Fact-checked by Grok 2 weeks ago

Tonsillar crypts

Tonsillar crypts are invaginations or pits within the surface epithelium of the tonsils, primarily the palatine tonsils, that form deep, branching structures increasing the internal surface area for immune interactions.^[1] These crypts, numbering approximately 10 to 30 per palatine tonsil, are lined by non-keratinized stratified squamous epithelium and reticulated crypt epithelium, which features a mesh-like network of cells facilitating antigen exposure.^[2] As components of the mucosa-associated lymphoid tissue (MALT) within Waldeyer's ring, tonsillar crypts play a critical role in mucosal immunity by trapping pathogens, debris, and foreign antigens entering through the oral and nasal cavities.^[3] Anatomically, the crypts extend into the tonsillar parenchyma, surrounded by dense lymphoid follicles containing germinal centers where B lymphocytes proliferate in response to antigens.^[4] Microfold (M) cells within the crypt epithelium specialize in antigen uptake and transport to underlying immune cells, including dendritic cells and T lymphocytes, initiating both humoral and cellular immune responses.^[1] The palatine tonsils, housing the most prominent crypts, are located bilaterally in the oropharynx between the palatoglossal and palatopharyngeal arches, while smaller crypts appear in the pharyngeal (adenoid) and lingual tonsils.^[2] Functionally, tonsillar crypts enable the tonsils to sample environmental antigens without an afferent lymphatic supply, supporting the production of immunoglobulins such as IgA and IgG for local mucosal defense.^[3] This structure enhances immune surveillance at the gateway to the respiratory and gastrointestinal tracts, promoting tolerance to harmless substances while mounting defenses against pathogens.^[4]^[5] However, the crypts' design can lead to accumulation of bacterial biofilms, food particles, and desquamated cells, potentially forming tonsilloliths (tonsil stones) that cause halitosis, chronic inflammation, or recurrent infections if not cleared.^[1]

Anatomy

Gross structure

Tonsillar crypts are invaginations of the stratified squamous epithelium covering the surface of the tonsils, forming pits that extend into the underlying lymphoid tissue. They are most prominent in the palatine tonsils but are also present in the lingual tonsils, while the pharyngeal tonsils (adenoids) feature smaller folds rather than true crypts.^[3]^[6]^[7] In the palatine tonsils, each tonsil typically contains 10 to 20 crypts, appearing as fissure-like openings on the medial surface that face the oropharynx. These crypts exhibit branched or tubular shapes, with a primary intratonillar crypt extending deepest and secondary branches arising from it, thereby increasing the internal surface area. The crypts are situated within the tonsillar fossa, bounded anteriorly by the palatoglossal arch and posteriorly by the palatopharyngeal arch, and their walls are in close proximity, often collapsed.^[8]^[9]^[6] The depth of tonsillar crypts varies, penetrating deeply into the tonsillar parenchyma, nearly the full thickness in some cases, though exact measurements depend on individual anatomy. Age-related changes are notable: in children, crypts are fewer and shallower, reflecting smaller tonsil size; they deepen and proliferate during growth, reaching maximum development around puberty when tonsils measure 20-25 mm vertically and 10-15 mm transversely; post-puberty, the tonsils and their crypts undergo involution, becoming smaller and less prominent with increased fibrosis in adulthood.^[8]^[3]^[6]

