Hemoglobin concentration and body mass index are determinants of plasma von Willebrand factor and factor VIII levels.

BACKGROUND: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder. VWD is characterized by an abnormal quantity or quality of von Willebrand Factor (VWF). Anemia is often found at presentation for a bleeding disorder evaluation due to chronic blood loss. OBJECTIVES/HYPOTHESIS: We hypothesized that anemia is associated with elevations in both VWF and factor VIII (FVIII) over baseline. We also hypothesized that obesity would be associated with increased levels of VWF. METHODS: We conducted a single-center review of the electronic health record for patients that had proximal von Willebrand profiles and Hb data. RESULTS: We identified 4552 unique subjects with VWF studies and a CBC within 24 h. We found that decreasing hemoglobin inversely correlated with VWF antigen, VWF ristocetin cofactor activity, and FVIII activity. We also found that obesity and Black race were independently associated with increased VWF antigen, activity, and FVIII activity. Hb, race, and body mass index (BMI) continued to be determinants of VWF and FVIII levels in multivariable analysis. CONCLUSION: Our study demonstrates that anemia, race, and BMI were found to be associated with elevation of VWF antigen, VWF activity, and FVIII levels. As many individuals with anemia present for evaluation for a bleeding disorder, these variables need to be considered. KEY POINTS: - Anemia was found to be associated with elevation of VWF antigen, VWF activity and FVIII levels. - Testing von Willebrand factor at times of anemia may mask a diagnosis of von Willebrand Disease.

Thrombotic risk associated with gender-affirming hormone therapy.

Transgender and gender-expansive (TG) people-those who identify with a gender other than their assigned sex at birth-frequently experience gender dysphoria, which is associated with negative health outcomes. One key strategy for improving gender dysphoria is the use of gender-affirming hormone therapy (GAHT): estrogen for feminization and testosterone for masculinization. Estrogen use in cisgender women is associated with well-established changes in hemostatic parameters, including increases in prothrombotic factors and decreases in inhibitors of coagulation. Cisgender women using estrogen have an increased risk of thrombosis. Studies of thrombosis risk associated with estrogen GAHT in TG people are less robust, with some studies limited by the use of hormones and hormone management strategies that are no longer recommended. However, TG women using estrogen appear to be at increased risk of both arterial and venous thrombosis, which may increase with longer time on estrogen. Testosterone use in both cisgender and transgender men is associated with increases in hemoglobin and hematocrit, which can lead to erythrocytosis and thus increased risk of thrombosis. The results of studies evaluating thrombosis risk in the setting of testosterone use are mixed. This review presents an overview of alterations in hemostatic parameters and thrombosis risk associated with use of exogenous estrogen and testosterone. Understanding what is known and unknown about thrombosis risk associated with use of these hormones is essential for hematologists who may be asked to evaluate TG people and provide guidance on management of those who may be at increased risk of thrombosis.

Multicenter assessment and longitudinal study of the prevalence of antibodies and related adaptive immune responses to AAV in adult males with hemophilia.

Adeno-associated virus (AAV) based gene therapy has demonstrated effective disease control in hemophilia. However, pre-existing immunity from wild-type AAV exposure impacts gene therapy eligibility. The aim of this multicenter epidemiologic study was to determine the prevalence and persistence of preexisting immunity against AAV2, AAV5, and AAV8, in adult participants with hemophilia A or B. Blood samples were collected at baseline and annually for ≤3 years at trial sites in Austria, France, Germany, Italy, Spain, and the United States. At baseline, AAV8, AAV2, and AAV5 neutralizing antibodies (NAbs) were present in 46.9%, 53.1%, and 53.4% of participants, respectively; these values remained stable at Years 1 and 2. Co-prevalence of NAbs to at least two serotypes and all three serotypes was present at baseline for ~40% and 38.2% of participants, respectively. For each serotype, ~10% of participants who tested negative for NAbs at baseline were seropositive at Year 1. At baseline, 38.3% of participants had detectable cell mediated immunity by ELISpot, although no correlations were observed with the humoral response. In conclusion, participants with hemophilia may have significant preexisting immunity to AAV capsids. Insights from this study may assist in understanding capsid-based immunity trends in participants considering AAV vector-based gene therapy.

Hemostatic considerations for gender affirming care.

