BMS 200 - Physiology of Hearing, Taste, and Olfaction MCQs PDF

BMS 200 – Physiology of hearing, taste, and olfaction Outcomes for today Describe the physiology of taste receptors and taste perception Describe the physiology of olfaction Describe the typical anatomy and physiology of the middle and external ears, including the structures responsible for...

BMS 200 – Physiology of hearing, taste, and olfaction Outcomes for today Describe the physiology of taste receptors and taste perception Describe the physiology of olfaction Describe the typical anatomy and physiology of the middle and external ears, including the structures responsible for the transmission and modulation of auditory stimuli Describe the relationship between extracellular matrix (ECM) components and other middle ear structures, such as the ossicles and tympanic membrane, in facilitating sound conduction Describe the anatomical structures of the organs of hearing and equilibrium, including the external, middle, and inner ear, as well as the vestibular system. Outcomes for today Describe the functions of each component of the auditory system, including the role of the pinna, external auditory canal, tympanic membrane, ossicles, cochlea, and vestibular apparatus. Discuss the physiological processes involved in sound transmission, from the capture of sound waves by the external ear to the transduction and amplification of auditory signals in the inner ear. Describe the intricate mechanisms of the cochlea, including the organization of the hair cells, the role of the basilar membrane, and the function of the cochlear duct in sound perception. Relate the structure of the semicircular canals and otolith organs to the function of detecting rotational and linear acceleration, respectively. The ear – general structure Outer ear - structures Auricle (pinna) – the “floppy” part of your ear, composed of the helix, lobule, and tragus Functions: Focuses sound waves onto the tympanic membrane Certain structures tend to emphasize certain frequencies of sound Structures of the auricle change the nature of the sounds coming from different directions Outer ear - structures Auditory meatus – the opening of the external auditory canal ▪ The external auditory canal contains ceruminous glands (modified apocrine sudoriferous glands) Traps foreign substances Protects the delicate skin lining the external canal Cerumen (earwax) is composed of: ▪ anti-microbial proteins ▪ saturated fatty acids ▪ sloughed keratinocytes Middle ear - structures The tympanic membrane is the border between the external/outer ear and the middle ear ▪ fibroelastic connective tissue covered externally with epidermis and internally by simple cuboidal epithelium Middle ear - structures The tympanic cavity is found within the petrous part of the temporal bone ▪ lined by simple cuboidal epithelium that forms the “top layer” of a thin mucosa ▪ Pseudostratified columnar epithelium lines the auditory tube (Eustachian tube) and projects inferiorly and anteriorly, opening into the nasopharynx Usually collapsed – when you swallow or yawn, it opens up and equalizes the pressure between the atmosphere and the middle ear  Middle ear - structures Ossicles (little bones) ▪ Malleus (latin for hammer) attaches to the tympanic membrane and incus (synovial joint) Tensor tympani muscle “dampens” the movements that are transmitted from the tympanic membrane to the malleus ▪ innervated by CN V ▪ Incus (latin for anvil) attaches to the malleus and the stapes (synovial joints) ▪ Stapes (latin for stirrup) Attaches to the incus and to the oval window ▪ Oval window: transition point between the middle and inner ear The stapedius muscle “dampens” the vibrations transmitted from the stapes to the oval window ▪ Innervation: CN VII Key middle ear structures  If you were building an ear at Home Depot… FIGURE 4.17 Model of the middle ear. Vibrations from the eardrum are transmitted by the lever system formed by the ossicular chain to the oval window of the scala vestibuli. The combination of the four suspensory ligaments produces a virtual pivot point (marked by a cross); its position varies with the frequency and intensity of the sound. The stapedius and tensor tympani muscles modify the lever function of the ossicular chain.  Middle ear - structures What is the point of all these little bones? ▪ They’re all levers Amplify the small movements of the tympanic membrane (TM) into larger movements at the oval window. The TM has 20X the surface area of the oval window This lever system, combined with the surface area difference, helps overcome the acoustic impedance mismatch between air and water. ▪ Air is “easier” to move than water 🡪 without this system in place, sound waves in air would simply bounce off the oval window, failing to transmit vibrations to the  Inner ear – structures for sound Cochlea – the snail-like structure ▪ Coiled 2.5 times, ~ 35 mm long, about the size of a large pea It has 1,000,000 moving parts when you count all of the stereovilli (often called stereocilia) 🡪 most complicated mechanical thing in your body Inner Ear – Lovely Diagram  Inner ear – structures for sound Cochlea – the snail thingy ▪ Scala vestibuli: Connects to the oval window, filled with perilymph Separated from the scala media by Reissner’s membrane ▪ Scala tympani: Connects to the round window, filled with perilymph Separated from the scala media by the basilar membrane Continuous with the scala  Inner ear – structures for sound Cochlea – cont… ▪ Scala media Houses inner and outer hair cells Contains endolymph – much different ionic composition than the perilymph The basilar membrane houses the inner and outer hair cells ▪ The inner and outer hair cells contact the tectorial membrane (see diagram) Reissner’s membrane simply serves as a barrier so that endolymph doesn’t mix with perilymph  Inner ear – structures for sound Cochlea – cont… ▪ Scala media – the organ of Corti The site of transduction for vibration 🡪 action potential ▪ Organ of Corti stretches along the basilar membrane, 4 rows of hair cells: Inner hair cells – one row, about 3500 cells ▪ Project freely into the endolymph Outer hair cells – three rows,  Inner ear – structures for sound Cochlea – cont… ▪ Endolymph has a very high K+ concentration (around 80 mmol/L, very strange composition) ▪ Perilymph is very similar to CSF Low protein,  Why is there so much K+ in endolymph? Stria vascularis is a highly vascularized tissue found in the peripheral part of the scala media ▪ Secretes K+ into the scala media, creating a massive K+ gradient between the endolymph and perilymph ▪ FYI: Composed of The process of hearing – step-by-step Sound wave enters external auditory canal 1. Stapes moves