Ashkenazi Research Articles

My Grandmothers Baked Cakes for the Queen of Heaven: A Journey from Judaism to Goddess Spirituality

In this article, I trace my story from Jewish ‘war baby’ to thealogian embracing Goddess talk; a search for spirituality, as well as for roots. I explore, in particular, Asherah, whom I accept as the Hebrew Goddess, and I share some of the insights of academics who illuminated my path. I also touch on the latest DNA evidence for the origins of Ashkenazi Jewry and my own search for identity.

Braided Challah

Abstract Braided bread for Shabbat, commonly referred to as challah (plural: challot), is the familiar and traditional form known to Ashkenazic Jews. While the challah itself takes on various shapes, and the number of strands varies, the braided appearance remains an essential and distinctive component of this bread. This defining characteristic of challah was adopted from the baking styles of the communities among which Ashkenazic Jews lived. This article will explore the origins of this particular custom.

Carrier screening in the Mexican Jewish community using a pan-ethnic expanded carrier screening NGS panel

PurposeThe Mexican Jewish community (MJC) is a previously uncharacterized, genetically isolated group composed of Ashkenazi and Sephardi-Mizrahi Jews who migrated in the early 1900s. We aimed to determine the heterozygote frequency of disease-causing variants in 302 genes in this population. MethodsWe conducted a cross-sectional study of the MJC involving individuals representing Ashkenazi Jews, Sephardi-Mizrahi Jews, or mixed-ancestry Jews. We offered saliva-based preconception pan-ethnic expanded carrier screening, which examined 302 genes. We analyzed heterozygote frequencies of pathogenic/likely pathogenic variants and compared them with those in the Genome Aggregation Database (gnomAD). ResultsWe recruited 208 participants. The carrier screening results showed that 72.1% were heterozygous for at least 1 severe disease-causing variant in 1 of the genes analyzed. The most common genes with severe disease-causing variants were CFTR (16.8% of participants), MEFV (11.5%), WNT10A (6.7%), and GBA (6.7%). The allele frequencies were compared with those in the gnomAD; 85% of variant frequencies were statistically different from those found in gnomAD (P <.05). Finally, 6% of couples were at risk of having a child with a severe disorder. ConclusionThe heterozygote frequency of at least 1 severe disease-causing variant in the MJC was 72.1%. The use of carrier screening in the MJC and other understudied populations could help parents make more informed decisions.

Jewish cultural and religious factors and uptake of population-based BRCA testing across denominations: a cohort study.

To evaluate the association of Jewish cultural and religious identity and denominational affiliation with interest in, intention to undertake and uptake of population-based BRCA (Breast Cancer Gene)-testing. Cohort-study set within recruitment to GCaPPS-trial (ISRCTN73338115). London Ashkenazi-Jewish (AJ) population. AJ men and women, >18 years. Participants were self-referred, and attended recruitment clinics (clusters) for pre-test counselling. Subsequently consenting individuals underwent BRCA testing. Participants self-identified to one Jewish denomination: Conservative/Liberal/Reform/Traditional/Orthodox/Unaffiliated. Validated scales measured Jewish Cultural-Identity (JI) and Jewish Religious-identity (JR). Four-item Likert-scales analysed initial 'interest' and 'intention to test' pre-counselling. Item-Response-Theory and graded-response models, modelled responses to JI and JR scales. Ordered/multinomial logistic regression modelling evaluated association of JI-scale, JR-scale and Jewish Denominational affiliation on interest, intention and uptake of BRCA testing. Interest, intention, uptake of BRCA testing. In all, 935 AJ women/men of mean age = 53.8 (S.D = 15.02) years, received pre-test education and counselling through 256 recruitment clinic clusters (median cluster size = 3). Denominational affiliations included Conservative/Masorti = 91 (10.2%); Liberal = 82 (9.2%), Reform = 135 (15.1%), Traditional = 212 (23.7%), Orthodox = 239 (26.7%); and Unaffiliated/Non-practising = 135 (15.1%). Overall BRCA testing uptake was 88%. Pre-counselling, 96% expressed interest and 60% intention to test. JI and JR scores were highest for Orthodox, followed by Conservative/Masorti, Traditional, Reform, Liberal and Unaffiliated Jewish denominations. Regression modelling showed no significant association between overall Jewish Cultural or Religious Identity with either interest, intention or uptake of BRCA testing. Interest, intention and uptake of BRCA testing was not significantly associated with denominational affiliation. Jewish religious/cultural identity and denominational affiliation do not appear to influence interest, intention or uptake of population-based BRCA testing. BRCA testing was robust across all Jewish denominations. Jewish cultural/religious factors do not affect BRCA testing, with robust uptake seen across all denominational affiliations.