Microscopic features

The lining epithelium of tonsillar crypts consists of stratified squamous non-keratinized epithelium, which forms irregular patches with minimal keratinization and invaginates deeply into the underlying lymphoid tissue.^[10] This epithelium is modified into a reticular form within the crypts due to heavy infiltration by lymphoid cells, creating a sponge-like structure that facilitates interaction between luminal contents and immune cells.^[10] Specialized microfold cells (M cells) are present in the crypt epithelium, particularly at the base and sides, enabling antigen uptake through their apical microfolds and transcytosis to underlying immune cells.^[11] Beneath the epithelium lie dense subepithelial layers composed primarily of lymphoid tissue, including primary and secondary follicles with prominent germinal centers rich in B cells undergoing proliferation and differentiation.^[12] These layers also contain abundant plasma cells producing immunoglobulins, scattered lymphocytes (both T and B types), and macrophages, with the reticular epithelium extending deeper into the crypt regions where epithelial cells are interspersed with these immune elements.^[10] The basement membrane is often discontinuous in crypt areas, allowing closer apposition between epithelial and lymphoid components.^[12] The crypt lumen typically harbors desquamated epithelial cells, bacteria, food debris, and cellular remnants, contributing to a debris-filled environment that can form tonsilloliths under chronic conditions.^[13] Goblet cells are absent in the tonsillar crypt epithelium, but mucus is provided by adjacent minor salivary glands, aiding in lubrication and partial clearance of luminal contents.^[1] Vascular supply to the crypts arises from arterioles branching from the tonsillar artery (a branch of the facial artery), ascending palatine artery, and other external carotid tributaries, forming a rich capillary network within the fibrovascular cores of the crypts to support immune cell activity.^[1] Neural innervation is provided by branches of the glossopharyngeal nerve and lesser palatine nerves (from the maxillary division of the trigeminal nerve), which convey sensory input responsible for pain responses during inflammation.^[1] Histological variations exist across tonsil types; palatine tonsils feature deep, branching crypts lined by non-keratinized stratified squamous epithelium with extensive reticulation, whereas tubal tonsils have shallower crypts with similar but less pronounced lymphoid infiltration, and pharyngeal tonsils exhibit fewer and shallower crypts or folds covered by pseudostratified ciliated columnar epithelium.^[2] Lingual tonsils display crypts with stratified squamous lining but incorporate taste buds and more variable lymphoid nodules compared to palatine types.^[2]

Function

Immune surveillance

The tonsillar crypt epithelium serves as a critical interface for antigen sampling in the oropharynx, exposing underlying lymphoid tissue to environmental antigens encountered through the upper respiratory and digestive tracts. Specialized microfold (M) cells within the crypt epithelium actively transport particulate antigens, such as bacteria and viruses, across the epithelial barrier via transcytosis, delivering them directly to subepithelial B and T lymphocytes for immune processing.^[14]^[15]^[16] This antigen delivery initiates lymphoid follicle activation within the crypt walls, where germinal centers form as sites of intense B-cell proliferation and differentiation. Stimulated by T helper cells and cytokines, B cells in these germinal centers undergo class-switch recombination and somatic hypermutation, maturing into plasma cells that secrete secretory IgA (sIgA) for mucosal defense and IgG for systemic responses.^[17]^[18]^[19] As components of Waldeyer's ring—a circular arrangement of lymphoid tissues encircling the nasopharynx and oropharynx—the tonsillar crypts provide first-line mucosal immunity against inhaled and ingested pathogens in the upper respiratory tract. This strategic positioning enables rapid detection and response to potential threats, contributing to both local barrier protection and priming of adaptive immunity.^[20]^[3] Tonsillar crypts become functionally active from infancy, supporting early immune maturation as lymphoid tissues develop postnatally in response to microbial exposure. Immune activity peaks during childhood, particularly between ages 3 and 10, when germinal center formation and antibody production are most robust, before gradual involution in adolescence.^[3]^[21] In comparative anatomy, human tonsillar crypts are notably deeper and more invaginated than the simpler, crypt-less structures in rodents, such as the nasal-associated lymphoid tissue (NALT) in rats and mice, which lacks equivalent epithelial folds for extensive antigen trapping. This structural difference enhances immune efficiency in humans by facilitating greater antigen exposure and lymphoid interaction, whereas rodent models rely on diffuse mucosal lymphoid aggregates with reduced sampling capacity.^[22]^[23]