Gender dysphoria or gender incongruence is defined as "persons that are not satisfied with their designated gender" [1]. The awareness and evidence-based treatment options available to this population have grown immensely over the last two decades. Protocols now include an Endocrine Society Clinical Practice Guideline [1] as well as the World Professional Association of Transgender Health Standards of Care (WPATH SOC) [2]. Hematologic manifestations, most notably thrombosis, are one of the most recognized adverse reactions to the hormones used for gender-affirming care. Therefore, hematologists are frequently consulted prior to initiation of hormonal therapy to help guide safe treatment. This review will focus on the scientific evidence related to hemostatic considerations for various gender-affirming therapies and serve as a resource to assist in medical decision-making among providers and patients.

Illustrated State-of-the-Art Capsules of the ISTH 2023 Congress.

This year's Congress of the International Society of Thrombosis and Haemostasis (ISTH) took place in person in Montréal, Canada, from June 24-28, 2023. The conference, held annually, highlighted cutting-edge advances in basic, translational, population and clinical sciences relevant to the Society. As for all ISTH congresses, we offered a special, congress-specific scientific theme; this year, the special theme was immunothrombosis. Certainly, over the last few years, COVID-19 infection and its related thrombotic and other complications have renewed interest in the concepts of thromboinflammation and immunothrombosis; namely, the relationship between inflammation, infection and clotting. Other main scientific themes of the Congress included Arterial Thromboembolism, Coagulation and Natural Anticoagulants, Diagnostics and Omics, Fibrinolysis and Proteolysis, Hemophilia and Rare Bleeding Disorders, Hemostatic System in Cancer, Inflammation and Immunity, Pediatrics, Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies, Platelets and Megakaryocytes, Vascular Biology, Venous Thromboembolism and Women's Health. Among other sessions, the program included 28 State-of-the-Art (SOA) sessions with a total of 84 talks given by internationally recognized leaders in the field. SOA speakers were invited to prepare brief illustrated reviews of their talks that were peer reviewed and are included in this article. These illustrated capsules highlight the major scientific advances with potential to impact clinical practice. Readers are invited to take advantage of the excellent educational resource provided by these illustrated capsules. They are also encouraged to use the image in social media to draw attention to the high quality and impact of the science presented at the Congress.

Whole-exome analysis of adolescents with low VWF and heavy menstrual bleeding identifies novel genetic associations.

Adolescents with low von Willebrand factor (VWF) levels and heavy menstrual bleeding (HMB) experience significant morbidity. There is a need to better characterize these patients genetically and improve our understanding of the pathophysiology of bleeding. We performed whole-exome sequencing on 86 postmenarchal patients diagnosed with low VWF levels (30-50 IU/dL) and HMB and compared them with 660 in-house controls. We compared the number of rare stop-gain/stop-loss and rare ClinVar "pathogenic" variants between cases and controls, as well as performed gene burden and gene-set burden analyses. We found an enrichment in cases of rare stop-gain/stop-loss variants in genes involved in bleeding disorders and an enrichment of rare ClinVar "pathogenic" variants in genes involved in anemias. The 2 most significant genes in the gene burden analysis, CFB and DNASE2, are associated with atypical hemolytic uremia and severe anemia, respectively. VWF also surpassed exome-wide significance in the gene burden analysis (P = 7.31 × 10-6). Gene-set burden analysis revealed an enrichment of rare nonsynonymous variants in cases in several hematologically relevant pathways. Further, common variants in FERMT2, a gene involved in the regulation of hemostasis and angiogenesis, surpassed genome-wide significance. We demonstrate that adolescents with HMB and low VWF have an excess of rare nonsynonymous and pathogenic variants in genes involved in bleeding disorders and anemia. Variants of variable penetrance in these genes may contribute to the spectrum of phenotypes observed in patients with HMB and could partially explain the bleeding phenotype. By identifying patients with HMB who possess these variants, we may be able to improve risk stratification and patient outcomes.

Thrombosis Risk in Transgender Adolescents Receiving Gender-Affirming Hormone Therapy.