DNA, Historical Evidence and The Settlement of Sephardic and Ashkenazic Jews in Colonial Texas

The Lone Star state has long been a symbol of the American West, complete with cowboys, Native Americans, buffalo, cattle drives and the Alamo. Using DNA and genealogical analysis, together with historical documents, this article shows that both the original Spanish settlers and the later “Anglo” arrivals were primarily of Sephardic and Ashkenazic Jewish descent. These findings challenge traditional narratives of “how the West was won”, as well as the prevailing ideology of Anglo-American culture.

Proposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher syndrome

Usher syndrome type I (USH1) is characterized by deafness, vestibular areflexia, and progressive retinal degeneration. The protein-truncating p.Arg245* founder variant of PCDH15 (USH1F) has an ~2% carrier frequency amongst Ashkenazi Jews accounts for ~60% of their USH1 cases. Here, longitudinal phenotyping in 13 USH1F individuals revealed progressive retinal degeneration, leading to severe vision loss with macular atrophy by the sixth decade. Half of the affected individuals were legally blind by their mid-50s. The mouse Pcdh15R250X variant is equivalent to human p.Arg245*. Homozygous Pcdh15R250X mice also have visual deficits and aberrant light-dependent translocation of the phototransduction cascade proteins, arrestin, and transducin. Retinal pigment epithelium (RPE)-specific retinoid cycle proteins, RPE65 and CRALBP, were also reduced in Pcdh15R250X mice, indicating a dual role for protocadherin-15 in photoreceptors and RPE. Exogenous 9-cis retinal improved ERG amplitudes in Pcdh15R250X mice, suggesting a basis for a clinical trial of FDA-approved retinoids to preserve vision in USH1F patients.

Obstetrical and Peri-Operative Management of Patients with Factor XI Deficiency - a Retrospective Observational Study