Pathogen trapping mechanism

The invaginated structure of tonsillar crypts dramatically expands the surface area of the tonsillar epithelium, estimated at approximately 5-10 times that of a flat epithelial surface, which facilitates greater exposure to airborne and ingested pathogens entering the oropharynx. This enhanced contact promotes initial mechanical capture of microbes and foreign particles as they pass through the upper respiratory and digestive tracts. The crypts function as tubular diverticula, drawing in material via airflow and saliva flow to initiate pathogen entrapment before deeper immune processing occurs.^[24]^[2] Adhesion and retention within the crypts are bolstered by the formation of bacterial biofilms in their narrow recesses, where polymicrobial communities adhere to the epithelial lining and resist dislodgement. Salivary proteins, including mucins, contribute to this process by binding and aggregating microbes, creating stable complexes that anchor pathogens to the crypt surfaces and prevent their immediate clearance. These biofilms serve as a scaffold for ongoing microbial colonization, with extracellular polymeric substances enhancing retention even under shear forces from swallowing or speech.^[25]^[26]^[27] Tonsillar crypts also accumulate debris such as food particles, desquamated epithelial cells, necrotic material, and salivary components, forming a nidus that supports microbial proliferation and biofilm maturation. This debris-laden environment provides nutrients and shelter, allowing trapped pathogens to persist and multiply in relative isolation from external washes. Over time, partial clearance occurs through salivary flow and mechanical actions like swallowing, which expel some surface residues, though the deep crypt architecture ensures incomplete removal, leading to chronic accumulation of residues.^[28]^[26] The microenvironment within tonsillar crypts favors anaerobic bacteria, such as Fusobacterium species, due to limited oxygen penetration and the accumulation of metabolic byproducts that create low-oxygen niches conducive to their growth. These conditions promote the establishment of a diverse microbial ecology dominated by anaerobes, which further contribute to pathogen retention by altering local adhesion dynamics and producing enzymes that degrade host defenses.^[29]^[30]

Clinical significance

Associated disorders

Tonsilloliths, also known as tonsil stones or cryptic tonsils, form when calcified accumulations of food particles, cellular debris, and bacteria collect within the tonsillar crypts, often leading to symptoms such as halitosis and throat pain.^[31]^[32] These concretions are more prevalent in individuals with deeper crypts, with reported detection rates ranging from 10% to 25% in adults based on radiographic and clinical studies.^[33]^[34] Chronic tonsillitis arises from recurrent infections where bacterial biofilms serve as reservoirs within the tonsillar crypts, perpetuating inflammation despite antibiotic treatment.^[35]^[36] Common etiologies include viral pathogens in 70% to 95% of cases and bacterial agents such as group A beta-hemolytic Streptococcus, alongside polymicrobial involvement in persistent infections.^[32] This condition often exaggerates the crypts' normal role in trapping pathogens, leading to cycles of acute exacerbations.^[37] Crypt abscesses represent an acute inflammatory response in the tonsillar crypts, characterized by pus formation from localized bacterial invasion, which can progress to peritonsillar abscess if the infection spreads beyond the tonsillar capsule.^[38]^[39] These intra-tonsillar collections typically stem from untreated or severe tonsillitis, involving streptococcal species and anaerobic bacteria.^[40] Actinomycosis of the tonsils involves rare overgrowth of Actinomyces species, often in polymicrobial biofilms within the crypts, presenting as chronic suppuration.^[41]^[42] As a commensal organism in oral flora, Actinomyces can invade damaged crypt epithelium, leading to granulomatous inflammation.^[43] Epidemiologically, disorders of the tonsillar crypts show higher incidence in adolescents and young adults, with chronic tonsillitis predominantly affecting those aged 11 to 20 years.^[44] Genetic factors contribute to increased risk by influencing crypt depth and susceptibility to recurrent infections, as evidenced by familial aggregation in tonsillectomy cases for severe tonsillitis.^[45]^[46]

Diagnostic and therapeutic approaches

Diagnosis of issues related to tonsillar crypts typically begins with a clinical oropharyngeal examination to visualize the tonsils and crypts for signs of inflammation, exudate, or debris such as tonsilloliths.^[32] For more detailed inspection, fiberoptic endoscopy may be employed to assess deep crypt structures and detect hidden abscesses or chronic infections.^[32] In cases suspecting peritonsillar or deep neck abscesses, contrast-enhanced computed tomography (CT) imaging is recommended to delineate the extent of involvement and guide intervention.^[32] Microbiological evaluation involves targeted throat swabs from the crypts to identify pathogens, with culture serving as the gold standard for bacterial detection, particularly group A beta-hemolytic Streptococcus.^[32] Rapid antigen detection tests provide quick results for streptococcal infection, though with variable sensitivity, while polymerase chain reaction (PCR) assays offer high sensitivity for both bacterial and viral pathogens in crypt-derived samples.^[32] Therapeutic management prioritizes conservative approaches, including antibiotics such as penicillin for confirmed bacterial infections and saline irrigation or gargling to dislodge crypt debris and reduce bacterial load.^[32] For recurrent crypt-related issues like chronic tonsillitis or halitosis, surgical options include tonsillectomy, indicated per American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guidelines for children with 7 or more episodes in one year, 5 or more per year for two years, or 3 or more per year for three years.^[47] Less invasive alternatives, such as cryptolysis using CO2 laser or temperature-controlled radiofrequency ablation, target crypt epithelium to smooth surfaces and prevent debris accumulation, performed under local anesthesia in outpatient settings.^[48] Preventive strategies emphasize oral hygiene practices, including regular brushing and saltwater rinses, to minimize crypt debris buildup, alongside prompt treatment of acute infections to avert recurrence.^[32] Tonsillectomy significantly reduces the frequency of recurrent throat infections, with studies showing a decrease in sore throat days by approximately 50% over two years, though benefits may wane after the first year.^[49] Cryptolysis procedures yield symptom improvement in 77-91% of cases for halitosis and foreign body sensation at six months, with low complication rates but potential for minor oozing (4-21%).^[48] Postoperative risks for tonsillectomy include bleeding in 2-5% of cases, primarily secondary hemorrhage requiring intervention in about 1%.^[50]