inwards 🡪 oval window moves inwards 🡪 drop in pressure of the scala vestibuli 2. Round window moves outward (fluid is not very compressible) and the scala tympani pressure is now higher than the scala vestibuli pressure The process of hearing – step-by- step 3. Basilar membrane bends upward and the organ of Corti (the whole thing) shears towards the tectorial membrane 4. The hair bundles of the outer hair cells tilt toward the longer stereovilli 5. Transduction channels open in the outer hair cells ▪ K+ floods in 🡪 depolarization of the outer hair cell 🡪 receptor potential The process of hearing – step- by-step 6. Depolarization 🡪 contraction of prestin 🡪 contraction of the outer hair cell ▪ Very fast, happens within 100 microseconds 7. The basilar membrane moves upwards even more due to the contraction of the outer hair cells 8. Endolymph moves beneath the tectorial membrane The process of hearing – step-by- step 9. Inner hair cells bend towards their longer stereovilli 10. Transduction channels open in the inner hair cells 🡪 depolarization (just like the outer hair cells) ▪ K+ floods in 🡪 depolarization of the outer hair cell 🡪 receptor potential The process of hearing – step-by-step 11. VG calcium channels open 🡪 release of glutamate 🡪 depolarization of the afferent neuron ▪ Afferent cell bodies are within the spiral ganglion ▪ Bipolar neurons – dendrites make contact with the inner hair cells – about 50,000 neurons  The process of hearing - details Differences in frequency are distinguished by where the basilar membrane vibrates the most: ▪ High-frequency sounds are detected closer to the oval window ▪ Low-frequency sounds are detected closer to the helicotrema Younger people can hear a range between 20 – 20,000 Hz ▪ Pitch is detected based on what part of the organ of Corti detects the sound Differences in loudness are distinguished by how much the basilar membrane vibrates  What is sound, anyway? Sound wave formation – compression waves (A) Sound waves generated from a tuning fork cause molecules ahead of the advancing arm to be compressed and the molecules behind the arm to be rarified (B) Sound waves are propagated as sinusoidal, alternating regions of compression and rarefaction of air molecules. The wavelength of a sinusoidal wave is the spatial period between two peak compression waves.  Sound 🡪 action potential (transduction) The movements of the oval window (and round window) result in deflections of the basilar membrane and movement of hair cells ▪ Where the basilar membrane resonates the most depends on the frequency of the sound See bottom diagram ▪ Amplitude is detected based on the size of the standing wave vibration The Home Depot ear and hearing See notes below for discussion Equilibrium and the vestibular apparatus Two types of equilibrium are detected by the ear ▪ Static Detects position of head with respect to pull of gravity when body is not moving ▪ Is head tilted up? Down? To the side? Detects linear acceleration/deceleration ▪ An elevator speeding up or slowing down ▪ Car speeding up or slowing down ▪ Dynamic Detects angular movements of the head ▪ Is head being turned to the side? To the front? Is it being tilted?  The vestibular system Each ear contains: ▪ three semicircular canals ▪ two otolithic organs, the utricle and the saccule Basic sensing elements of the vestibular system are neurosensory hair cells Semicircular canals are arranged within the temporal bone in planes that are at approximately right angles to each other ▪ horizontal (lateral), anterior (superior), and the posterior (inferior) semicircular canals. The three pairs of canals work in a push–pull fashion—when one canal is stimulated, its corresponding partner on the  Vestibular apparatus FIGURE 4.22 The vestibular apparatus in the bony labyrinth of the inner ear (A) Activation of hair cells in the semicircular canals (B) The semicircular canals sense rotary acceleration and motion, whereas the utricle and saccule sense linear acceleration and static position Semicircular canal function Each canal has a dilated portion called the ampulla (near the utricle) Each ampulla contains the crista ampullaris ▪ ridge of tissue that is lined on its apical surface by vestibular hair cells, similar to those in the auditory system, and supporting cells ▪ Each vestibular hair cell contains up to a 100 stereocilia and a single longer kinocilium ▪ tips of the stereocilia and kinocilium are embedded in the undersurface of a dome-shaped gelatinous covering called the cupula.  Semicircular canal function Three canals at right angles to each other Anterior canal: Vertical in frontal plane ▪ Detects side tilts Posterior canal: Vertical in sagittal plane ▪ Detects “Yes” nod Lateral canal: Horizontal ▪ Detects “No” nod  Utricle and the Saccule Otolithic organs sense: ▪ static equilibrium (i.e., the resting position of the head while sitting, standing, or lying down) ▪ linear accelerations and decelerations The utricle and the saccule are saclike structures located in the vestibule, the bony chamber located between the semicircular canals and the cochlea. ▪ Saccule is oriented more vertically, utricle is oriented more horizontally  Utricle and the Saccule Macula – plaque-like mound of specialized neurosensory tissue similar to the crista ampullaris Consists of three basic components: neurosensory hair cells, supporting cells, and a gelatinous covering known as the otolithic membrane During surfacelinear of theacceleration otolithic membrane or is embedded with calcium carbonate crystals, deceleration, (like incalled otoliths or otoconia, which make the a car or membrane elevator) thedenser than the endolymph otolithic membranes slide because of inertial lag, which is accentuated by the weight of the otolith This sliding over the surface of the maculae deflects hair cell stereocilia producing sensory Smell and Taste Chemoreceptors dedicated to smell and taste are activated by chemical molecules found in mucus within the nose (odorants) and saliva in the mouth (tastants) Taste – approximately 5000 taste buds Found in papilla along the dorsum and sides of the tongue Types of papillae: ▪ Fungiform tip papillae - near the tongue's ▪ Circumvallate papillae, forming a V- shape on the back of the tongue ▪ foliate edge papillae, located on the posterior  Taste buds Fungiform papillae typically harbor up to five taste buds, primarily at their apex. In contrast, each circumvallate and foliate papilla can contain up to 100 taste buds, mainly along the papillae's sides filiform papillae – lack taste buds contribute to the tongue's rough texture and aid in the detection of food textures.  