Distinctive patterns of sequential platelet counts following blunt traumatic brain injury predict outcomes.

OBJECTIVE: To determine the role of platelet counts in the context of the decision to treat patients with non-compounded, non-surgically-treated blunt traumatic brain injury (NCNS-bTBI) with anticoagulants/antiaggregants. METHODS: A retrospective analysis of 141 anticoagulants/antiaggregants-naïve patients with NCNS-bTBI. Changes in PT-INR and prolonged aPTT were examined and correlated with Marshall and Rotterdam scores, clinical and neuroradiological outcomes. RESULTS: Three groups of platelet counts were identified. Group 1 (83% of patients) had normal platelet counts (150,000-450,000 platelets/mm3) from admission to discharge. Group 2 (13%) developed transient thrombocytopenia (<150,000 platelets/mm3) 2-3 days post-trauma. Group 3 (4%) developed extreme thrombocytosis > 1,000,000/mm3 platelets 6-9 days post-trauma. Neither acute coagulopathy of trauma nor progressive hemorrhagic insults followed NCNS-bTBI. Moreover, while patients with thrombocytosis/extreme thrombocytosis presented with a worse Glasgow coma score (GCS) on admission (8.8 ± 2.9 vs. 13 ± 2, p < 0.01) and had longer hospitalization (13.5 ± 10.4 vs. 4.5 ± 2.1 days), their improvement at discharge was the highest (delta GCS, 4 ± 2.8 vs. 1.2 ± 2.1, p = 0.05). Traumatic subarachnoid hemorrhage was associated with isolated thrombocytosis and 'best improvement.' No thromboembolic or hemorrhagic complications occurred. CONCLUSION: NCNS-bTBI, thrombocytosis was correlated with better outcomes and was not associated with an increased risk for developing thromboembolism or hemorrhage, precluding the immediate need for any additional antiaggregates.

Maternal Anti-HPA-1a Antibodies Increase Endothelial Cell Apoptosis and Permeability.

Intracranial hemorrhage (ICH) associated with fetal/neonatal alloimmune thrombocytopenia (FNAIT) is attributed mainly to endothelial damage caused by binding of maternal anti-HPA-1a antibodies to the αvß3 integrin on endothelial cells (ECs). We examined the effect of anti-HPA-1a antibodies on EC function using 2 EC lines from different vascular beds, HMVEC of dermal origin and hCMEC/D3 of cerebral origin. Anti-HPA-1a sera significantly increased apoptosis in both HMVEC and hCMEC/D3 cells and permeability in hCMEC/D3 cells only. This increase in both apoptosis and permeability was significantly inhibited by a monoclonal anti-ß3 antibody (SZ21) binding to the HPA-1a epitope. Our results indicate that (1) maternal anti-HPA-1a antibodies impair EC function by increasing apoptosis and permeability and (2) ECs from different vascular beds vary in their susceptibility to pathological effects elicited by maternal anti-HPA-1a antibodies on EC permeability. Examination of maternal anti-HPA-1a antibodies for their effect on EC permeability may predict potential ICH associated with FNAIT.

An impact of lipid profile and lipid lowering drugs on ≥70 year olds of an upper socioeconomic class: a retrospective cohort study.

BACKGROUND: Life expectancy has greatly increased, generating an improvement in screening programs for disease prevention, lifesaving drugs and medical devices. The impact of lowering low-density lipoprotein cholesterol (LDL-C) in the very elderly is not well-established. Our aim was to explore the association of LDL-C, high density lipoprotein cholesterol (HDL-C) and lipid lowering drugs (LLDs) on cognitive decline, malignancies and overall survival. METHODS: This was a retrospective cohort study. Our study comprised 1498 (72.7%) males and 561 (27.3%) females, aged ≥70 who had attended the Institute for Medical Screening (IMS), Sheba Medical Center, Israel at least twice during 2013-2019. Data were obtained from the computerized database of the IMS. A manual quality control to identify potential discrepancies was performed. RESULTS: Overall, 6.3% of the subjects treated with LLDs (95/1421) versus 4.2% not treated (28/638), cognitively declined during the study years. No statistically significant effects of LDL-C, HDL-C and LLDs on cognitive decline were observed after correcting for age, prior stroke and other vascular risk factors. With regard to cancer, after adjusting for confounders and multiple inferences, no definite relationships were found. CONCLUSIONS: This analysis of an elderly, high socioeconomic status cohort suggests several relationships between the use of LLDs and health outcomes, some beneficial, especially, with regard to certain types of cancer, but with a higher risk of cognitive decline. Further studies are warranted to clarify the health effects of these medications in the elderly.