BACKGROUND AND OBJECTIVES: Many transgender youth experience gender dysphoria, a risk factor for suicide. Gender-affirming hormone therapy (GAHT) ameliorates this risk but may increase the risk for thrombosis, as seen from studies in adults. The aim with this study was to examine thrombosis and thrombosis risk factors among an exclusively adolescent and young adult transgender population. METHODS: This retrospective chart review was conducted at a pediatric hospital-associated transgender health clinic. The primary outcome was incidence of arterial or venous thrombosis during GAHT. Secondary measures included the prevalence of thrombosis risk factors. RESULTS: Among 611 participants, 28.8% were transgender women and 68.1% were transgender men. Median age was 17 years at GAHT initiation. Median follow-up time was 554 and 577 days for estrogen and testosterone users, respectively. Individuals starting GAHT had estradiol and testosterone levels titrated to physiologic normal. Multiple thrombotic risk factors were noted among the cohort, including obesity, tobacco use, and personal and family history of thrombosis. Seventeen youth with risk factors for thrombosis were referred for hematologic evaluation. Five individuals were treated with anticoagulation during GAHT: 2 with a previous thrombosis and 3 for thromboprophylaxis. No participant developed thrombosis while on GAHT. CONCLUSIONS: In this study, we examined thrombosis and thrombosis risk factors in an exclusively adolescent and young adult population of transgender people receiving GAHT. These data suggest that GAHT in youth, titrated within physiologic range, does not carry a significant risk of thrombosis in the short-term, even with the presence of preexisting thrombosis risk factors.

Characterization of Dental Pulp Stem Cell Responses to Functional Biomaterials Including Mineralized Trioxide Aggregates.

INTRODUCTION: Many studies in stem cell biology have demonstrated that dental pulp stem cells (DPSC) may be highly proliferative and capable of pluripotent differentiation into many different tissue types. Recent advances in stem cell research have outlined methods for directing in vitro or in vivo growth, viability, and proliferation, as well as differentiation of DPSC-although much remains to be discovered. Based upon this information, the primary objective of this study was to understand the functional biomaterials needed to more effectively direct DPSC viability, growth, and proliferation. METHODS: Using an approved protocol, previously collected and isolated samples of DPSC from an existing repository were used. Previously established stem cell biomarkers (Sox-2, Oct-4, NANOG) from each isolate were correlated with their proliferation rates or doubling times to categorize them into rapid, intermediate, or slow-dividing multipotent DPSC. Growth factors and other functional dental biomaterials were subsequently tested to evaluate DPSC responses in proliferation, viability, and morphology. RESULTS: Differential responses were observed among DPSC isolates to growth factors, including vascular endothelial growth factor (VEGF) and bone morphogenic protein (BMP-2), and functional biomaterials such as mineralized trioxide aggregates (MTA). The responsiveness of DPSC isolates did not correlate with any single factor but rather with a combination of proliferation rate and biomarker expression. CONCLUSIONS: These data strongly suggest that some, but not all, DPSC isolates are capable of a robust and significant in vitro response to differentiation stimuli, although this response is not universal. Although some biomarkers and phenotypes that distinguish and characterize these DPSC isolates may facilitate the ability to predict growth, viability, and differentiation potential, more research is needed to determine the other intrinsic and extrinsic factors that may contribute to and modulate these DPSC responses to these functional biomaterials for biotechnology and bioengineering applications.

Host fibrinogen drives antimicrobial function in Staphylococcus aureus peritonitis through bacterial-mediated prothrombin activation.

The blood-clotting protein fibrinogen has been implicated in host defense following Staphylococcus aureus infection, but precise mechanisms of host protection and pathogen clearance remain undefined. Peritonitis caused by staphylococci species is a complication for patients with cirrhosis, indwelling catheters, or undergoing peritoneal dialysis. Here, we sought to characterize possible mechanisms of fibrin(ogen)-mediated antimicrobial responses. Wild-type (WT) (Fib+) mice rapidly cleared S. aureus following intraperitoneal infection with elimination of ∼99% of an initial inoculum within 15 min. In contrast, fibrinogen-deficient (Fib-) mice failed to clear the microbe. The genotype-dependent disparity in early clearance resulted in a significant difference in host mortality whereby Fib+ mice uniformly survived whereas Fib- mice exhibited high mortality rates within 24 h. Fibrin(ogen)-mediated bacterial clearance was dependent on (pro)thrombin procoagulant function, supporting a suspected role for fibrin polymerization in this mechanism. Unexpectedly, the primary host initiator of coagulation, tissue factor, was found to be dispensable for this antimicrobial activity. Rather, the bacteria-derived prothrombin activator vWbp was identified as the source of the thrombin-generating potential underlying fibrin(ogen)-dependent bacterial clearance. Mice failed to eliminate S. aureus deficient in vWbp, but clearance of these same microbes in WT mice was restored if active thrombin was administered to the peritoneal cavity. These studies establish that the thrombin/fibrinogen axis is fundamental to host antimicrobial defense, offer a possible explanation for the clinical observation that coagulase-negative staphylococci are a highly prominent infectious agent in peritonitis, and suggest caution against anticoagulants in individuals susceptible to peritoneal infections.