▪IntroductionFactor XI deficiency (FXI) is an autosomally inherited injury-related bleeding disorder. Although relatively rare worldwide, it is common amongst Ashkenazi and Iraqi Jewish ancestry with a heterozygosity rate as high as 8 to 9%. FXI deficiency does not provoke spontaneous bleeding; however, it predisposes to a potential risk of life-threatening bleeding at childbirth or surgery. Unfortunately, data regarding obstetrical and perioperative management of this condition is scarce, with less than 500 cases reviewed in the last 20 years. Therefore, this study aimed to expand this database and identify factors associated with increased bleeding risk.MethodsWe performed a retrospective chart review of patients (pts) with FXI deficiency who underwent childbirth or other surgical procedures between August 2011 to April 2021 within the Mount Sinai Health System in New York City. Data on age, sex, ethnicity, genotype, family or personal history of bleeding, type of anesthesia, estimated blood loss, peri-procedural bleeding complication, and type and timing of blood product or hemostatic agent administered in the peri-operative period were collected. Prior history of bleeding was defined as 1 or more of the following: easy bruisability, epistaxis, heavy menstrual bleeding, bleeding related to dental, surgical or obstetrical procedure. The paired t-test was used to compare the initial and subsequent FXI levels measured during pregnancy. We performed logistic regression to test the association between historical, laboratory, and procedural variables with the bleeding endpoint (defined as acute postpartum or postoperative hemorrhage or any bleeding warranting non-prophylactic administration of packed red blood cells, fresh frozen plasma [FFP], or tranexamic acid). Receiver operative characteristic (ROC) curve was plotted for FXI levels to identify the cutoff for optimal sensitivity and specificity. Analyses were performed using SPSS software.ResultsWe identified 198 pts who underwent 252 procedures in total- including 143 vaginal deliveries, 64 C-sections and 45 other surgical procedures. Mean age was 36 years with 94% females, and ~70% were Ashkenazi Jews. c.403G>T p.E135X (42%) and c.901T>C p.F301L (44.8%) were the most common genotypes identified. 38 out of 252 procedures resulted in bleeding complications. In multivariable logistic regression, both prior history of bleeding (odds ratio (OR) 8.97, p=0.02) and lower FXI levels ( OR 1.03 per U/dL increase, p=0.05) were independently associated with the bleeding endpoint. Family history of bleeding, ethnicity, genotype, pre-procedural PTT and platelet levels were not associated with bleeding risk. There were no cases of epidural or spinal hematomas associated with neuraxial anesthesia in our cohort. Mean FXI level for pts receiving neuraxial anesthesia was 50 U/dl (3-118 U/dl). Five pts who had a negative bleeding history despite surgical challenges received neuraxial anesthesia at FXI level <10 U/dl without any complications (only 1/5 received prophylactic FFP). Mean FXI level for pts receiving prophylactic FFP was 25.6 U/dl (range 1-71 U/dl). 8 out of 21 (38%) pts suffered a bleeding complication despite prophylactic FFP use. ROC analyzing FXI levels as a risk factor for the bleeding endpoint resulted in an AUC of 0.605 with specificity of 96%, 94%, 91%, 83%, 49% and sensitivity of 11%, 12%, 19%, 35%, 65% respectively for cut-off values of 10, 20, 30, 40 and 50 U/dl. Of note, there was no significant variation in FXI levels during pregnancy [mean first measurement was 49.7 U/dl vs final measurement of 48.3 U/dl, p=0.3].ConclusionsPersonal history of bleeding is the strongest predictor of perioperative or obstetrical bleeding in pts with FXI deficiency. Higher FXI levels correlate with a slightly lower but statistically significant odds of surgical bleeding. Although a FXI level cut-off of 40 U/dl may predict bleeding risk with reasonable specificity (83%), it lacks sensitivity and must be interpreted in the context of personal bleeding history. FXI levels remain stable during pregnancy and repeat measurements may not be necessary. Neuraxial anesthesia appears to be safe to use in this cohort. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Ethnic-specific BRCA1/2 variation within Asia population: evidence from over 78 000 cancer and 40 000 non-cancer cases of Indian, Chinese, Korean and Japanese populations

BackgroundGermline mutation in BRCA1 and BRCA2 (BRCA) is genetic predisposition for breast and ovarian cancer. Identification of mutation carriers is a critical step to prevent and treat the cancer in...

Re-evaluating cancer risks associated with the CHEK2 p.Ser428Phe Ashkenazi Jewish founder pathogenic variant.

A missense variant (p.Ser428Phe [S428F]) in the CHEK2 gene is reportedly associated with a 2-3 fold increase in breast cancer risk in Ashkenazi Jews. This study aimed to re-evaluate cancer risks conferred by the CHEK2 S428F variant in Ashkenazi Jews. De-identified data from CHEK2 S428F variant carriers sequenced with multigene panels were analyzed. Overall, 486/341,531 (0.14%) cases of all ethnicities diagnosed with any cancer type were CHEK2 S428F carriers, of whom 243/9980 self-identified as Ashkenazi Jews and carried this risk variant only. Compared with ethnically matched non-cancer controls, across all cancer cases, this variant was not more prevalent (p = 0.271). Specifically, variant prevalence was not different in breast cancer cases compared with controls. Though the variant was shown to be enriched in pancreatic cancer cases (p = 0.008), sample size was small. The CHEK2 S428F variant was not overrepresented in Ashkenazi Jews with breast cancer and most other cancer types analyzed, except for pancreatic cancer, compared with ethnically matched non- cancer controls. These findings should prompt reevaluating ethnic-specific CHEK2 S428F cancer attributable risk.