The effect of civil and military flights on coagulation, fibrinolysis and blood flow: insight from a rat model.

BACKGROUND: Air travel thrombosis continues to be a controversial topic. Exposure to hypoxia and hypobaric conditions during air travel is assumed a risk factor. The aim of this study is to explore changes in parameters of coagulation, fibrinolysis and blood flow in a rat model of exposure to hypobaric conditions that imitate commercial and combat flights. METHODS: Sixty Sprague-Dawley male rats, aged 10 weeks, were divided into 5 groups according to the type and duration of exposure to hypobaric conditions. The exposure conditions were 609 m and 7620 m for 2 and 12 h duration. Blood count, thrombin- antithrombin complex, D-dimer, interleukin-1 and interleukin-6 were analyzed. All rats went through flight angiography MRI at day 13-post exposure. RESULTS: No effect of the various exposure conditions was observed on coagulation, fibrinolytic system, IL-1 or IL-6. MRI angiography showed blood flow reduction in lower limb to less than 30% in 50% of the rats. The reduction in blood flow was more pronounced in the left vessel than in the right vessel (p = 0.006, Wilcoxon signed rank test). The extent of occlusion differed across exposure groups in the right, but not the left vessel (p = 0.002, p = 0.150, respectively, Kruskal-Wallis test). However, these differences did not correlate with the exposure conditions. CONCLUSION: In the present rat model, no clear correlation between various hypobaric conditions and activation of coagulation was observed. The reduction in blood flow in the lower limb also occurred in the control group and was not related to the type of exposure.

Exploring the global landscape of genetic variation in coagulation factor XI deficiency.

Factor XI (FXI) deficiency is an autosomal bleeding disorder, usually posttrauma or postsurgery, characterized by reduced levels of coagulation FXI in plasma. The disease is highly prevalent in Ashkenazi Jews (heterozygote frequency, ∼9%), whereas it is considered a rare condition in most populations (prevalence of the severe deficiency, 1 in 106 in the white population). So far, >190 causative mutations have been identified throughout the F11 gene. To have a global landscape of genetic variation of F11, we explored publicly available exome-based data obtained from >60 000 individuals belonging to different ethnicities (Exome Aggregation Consortium resource). This analysis revealed profound differences in heterozygote frequencies among populations (allele frequencies: African = 0.0016; East Asian = 0.0045; European = 0.0036; Finnish = 0.00030; Latino = 0.0021; South Asian = 0.0015), and a prevalence significantly higher than that reported so far (eg, the calculated prevalence of the severe deficiency in Europeans would be: 12.9 in 106). In addition, this analysis allowed us to evidence recurrent and ethnic-specific mutations: p.Phe223Leu in Africans (23.5% of all mutated alleles), p.Gln263X and p.Leu424CysfsX in East Asians (28.2% and 20.5%, respectively), and p.Ala412Thr in Latinos (25%).

Safety of cataract surgery in patients treated with the new oral anticoagulants (NOACs).

PURPOSE: To evaluate the safety of phacoemulsification of cataract in patients taking new oral anticoagulants (NOACs). METHODS: In a prospective case series, consecutive patients on NOACs (dabigatran, rivaroxaban, or apixaban) who were referred for uncomplicated cataract surgery to the eye institute underwent a thorough ophthalmological and hematological evaluation. Rivaroxaban and apixaban anti-factor Xa tests, and diluted thrombin time for dabigatran, were used for monitoring anticoagulation levels in blood. Blood was drawn for these tests just prior to surgery and at a peak level of the drug at about 4 h post-surgery (2 h after the drug was given). All surgeries were videotaped and patients were examined at 1 and 7 days after the operation. The main outcome measures included assessment of intra-operative, postoperative ocular bleeding, and other related complications. RESULTS: Thirty-five eyes of 25 unrelated patients ranging in age from 63 to 92 years (mean 77.6 years) underwent phacoemulsification. Intra-operative bleeding was observed in 5 eyes from the conjunctiva or limbus at the main incision site. No intraocular bleeding occurred. No hemorrhagic complications were observed during the 1-week follow-up. According to anti-factor Xa levels prior to surgery and following surgery, 85% of the patients were on therapeutic levels of NOACs. CONCLUSIONS: Clear corneal incision phacoemulsification performed under topical anesthesia can be safely performed in simple cases of cataract without discontinuing NOAC treatment.

