Neonatal hemophagocytic lymphohistiocytosis: A meta-analysis of 205 cases.

BACKGROUND: Neonatal hemophagocytic lymphohistiocytosis (nHLH), defined as HLH that presents in the first month of life, is clinically devastating. There have been few large descriptive studies of nHLH. OBJECTIVES: The objective of this study was to perform a meta-analysis of published cases of nHLH. METHODS: A comprehensive literature database search was performed. Cases of HLH were eligible for inclusion if clinical analysis was performed at age ≤30 days. Up to 70 variables were extracted from each case. RESULTS: A total of 544 studies were assessed for eligibility, and 205 cases of nHLH from 142 articles were included. The median age of symptom onset was day of life 3 (interquartile range [IQR]: 0-11, n = 141). Median age at diagnosis was day of life 15 (IQR: 6-27, n = 87). Causes of HLH included familial HLH (48%, n = 99/205), infection (26%, n = 53/205), unknown (17%, n = 35/205), macrophage activation syndrome/rheumatologic (2.9%, n = 4/205), primary immune deficiency (2.0%, n = 5/205), inborn errors of metabolism (2.4%, n = 5/205), and malignancy (2.0%, n = 4/205). Fever was absent in 19% (n = 28/147) of all neonates and 39% (n = 15/38) of preterm neonates. Bicytopenia was absent in 26% (n = 47/183) of patients. Central nervous system (CNS) manifestations were reported in 63% of cases (n = 64/102). Liver injury (68%, n = 91/134) and/or liver failure (24%, n = 32/134) were common. Flow cytometry was performed in 22% (n = 45/205) of cases. Many patients (63%, n = 121/193) died within the period of reporting. Discernable values for HLH diagnostic criteria were reported between 30% and 83% of the time. CONCLUSIONS: Evaluation of nHLH requires rapid testing for a wide range of differential diagnoses. HLH diagnostic criteria such as fever and bicytopenia may not occur as frequently in the neonatal population as in older pediatric populations. Neurologic and hepatic manifestations frequently occur in the neonatal population. Current reports of nHLH suggest a high mortality rate. Future publications containing data on nHLH should improve reporting quality by reporting all clinically relevant data.

[Hemophagocytic lymphohistiocytosis: A retrospective analysis of 66 patients]. / Lymphohistiocytose hémophagocytaire : analyse rétrospective de 66 patients.

CONTEXT: Hemophagocytic lymphohistiocytosis is a rare syndrome with a poor prognosis, characterized by an uncontrolled dysregulation of the immune system. The rarity of this disease makes it difficult to obtain large cohorts. In this study, we analyzed the data of 66 patients: the objective was to describe the epidemiological, clinical, biological and therapeutic characteristics and to compare our results with those already published. METHODS: We conducted a retrospective study at the University Hospital of Montpellier from 2015 to 2021. Patients were included when the diagnosis of HLH was mentioned on the hospitalization report and when the HSCORE was higher than 50% (169). Prognostic analyses were performed by comparing the patients who died from HMH to those who didn't. RESULTS: The mean age the 66 patients included was 49.2 years, 62% were men. The percentage of deaths was 45.9%. Lymphoma was the main etiology, followed by infections, then autoimmune/autoinflammatory diseases. Fever, splenomegaly, hepatomegaly and organ failure were the main clinical manifestations. Pancytopenia was present in 62% of cases. Ferritin, triglycerides, LDH and AST were highly increased. Advanced age, associated lymphoma, and the severity of cytopenias were linked to a poor prognosis. DISCUSSION: The study of the clinico-biological, epidemiological and survival data of the patients in our cohort allowed us to confirm previously published data but also to discuss some of them.

Delay in treatment of adult hemophagocytic lymphohistiocytosis is associated with worse in-hospital outcomes.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by uncontrolled activation of the immune system leading to multiorgan failure. Timely initiation of HLH-specific treatment is believed to be essential and lifesaving. Due to the rarity of the condition in adults, there is no data available in the literature to investigate the effects of treatment delay in this age group. We used data from the National Inpatient Sample (NIS) to evaluate the inpatient practices of HLH treatment initiation over 13 years (2007-2019) and their association with clinically relevant inpatient outcomes. Patients were divided into early treatment group (<6 days) and late treatment group (≥ 6 days). We compared outcomes using multivariate logistic regression models adjusting for age, sex, race, and HLH-triggering conditions. There were 1327 and 1382 hospitalizations in the early and late treatment groups, respectively. Hospitalization in the late treatment group had higher rates of in-hospital mortality (OR 2.00 [1.65-2.43]), circulatory shock (OR 1.33 [1.09-1.63]), requiring mechanical ventilation (OR 1.41 [1.18-1.69]), venous thromboembolism (OR 1.70 [1.27-2.26]), infectious complications (OR 2.24 [1.90-2.64]), acute kidney injury (OR 2.27 [1.92-2.68]), and requiring new hemodialysis (OR 1.45 [1.17-1.81]). Additionally, we observed no significant trend in the mean time to treatment over the study period. This study shows the importance of early initiation of HLH treatment and highlights the adverse outcomes of treatment delay.