HEMOPHILIA C: A RARE CASE REPORT IN WOMAN

Factor XI deficiency (Hemophilia C) is a rare bleeding disorder that was first described in 1953 by Rosenthal et al. in patients who experienced severe bleeding after dental extractions. The estimated prevalence is about 1 in 1 million with increased prevalence among Ashkenazi Jews (8-9%). Patients are generally classified into three categories based on the factor XI levels: severe (<15-20% of normal), intermediate (20- 40%) and mild (>40%). Distinct from hemophilia A and B, FXI deficiency usually presents as post-traumatic bleeding and rarely manifests as spontaneous bleeding. To report a case of severe Hemophilia C in a 70-year-old woman. A 70-year-old woman was referred to Fundação Hemominas Juiz de Fora, Brazil due to gingivorrhagia and recurrent epistaxis. She reports having already received blood transfusions due to massive bleeding after surgeries, including cholecystectomy, cesarean section and hysterectomy. The patient is the sixth daughter of a seven children family. Her mother, three siblings and one nephew also have coagulation disorders, unknown Jewish descendancy. The laboratory study showed normal whole blood count, screening tests for coagulation disorders showed normal platelet count and an increase of activated partial thromboplastin time (aTTP). A plasma dosage of coagulation factors was performed, with results shown in Table 1. With the reduction of factor XI activity levels (3.59%), the increase of aTTP and the normality of other tests, the diagnosis of Hemophilia C was established. A family study was performed with heredogram, shown in Figure 1. Hemophilia C is a rare bleeding disorder with a wide variability in clinical presentation. Adequate diagnosis is essential to minimize severe hemorrhagic conditions, specially in surgical procedures. Family screening is recommended if a member has FXI deficiency and prevalence may vary in Brazil due to the wide miscegenation.

Bright Star, Green Light: The Beautiful Works and Damned Lives of John Keats and F. Scott Fitzgerald

Bright Star, Green Light: The Beautiful Works and Damned Lives of John Keats and F. Scott Fitzgerald

Glucocerebrosidase Activity is not Associated with Parkinson's Disease Risk or Severity.

ABSTRACTBackgroundMutations in the GBA gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are risk factors for Parkinson's disease (PD).ObjectiveTo explore the association between GCase activity, PD phenotype, and probability for prodromal PD among carriers of mutations in the GBA and LRRK2 genes.MethodsParticipants were genotyped for the G2019S‐LRRK2 and nine GBA mutations common in Ashkenazi Jews. Performance‐based measures enabling the calculation of the Movement Disorder Society (MDS) prodromal probability score were collected.ResultsOne hundred and seventy PD patients (102 GBA‐PD, 38 LRRK2‐PD, and 30 idiopathic PD) and 221 non‐manifesting carriers (NMC) (129 GBA‐NMC, 45 LRRK2‐NMC, 15 GBA‐LRRK2‐NMC, and 32 healthy controls) participated in this study. GCase activity was lower among GBA‐PD (3.15 ± 0.85 μmol/L/h), GBA‐NMC (3.23 ± 0.91 μmol/L/h), and GBA‐LRRK2‐NMC (3.20 ± 0.93 μmol/L/h) compared to the other groups of participants, with no correlation to clinical phenotype.ConclusionsLow GCase activity does not explain the clinical phenotype or risk for prodromal PD in this cohort. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

PD43-07 CLINICAL CHARACTERISTICS ASSOCIATED WITH HIGH-RISK CANCER-PREDISPOSITION GERMLINE MUTATIONS IN PATIENTS WITH UROTHELIAL CARCINOMA: IMPLICATIONS FOR GENETIC TESTING

PD43-07 CLINICAL CHARACTERISTICS ASSOCIATED WITH HIGH-RISK CANCER-PREDISPOSITION GERMLINE MUTATIONS IN PATIENTS WITH UROTHELIAL CARCINOMA: IMPLICATIONS FOR GENETIC TESTING

Major Trends in the Historiography of European Ashkenazic Jews from the 1970s to the Present

This article focuses on shifts in Jewish historiography of Ashkenazic Jews in Europe of the pre-modern period. It describes the denouement of traditional historiography— which generally assumes that more often than not Jews and non-Jews lived separate from one another—and compares it to two trends that I denominate exchange and interaction historiography that have gained momentum from the last third of the twentieth century. In contrast to scholars working in the traditional vein, exchange and interaction historians view Jews and non-Jews as interconnected and entangled. Exchange historians deal primarily with Jewish and non-Jewish cultural interrelatedness, whereas interaction historians overwhelmingly focus on interpersonal contacts. I use the terms exchange and interaction historiography because they comprehensibly flag as well as qualify distinctions in post-traditional historiography’s conception of Jewish and non-Jewish relations. Methodologically, however, there is considerable overlap between these three historiographical approaches insofar as they all employ the concept of difference as a central analytical tool. The notion of difference prompts scholars to focus first and foremost on what distinguished Jews and non-Jews instead of what they shared, and consequently to depict their relations as dichotomous. In this article, I argue that the insistence on the Jewish/non-Jewish binary forestalls possible innovations that exchange and interaction historians might otherwise pioneer in their approaches. The proposed remedy for this predicament is to replace difference with similarity as an analytical instrument and to focus on intercultural commonalities rather than distinctions. Various scholars have already made efforts to transcend the Jewish/non-Jewish binary but have fallen short of achieving their goal by failing to base their work on a sufficiently rigorous conceptual framework, such as similarity.