References

[1]
Anatomy, Head and Neck, Palatine Tonsil (Faucial Tonsils) - NCBI
Jun 5, 2023 · Structure and Function Palatine tonsils consist of approximately 15 crypts, which provide a large internal surface area. The follicular ...
[2]
Anatomy and physiology of the palatine tonsils, adenoids, and ... - NIH
Their primary function is to participate in the secondary immune system by immunologically sampling antigens and local pathogens. They are strategically located ...
[3]
Anatomy, Head and Neck: Tonsils - StatPearls - NCBI Bookshelf
Jul 26, 2025 · Structure and Function ... Like other lymphoid tissues, the tonsils contribute to immune defense by responding to infections and foreign antigens.Introduction · Structure and Function · Surgical Considerations
[4]
Histology at SIU, gastrointestinal system
Jun 14, 2022 · Tonsilar crypts provide sites where immune surveillance cells (lymphocytes) can encounter foreign antigens which are entering the body through ...
[5]
Anatomy and physiology of the palatine tonsils, adenoids, and ...
The crypts resemble tubular diverticula and have a fibrovascular core surrounded by lymphoid tissue and the epithelial surface is comprised of non-keratinized ...
[6]
The Tonsils (Waldeyer's Ring) - Lingual - Pharyngeal - Palatine - Tubal
The tonsils are collections of lymphatic tissue located within the pharynx. They collectively form a ringed arrangement, known as Waldeyer's ring.
[7]
Tonsil and Adenoid Anatomy - Medscape Reference
Apr 4, 2025 · The palatine tonsils are dense compact bodies of lymphoid tissue that are located in the lateral wall of the oropharynx, bounded by the palatoglossus muscle ...
[8]
Palatine tonsil: anatomy and histology | Kenhub
Apr 18, 2024 · The palatine tonsils are a pair of tonsils found on either side of the oropharynx. They provide immunological protection to the body.
[9]
The specialised structure of crypt epithelium in the human palatine ...
The reticulated epithelium lining the tonsillar crypts represents a specialised compartment, important in the immunological functions of the tonsil as a whole.
[10]
Biological significance of palatine tonsillar epithelium
The number of crypts in a palatine tonsil correlates with the extent and reactivity of the lymphoid component. Enlargement and branching of crypts increase ...
[11]
Characterization of Epithelial Progenitors in Normal Human Palatine ...
Oct 29, 2015 · The outer surface of the human palatine tonsil is lined with a stratified squamous epithelium that invaginates into the underlying lymphoid ...
[12]
The cells in tonsillar crypts - PubMed
Many of the cells were degenerating and there was a great deal of cellular debris. The non-epithelial cells seemed to have entered the crypts from the lining ...Missing: contents bacteria goblet
[13]
An atlas of cells in the human tonsil - PMC - PubMed Central - NIH
Jan 31, 2024 · We validated tonsillar cell-type annotations and marker genes in an independent validation cohort, which also identified age-related ...
[14]
Unveiling the Enigmatic Adenoids and Tonsils - PubMed Central - NIH
Jun 21, 2023 · The tonsillar crypts and M cells facilitate antigen uptake and transport, initiating immune responses. Secondly, adenoids and tonsils ...
[15]
Vaccination Strategies to Promote Mucosal Antibody Responses
Oct 29, 2010 · ... microfold or membranous cells (M cells) specialized in antigen sampling. Similar M cells are present in the crypts of tonsils and adenoids.Main Text · Follicular Pathways For... · Yin And Yang Of Mucosal...
[16]
Short and long term impact of adenotonsillectomy on the immune ...
In the follicular germinal centers, B-cells stimulated by T helper cells (CD4+) and cytokines start proliferating and turning into plasmocytes, which results ...
[17]
The mucosal immune system and IgA nephropathy - PubMed Central