1-year survival in haemophagocytic lymphohistiocytosis: a nationwide cohort study from England 2003-2018.

Haemophagocytic lymphohistiocytosis (HLH) is a lethal syndrome of excessive immune activation. We undertook a nationwide study in England of all cases of HLH diagnosed between 2003 and 2018, using linked electronic health data from hospital admissions and death certification. We modelled interactions between demographics and comorbidities and estimated one-year survival by calendar year, age group, gender and comorbidity (haematological malignancy, auto-immune, other malignancy) using Cox regression. There were 1628 people with HLH identified. Overall, crude one-year survival was 50% (95% Confidence interval 48-53%) which varied substantially with age (0-4: 61%; 5-14: 76%; 15-54: 61%; > 55: 24% p < 0.01), sex (males, 46%, worse than females, 55% p < 0.01) and associated comorbidity (auto-immune, 69%, haematological malignancy 28%, any other malignancy, 37% p < 0.01). Those aged < 54 years had a threefold increased risk of death at 1-year amongst HLH associated with malignancy compared to auto-immune. However, predicted 1-year survival decreased markedly with age in those with auto-immune (age 0-14, 84%; 15-54, 73%; > 55, 27%) such that among those > 55 years, survival was as poor as for patients with haematological malignancy. One-year survival following a diagnosis of HLH varies considerably by age, gender and associated comorbidity. Survival was better in those with auto-immune diseases among the young and middle age groups compared to those with an underlying malignancy, whereas in older age groups survival was uniformly poor regardless of the underlying disease process.

Nationwide analysis of adult hospitalizations with hemophagocytic lymphohistiocytosis and systemic lupus erythematosus.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a well-recognized complication of systemic lupus erythematosus (SLE). This study aims to characterize HLH with and without SLE in the US adult inpatient population. METHODS: We performed a retrospective study of HLH with and without SLE from the 2016-2019 National Inpatient Sample (NIS) database. We described the demographic characteristics of HLH with and without SLE. Multivariable analysis was performed to calculate odds ratios (OR) for in-hospital death. RESULTS: A total of 8690 hospitalizations had HLH. Of those 605 (7%) had SLE, and 8085 (93%) did not have SLE. Relative to the non-SLE group, the SLE group was younger, had more females, less whites, more African Americans, more Hispanics, and more Asian/Pacific Islanders. Over 60% of HLH with or without SLE had a concurrent infection. Sixty (9.9%) of HLH hospitalizations with SLE died compared to 1735 (21.5%) of those without SLE. Among HLH hospitalizations, multivariable analysis showed that age (OR 1.02; 95% C.I. 1.016-1.031), Charlson Comorbidity Index (OR 1.15; 95% C.I. 1.091-1.213), infections (OR 3.35; 95% C.I. 2.467-4.557), and leukemia/lymphoma (OR 1.46; 95% C.I. 1.112-1.905) had higher odds of in-hospital death. SLE did not increase the odds of death. CONCLUSIONS: Inpatients with both HLH and SLE were younger, had a higher proportion of racial/ethnic minorities, and were predominately female. One out of every 10 hospitalizations for HLH ended in death but SLE itself was not an independent risk factor for death. Concurrent infection was the variable most associated with HLH death. Key Points • HLH and SLE group were younger and had higher proportions of female and racial/ethnic minorities. • SLE was not an independent risk factor for death in HLH patients.