Genetic and phylogeographic evidence for Jewish Holocaust victims at the Sobib\xf3r death camp

Six million Jews were killed by Nazi Germany and its collaborators during World War II. Archaeological excavations in the area of the death camp in Sobibór, Poland, revealed ten sets of human skeletal remains presumptively assigned to Polish victims of the totalitarian regimes. However, their genetic analyses indicate that the remains are of Ashkenazi Jews murdered as part of the mass extermination of European Jews by the Nazi regime and not of otherwise hypothesised non-Jewish partisan combatants. In accordance with traditional Jewish rite, the remains were reburied in the presence of a Rabbi at the place of their discovery.

Homologous Recombination Deficiency in Pancreatic Cancer: A Systematic Review and Prevalence Meta-Analysis.

PURPOSETo analyze the prevalence of homologous recombination deficiency (HRD) in patients with pancreatic ductal adenocarcinoma (PDAC).MATERIALS AND METHODSWe conducted a systematic review and meta-analysis of the prevalence of HRD in PDAC from PubMed, Scopus, and Cochrane Library databases, and online cancer genomic data sets. The main outcome was pooled prevalence of somatic and germline mutations in the better characterized HRD genes (BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, RAD51, and the FANC genes). The secondary outcomes were prevalence of germline mutations overall, and in sporadic and familial cases; prevalence of germline BRCA1/2 mutations in Ashkenazi Jewish (AJ); and prevalence of HRD based on other definitions (ie, alterations in other genes, genomic scars, and mutational signatures). Random-effects modeling with the Freeman-Tukey transformation was used for the analyses. PROSPERO registration number: (CRD42020190813).RESULTSSixty studies with 21,842 participants were included in the systematic review and 57 in the meta-analysis. Prevalence of germline and somatic mutations was BRCA1: 0.9%, BRCA2: 3.5%, PALB2: 0.2%, ATM: 2.2%, CHEK2: 0.3%, FANC: 0.5%, RAD51: 0.0%, and ATR: 0.1%. Prevalence of germline mutations was BRCA1: 0.9% (2.4% in AJ), BRCA2: 3.8% (8.2% in AJ), PALB2: 0.2%, ATM: 2%, CHEK2: 0.3%, and FANC: 0.4%. No significant differences between sporadic and familial cases were identified. HRD prevalence ranged between 14.5%-16.5% through targeted next-generation sequencing and 24%-44% through whole-genome or whole-exome sequencing allowing complementary genomic analysis, including genomic scars and other signatures (surrogate markers of HRD).CONCLUSIONSurrogate readouts of HRD identify a greater proportion of patients with HRD than analyses limited to gene-level approaches. There is a clear need to harmonize HRD definitions and to validate the optimal biomarker for treatment selection. Universal HRD screening including integrated somatic and germline analysis should be offered to all patients with PDAC.

Without a compass: Salonikan Jews in Nazi Concentration Camps and later

During the Holocaust, the largest Sephardi community in the world located in Saloniki was almost completely destroyed. Despite their limited number in comparison with that of Ashkenazi Jews, the Salonikan Jews, initially deported to Auschwitz Birkenau and Bergen Belsen, went through all the hardest experiences and were sent to many camps in occupied Poland, and in Germany. This article explores, using archival documents and the testimonies, the geographical directions of their deportations. It also analyses historical coordinates and the Salonikan Jews’ characteristics which affected their destinations and the itinerary with which they were forced to cope.