The spectrum and severity of bleeding in adolescents with low von Willebrand factor-associated heavy menstrual bleeding.

Low von Willebrand factor (VWF) in adults is associated with significant bleeding, most notably heavy menstrual bleeding (HMB) and postpartum hemorrhage, although this has not been characterized in adolescents. The objectives of this analysis of a multicenter single arm observational cohort study in adolescents with low VWF-associated HMB were to describe the bleeding phenotype, HMB severity, and related complications. Eligibility criteria included postmenarchal females <21 years of age with HMB (Pictorial Blood Assessment Chart [PBAC] score >100) and low VWF (2 values of VWF activity ≥30 and ≤50 IU/dL). Patients diagnosed with other bleeding disorders were ineligible. Clinical phenotype data, including PBAC and Bleeding Assessment Tool (BAT) scores, laboratory data, and HMB management/outcome details, were extracted. Patient demographics and clinical characteristics were summarized as medians with minimum/maximum values or frequencies with percentages. Groups were compared using a Wilcoxon rank-sum test or Fisher's exact test. A total of 113 patients met inclusion criteria, and 2 were excluded. Ninety four percent had a significant bleeding phenotype (BAT score >2), with predominantly mucocutaneous bleeding (32%-44%), postprocedural/surgical bleeding (15%), and severe HMB (BAT HMB domain score ≥2; 90%). Bleeding complications included iron deficiency (60%), anemia (21%), transfusion (12%), and hospitalization (10%). Desmopressin challenge response in subjects tested was good and sustained. Several (48%) required combined therapy for HMB (hormonal/hemostatic), and one third did not show improvement despite therapy. Our results suggest that adolescent females with low VWF have a significant bleeding phenotype and resultant complications warranting a focus on prompt diagnosis, appropriate therapy, and prevention of complications.

Long-term safety and efficacy results from the phase 3b, open-label, multicentre Continuation study of rurioctocog alfa pegol for prophylaxis in previously treated patients with severe haemophilia A.

INTRODUCTION: Previous studies reported the efficacy and safety profile of extended half-life PEGylated recombinant factor VIII (FVIII) rurioctocog alfa pegol (TAK-660, SHP660, BAX 855) in preventing bleeding in haemophilia A patients. AIM: This study evaluated long-term safety and efficacy of rurioctocog alfa pegol for prophylaxis and treatment of bleeding in previously treated children and adults. METHODS: In this phase 3b, prospective, open-label, multicentre study (NCT01945593), eligible patients ≤ 75 years with severe haemophilia A (FVIII < 1%) received prophylactic rurioctocog alfa pegol in a fixed dose (FD, twice-weekly or less frequent) or pharmacokinetic (PK)-tailored dose regimen. Co-primary endpoints were incidence of confirmed FVIII inhibitory antibody development and spontaneous annualized bleed rate (ABR), analysed using a generalised linear model. Secondary endpoints included overall haemostatic efficacy, occurrence of adverse events and health-related quality of life (HRQoL). RESULTS: Overall, 216 patients were included; mean (SD) age at enrolment was 22.8 (15.7) years. No patients developed confirmed FVIII inhibitors. The point estimate (95% CI) of mean spontaneous ABR was 1.20 (0.92-1.56) among 186 patients receiving twice-weekly FD prophylaxis and 0.96 (0.54-1.71) among 25 patients receiving PK-tailored prophylaxis. Overall haemostatic efficacy was rated good or excellent in 88.6% of all bleeds. No new safety signals were observed. Patients reported improvements in HRQoL measures of pain, and physical and mental well-being. CONCLUSION: These results highlight the long-term safety and efficacy of rurioctocog alfa pegol prophylaxis in previously treated children and adults with severe haemophilia A, with a safety profile similar to previous studies and continuing ABR reduction.

Heparin Mimic Material Derived from Cellulose Nanocrystals.