Clinical and Laboratory Characteristics of Hemophagocytic Lymphohistiocytosis in Children With Severe Dengue During the 2019-2020 Outbreak in Southern Colombia.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled activation of inflammatory cells and an exaggerated release of cytokines. It can be triggered by different factors, including viruses, such as dengue. The objective of this study was to characterize the clinical and laboratory profiles of children with severe dengue and HLH, and to identify the risk factors for this clinical complication. METHODS: An analytical study was conducted in children with severe dengue who were treated in an intensive care unit between January 2019 and March 2020. Clinical and laboratory factors were compared between patients with and without HLH. RESULTS: HLH represented 13.4% (15/112) of children with severe dengue. Patients with HLH had a long-lasting fever (10.1 vs. 5.8 days; P = 0.012), low hemoglobin levels (7.6 vs. 10.8 g/dL; P = 0.000) and high aspartate aminotransferase values (4443 vs. 1061 U/L; P = 0.002), alanine transaminase (1433 vs. 487 U/L; P = 0.004), partial thromboplastin time (80.6 vs. 51.8 seconds; P = 0.010), prothrombin time (23.5 vs. 19.6 seconds; P = 0.024), triglycerides (333.7 vs. 223.2 mg/dL; P = 0.005), lactate dehydrogenase (4209 vs. 1947 U/L; P = 0.006), soluble CD25 (3488 vs. 1026 pg/mL; P = 0.014), and presented with higher frequency of myocarditis (66.7% vs. 38.3%; P = 0.048), hepatitis (5.3% vs. 1.3%; P = 0.014), bacterial coinfection (73.3% vs. 26.7%; P = 0.010) and fatal outcome (26% vs. 5%; P = 0.037). CONCLUSIONS: HLH is a serious life-threatening clinical complication of dengue virus infection that must be considered, particularly during outbreaks.

Changing Disease Course of Crimean-Congo Hemorrhagic Fever in Children, Turkey.

Crimean-Congo hemorrhagic fever (CCHF), endemic in certain regions of the world, is listed as a priority disease with pandemic potential. Since CCHF was first identified in Turkey, children have been known to experience milder disease than adults. However, during the COVID-19 pandemic, we observed an unusually severe disease course, including hemophagocytic lymphohistiocytosis (HLH). We examined cytokine/chemokine profiles of 9/12 case-patients compared with healthy controls at 3 time intervals. Interferon pathway-related cytokines/chemokines, including interleukin (IL) 18, macrophage inflammatory protein 3α, and IL-33, were elevated, but tumor necrosis factor-α, IL-6, CXCL8 (formerly IL-8), and cytokines acting through C-C chemokine receptor 2 and CCR5 were lower among case-patients than controls. Interferon pathway activation and cytokines/chemokines acting through CCR2 and CCR5 improved health results among children with severe CCHF. Children can experience severe CCHF, including HLH, and HLH secondary to CCHF can be successfully treated with intravenous immunoglobulin and steroid therapy.

Epidemiology of haemophagocytic lymphohistiocytosis at the population level in Germany.

We retrospectively analysed all German inpatient cases of haemophagocytic lymphohistiocytosis (HLH) from 2014 to 2020 to describe the epidemiology, clinical course, and underlying diseases of 4065 HLH patients. The age-standardized incidence rate of HLH in Germany was 0.52/100 000 people in 2014 and steadily increased by 10% per year to 0.97/100 000 in 2020 (mean 0.70/100 000). Inpatient deaths related to HLH increased from 0.84/1 000 000 people in 2014 to 2.32/1 000 000 people in 2020, caused by rising numbers of older HLH patients. Overall, HLH is more frequent than previously expected and incidence as well as HLH-related deaths increased significantly.

Practice patterns and outcomes of hemophagocytic lymphohistiocytosis in adults: a 2-decade provincial retrospective review.

Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous, life-threatening clinical syndrome. There are scarce data on the quality of care in HLH or data comparing treatment patterns and outcomes between different triggers. We aimed to examine quality-of-care indicators and outcomes in adults with various HLH triggers. In this multi-centre retrospective cohort study of adult HLH in the province of Alberta, Canada (1999-2019), we examined quality indicators including diagnostic testing, time to diagnosis and treatment and trigger identification. We also compared treatment regimens and outcomes across HLH triggers. Logistic regression was used to identify predictors of etoposide use. Overall survival (OS) was estimated using the Kaplan-Meier method. We identified 97 patients; 66 (68%) were male. Triggers included malignancy (36%), infection (35%), autoimmune disease (21%) and idiopathic/others (8%). Specialized tests such as sCD25 (53%) and natural killer degranulation assay (19%) were under-performed, as were testing for infectious triggers. Etoposide was administered in only 33 (34%). Neutropenia, hyperbilirubinemia and hyperferritinemia, but not age, sex and comorbidities, were significant predictors of etoposide use. At median follow-up of 32 months, median OS was 18.8 months. Worse OS was seen in malignancy-associated and idiopathic HLH (log-rank P < 0.001). Our study showed low rates of specialized testing such as sCD25 and a low rate of etoposide use. Development of a standardized provincial protocol has the potential to improve quality of care in adult HLH.