Taste buds ∙ Beyond the tongue, taste buds are also present in the soft palate, epiglottis, and pharynx. ∙ Taste buds: ∙ 50–100 taste receptor cells – modified epithelial cells with microvilli at the apex, studded with receptors for tastants ∙ Microvilli project through the taste pore Taste ∙ Saliva in the oral cavity serves as a solvent for tastants, facilitating their dissolution. This dissolved chemical then diffuses to the taste receptor sites. ∙ Additional function for saliva: bicarbonate secretion, aiding in swallowing, limited chemical digestion ∙ Each taste bud is innervated by approximately 50 nerve fibers, while each nerve fiber receives input from an average of five taste buds. ∙ Basal cells, originating from the epithelial cells surrounding the taste bud, differentiate into new taste cells, as taste cells have a lifespan of about 10 days ∙ Human taste perception is characterized by five fundamental modalities: salt, sweet, sour, bitter, and umami ∙ The central nervous system distinguishes between tastes because each taste receptor cell connects to a specific gustatory axon.  Taste perception Salt sensitivity involves the activation of epithelial sodium channels (ENaC), leading to membrane depolarization through Na+ entry. Sour taste results from proton (H+) stimulation, facilitated by ENaCs that permit proton entry. Additionally, H+ ions may block K+-sensitive channels, causing membrane depolarization Sour transduction may involve hyperpolarization-activated cyclic nucleotide- gated cation channels (HCN) and other mechanisms.  Taste perception Sweet taste perception involves at least two G protein- coupled receptors (GPCRs), T1R2 and T1R3. Both natural sugars and structurally different compounds like saccharin activate sweet receptors Bitter taste is evoked by a range of unrelated compounds, often serving as a warning against poisons. Some bitter compounds, such as quinine, block K+-selective channels, while others, like strychnine, bind to GPCRs (T2R family), Umami tastants activate a receptor composed of T1R1 and T1R3. The umami taste may also involve the activation of a truncated metabotropic glutamate receptor, mGluR4, within taste buds. BMS 200 – Physiology of hearing, taste, and olfaction P2  Structure of the Olfactory Epithelium ∙ Specialized segment of the nasal mucosa that houses olfactory sensory neurons ∙ approximately 10 cm² ∙ upper part of the nasal cavity, near the septum in humans. ∙ Major cell types of the olfactory epithelium: ∙ olfactory sensory neurons – bipolar neuron responsible for signal transduction of odorant 🡪 receptor potential ∙ These neurons feature a short, thick dendrite that Structure of the Olfactory Epithelium ∙ The axons of olfactory sensory neurons, forming the olfactory nerve, traverse the cribriform plate of the ethmoid bone to reach the olfactory bulbs. ∙ Supporting cells within the olfactory epithelium are responsible for secreting mucus, creating an optimal molecular and ionic environment for detecting odors. ∙ Odor-producing molecules, or odorants, dissolve in the mucus and bind to odorant receptors on the cilia of olfactory sensory neurons. Structure of the Olfactory Epithelium ∙ Odorant-binding proteins present in the mucus may enhance the diffusion of odorants to and from the odorant receptors. ∙ Basal stem cells replace olfactory neurons ∙ Olfactory sensory neurons typically have a lifespan of only 1–2 months. Odorant Receptors and Signal Transduction Odorant receptors considerable diversity in their amino acid sequences, but all are G-protein-coupled receptors (GPCRs). Typical Gs proteins for the most part What is the signal transduction cascade? Usually results in the opening of Cl- and Ca+2 channels  Olfactory Sensory Pathway Overview ∙ Within the olfactory bulb, olfactory sensory neurons' axons synapse on the primary dendrites of mitral cells and tufted cells, forming distinctive olfactory glomeruli. ∙ Each olfactory sensory neuron expresses a single one of the 400 functional olfactory genes, while  Olfactory Sensory Pathway Overview ∙ A unique two-dimensional map in the olfactory bulb is created, as each olfactory sensory neuron projects to only one or two glomeruli, providing specificity to the associated odorant. ∙ Mitral cells, along with their glomeruli, project to various regions of the olfactory cortex. Otosclerosis Definition: Abnormal bone deposition in the middle ear – Occurs around the rim of the oval window where the footplate of the stapes fits (obviously will affect hearing) – Both ears are usually affected Pathogenesis – Familial (autosomal dominant), but cause of the bony overgrowth, genes involved, are unknown… which is hard to believe because it’s so common May be related to measles infection – Begins with fibrous ankylosis of the footplate 🡪 bony overgrowth anchoring it into the oval window Seems to be caused by an imbalance between bone deposition and resorption Otosclerosis Clinical features ▪ Progressive hearing loss due to immobilization of the oval window is the main symptom Epidemiology ▪ Usually begins in the early decades of life; minimal degrees of this derangement are very common (10%!!) More severe symptomatic otosclerosis is relatively uncommon Even those without severe disease can progress to significant hearing loss over decades HEENT 2 Ear and vestibular apparatus pathologies General anatomy of the mouth and sinuses BMS Neurology of the olfactory and 200 pathways gustatory Pathologies of the ear Conductive vs. sensorineural hearing loss Otitis externa & otomycosis Otitis media ▪Acute otitis media (AOM) ▪Otitis media with effusion (OME) ▪Chronic otitis media Cholesteatoma Tympanic membrane perforations Hearing loss - generalities One of the most common sensory defects ▪ 15% between 20 and 69 years have some degree of high-frequency hearing loss due to noise Outer and inner hair cells are damaged by noise, but the outer are more vulnerable ▪ Presbycusis (age-induced) hearing loss is likely due to a combination of neuronal loss and hair cell loss ▪ Many substances are ototoxic Antibiotics, chemotherapeutic agents, diuretics are often implicated Many of these substances damage either the outer hair cells or the stria vascularis Hearing loss - generalities Conductive hearing loss – impaired sound transmission in the external or middle ear, impacts all frequencies ▪ Trauma to the tympanic membrane, infection, plugging of the external auditory meatus/canal, otosclerosis, cholesteatoma Sensorineural hearing loss – often loss of higher frequencies more than lower ▪ Presbycusis, ototoxic agents, noise (most common) ▪ Problems with endolymph (Meniere’s), infections of the labyrinth or 8 th CN, tumours (acoustic neuroma, brainstem tumours)  Tuning fork investigation of hearing Rinne Weber Method Base of