This study analyzes and evaluates the use of cellulose nanocrystals (CNCs), stiff nanosized natural materials that have been modified to mimic heparin. These CNCs are simple polysaccharides with a similar backbone structure to heparin, which when modified reduces coagulation and potentially the long-term effects of solution-based anticoagulants. Thus, CNCs represent an ideal foundation for generating materials biocompatible with blood. In this study, we developed a biocompatible material that inhibits blood clotting through surface functionalization to mimic heparin. Surface chemistry of CNCs was modified from "plain" CNCs (70 mmol SO3-/kg) to 500 mmol COO-/kg (TEMPO-oxidized CNCs) and 330 mmol SO3-/kg CNCs (sulfonated CNCs). Platelet adherence and blood assays show that changes in functionalization reduce coagulation. By utilizing and modifying CNCs reactive functional groups, we create a material with unique and favorable mechanical properties while also reducing clotting.

Neuron-generated thrombin induces a protective astrocyte response via protease activated receptors.

Astrocytes protect neurons during cerebral injury through several postulated mechanisms. Recent therapeutic attention has focused on enhancing or augmenting the neuroprotective actions of astrocytes but in some instances astrocytes can assume a neurotoxic phenotype. The signaling mechanisms that drive astrocytes toward a protective versus toxic phenotype are not fully known but cell-cell signaling via proteases acting on cell-specific receptors underlies critical mechanistic steps in neurodevelopment and disease. The protease activated receptor (PAR), resides in multiple brain cell types, and most PARs are found on astrocytes. We asked whether neuron-generated thrombin constituted an important astrocyte activation signal because our previous studies have shown that neurons contain prothrombin gene and transcribed protein. We used neuron and astrocyte mono-cell cultures exposed to oxygen-glucose deprivation and a model of middle cerebral artery occlusion. We found that ischemic neurons secrete thrombin into culture media, which leads to astrocyte activation; such astrocyte activation can be reproduced with low doses of thrombin. Media from prothrombin-deficient neurons failed to activate astrocytes and adding thrombin to such media restored activation. Astrocytes lacking PAR1 did not respond to neuron-generated thrombin. Induced astrocyte activation was antagonized dose-dependently with thrombin inhibitors or PAR1 antagonists. Ischemia-induced astrocyte activation in vivo was inhibited after neuronal prothrombin knockout, resulting in larger strokes. Restoring prothrombin to neurons with a lentiviral gene vector restored astrocyte activation and reduced stroke damage. We conclude that neuron-generated thrombin, released during ischemia, acts via PAR1 and may cause astrocyte activation and paracrine neuroprotection.

Thrombin Signaling Promotes Pancreatic Adenocarcinoma through PAR-1-Dependent Immune Evasion.

Pancreatic ductal adenocarcinoma (PDAC) is associated with robust activity of the coagulation system. To determine mechanisms by which clotting factors influence PDAC tumor progression, we generated and characterized C57Bl/6-derived KPC (KRasG12D, TRP53R172H ) cell lines. Tissue factor (TF) and protease-activated receptor-1 (PAR-1) were highly expressed in primary KPC pancreatic lesions and KPC cell lines similar to expression profiles observed in biopsies of patients with PDAC. In allograft studies, tumor growth and metastatic potential were significantly diminished by depletion of TF or Par-1 in cancer cells or by genetic or pharmacologic reduction of the coagulation zymogen prothrombin in mice. Notably, PAR-1-deleted KPC cells (KPC-Par-1KO) failed to generate sizable tumors, a phenotype completely rescued by restoration of Par-1 expression. Expression profiling of KPC and KPC-Par-1KO cells indicated that thrombin-PAR-1 signaling significantly altered immune regulation pathways. Accordingly, KPC-Par-1KO cells failed to form tumors in immune-competent mice but displayed robust tumor growth comparable to that observed with control KPC cells in immune-compromised NSG mice. Immune cell depletion studies indicated that CD8 T cells, but not CD4 cells or natural killer cells, mediated elimination of KPC-Par-1KO tumor cells in C57Bl/6 mice. These results demonstrate that PDAC is driven by activation of the coagulation system through tumor cell-derived TF, circulating prothrombin, and tumor cell-derived PAR-1 and further indicate that one key mechanism of thrombin/PAR-1-mediated tumor growth is suppression of antitumor immunity in the tumor microenvironment. SIGNIFICANCE: The tissue factor-thrombin-PAR-1 signaling axis in tumor cells promotes PDAC growth and disease progression with one key mechanism being suppression of antitumor immunity in the microenvironment.