Intrathoracic infections in Hodgkin lymphoma (HL) patients may cooperate with HL to trigger hemophagocytic lymphohistiocytosis: A retrospective study.

Hodgkin lymphoma (HL)-related hemophagocytic lymphohistiocytosis (HLH) has been reported in the literature; however, there is almost no literature on the factors related to HL triggering HLH. One hundred forty patients with HL were retrospectively analyzed. The incidence of HL-related HLH (we call HL-related HLH as HL-HLH). And all HL-HLH patients in our cohort had HLH as the first manifestation and its clinical characteristics and the role of intrathoracic infection (ITI) in triggering HLH are discussed. The 140 patients with HL mainly included mixed-cellularity classic HL (MCCHL) in 81 (57.9%), nodular sclerosis classic HL (NSCHL) in 36 (25.7%), and lymphacyte-rich classic HL in 14 (10.0%) patients. Of the 137 patients who underwent chest computed tomography scans on admission, 44 had ITI, and most of these ITI were mildly ill and had no respiratory symptoms. Among 140 HL patients, 8 patients from MCCHL were diagnosed as HL-HLH. Among 81 MCCHL patients, 26 patients with ITI had a significantly higher incidence of HL-HLH than those without ITI (26.9% vs 1.8%, P = .002). The median survival time of 8 cases of HL-HLH was only 2 months. When HL patients were first admitted to the hospital, 5.7% had HLH as the first manifestation, and 32.1% had ITI. These ITI can cooperate with HL to trigger HLH, despite their mild illness. The prognosis of HL-HLH was poor.

High Prevalence of Hemophagocytic Lymphohistiocytosis in Acute Liver Failure of Infancy.

OBJECTIVES: To investigate the prevalence of hemophagocytic lymphohistiocytosis (HLH) syndrome in pediatric acute liver failure (PALF) of infancy and assess the diagnostic role of rapid immunologic tests, genotype/phenotype correlations, and clinical outcomes. STUDY DESIGN: We retrospectively analyzed 78 children with PALF aged <24 months referred over almost 2 decades. The studied patients with a phenotype of HLH syndrome had a comprehensive immunologic workup, including additional genetic analysis for primary immunologic causes. RESULTS: Thirty of the 78 children had the HLH phenotype and underwent genetic assessment, which demonstrated positive findings in 19 (63.3%), including 9 (30%) with biallelic primary HLH mutations and 10 (33.3%) with heterozygous mutations and/or polymorphisms. The most common form of primary HLH was familial hemophagocytic lymphohistiocytosis (FHL)-2, diagnosed in 6 children, 4 of whom had a c.50delT (p.Leu17ArgfsTer34) mutation in the PRF1 gene. Three patients with primary HLH received genetic diagnoses of FHL-3, Griscelli syndrome, and LRBA (lipopolysaccharide-responsive vesicle trafficking, beach- and anchor-containing) protein deficiency. Overall mortality in the series was 52.6% (10 of 19), and mortality in children with a documented biallelic pathogenic HLH mutation (ie, primary HLH) was 66.6% (6 of 9). Two children underwent liver transplantation, and 4 children underwent emergency hematopoietic stem cell transplantation; all but 1 child survived medium term. CONCLUSIONS: Primary HLH can be diagnosed retrospectively in approximately one-third of infants with indeterminate PALF (iPALF) who meet the clinical criteria for HLH, often leading to their death. The most common HLH type in iPALF is FHL-2, caused by biallelic mutations in PRF-1. The clinical relevance of observed heterozygous mutations and variants of uncertain significance requires further investigation. Prompt hematopoietic stem cell transplantation could be life-saving in infants who survive the liver injury.

The prevalence and prognosis of hyponatraemia in non-Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis.

Non-Hodgkin lymphoma associated hemophagocytic lymphohistiocytosis (NHL-HLH) in adult secondary HLH is a common and universally highly lethal critical disorder. Hyponatraemia is the most common electrolyte disorder in the critical illness setting and acts as a negative prognostic factor. The aim of our study was to evaluate the prognostic role of hyponatraemia among patients with NHL-HLH. The results showed that 81 (52.9%) patients had hyponatraemia. After a median follow up 47 (range 14-180) days, there were 72 (88.9%) cumulative deaths in hyponatraemia group while 50 (69.4%) in normonatremia group. After adjustment for confounders, multivariate analysis revealed that hyponatraemia was an independent prognostic factor for OS (HR:1.51, 95% CI: 1.03-2.20; p = 0.033). Restricted cubic spline confirmed a linear and positive association between serum sodium and the risk of mortality. Hyponatraemia is relatively frequent in NHL-HLH. As a readily available biomarker in clinical routine, it was a promising prognostic predictor for NHL-HLH.