vibrating tuning fork placed on vertex of skull Base of vibrating tuning fork placed on mastoid process until subject no longer hears it, then held in air next to ear Normal Hears equally on both sides Hears vibration in air after bone conduction is over Conduction deafness Sound louder in diseased ear because masking effect Vibrations in air not heard after bone (one ear) of environmental noise is absent on diseased side conduction is over Sensorineural Sound louder in normal ear Vibration heard in air after bone deafness (one ear) conduction is over, as long as nerve deafness is partial  Audiometry Human ear can hear from 20 – 20000 Hz ▪We’re best at hearing 1000 – 4000, human speech ranges from 500 – 2000 Hz Audiometry assesses hearing at particular tones (see FYI graphic below) and is much better at characterizing hearing loss than tuning fork tests Different forms of audiometry ▪ i.e. speech audiometry  Otitis externa 90% of otitis externa is bacterial ▪ Usually staphylococcal, pseudomonas aeruginosa, or E. coli Risk factors include: ▪ Humidity, loss of cerumen (trauma, excessive Q-tip use), heat, increased pH, obstruction of the ear canal, exposure The secretions of the ear are somewhat acidic, and this acts as a form of barrier immunity Infection can lead to an increase in pH (occlusion of secretions) Water (especially water colonized by bugs) in the ear canal is a prominent risk factor Otitis externa Clinical Features ▪ Otalgia – movement of the pinna/tragus can elicit this Movement of the outer ear doesn’t exacerbate otitis media ▪ Otorrhea (ear discharge) which can be purulent ▪ Itching of the external canal ▪ Edema 🡪 occlusion of the ear canal 🡪 conductive hearing loss ▪ Severe infection can lead to cellulitis (deeper layers, skin involvement) Treatment – topical antibiotics ▪ Make sure not to use ototoxic antibiotics with a perforated TM Otitis externa - variations Furunculosis – otitis externa of the outer 1/3 of the ear canal, usually staphylococcal Chronic otitis externa – less painful, more itchy ▪ Usually caused by repetitive trauma, chronic drainage from a middle ear infection Malignant/necrotizing otitis externa – bad news ▪ Progressive, slowly developing infection, severe otalgia, lots of otorrhea, granulation/necrotic tissue in the auditory canal Can be life-threatening if the infection colonizes temporal bone, intracranial structures Cranial nerve palsies and systemic infection also possible ▪ More common in the elderly, diabetics, immunocompromised – usually P. aeruginosa ▪ Medical emergency Otitis externa - variations Otomycosis – fungal infection of the external auditory canal, up to 10% of otitis externa ▪ Usual agent is Aspergillus (80%), next most common is Candida species ▪ More likely in: Diabetes, elderly, past history of HEENT surger in the mastoid ▪ Often seen in those with poor response to antibacterial antibiotics Fungal debris is often present on otoscopy Otitis Media This has been discussed to some degree in CMS Acute otitis media (AOM): rapid onset of signs and symptoms, including fever and otalgia Recurrent AOM = 3 or more episodes within a 6-month period or four or more episodes within a 12-month period - complete resolution of symptoms between episodes Usually due to auditory tube dysfunction Up to age 7, eustachian tube is shorter, wider, and more horizontal than in adults – predisposes to upper airway/oral bacteria colonization Blockage of the tube – swelling of adenoid lymphatic tissue, swelling due to URTI or allergic rhinitis, inadequate tensor palatini function Lack of breastfeeding (breast milk has antimicrobial sustances in it) Otitis Media AOM – General pathogenesis ▪ Obstruction of the auditory tube 🡪 air absorbed in middle ear 🡪 negative pressure 🡪 edema of mucosa with exudate and fluid accumulation 🡪 infection from nasopharyngeal secretions ▪ Major bacteria implicated: H. influenzae, S. pneumoniae, M. catarrhalis ▪ Major viruses implicated: RSV, influenza, parainfluenza, adenovirus (more next semester) AOM – Clinical Features ▪ Triad of otalgia, fever, and conductive hearing loss Rare to have tinnitus, vertigo, or facial nerve paralysis ▪ Otorrhea can occur if the TM is perforated  Otitis Media AOM – Clinical Features cont… ▪ Bulging, red TM (middle ear inflammation) ▪ Often the TM is opaque, bony landmarks are lost ▪ effusion can often be seen behind it, and mobility is limited (pneumatoscopy) Otitis Media OME (AKA serous otitis media) ▪Often due to untreated or unresolved AOM Persistent effusion in up to 40% of children 30 days after initial AOM, continued for 3 months in 10% Main concern in pediatric population is impact on hearing at early ages (prior to a year) ▪ Delay in language development ▪Risk factors are similar to those for AOM OME – Clinical Features ▪Conductive hearing loss with or without tinnitus ▪Feeling of fullness in the ear, low-grade fever ▪May or may not involve otalgia  Otitis Media OME on otoscopy: ▪TM is translucent/gray (limited inflammation) Fluid behind the ear, can often see air-fluid levels or bubbles ▪Loss of light reflex, reduced mobility on pneumatoscopy Most cases resolve on their own ▪ Tympanostomy tubes can improve hearing ▪ Case-by-case treatment depending on presentation Tympanic membrane perforations Most common causes: ▪ Middle ear infections ▪ Trauma – can be barotrauma or physical injury to the ear TM perforation – Clinical Features ▪ Sudden onset of pain, hearing loss ▪ Can include bloody otorrhea ▪ Vertigo or tinnitus Usually transient Perforations usually heal spontaneously – advisable to wear earplugs while swimming, bathing ▪ Postero-superior damage to the TM is more likely to damage the function of ossicles – more urgent referral to the HEENT Chronic otitis media TM perforation in the setting of recurrent or chronic ear infections ▪ chronic inflammation affecting both the middle ear and the mastoid cavity ▪ Dysfunction of the Eustachian tube is a significant factor in this disease, observed in approximately 70% of patients undergoing middle ear surgery Types include: ▪ Suppurative or serous chronic otitis media – describes character of the drainage through the perforated TM ▪ Benign chronic otitis media – “dry” – no active infection Chronic otitis media Viruses usual cause, though bacteria are more likely to contribute in children ▪ Pathogens invade via the external canal 🡪 edema, fibrosis, perforation and persistent infection ▪ Can also be a complication of tympanostomy tubes Clinical features: ▪ Otorrhea ▪ May or may not involve conductive hearing loss, tinnitus, or aural fullness ▪ Can have occasional severe intracranial complications in children Cholesteatomas Very little cholesterol, and not a neoplasm, so may be one