of thrombosis was observed in the neurosurgical population as compared to the patients undergoing other surgical procedures. On multivariate logistic regression analysis, neurosurgical patients had 3.4 fold increased risk of post operative thrombosis (CI 1.3-9.3) when compared to the rest of the surgical population studied, irrespective of the utilization of thromboprophylaxis.Conclusion: The incidence of thrombosis for patients with an incidental finding of LA indeterminate is 21.6%, comparable to that seen in the general population of patients undergoing similar procedures. This implies that standard guidelines should be used in choosing appropriate post-operative thromboprophylaxis in patients with this laboratory finding. More aggressive anticoagulant regimens do not appear to be necessary, although this remains to be confirmed in a controlled randomized study. DisclosuresNo relevant conflicts of interest to declare.

Thromboprophylaxis In Pregnancy: Are Current Guidelines Working?

Thromboprophylaxis in pregnancy poses many challenges for physicians given the potential complications to both mother and fetus. Given the difficulty of enrolling this population in appropriately designed studies, current guidelines rely on results extrapolated from other populations and observational studies. The purpose of this quality assurance project is to examine thromboprophylaxis in pregnancy and ensure that, by following current practice-based guidelines, we are meeting treatment goals by providing therapy that is both safe and efficacious. A retrospective chart review was completed on all patients between 2008 and 2013 who were treated with prophylactic doses of anticoagulation during their antepartum/postpartum period. Each pregnancy was followed throughout gestation and postpartum to assess for thrombotic events, major bleeding (as per the International Society for Thrombosis and Haemostasis (ISTH) definition), and outcomes. A total of 44 patients were reviewed. Of these, 21 (48%) met criteria for recurrent miscarriage and 19 (43%) had documented thrombophilia. 19 (43%) had a previous history of VTE, and 18 of the 19 (95%) previous VTE were associated with increased hormonal states. There were no antepartum or postpartum thrombotic events. 4 (9%) patients underwent Doppler ultrasound for clinical suspicion of DVT, but all were negative studies. There were no major bleeding episodes. 15 (34%) patients reported some form of minor bleeding, which did not meet ISTH criteria for major bleeds. Of the 21 pregnancies that met criteria for previous recurrent miscarriage, 15 (71%) had successful term deliveries, 1 (5%) had fetal loss, and 5 (24%) unknown outcomes. Given the absence of recurrent thrombosis and major bleeding events in the population examined, it would appear that following current practice guidelines is both a safe and efficacious practice. Disclosures: No relevant conflicts of interest to declare.

The prognostic value of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) deficiency in septic shock patients involves interleukin-6 and is not dependent on disseminated intravascular coagulation

IntroductionADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) deficiency has been reported in patients with sepsis but its clinical relevance and pathophysiology remain unclear. Our objectives were to assess the clinical significance, prognostic value and pathophysiology of ADAMTS13 deficiency in patients with septic shock with and without disseminated intravascular coagulation (DIC).MethodsThis was a prospective monocenter cohort study of patients with septic shock. Von Willebrand Factor, ADAMTS13-related parameters and plasma IL-6 concentration were measured at inclusion to the study. Patients were categorized into three groups according to the presence of ADAMT13 deficiency (<30%) or DIC.ResultsThis study included 72 patients with a median age of 59 years (interquartile range (IQR) 50 to 71). Each of the included patients received vasopressors; 55 (76%) were under mechanical ventilation and 22 (33%) underwent renal replacement therapy. Overall, 19 patients (26%) had DIC, and 36 patients had ADMTS13 deficiency (50%). Patients with DIC, ADAMTS13 deficiency or both were more severe at ICU admission. Mortality was higher in septic shock patients from group one. By multivariate analysis, Simplified Acute Physiology Score 2 (SAPS2) score (odds ratio (OR) 1.11/point; 95% CI 1.01 to 1.24) and ADAMTS13 activity <30% (OR 11.86; 95% CI 1.36 to 103.52) were independently associated with hospital mortality. There was no correlation between ADAMTS13 activity and the International Society for Thrombosis and Haemostasis (ISTH) score (rs = -0.97, P = 0.41) suggesting that ADAMTS13 functional deficiency and DIC were independent parameters. IL-6 level was higher in patients with ADAMTS13 activity <30% [895 (IQR 330 to 1843) pg/mL versus 83 (IQR 43 to 118), P = 0.0003).ConclusionsSeptic shock was associated with a functional deficiency of ADAMTS13, independently of DIC. ADAMTS13 functional deficiency is then a prognostic factor for mortality in septic shock patients, independently of DIC.

DIC Score: Statistical Relationship with PT, APTT, and Simplified Scoring Systems with Combinations of PT and APTT

We looked into the statistical association of prothrombin time (PT) and activated partial thromboplastin time (APTT) with disseminated intravascular coagulation (DIC) score calculated using the International society for thrombosis and haemostasis (ISTH) scoring system. The PT, APTT, PT + APTT, and PT/APTT ratios were evaluated against the DIC score by linear regression analysis in fifty inpatients with suspected DIC. The PT, PT + APTT, and PT/APTT ratios were all found to be statistically significant in predicting DIC scores with P values of 0.02, 0.03, and 0.02, respectively. The APTT alone was not found to be statistically significant in predicting DIC score and had a P value of 0.09. This scoring system does not need d-dimer levels and the platelet count.

Disseminated Intravascular Coagulopathy in the First 24 Hours After Trauma: The Association Between ISTH Score and Anatomopathologic Evidence

Recent studies questioned "classical" concepts in trauma care, including whether disseminated intravascular coagulation (DIC) occurs in trauma. The knowledge on trauma DIC is limited to few studies built on diagnosing DIC with laboratory-based scores. This study explores whether DIC diagnosed by the well-established ISTH (International Society for Thrombosis and Hemostasis) score is corroborated by anatomopathologic findings. Prospective observational cohort study of severely injured (ISS ≥ 16) patients. DIC was diagnosed by the ISTH score throughout the first 24 hours after trauma. All organs surgically removed within 24 hours of trauma were reviewed by two independent pathologists. All autopsy reports were reviewed. Of 423 patients enrolled, ∼11% had "overt DIC" and 85% had "suggestive of non-overt DIC" scores throughout the 24 hours after trauma. "Overt DIC" patients had higher mortality and worse bleeding, receiving more blood and plasma transfusions. One hundred and sixteen patients underwent surgery within 24 hours of trauma, and all 40 excised organs were reviewed by two pathologists. Twenty-seven autopsies reports were reviewed. No anatomopathologic evidence of DIC was identified in the first 24 hours, even after additional histochemical staining. d-dimer was universally elevated after trauma. Common DIC features: platelet count, fibrinogen, clotting time, and factor VIII drop were mostly absent. d-dimer has a disproportional participation in trauma DIC scores. Within 24 hours of trauma, most severely injured patients have DIC scores "suggestive for" or of "overt DIC" but no anatomopathologic evidence of DIC. Considering pathologic findings as the gold standard diagnosis, then DIC is exceptionally uncommon and the ISTH score should not be used for trauma.