Pediatric Hemophagocytic Lymphohistiocytosis - A Single Center Study.

OBJECTIVE: To describe the epidemiological features, outcomes and prognostic factors in diagnosis of pediatric hemophagocytic lymphohistiocytosis (HLH). METHODS: 118 children fulfilling the inclusion criteria for HLH were identified from review of hospital records for period January, 2010 to December, 2019. RESULT: Median age at diagnosis was 4 years (range13 days-15 years). Presenting features were fever (100%), hepatosplenomegaly (91%), neurological symptoms (23%), bicytopenia (76%), transaminitis (67.3%), increased soluble interleukin-2 receptor) (sIL-2R) (78%) and hemophagocytosis on bone marrow (75%). Median follow-up duration was 13.5 months (3 days to 102 months). Primary HLH was identified in 27 (23%) patients. Etiology of secondary HLH was infections in 53 (45%), rheumatologic illnesses in 21 (18%) and malignancies in 8 (6%) children. Treatment modalities were steroid only (25%), anti-infectious agent (58%), multi-agent chemotherapy (43%) and HSCT (40%); mortality among above treatment groups were 25%, 58%, 43% and 40%, respectively. 15 patients (13%) had relapsed/refractory HLH who were treated with salvage chemotherapy and hematopoietic stem cell transplantation (HSCT). The overall mortality rate was 39%; mortality within 30 days seen in 23%. Estimated overall survival (OS) and event free survival (EFS) at 3 years were 62% and 61%, respectively. CONCLUSION: Pediatric HLH is an aggressive disease with high mortality. Hyponatremia, hyperbilirubinemia, coagulopathy and increased sIL2 receptor level at diagnosis predicts poor outcome.

Hemophagocytic Lymphohistiocytosis Hospitalizations in Adults and Its Association With Rheumatologic Diseases: Data From Nationwide Inpatient Sample.

OBJECTIVE: Hemophagocytic lymphohistiocytosis (HLH) is a rare potentially fatal multisystem inflammatory condition that is often triggered by an underlying medical condition. Epidemiologic data of HLH in adults with rheumatologic diseases are limited. The aim of our study was to characterize HLH hospitalizations in the US adult population with a special focus on patients with concomitant rheumatologic diseases. METHODS: We conducted a medical records review of hospitalizations in the United States during 2016 and 2017 with a diagnosis of HLH. Hospitalizations were selected from the National Inpatient Sample. International Classification of Diseases, Tenth Revision codes were used to identify rheumatologic diseases. A multivariate logistic regression analysis was used to calculate adjusted odds ratios (ORadj) for the association of HLH and rheumatologic diseases. RESULTS: Seven hundred fifty hospitalizations had a principal billing diagnosis of HLH. The median age of our study population was 47.5 years, and males made up 55% of the population. Overall mortality was 17%, and the median length of stay was 12 days. Twenty-five percent of the HLH cases had a concomitant rheumatologic diagnosis. Multivariate logistic regression analysis showed systemic lupus erythematosus (SLE) with nephritis (ORadj, 5.7), SLE without nephritis (ORadj, 9.2), adult-onset Still disease (ORadj, 338.9), and ankylosing spondylitis (ORadj, 10.7) were significantly associated with HLH. CONCLUSIONS: This analysis represents the largest sample to date to assess HLH hospitalizations. Our study showed that SLE, adult-onset Still disease, and ankylosing spondylitis were strongly associated with HLH.

Incidence and survival of haemophagocytic lymphohistiocytosis: A population-based cohort study from England.