Are transient and shear wave elastography useful tools in Gaucher disease?

Up to now, there are no reliable biochemical markers or imaging that could reveal early tissue damage in Gaucher disease. Therefore, we addressed whether elastography technique can serve as a tool for evaluating patients with Gaucher disease. The study included 42 patients with Gaucher disease type I and 33 patients with liver cirrhosis as well as 22 healthy volunteers. Ultrasound and Doppler examination was performed on each participant prior to apply transient and 2D shear wave elastography. In Gaucher disease the median stiffness of the spleen as assessed by transient elastography (TE) and shear wave elastography (SWE) was 35KPa and 22KPa respectively in contrast to the median stiffness of healthy controls (16.95 and 17.5KPa, p=0.0028 and p=0.0002, respectively) and of patients with cirrhosis (45KPa and 34.5KPa, p=0.015 and p<0.0001 respectively). The liver stiffness in GD as measured by TE and SWE had median values of 7.1KPa and 7KPa respectively, slightly higher than in the healthy controls, but much smaller than for the cirrhotic patients (medians of 24.2KPa and 21KPa). In conclusion, a transient and shear wave elastography show a significant promise as noninvasive and reproducible tools to differentiate Gaucher disease from healthy controls and among those with splenomegaly from cirrhotic patients.

Factor XI Deficiency Protects Against Atherogenesis in Apolipoprotein E/Factor XI Double Knockout Mice.

OBJECTIVE: Atherosclerosis and atherothrombosis are still major causes of mortality in the Western world, even after the widespread use of cholesterol-lowering medications. Recently, an association between local thrombin generation and atherosclerotic burden has been reported. Here, we studied the role of factor XI (FXI) deficiency in the process of atherosclerosis in mice. APPROACH AND RESULTS: Apolipoprotein E/FXI double knockout mice, created for the first time in our laboratory. There was no difference in cholesterol levels or lipoprotein profiles between apolipoprotein E knockout and double knockout mice. Nevertheless, in 24-week-old double knockout mice, the atherosclerotic lesion area in the aortic sinus was reduced by 32% (P=0.004) in comparison with apolipoprotein E knockout mice. In 42-week-old double knockout mice, FXI deficiency inhibited atherosclerosis progression significantly in the aortic sinus (25% reduction, P=0.024) and in the aortic arch (49% reduction, P=0.028), with a prominent reduction of macrophage infiltration in the atherosclerotic lesions. CONCLUSIONS: FXI deprivation was shown to slow down atherogenesis in mice. The results suggest that the development of atherosclerosis can be prevented by targeting FXI.

Fluorescence lifetime imaging of DAPI-stained nuclei as a novel diagnostic tool for the detection and classification of B-cell chronic lymphocytic leukemia.

B-cell chronic lymphocytic leukaemia (B-CLL) and B-cell precursor acute lymphoblastic leukaemia (B-ALL) are the most common type of leukaemia in adults and children, respectively. Today, fluorescence in situ hybridization (FISH) is the standard for detecting chromosomal aberrations that reflect adverse and favorable outcome. This study revealed a new, simple, and fast diagnostic tool to detect pathological cells by measuring and imaging the fluorescence lifetime (FLT) using FLT imaging microscopy (FLIM) of the peripheral blood (PB) cells of B-CLL samples that were labeled with the DNA binder, DAPI. The FLT of DAPI in healthy individuals was found to be 2.66 ± 0.12 ns. In contrast, PB cells of B-CLL and BM cells of B-ALL patients were characterized by a specific group distribution of the FLT values. The FLT of DAPI was divided into four subgroups, relative to 2.66 ns: short+, normal, prolonged, and prolonged+. These alterations could be related to different chromatin arrangements of B-CLL and B-ALL interphase nuclei. Notably, extremely long FLT of nuclear DAPI correlate with the presence of extra chromosome 12, while moderate increases compared to normal characterize the deletion of p53. Such correlations potentially enable a FLT-based rapid automatic diagnosis and classification of B-CLL even when the frequency of genetic and chromosomal abnormalities is low. © 2016 International Society for Advancement of Cytometry.

Acute renal artery occlusion: Presentation, treatment, and outcome.