Oct 12, 2021 · Under microbe trigger, B cells can be stimulated, differentiated, and proliferated in germinal centers of tonsils, leading to polymeric IgA ...Immunoglobulin A Nephropathy · Immunoglobulin A And Iga... · New Prospective Therapy...
[18]
Perspectives on how mucosal immune responses, infections and gut ...
B-cells can be activated and proliferate in germinal centers in the tonsil. Germinal centers are critical sites where B memory cells are created and secretory ...
[19]
Recent advances in the immunological understanding of association ...
Apr 7, 2019 · In vitro study showed that tonsillar mononuclear cells of IgAN patients showed significantly higher productions of IgA and interferon‐γ (IFN‐γ) ...
[20]
Analysis of Tonsil Tissues from Patients Diagnosed with Chronic ...
Chole and Faddis [38] confirmed, by histological analysis, the presence of bacteria in the form of biofilm in the crypts of palatine tonsil tissue. Dense ...Missing: features | Show results with:features
[21]
The Tonsils Revisited: Review of the Anatomical Localization and ...
Aug 21, 2011 · On histology, the lymphoid tissue is scattered and varies from aggregated lymphoid cells to primary and secondary lymphoid follicles. In areas ...
[22]
Factors Limiting the Translatability of Rodent Model–Based ... - NIH
Jul 12, 2022 · In this review, we explored the factors that limit the translatability of rodent-based intranasal vaccine research to humans.
[23]
Ex Vivo Modeling of Oral HIV Transmission in Human Palatine Tonsil
... (tonsillar crypts) that increase the total surface area of tonsil ∼6-fold (Perry and Whyte 1998). The crypts are lined by a reticulated epithelium that is ...<|control11|><|separator|>
[24]
Anatomical evidence of microbial biofilms in tonsillar tissues - PubMed
The presence of bacterial biofilms within the tissue and crypts of inflamed tonsils may explain the chronicity and recurrent characteristics of some forms of ...
[25]
Tonsillolith: A polymicrobial biofilm - PMC - NIH
Tonsilloliths are rare concretions found in the tonsillar crypt. Tonsillolith occurs rarely in children compared to the adults. The size of tonsillolith ranges ...Missing: depth | Show results with:depth
[26]
Compositional analysis of the tonsil microbiota in relationship ... - NIH
Jan 21, 2022 · They produce mucin to prevent bacterial adherence, have physical barriers consisting of the epithelium and lumen of the crypts, produce ...
[27]
Alimentary System - PMC - PubMed Central
Intestinal immune elements are sparse and quiescent at birth; immune activity in the gut is probably stimulated in response to colonization by normal ...
[28]
Low usefulness of reporting tonsillar PCR Ct-values in pharyngeal ...
Hypothetically, pharyngeal inflammation might expose bacteria of tonsillar crypts, where anaerobic conditions occur, to the tonsillar surface. This could ...Missing: acidic microenvironment
[29]
Analysis of the tonsillar microbiome in young adults with sore throat ...
Jan 19, 2018 · Analysis of the tonsillar microbiome in young adults with sore throat reveals a high relative abundance of Fusobacterium necrophorum with low diversity.
[30]
A giant tonsillolith - PMC - NIH
3 Tonsillar crypts are fissure-like invaginations in the medial side of the palatine tonsils and serve to increase the surface area of the tonsils with more ...
[31]
Tonsillitis and Tonsilloliths: Diagnosis and Management - AAFP
Tonsilloliths smaller than 5 mm are common, and tonsilloliths larger than 5 mm are rare. ... deep tonsillar crypts (Figure 3). Symptoms include recurrent sore ...Missing: depth | Show results with:depth
[32]
Prevalence and Imaging Characteristics of Palatine Tonsilloliths ...
The prevalence of tonsilloliths was 16 to 24% in previous reports, but it is inconsistent with clinical experience.
[33]
Prevalence and imaging characteristics of detectable tonsilloliths on ...
Oct 14, 2013 · It has been reported that the detection rate of tonsilloliths was under 25% [1–4], although experience suggests otherwise. Furthermore, recent ...