of the worst-named entities in medicine – Definition - non-neoplastic, cystic lesions lined by keratinizing squamous epithelium or metaplastic mucus-secreting epithelium, and filled with debris Occur in the middle ear, mostly in the posterior-superior region (sometimes called the attic) Debris contains mostly keratin, other cellular debris Cyst is usually between 1 and 4 cm Three main types: – Primary congenital – keratined epithelium is “misplaced” into area that should only have bone or simple cuboidal mucosa (not very common, will not discuss pathogenesis) – Secondary acquired, Primary acquired – see next few slides Cholesteatoma - complications Why do we care about cholesteatomas? – Lead to conductive hearing loss (most minor complication) Even after surgical intervention, some degree of hearing loss usually ensues – Can cause serious bony destruction of the temporal bone 🡪 infected cyst gains access to the dura and intracranial structures 🡪 meningitis and death Cholesteatoma should almost always be removed to avoid this Can also migrate and rupture into deep neck structures 🡪 another source of potentially life-threatening infection  Cholesteatoma - pathogenesis Secondary acquired: – Traumatic “implantation” of keratined epithelial cells from the “external-ear” side of the tympanic membrane or auditory canal Traumatic causes include blast damage, iatrogenic (surgical, insertion of ear tubes) – not as common as primary acquired Primary acquired: – Most common type – Recent investigations implicate a combination of chronic inflammation and secondary abnormal TM cell migration acquired…  Primary Acquired Cholesteatoma - Pathogenesis Most recent and likely best hypothesis: – Inner surface of the TM consists of respiratory epithelium (simple cuboidal ciliated epithelium with goblet cells) that migrates over its surface in postero-superior direction – As it migrates more rapidly in This migration tends to response to chronic occur as a response to inflammation, it becomes “stuck” to the incus inflammation in teenage – adult years Primary acquired cholesteatoma - pathogenesis Next stage – mucous accumulates in the pouch 🡪 chronic inflammation (often pseudomonas implicated) if it gets infected This is followed by implantation/conversion of some of the cells in this cyst to keratinized epithelial cells – Note that the “outer” surface of the TM is pulled into the cystic structure Outer surface formed from keratinized epithelium, not respiratory epithelium  Primary acquired cholesteatoma - pathogenesis The “stuck” keratinized cells keep dividing, and continued inflammation is likely linked to: – Growth of the cystic structure – Activation of osteoclasts and invasion of the temporal bone Tend to see them develop in the – Conductive hearing loss as the pars flaccida (postero-superior mobility of the ossicles is impaired (remember, the inner surface of the to handle of malleus) because: TM got stuck to the incus) This is the direction the inner surface of the TM “likes” to migrate This part of the TM has a lot Primary acquired cholesteatoma – appearance on otoscopy Normal A small ear cholesteatoma A huge one 🡪 Cholesteatomas Not terribly common, but not terribly rare – about 10/100,000/year (about 300 or so in Lower Mainland/year) – By far most common type is primary acquired, but a history of head trauma or HEENT surgeries may imply presence of a secondary acquired Clinical Features: – Painless otorrhea (hallmark finding) Otorrhea increases as infection worsens, almost impossible to treat non-surgically – Conductive hearing loss (sometimes sensorineural as well) Prognosis: very few die from cholesteatomas, as they are usually discovered and surgically treated – Usually results in some hearing loss post-op – With new theories of pathophysiology many existing and new drugs, as well as less invasive procedures, have potential to treat and perhaps better preserve hearing  Cholesteatoma Other clinical features Rarely vertigo or dysequilibrium may arise due to the inflammatory process within the middle ear or due to invasion of the labyrinth Facial nerve palsy, can also result from the inflammatory process or mechanical Dizziness How is “dizziness” classified? – Vertiginous (vertigo) The environment seems to be moving Caused by inner ear or brainstem-cerebellar disorders – Inner ear = peripheral – Brainstem-cerebellar = central – Non-vertiginous Organic –a pathology that usually involves visual compromise or low blood pressure Functional – common in a wide range of mood disorders Benign paroxysmal positional vertigo Acute attacks of transient rotatory vertigo lasting seconds to minutes initiated by certain head positions – Accompanied by rotatory nystagmus Most common form of positional vertigo (50% of patients with peripheral vestibular dysfunction) – Symptoms are usually brief, caused by changing head position – Typical history = worsening when getting out of bed, extending the neck Usually caused by migration of a free-floating otolith (should not be free- floating, should be attached) BPPV Diagnosis? – Dix-Hallpike Positional Testing Patient rapidly moved from a sitting position to a supine position with the head hanging over the end of the table, turned to one side at 45° and neck extended 20° holding the position for 20 s – Onset of vertigo and rotatory nystagmus indicate a positive test for the dependent side Meniere’s disease Episodic attacks of tinnitus, hearing loss, and vertigo lasting minutes to hours – Inadequate absorption of endolymph leads to endolymphatic over-accumulation that distorts the membranous labyrinth – Usually begins in middle age – Triggered by high salt intake, caffeine, stress, nicotine, and alcohol Diagnostic Criteria for Menière’s Disease (must have all three) – Two spontaneous episodes of Rotational vertigo ≥20 min Audiometric confirmation of Sensorineural Hearing Loss Tinnitus and/or aural fullness Vestibular Neuronitis Acute onset of disabling vertigo often accompanied by nausea, vomiting, and imbalance without hearing loss that resolves over days leaving a residual imbalance that lasts days to weeks – Could be viral, often associated with URTI Acute phase – Severe vertigo with nausea, vomiting, and imbalance lasting 1-5 days – Nystagmus – Patient tends to veer towards affected side Convalescent phase – Imbalance and motion sickness lasting days to weeks – Spontaneous nystagmus away from affected side – Gradual vestibular adaptation requires weeks to months Labyrinthitis Acute infection of the inner ear resulting in vertigo and hearing loss May be serous (viral) or purulent (bacterial) – Occurs as a complication of acute and chronic otitis media, bacterial meningitis Bacterial: S. pneumoniae, H, influenzae, M. catarrhalis, P. aeruginosa, P. mirabilis Viral: rubella, CMV, measles, mumps, varicella zoster Sudden onset of vertigo, N/V, tinnitus, and unilateral hearing loss with no associated fever or pain – Meningitis is a serious complication  Acoustic neuroma Intracranial tumours that develop from Schwann cells that myelinate the vestibular and/or cochlear nerve – Can take up much of the space of the cerebellopontine angle (80% of tumours in this area are acoustic neuromas) – Most are from the vestibular component of the nerve Clinically relevant (i.e. big, or impair hearing) acoustic neuromas occur in ~ 1/100,000 – There’s quite a bit of room in that area of the brain, so often do not elevate intracranial pressure until they are quite large – Can also impinge on the nearby facial nerve and trigeminal nerve Acoustic neuromas  Acoustic neuroma Clinical Features: Hearing loss by far the most common – Can be sudden or gradual, constant or fluctuating – Assume that all unilateral neurosensory hearing loss is due to an acoustic neuroma until proven otherwise Vertigo is fairly uncommon, but balance difficulties are common Facial weakness or numbness due Treatment/Prognosis: to CN VII or V impingement Microsurgery or radiation Headache due to elevated used to treat, generally intracranial pressure survival is quite good Hematology 4 Assorted Anemias and Disorders of Coagulation Outcomes Describe etiology and pathophysiology and relate to clinical presentation, and laboratory assessments of megaloblastic anemias and differentiate from iron deficiency Briefly describe pathophysiology of additional rare causes of anemia such as copper deficiency and lead toxicity Describe pathogenesis and relate to clinical features, laboratory assessment, and complications for the common disorders of excessive coagulation such as activated protein C resistance Relate pathophysiology of excessive coagulation to impact on laminar blood flow and endothelial damage Relate the major components of Virchow's triad (hypercoagulability, impaired blood flow, endothelial damage) to the disorders that frequently give rise to pathological thromboses Describe the etiology and pathophysiology of polycythemia vera and predict its complications Describe the etiology and pathophysiology of immune  Babesiosis Babesiosis is a parasitic infection caused by protozoa of the genus Babesia. It is primarily transmitted through the bite of an infected tick Emerging infectious disease in the US, not particularly common in Canada ▪ Most cases occur in the summer – transmitted by tick bites (June – August) ▪ Babesia microti is responsible for almost all NA cases (red in map) Protozoan disease – infectious agent is found in small rodents and transmitted by a deer tick ▪ Tick (Ixodes scapularis - black- legged tick ▪ Only 1/2 of patients recall being bitten by a tick Babesiosis General Pathogenesis: ▪ B. microti invades RBCs and alters their morphology increases splenic clearance of RBCs If anemia is severe and results in significant splenomegaly, then splenic infarction and splenic rupture (very dangerous) can occur Hemolytic anemia is one of the most common severe complications of babesiosis ▪ about 50% of patients who have recognized infection have severe babesiosis ▪ General systemic inflammation can also contribute to symptomatology – increased production of TNF-alpha and IL-6 can contribute to nonspecific systemic symptoms as well as more severe manifestations in the lungs Babesiosis Risk factors for symptomatic include: ▪ Age – 80% present when > 50 years of age, more severe disease tends to be in older populations ▪ Asplenia, immunosuppression are also risk factors Signs and symptoms – 1-4 weeks after the bite of a tick: ▪ Gradual onset of fatigue, malaise, then fever, chills, sweats, headache, myalgias Neck stiffness, cough, sore throat, nausea/vomiting are less common ▪ Severe babesiosis – 50% of detected infections, hospital admission for a median of 4 days: Hemolytic anemia and clinically significant splenomegaly or infarction – often accompanied Acute respiratory distress syndrome (more in 250) Acute kidney injury due to increased intravascular Hb (more in 250) – hemoglobinuria is common Heart failure (reduced oxygen-carrying capacity of blood) Babesiosis Disorder can be fatal – 1-2% can die from the infection Infection is much, much more common than symptomatic disease ▪ Seroprevalence can be as high as 9% in those who live in endemic states ▪ Common enough that cases have been reported where the parasite was transmitted via blood transfusion ▪ Under-reported disorder, likely because a minority are symptomatic enough to report to an HCP ▪ 1/10 of those with Lyme disease are co-infected with B. microti Diagnosis and Treatment: ▪ Microscopic examination of a blood smear or PCR for B. microti DNA in blood ▪ Treated with macrolide antibiotics + antiparasitic agents  Babesiosis – Diagnosis (FYI) FIGURE 225-2 Giemsa-stained thin blood films showing Babesia microti parasites. B. microti is an obligate parasite of erythrocytes. Trophozoites may appear as ring forms (A) or as ameboid forms (B). C. Merozoites can be arranged in tetrads that are pathognomonic. D. Extracellular parasites can be noted, particularly when parasitemia is high. (Reproduced with permission from E Vannier, PJ Krause: Human babesiosis. N Engl J Med 366:2397, 2012.) Coagulation Pathology – Hyper- and hypocoagulability Hypercoagulability Virchow’s triad and pathological coagulation Inherited disorders of the (anti)-coagulation cascade Polycythemia vera Hypocoagulability Von Willebrand’s disease Acquired thrombocytopenias Disseminated intravascular coagulation  Why does pathological coagulation occur? Virchow’s triad – coined by Rudolph Virchow in 1856 – is comprised of: ▪ Hypercoagulability of blood ▪ Abnormal blood flow – excessive turbulence or, more frequently, stasis ▪ Injury to the vessel wall/endothelium We’re already aware of how a healthy endothelium functions to prevent the development of clots (see right)  Why does pathological coagulation occur? How do abnormalities of blood flow contribute to hypercoagulability? Shear stress is one of the major factors that increase nitric oxide release, prostacyclin release, and tPA from the healthy endothelium ▪ Shear stress = the “friction” of fluid flow against the vessel wall ▪ In sites of decreased shear stress – stagnant flow, or after irregularities in blood vessels – then these molecules are less expressed 🡪 platelet adhesion ▪ Excessive shear stress caused by narrowing or irregularities in flow can also activate platelets ▪ Therefore if fluid flow is not at a normal rate, and laminar, with a normal pressure 🡪 increases likelihood of coagulation  