Elimination of the fibrinogen integrin αMß2-binding motif improves renal pathology in mice with sickle cell anemia.

Sickle cell anemia (SCA) is caused by a point mutation in the ß-globin gene that leads to devastating downstream consequences including chronic hemolytic anemia, episodic vascular occlusion, and cumulative organ damage resulting in death. SCA patients show coagulation activation and inflammation even in the absence of vascular occlusion. The coagulation factor fibrinogen is not only central to hemostasis but also plays important roles in pathologic inflammatory processes, in part by engaging neutrophils/macrophages through the αMß2 integrin receptor. To determine whether fibrin(ogen)-mediated inflammation is a driver of SCA-associated pathologies, hematopoietic stem cells from Berkeley sickle mice were transplanted into homozygous Fibγ390-396A mice that express normal levels of a mutant form of fibrin(ogen) that does not engage αMß2 Fibγ390-396A mice with SCA displayed an impressive reduction of reactive oxygen species (ROS) in white blood cells (WBCs), decreased circulating inflammatory cytokines/chemokines, and significantly improved SCA-associated glomerular pathology highlighted by reduced glomerulosclerosis, inflammatory cell infiltration, ischemic lesions, mesangial thickening, mesangial hypercellularity, and glomerular enlargement. In addition, Fibγ390-396A mice with SCA had improved glomerular protective responses and podocyte/mesangial transcriptional signatures that resulted in reduced albuminuria. Interestingly, the fibrinogen γ390-396A mutation had a negligible effect on cardiac, lung, and liver functions and pathologies in the context of SCA over a year-long observation period. Taken together, our data support that fibrinogen significantly contributes to WBC-driven inflammation and ROS production, which is a key driver of SCA-associated glomerulopathy, and may represent a novel therapeutic target against irreversible kidney damage in SCA.

Plasmin-mediated fibrinolysis enables macrophage migration in a murine model of inflammation.

Efficient migration of macrophages to sites of inflammation requires cell surface-bound plasmin(ogen). Here, we investigated the mechanisms underlying the deficits of plasmin(ogen)-mediated macrophage migration in 2 models: murine thioglycollate-induced peritonitis and in vitro macrophage migration. As previously reported, macrophage migration into the peritoneal cavity of mice in response to thioglycollate was significantly impaired in the absence of plasminogen. Fibrin(ogen) deposition was noted in the peritoneal cavity in response to thioglycollate, with a significant increase in fibrin(ogen) in the plasminogen-deficient mice. Interestingly, macrophage migration was restored in plasminogen-deficient mice by simultaneous imposition of fibrinogen deficiency. Consistent with this in vivo finding, chemotactic migration of cultured macrophages through a fibrin matrix did not occur in the absence of plasminogen. The macrophage requirement for plasmin-mediated fibrinolysis, both in vivo and in vitro, was negated by deletion of the major myeloid integrin αMß2-binding motif on the γ chain of fibrin(ogen). The study identifies a critical role of fibrinolysis in macrophage migration, presumably through the alleviation of migratory constraints imposed by the interaction of leukocytes with fibrin(ogen) through the integrin αMß2 receptor.

Pericyte degeneration causes white matter dysfunction in the mouse central nervous system.

Diffuse white-matter disease associated with small-vessel disease and dementia is prevalent in the elderly. The biological mechanisms, however, remain elusive. Using pericyte-deficient mice, magnetic resonance imaging, viral-based tract-tracing, and behavior and tissue analysis, we found that pericyte degeneration disrupted white-matter microcirculation, resulting in an accumulation of toxic blood-derived fibrin(ogen) deposits and blood-flow reductions, which triggered a loss of myelin, axons and oligodendrocytes. This disrupted brain circuits, leading to white-matter functional deficits before neuronal loss occurs. Fibrinogen and fibrin fibrils initiated autophagy-dependent cell death in oligodendrocyte and pericyte cultures, whereas pharmacological and genetic manipulations of systemic fibrinogen levels in pericyte-deficient, but not control mice, influenced the degree of white-matter fibrin(ogen) deposition, pericyte degeneration, vascular pathology and white-matter changes. Thus, our data indicate that pericytes control white-matter structure and function, which has implications for the pathogenesis and treatment of human white-matter disease associated with small-vessel disease.