OBJECTIVE: Acute renal artery occlusion is an uncommon disease requiring rapid diagnosis for prevention of kidney loss or permanent kidney damage. The purpose of this study was to identify patients with acute kidney infarction; to characterize their presentation, imaging, and treatment; and to compare the subgroup of patients who underwent catheter-directed thrombolysis (CDT) with those who were treated without intervention. METHODS: Hospital records between 2005 and 2015 were queried for keywords suggestive of kidney infarction. Patients were divided into two groups: the CDT group and the noninterventional group. Data collected included demographics, comorbidities, methods of diagnosis, and time from presentation to diagnosis. For patients treated with CDT, additional data collected included details of thrombolytic therapy and follow-up studies. The two groups were compared regarding their clinical characteristics and outcome. RESULTS: Forty-two patients were diagnosed with acute kidney infarction; 13 (31%) were treated with CDT and 29 (69%) were treated conservatively. Median time from presentation to diagnosis was 42 hours in the CDT group and 32 hours in the untreated group. Among the CDT group, complete or partial resolution of the thrombus was seen in all patients. Two required permanent dialysis, both renal transplant patients. Median follow-up was 30 months (interquartile range, 2.7-46.2) in the CDT group and 13 months (interquartile range, 0.11-16) in the noninterventional group. Mean creatinine clearance at diagnosis and at last follow-up was 74.3 and 54.6 mL/min, respectively, in the CDT group (a decrease of 27%; P = .032) and 66.1 and 60 mL/min in the conservatively treated group (a decrease of 9%; P = .04). Follow-up imaging was available in nine patients treated with CDT. Mean interval from treatment to follow-up imaging was 13 months (range, 1-35 months) and consistently showed a functional but smaller treated kidney. (Mean pole-to-pole kidney length at baseline and late follow-up: 10.4 cm and 8.5 cm, respectively). CONCLUSIONS: Most patients presenting with acute kidney infarction are managed conservatively. A subset of patients with complete occlusion of the renal artery undergo CDT with good angiographic results. The treated kidney is expected to decrease in size over time, and overall kidney function is expected to decrease compared with baseline. Deterioration in renal function appears to stabilize and does not continue over time. CDT for acute renal artery occlusion is a safe modality of therapy and should be attempted for the purpose of kidney salvage, even in the setting of prolonged ischemia.

Calreticulin mutation burden--is it a stable clone in patients with essential thrombocythemia and myelofibrosis?

Calreticulin mutation represents the second most frequent mutation after JAK2 V617F in myeloproliferative disorder and is considered to be a driving mutation. Herein the mutation burden was evaluated in patients with essential thrombocythemia or myelofibrosis and found to increase by 5.7% over time unrelated to the time elapsed from the initial to the final positive test. The longer the course of the disease when first tested (range 0-30 years, mean 7.9 years) the lower mutation burden was observed. The mutated clone was larger in type II in comparison with type I mutation when first tested but the difference in mutation burden from the final to the first positive test was significantly higher in those with type I. Similarly, the difference in mutation burden was higher in patients with essential thrombocythemia reaching almost 8% in comparison to 1.3% in post-essential thrombocythemia myelofibrosis. Thus a repeat calreticulin quantitative test is not warranted.

Predicting risk severity and response of fetal neonatal alloimmune thrombocytopenia.

Fetal neonatal alloimmune thrombocytopenia (FNAIT) is a devastating bleeding disorder in the fetus or neonate caused by transplacental transport of maternal alloantibodies to paternal-derived antigen on fetal platelets. In Caucasians, up to 80% of FNAIT cases result from maternal immunization to human platelet antigen (HPA)-1a. New methods have developed facilitating detection of common and private antibodies against HPAs triggering FNAIT. Understanding the pathogenesis of FNAIT made it possible to develop a novel strategy to treat this disorder. To date, recombinant monoclonal antibodies directed against the ß3 integrin and Fc receptors have been tested in a mouse model of FNAIT, and seem to be promising. Whether those novel treatments will eventually replace the conventional high dose immunoglobulin G in women with FNAIT is yet unknown.

Congenital factor XI deficiency: an update.