Why does pathological coagulation occur? What are the common inherited hypercoagulable conditions? Factor V Leiden – activated protein C resistance* ▪ Most common Protein C or protein S deficiency Antithrombin deficiency Prothrombin mutations (excessive activation) What are common acquired conditions that increase activity of the coagulation cascade? Estrogen-containing OCPs increase the production of factors II (prothrombin), VII, X, XII, VIII, I (fibrinogen) Genetic pro-thrombotic states Factor V Leiden (activated protein C resistance) ▪ Autosomal dominant disorder where, factor V is resistant to inactivation by activated protein C ▪ Therefore there is excessive activity in the final common pathway 2-15% of Caucasians have one copy of FV that is resistant to activated protein C ▪ In those with recurrent venous thrombotic problems, increases to 60% heterozygotes = 5X increased risk of thromboembolism, homozygotes 50X increased risk Signs and Symptoms ▪ Major one is deep vein thrombosis of the legs or pelvis Leg swelling (edema), leg pain, sometimes colour changes… but small thromboses can be silent If the clot travels to the lungs, can have acute onset of chest pain, shortness of breath due to pulmonary embolism – more to be done next semester Genetic pro-thrombotic states Prothrombin mutations: 3X risk of VTE (venous thromboembolism), present in 1 – 2% of population ▪ Increased conversion of prothrombin 🡪 thrombin Rare deficiencies in: Protein C Protein S Antithrombin III ▪ All of these confer a very high risk of venous thromboembolism Acquired causes of increased clotting: Anti-phospholipid antibody syndrome (APS): ▪ Poorly-understood hypercoagulable state, where multiple autoantibodies are produced Antibodies to proteins C, S? Endothelial activation or damage? ▪ Prevalence is 40-50/100,000, so not rare ▪ Can be venous or arterial thrombi ▪ To be discussed more in 250 (common cause of pregnancy loss) Deficient clotting – acquired thrombocytopenias Most thrombocytopenias are due to: ▪ Hypersplenism (usually minimal coagulopathy) ▪ Destruction of platelets by autoantibodies Drug-induced (usually heparin) Viral infections (i.e. HCV) Idiopathic (ITP) ▪ Destruction of platelets by excessive intravascular coagulation (DIC, hemolytic-uremic syndromes) ▪ Pancytopenia due to myelodysplastic syndromes, myelofibrosis, or bone marrow infiltration by a leukemia Immune thrombocytopenia (ITP) Most common cause of isolated thrombocytopenia ▪ Isolated = no other underlying disease or substance that can cause thrombocytopenia Can occur in children or adults ▪ In children, can follow a viral illness or vaccination – tends to resolve completely in weeks – months ▪ In adults, ITP is chronic and often does not resolve spontaneously (~ 50%) There are no deficiencies in coagulation factors, so bleeding clinical features tend to be typical of thrombocytopenia Used to be known as idiopathic thrombocytopenic purpura ▪ However, the cause is fairly well-known (autoimmune) now and few patients exhibit purpura ITP - Pathogenesis Although a common cause of isolated thrombocytopenia, not a particularly common disease (10 in 100,000) Platelets are destroyed in the spleen, and often splenectomy greatly improves clinical features Discrete immune mechanisms have been difficult to identify ▪ Poorly-characterized deficit in platelet production Cytotoxic T-cells may attack megakaryocytes Inadequate TPO for platelet deficit ▪ Autoantibodies to platelet antigens – GP Ib/IX has been suggested ▪ Th1 and Th17 Th cells are thought to be over-activated – not sure if this is causative or an association ▪ Specific HLA haplotypes have been difficult to identify  ITP – Clinical Features Purpura (small bruises) and petechia (very tiny bruises) are common over the extremities Epistaxis Menorrhagia Prolonged bleeding due to trauma, surgery, dental work Dangerously low platelet counts increase the risk of intracranial bleeding (counts < 5000) ▪ This is fairly rare, however (less than 3% Purpura in an ITP of those with refractory disease) patient Conditions that increase bleeding risk: ▪ NSAIDs, antiplatelet drugs, GI bleeding https:// disorders, older age, high blood pressure en.wikipedia.org/ wiki/ ITP Most platelet disorders such as ITP present with mucocutaneous bleeding ▪ Purpura, epistaxis, gingival bleeding, menorrhagia, worsening of GI bleeds, etc ▪ Deficits in coagulation factors that are serious (i.e. the hemophilias) tend to result in deeper bleeds (internal organs, intracranial bleeds, intramuscular bleeds, hemoarthrosis) Can also present with mucocutaneous bleeding Glucocorticoids can increase platelet count, splenectomy can reduce platelet destruction ▪ IVIG can reduce endogenous antibody production ▪ Some patients are given immunosuppressants or thrombopoietin analogues  Von Willebrand disease Background/epidemiology ▪ Most common inherited bleeding disorder of humans, affects ~ 1% of adults in US ▪ Bleeding tendency is mild in most of those affected Pathophysiology ▪ Type 1 vWD: mild disease, autosomal dominant, results in deficiency of vWF ▪ Type 2 vWD: autosomal dominant, variable disease severity (mild- moderate), lots of vWF in circulation but it does not function effectively ▪ Type 3 vWD: more severe disease, autosomal recessive, severe deficiency of vWF Von Willebrand Disease Pathophysiology ▪ What does vWF do? Stabilizes factor VIII (greatly increases half life, gives FVIII somewhere to bind) Forms huge multimers that facilitate platelet adhesion to the subendothelial matrix (most important function, GPIb/IX and GPIIb/IIIa bind to vWF) Produced by endothelial cells (inserts into basement membrane, releases acutely in response to vascular damage), found in platelet granules Von Willebrand Disease Signs, symptoms, and complications: ▪ Defects in platelet function despite normal platelet count Usually mucosal bleeding, easy bruising, epistaxis, and menorrhagia ▪ Prolonged bleeding from wounds can also occur, but hemarthroses are uncommon Type 3 looks like a combination of a thrombocytopenia and a hemophilia Can be treated with vasopressin (causes release of extra vWF from endothelial cells) Disseminated Intravascular Coagulation a life-threatening condition characterized by the widespread activation of the coagulation system leading to the formation of microthrombi throughout the blood vessels, and subsequently to hemorrhage (bleeding) due to the consumption of clotting factors and platelets. It is a secondary disorder, often occurring in response to an underlying condition, such as infection, trauma, or malignancy. Disseminated Intravascular Coagulation Background: ▪ Acute, subacute, or chronic thrombohemorrhagic disorder Excessive activation