[34]
Chronic tonsillitis and biofilms: a brief overview of treatment modalities
A study utilizing an innovative imagining technique in single sections of human mucosal tissue reports the presence of biofilms in 70.8% of chronic tonsillitis ...Missing: crypts | Show results with:crypts
[35]
Evidence of Bacterial Biofilms among Infected and Hypertrophied ...
In the case of tonsillar infection, bacteria that inhabit the crypts can spread into the tissue and secret their toxins leading to infiltration of leukocyte and ...
[36]
Anatomical evidence of microbial biofilms in tonsillar tissues
Jun 1, 2003 · The presence of bacterial biofilms within the tissue and crypts of inflamed tonsils may explain the chronicity and recurrent characteristics of ...
[37]
Peritonsillar Abscess - StatPearls - NCBI Bookshelf - NIH
Peritonsillar abscesses are localized collections of pus in peritonsillar space between the tonsillar capsule and superior constrictor muscle.Continuing Education Activity · History and Physical · Treatment / Management
[38]
Intratonsillar abscess | Radiology Reference Article - Radiopaedia.org
Nov 17, 2019 · Intratonsillar abscesses, or simply tonsillar abscesses, are uncommon complications of tonsillitis in which pus accumulates focally in the parenchyma of the ...On This Page · Radiographic Features · Promoted Articles...
[39]
Tonsillitis and Peritonsillar Abscess - PMC - PubMed Central - NIH
Peritonsillar abscess is one of the most common deep space head and neck infections in children. This collection of pus is thought to be formed most commonly ...
[40]
Actinomycosis: etiology, clinical features, diagnosis, treatment, and ...
... tonsillar crypts, periodontal pockets and ... Patients with esophageal actinomycosis are usually immunosuppressed by malignancy, HIV, or solid transplant.
[41]
Actinomyces - Pathology Outlines
Jan 17, 2023 · Affects immunocompetent and immunocompromised ... Commensal organism frequently encountered histologically in tonsillar crypts, resembling ...
[42]
Fatally invasive actinomycosis masquerading as a tonsillar carcinoma
Mar 4, 2014 · Methods and Results. We present the case of an elderly, immunosuppressed woman who presented with a herald bleed from a tonsillar lesion.
[43]
The Prevalence and Management of Chronic Tonsillitis - NIH
Feb 13, 2023 · The present study revealed that the majority of the participants suffering from CT were teenagers between the age of 11-20 years. This is in ...
[44]
Familial and Environmental Risk Predisposition in Tonsillectomy - NIH
Jul 21, 2020 · This study reveals that genetic predisposition factors may have a role for tonsillectomy and its underlying causative indications.Missing: epidemiology | Show results with:epidemiology
[45]
Familial aggregation of tonsillectomy in early childhood and ... - NIH
Jan 12, 2018 · Our findings suggest that genetic factors predispose to severe tonsillitis underlying tonsillectomy, regardless of age and sex.
[46]
Clinical Practice Guideline: Tonsillectomy in Children (Update)
This clinical practice guideline (CPG), which is intended for all clinicians in any setting who interact with children aged 1 to 18 years who may be candidates ...
[47]
Comparing the Efficacy of Temperature-Controlled Radiofrequency ...
In our study, 6 months following the procedure, patients who underwent TC-RF tonsil ablation showed improvement of halitosis and foreign body sensation by 78.9% ...
[48]
Treatment of recurrent acute tonsillitis—a systematic review ... - NIH
Oct 10, 2023 · Tonsillectomy reduces sore throat days by almost 53% in over 2 years. Table 2. Most important randomized controlled clinical trials analyzing ...Missing: percentage | Show results with:percentage
[49]
Tonsillectomy Bleed Rates across the CHEER Practice Research ...
Jul 1, 2017 · There has been reported a 0.2%–2% risk of primary bleeding (within 24 hours of the procedure) and a 0.1%–3% risk of secondary bleeding (>24 ...