Severe factor XI (FXI) deficiency is an injury-related bleeding disorder, common in Ashkenazi Jews (with two mutations prevailing), but rare worldwide (with heterogeneous mutations). In the past two decades, more than 220 mutations in the FXI gene have been reported in patients with FXI deficiency, of which 7 showed a founder effect. Inhibitors to FXI were described in patients with null-allele mutations, following exposure to plasma, FXI concentrates, or anti-RhD immunoglobulin. Treatment of patients with severe FXI deficiency remains challenging because factors influencing bleeding risks are still unknown. The use of lower doses of recombinant activated factor VII in comparison with the doses commonly applied in hemophilia A or B seems promising also when assessed in vitro by thrombin generation test. Recently, FXI has been shown to have a separate role in hemostasis and in thrombosis. In animal models, targeting FXI by knocking out the gene or by using FXI-neutralizing antibodies, antisense oligonucleotides, and peptidomimetic inhibitors, prevents arterial and vein thrombosis. The homology between human and murine FXI and the significant antithrombotic effect of FXI deficiency in animal models resulted in the development of a novel approach of targeting FXI for prevention of thrombosis without impairing hemostasis in high-risk patients. The acceptance of FXI as a risk factor for thrombosis is a new concept, and patients with severe FXI deficiency might gain profit during life course.

Compound heterozygosity of HLA-DRB3*01:01 and HLA-DRB4*01:01 as a potential predictor of fetal neonatal alloimmune thrombocytopenia.

BACKGROUND: Fetal neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder in the fetus or neonate caused by maternal alloantibodies directed against fetal platelet (PLT) antigens inherited from the father. The immune-dominant antigen leading to severe FNAIT is the human PLT antigen (HPA)-1, whose polymorphism constitutes an epitope for human leukocyte antigens (HLAs), usually DRB3*0101 leading to an immune response. STUDY DESIGN AND METHODS: In this study our aims were to find whether other allele variants of the ß subunit of the HLA-DR family specifically focused on the HLA residues that bind Position 33 of the HPA-1 integrin contribute to FNAIT development and affect response to treatment and whether coexistence of both anti-HPA-1a and anti-HLA class I specific against the father's antigens leads to a more severe thrombocytopenia in the newborn. We examine the genotype of 23 mothers to newborns with FNAIT compared to a control group. RESULTS: Our results suggested that, when HPA-1 incompatibility with the husband is found, the presence of two HLA alleles (DRB3*01:01 and DRB4*01:01) in the mother increases the risk and severity of FNAIT and reduces the success of a preventive immunoglobulin G treatment. We provide a structural model for the molecular basis of the rational effects of the different HLA alleles. In addition, we found that the presence of both anti-HPA-1 and anti-HLAs did not aggravate FNAIT in comparison to mothers harboring only anti-HPA-1. CONCLUSION: Overall, we suggest that a specific genotyping of the mother in relation to HLA-DRB as well as HPA-1 can serve as an antenatal diagnostic tool, particularly in siblings of women who gave birth to neonates with FNAIT.

Nsaids Linked to IgA-Mediated Hypersensitivity Vasculitis and Purpura Fulminans-Like Eruption.

Background: IgA vasculitis and hypersensitivity reactions following exposure to non-steroidal anti-inflammatory drugs (NSAIDs) are very rarely associated with purpura fulminans (PF). The latter is a coagulation event characterised by decreased levels of protein C and a rapidly progressive purpuric rash, often leading to ischaemia, amputations and death. Case summary: A previously healthy 66-year-old man presented with a vasculitic rash and abdominal pain following exposure to naproxen (NSAID), which quickly deteriorated to purpura fulminans-like eruption and skin necrosis, mainly involving the face and hands. The presence of IgA sediments on skin biopsy and decreased levels of complement as well as protein C pointed to an immune-mediated inflammatory process. Dramatic clinical escalation with immediate risk to organs and life required an aggressive and broad-spectrum therapeutic approach in an intensive care setting. Clinical improvement and complete reconstitution of protein C were achieved following plasma exchange with fresh frozen plasma (FFP) and immunosuppression with glucocorticoids with no persistent organ damage. Conclusions: This rare case illustrates the catastrophic cross links between NSAIDs, IgA-mediated hypersensitivity vasculitis and purpura fulminans-like syndrome. A high index of suspicion is required for the evaluation of environmental exposures such as drugs and infections in patients with vasculitis and/or purpura. A rapid and comprehensive therapeutic approach should be implemented to avoid multi-organ damage, amputations and death. Complete avoidance of the offending agent is key for future prevention of recurrence. LEARNING POINTS: This case illustrates a rare cross link between a commonly used drug (NSAIDs) and severe, life-threatening hypersensitivity reactions (IgA vasculitis and purpura fulminans-like eruption).These events require a high index of suspicion and emphasise the importance of considering environmental exposures such as drugs in the immediate diagnosis of both conditions.In addition to long-term drug avoidance, early and aggressive interventions are required to avoid organ damage, amputations or death.