BACKGROUND: Haemophagocytic lymphohistiocytosis (HLH) is a rare hyper-inflammatory condition with poor outcomes. OBJECTIVES: Few population-based estimates of the incidence and survival in adults exist. We aimed to provide these data for England. METHODS: We used population-based linked data from primary care, secondary care, cancer registries and mortality databases in England to identify people diagnosed with HLH between 1 January 2000 and 31 December 2016. We calculated annual incidence rates by age and sex, modelled change in incidence over time with Poisson regression, calculated overall 1-year survival using Kaplan-Meier methods and estimated adjusted hazard ratios (HRs) of death using a Cox proportional hazards model. RESULTS: We identified 214 patients with HLH. The reported age and sex-adjusted incidence increased twofold over the period, from around one to around two per million. Incidence was highest in those below 1 year (14.6 per million) and ≥75 years (2.2 per million), and lowest in those aged 15-44 years (0.8 per million). One-year survival varied by age and sex from 77% (95% confidence interval [CI] 63%-86%) in those <15 years to 30% (95% CI 14%-49%) in those ≥75. In patients with haematological cancer, the adjusted HR for death was 2.60 (95% CI 1.45-4.66) compared to patients with no malignant or rheumatological disease. CONCLUSION: The incidence of HLH diagnosis in England has increased between 2000 and 2016 and occurs in all ages with varying underlying diseases. One-year survival varies substantially, being particularly poor in those aged over 75 years and those with haematological malignancy.

Outcome of Viral-associated Hemophagocytic Lymphohistiocytosis at a Tertiary Hospital.

BACKGROUND: Little is known about viral-associated hemophagocytic lymphohistiocytosis (HLH) in Oman. This study was done to assess the epidemiology, clinical features and outcome of viral-associated HLH in our setting. METHODS: We retrospectively reviewed children (0-18 years) managed for viral-associated HLH at the Sultan Qaboos University Hospital, Oman, over a 15-year period (2006-2020). Patients' medical records were used to describe their demographic, clinical and laboratory features, management and outcome. RESULTS: Fifty-six children were managed for HLH at Sultan Qaboos University Hospital over the last 15 years (2006-2020) of whom a third (19; 34%) had a viral trigger. The median age at the time of diagnosis of viral-associated HLH was 83 (13-96) months. Fever, cytopenia, hyperferritinemia and evidence of hemophagocytosis in bone marrow were the most consistent findings. Most of these children had either genetic predisposition to HLH (8/19; 42%) or underlying immunodeficiency secondary to malignant conditions or chemotherapy/hematopoietic stem cell transplantation (6/19; 32%). Epstein-Barr virus (9; 47%) followed by cytomegalovirus (6; 31%) was the most common viral trigger in our setting. Treatment included antivirals (8; 42%), HLH 2004 protocol (4; 21%), rituximab (4; 21%) and hematopoietic stem cell transplantation (3; 16%). Fourteen children (74%) had full recovery. CONCLUSIONS: In our small cohort, viral-associated HLH was more frequently encountered in children with genetic predisposition to HLH or children with underlying immunodeficiency. In addition, we found that the outcome is overall good for children who have no genetic predisposition to HLH and children with genetic predisposition who underwent hematopoietic stem cell transplantation.

Incidence of bleeding and thromboembolism and impact on overall survival in adult patients with hemophagocytic lymphohistiocytosis: A 20-year provincial retrospective cohort study.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by uncontrolled immune activation and high risk of death. There is scarce data on the incidence of bleeding and thromboembolism in HLH. OBJECTIVES: To determine the cumulative incidence of bleeding and thromboembolism and impact on survival in adults with HLH. PATIENTS/METHODS: We conducted a multicenter retrospective cohort study of adults with HLH in Alberta, Canada (1999-2019). The cumulative incidence of bleeding and thromboembolism were calculated, accounting for competing risks. Cox proportional hazards models were used to assess the impact of bleeding and thromboembolism on overall survival (OS). RESULTS: We identified 97 adults with HLH (median age 46 years). Venous thromboembolism (VTE) occurred in 11 (11%) patients at a median of 9 days from admission. ISTH major bleeding and clinically relevant non-major bleeding occurred in 39 (40%) patients, at a median of 16 days after admission. Nadir platelet count (adjusted odds ratio [aOR] 1.8 per log decrease, 95% confidence interval [CI] 1.2-2.8) and mechanical ventilation (aOR 4.9, 95% CI 1.8-14.8) were independent predictors of bleeding on multivariable analysis. Adjusting for competing risks, the 90-day cumulative incidences of bleeding and thromboembolism were 39% and 13%, respectively. The median OS was 18.8 months. VTE, but not bleeding, was significantly associated with adverse OS (adjusted hazard ratio 2.5, 95% CI 1.1-5.7). CONCLUSIONS: In adults with HLH, VTE appears more common than previously described and is a predictor of mortality, although this may be due to unadjusted confounding. VTE prevention and treatment are challenging due to high bleeding rates.