Factor XI Deficiency Is Not Associated with Increased Risk of Pneumonia in Adults

Background: Factor XI (FXI) deficiency is a rare bleeding disorder, common in Ashkenazi Jews. Recently, target FXI as antithrombotic therapy became real issue as FXI antisense oligonucleotide appeared safe and efficient for preventing post- operative deep vein thrombosis following knee replacement (Buller et al. NEJM2015). The fact that in two models of Klebsiella pneumonia and Streptococcus pneumonia of FXI knock out (KO) mice there was an increased lethality as a result of enhanced bacterial overgrowth and dissemination along with augmented inflammatory response (Stroo et al. JTH 2017), incited us to explore whether patients with FXI deficiency harbor increased risk of pneumonia or increased pneumonia fatality in comparison to individuals with normal factor XI activityMethods: This historical cohort study was performed by using the electronic database of the largest health care provider in Israel. All adults tested for FXI activity between 2002 and 2014 were included in the study. FXI activity was classified into three categories; normal (activity >50%), mild-moderate deficiency (activity: 20-50%), and severe deficiency (activity <20%). The cohort was followed until December 31, 2015 for incident overall pneumonia and severe pneumonia defined as pneumonia requiring hospitalization. The association was assessed using Cox proportional regression models with adjustment for age, gender, smoking status , diabetes, chronic obstructive disease ,ischemic heart disease, cirrhosis, previous stroke, malignancy, previous pneumonia, influenza vaccine, as well as pneumococcal vaccineResults: Of the 10,193 included patients; 8,958 (87.9%) had normal FXI activity, 804 (7.9%) had mild-moderate deficiency and 431 (4.2%) had severe deficiency. A total of 579 individuals had pneumonia and 221 individuals had severe pneumonia during follow up. Compared to individuals with normal FXI activity the adjusted HR for overall pneumonia was 0.81 (95% CI, 0.60-1.10) in those with mild-moderate deficiency, and 0.97 (0.68-1.37) in those with severe factor XI deficiency. The adjusted HR for severe pneumonia was 0.86 (95% CI, 0.56-1.30) in those with mild-moderate deficiency, and 0.86 (0.51-1.40) in those with severe FXI deficiency.Of the 579 patients with pneumonia; 33 (5.7%) and 47 (8.1%) patients died within 30 days and 90 days, respectively. Compared to individuals with normal FXI activity the adjusted HRs for 30 days and 90 days mortality were 0.50 (0.15-1.7) and 0.47 (0.17-1.30), respectivelyin those with mild-moderate deficiency, and 0.81 (0.23-2.9) and 0.47 (0.14-1.60), respectively in those with severe FXI deficiencyConclusions: FXI deficiency is not associated with increased incidence of pneumonia or with increased mortality among patients with pneumonia and as such it is suggested that FXI target therapy can be applied in adult patients without the fear of exposing them to increased risk of pneumonia DisclosuresNo relevant conflicts of interest to declare.

The Risk for Major Cardiovascular Event and Venous Thromboembolism in Patients with Factor VII and Factor V Deficiency.