A proposal for managing bleeding in patients on therapeutic factor XI(a) inhibitors.

Several drugs that reduce functional levels of the plasma protease zymogen factor XI (FXI), or that inhibit its activated form (FXIa), are being evaluated as treatments to prevent thrombosis. Based on the observation that individuals with inherited FXI deficiency have a relatively mild bleeding disorder, it is anticipated that therapeutic FXI(a) inhibitors will have a smaller impact on hemostasis than anticoagulants targeting thrombin or factor Xa. However, even if FXI(a) inhibitors are determined to be safer than currently used anticoagulants, some patients on these drugs will experience abnormal bleeding or require emergent surgery. Strategies for dealing with such situations are required. Treatment with antifibrinolytic agents and low doses of recombinant factor VIIa effectively prevent abnormal bleeding in FXI-deficient patients with alloantibody inhibitors to FXI who undergo surgery. We propose that a similar strategy can be used for patients on therapeutic FXI(a) inhibitors who are bleeding or require invasive procedures.

JAK2V617F Is a Risk Factor for TIA/Stroke in Young Patients.

The objective of this study was to assess the risk of arterial thrombosis in patients who harbor the JAK2V617F allele burden ≥1% detected during workup for myeloproliferative neoplasms (MPNs). We conducted a large cross-sectional analysis consisted of 5,220 patients who were tested for JAK2V617F and 1,047,258 people matched in age from health care insurance provider, taking into account age, sex, hypertension, diabetes, atrial fibrillation. Compared with noncarriers, mutation carriers were older, less likely to be current or past smokers and had lower body mass index. There was no significant difference between the groups regarding myocardial infarction and peripheral vascular disease. However, JAK2V617F ≥1% at age 34 to 54 years was associated with eightfold more likely to have transient ischemic attack (TIA)/stroke history unrelated to hypertension, diabetes, or atrial fibrillation. Association of JAK2V617F with TIA/stroke was also observed in the older age group, albeit a weaker association and not statistically significant. Prevalence of TIA/stroke was higher in patients with JAK2V617F negative, with odds ratio of 3.93 when compared with the general population after confounder adjustments. Further research is warranted to verify the relation between allele burden of JAK2V617F mutation and TIA/stroke and the role of JAK2V617F per se as a risk factor for arterial thrombosis in the absence of overt MPN. Also, consideration should be paid to the screened group with JAK2V617F negative due to the high incidence of TIA/stroke among them in comparison to the general population.

The Association between Factor XI Deficiency and the Risk of Bleeding, Cardiovascular, and Venous Thromboembolic Events.

The objective of this study was to assess the relationship between factor XI (FXI) deficiency and the risks of bleeding and cardiovascular (CV) events. We conducted a retrospective cohort study using data from Maccabi Healthcare Services (MHS). We identified adults with FXI deficiency (severe: <15%, partial: 15 to <50%, any deficiency: <50%) that had been tested for FXI between 2007 and 2018 and matched to patients from the general MHS population. We estimated 10-year risks of outcomes using the Kaplan-Meier approach. Using Cox proportional hazards regression, we compared outcomes among patients with versus without FXI deficiency. Less than 10% of patients tested for FXI activity had activity levels <50% (mean age: 39 years; 72.2% females). Compared with the general population, patients with any FXI deficiency were at higher risk of severe bleeding (adjusted hazard ratio [aHR]: 2.56, 95% confidence interval [CI]: 1.13-5.81; 10-year risk: 1.90%, 95% CI: 0.50-3.20% vs. 0.90%, 95% CI: 0.50-1.30%) and clinically relevant nonsevere bleeding (CRNSB) (aHR: 1.45, 95% CI: 1.08-1.97; 10-year risk: 11.60%, 95% CI: 8.30-14.80% vs. 9.20%, 95% CI: 8.00-10.40%). Severe FXI deficiency was associated with a greater risk of CRNSB. While few CV events (N = 2) and venous thromboembolisms (VTE) (N = 1) were observed in the FXI overall deficient group, there was a nonsignificant negative association between any FXI deficiency and CV events (aHR: 0.55; 95% CI: 0.13-2.36) and VTEs (aHR: 0.45; 95% CI: 0.06-3.47). Overall FXI deficiency was associated with an increased risk of severe bleeding and CRNSB. Further research is warranted to explore the lower risk of CV and VTE among patients with FXI deficiency compared with the general population.