IntroductionIsrael contains within it a unique variety of groups predisposed to autosomal recessive diseases secondary to the history of segregated religious communities. Indicated groups include Ashkenazi Jews and Israeli Arabs. Factor VII deficiency and Factor V deficiency are among the conditions that can be included in this group of diseases. Due to the risk for bleeding and delayed coagulation as a result of a deficiency in one of these factors, it has been postulated that an underlying cardiovascular benefit may protect the factor VII or factor V deficient individuals from developing an adverse cardiovascular event or venous thromboembolism. The objective of this study is to assess the association between Factor V and Factor VII deficiency with adverse cardiovascular event and venous thromboembolismMethodsThis historical cohort study was performed using the electronic database of Clalit Health Services, the largest health care provider in Israel. The study was approved by a centralized IRB committee. We identified all individuals who were tested for either Factor V activity or Factor VII activity between January 1, 2004 and June 30, 2017. We excluded individuals with liver cirrhosis who were tested for Factor V and Factor VII activity and patients treated with vitamin K antagonists who were tested for factor VII activity. Follow up started in January 2004 and ended in June 30, 2017. Subjects were included if they were 18 years or older at the start of follow up. Factor activity was classified into three categories; normal (activity >50%), mild deficiency (activity = 30-50%), and moderate-severe deficiency (activity ≤30%). The study outcomes included incidence of cardiovascular events (composite of myocardial infarction, stroke, and TIA) and venous thromboembolism (VTE). We used Cox proportional hazard regression analysis to assess the association between time to event and coagulations factors activity using normal activity (>50%) as reference category, and adjusting for potential confounders.ResultsOf the 2,021 included individuals tested for Factor V activity 1,681 (83.2%) had normal factor V activity, 195 (9.6%) had mild deficiency, and 145 (7.2%) had moderate-severe deficiency. Compared to individuals with normal activity the adjusted hazard ratio (HR) for cardiovascular events was 1.10 (95% CI, 0.63-1.90) in those with mild deficiency, and 0.95 (95% CI, 0.49-1.8) in those with moderate-severe factor XI deficiency. None of the 195 patients with mild Factor V deficiency had VTE during follow up, therefore those with Factor V deficiency (activity <50%) were classified into one group. The incidence of VTE was lower in those with factor V deficiency (activity <50%) compared to those with normal activity; adjusted HR = 0.28 (95% CI, 0.09-0.91).Of the 2,558 included individuals tested for Factor VII activity 1,440 (56.3%) had normal factor VII activity, 545 (21.3%) had mild deficiency, and 573 (22.4%) had moderate-severe deficiency. Compared to individuals with normal activity the adjusted hazard ratio (HR) for cardiovascular events was 1.38 (95% CI, 0.89-2.10) in those with mild deficiency, and 1.28 (95% CI, 0.84-1.9) in those with moderate-severe factor VII deficiency. Compared to individuals with normal activity the adjusted hazard ratio (HR) for VTE was 1.40 (95% CI, 0.65-3.20) in those with mild deficiency, and 0.75 (95% CI, 0.29-1.9) in those with moderate-severe factor VII deficiency.DiscussionFactor V deficiency but not Factor VII deficiency is associated with significant decreased incidence of VTE. No significant association was detected between Factor V deficiency or Factor VII deficiency and cardiovascular events. DisclosuresNo relevant conflicts of interest to declare.

Risk for Major Bleeding in Patients with Severe Factor XI Deficiency Treated with Aspirin and Clopidogrel

IntroductionIsrael contains within it a unique variety of groups predisposed to autosomal recessive diseases secondary to the history of segregated religious communities. Indicated groups include Ashkenazi Jews and Israeli Arabs. Factor XI deficiency is one of the conditions that can be included in this group of diseases. It is reported to have a prevalence of 8-13.4% within the Ashkenazi Jewish community. Due to the risk for bleeding and delayed coagulation as a result of a deficient Factor XI, it has been suggested to avoid use of Aspirin and Clopidogrel in patients with severe deficiency. However, cardiovascular interventions mandate use of anti-aggregation therapy. We investigated the risk for major bleeding events in patients with severe factor XI deficiency treated with Aspirin and Clopidogrel.MethodsThis is an observational, historical cohort study performed using the electronic data base of Clalit Health organization, largest HMO in Israel. The objective of this study is to determine the incidence of major bleeding in patients with severe Factor XI deficiency (activity ≤ 15%). The study was approved by a centralized IRB committee. In the population of subjects with severe factor XI deficiency we identified subjects treated with Aspirin alone (n=126), Clopidogrel alone (n=38), and subjects treated with both simultaneously (n=21). Individuals were followed retrospectively, during the time on anti-aggregation treatment, for the occurrence of bleeding episodes classified according to bleeding severity; life threatening bleeding, severe bleeding (needed blood transfusion), and minor bleedingResultsOne hundred and eighty five subjects with severe factor XI deficiency were treated with anti-aggregation therapy. Most of the patients treated with Aspirin (68%) followed by Plavix (21%) and both (11%). Among patients treated with aspirin 4.7% (6/126) had life threatening bleeding and 2.3% (3/126) had minor bleeding. Among patients treated with Clopidogrel 2.6% (1/38) had life threatening bleeding, 2.6% (1/38) had severe bleeding, and 2.6% (1/38) had minor bleeding. Among patients treated with Aspirin and Plavix 4.7% (1/21) had life threatening bleeding following a trauma but no other bleeding was observed.DiscussionUse of Aspirin and/or clopidogrel in patients with severe factor XI deficiency is associated with overall low risk for major bleeding. The use of Clopidogrel doesn't seem to add significantly to the risk of bleeding in this unique population. DisclosuresNo relevant conflicts of interest to declare.