of coagulation, which leads to the formation of thrombi in the microvasculature Can be localized to an organ or tissue, or can be systemic Serious disorder secondary to other (usually systemic) illnesses Epidemiology: ▪ Can occur in 30-50% of cases of sepsis ▪ Common with severe trauma and burns as well ▪ Many cases of DIC are due to bleeding problems associated with parturition (childbirth) Disseminated Intravascular Coagulation Pathophysiology ▪ Release of tissue factor or thromboplastic substances into the circulation Thromboplastic substances can be derived from the placenta in obstetric complications and the cytoplasmic granules of acute promyelocytic leukemia cells Mucus from adenocarcinomas Local damage to tissues ▪ Widespread injury to the endothelial cells Sepsis (some organisms cause direct damage to endothelium), burns, cytokines (procoagulant effects of TNF on endothelium), immune complexes Disseminated Intravascular Coagulation Pathophysiology ▪ Coagulopathy that consumes platelets and clotting factors Widespread deposition of fibrin and fibrin degradation products that consumes clotting factors Small vessels become occluded, obstructing blood vessels to many organs Loss of fibrin and consumption of platelets can result in severe hemorrhage ▪ Fibrin degradation products reduce platelet function and inhibit thrombin Disseminated Intravascular Coagulation Signs, symptoms, and complications ▪ Can be acute and catastrophic (sepsis or burns) or insidious and chronic (cancer, intra-uterine fetal demise) 50% of the affected are obstetric patients having complications of pregnancy ▪ Microangiopathic hemolytic anemia ▪ Dyspnea, cyanosis, and respiratory failure ▪ Convulsions and coma ▪ Oliguria and acute renal failure ▪ Sudden or progressive circulatory failure and shock ▪ Hemorrhage - more common in acute ▪ Thrombosis – more common in chronic onset Assorted RBC disorders Excessive RBC production ▪ Polycythemia vera Anemias ▪ Megaloblastic anemias ▪ Autoimmune hemolytic anemias ▪ Rare environmental/nutritional causes Copper deficiency, lead toxicity, vitamin B6 deficiency Polycythemia vera Myeloproliferative disorder ▪ CML, essential thrombocytosis, and myelofibrosis are all myeloproliferative disorders ▪ Clonal stem cell disorder 🡪 normal RBCs as well as platelets and assorted granulocytes accumulate excessively ▪ Not a common disorder – 2.5/100,000, increases with age Pathogenesis ▪ In many, a mutation in the autoinhibitory region of the JAK2 tyrosine kinase is a common pathway for many patients (95%) Part of the signaling cascade for EPO and TPO Polycythemia vera Clinical Features ▪ Usually presents as an asymptomatic high Hb or hematocrit ▪ Often presents with neurologic symptoms due to hyperviscosity Headache, vertigo, tinnitus, visual disturbances, TIAs Hypertension Venous or arterial thrombosis ▪ Most common arterial vessels: ○ Cerebral, cardiac, mesenteric vessels ▪ Venous vessels ○ Hepatic vein thrombosis (Budd-Chiari syndrome), DVT, PE Increased cellular turnover 🡪 increased uric acid 🡪 exacerbation of gout Polycythemia vera Clinical Features ▪ Erythromelalgia – burning pain in hands & feet, erythema in skin ▪ Can also include pruritis after a warm bath or shower – thought to be due to mast cell activation and release of histamine Increased histamine from basophils in stomach can lead to peptic ulcer disease, abdominal pain, bleeds ▪ Patients are often plethoric – ruddy complexion, cyanosis easy observable if hypoxemia ▪ Splenomegaly and hepatomegaly are often present Polycythemia vera In general thrombotic complications are the most severe complications ▪ phlebotomy + hydroxyurea treatment is intended to decrease RBC counts and reduce frequency of thrombotic events Splenomegaly and splenic infarcts/abdominal pain can occur Other causes of polycythemia (not PCV): ▪ COPD ▪ Renal artery stenosis ▪ Chronic pulmonary disease, life at high altitudes ▪ Obstructive sleep apnea Megaloblastic Anemias Caused by impairment of DNA synthesis Two common causes – B12 and folate deficiencies ▪ B12 deficiency: inadequate diet pernicious anemia inflammation or other malfunction of the ileum, intestinal bacterial overgrowth ▪ Folate deficiency: inadequate diet, malabsorption, folate antagonist drugs (methotrexate) Malabsorption tends to be in the proximal intestine for folate deficiency Megaloblastic Anemias Megaloblastic Anemias B12 and folate required to synthesize thymidine Red cells and red cell precursors in the marrow are large and oval-shaped – the marrow actually looks hypercellular ▪ Why? Impaired nuclear maturation, and “extended” hemoglobin and cytosol accumulation ▪ Might not see the pale portion in the erythrocyte center – however, no increase in hemoglobin concentration ▪ Hypercellular marrow despite the fact it is hypoproliferative – “delay” in maturation of blasts Hemolysis is mild or absent Other cells (platelets, leukocytes) also lowered Pernicious anemia Usually due to autoimmune attack on parietal cells ▪ Cells in the stomach that secrete gastric acid and intrinsic factor, which is necessary for the absorption of vitamin B12 ▪ Often associated with thyroiditis More common in Caucasians, but prevalent in all races – tends to occur with older age ▪ 120 cases/100,000 Pernicious anemia Clinical features ▪ Very slow onset anemia, so often people are quite anemic when they first present ▪ Neurological findings can also be present – includes degeneration of the posterior columns of the spinal cord and impaired proprioception and vibration sense, which can progress to paresthesias Treatment, prognosis ▪ Good prognosis, as long as it is recognized and treated with B12 supplementation ▪ Increased risk for gastric carcinoma Folate deficiency anemia Can be due to decreased intake or increased requirements – Richest source is green, leafy vegetables – Requirements can increase with pregnancy, malignancy Clinical picture is identical to that of pernicious anemia, without the neurological symptoms Supplement folate, rule out pernicious anemia constitutes management Megaloblastic anemia due to folate deficiency is not particularly common Clinically – B12, folate deficiency Onset of anemia is insidious and associated with nonspecific symptoms such as weakness and easy fatigability ▪ Clinical picture complicated by coexistent deficiency of other vitamins, especially in those with alcohol use disorder ▪ GI tract like the hematopoietic system is site of rapid cell turnover Symptoms referable to alimentary tract common and often severe ▪ These include sore tongue and cheilosis (cracking, soreness at the angle of the lips) 12 5  General Diagnostic Considerations Diagnosis of a megaloblastic anemia readily made from examination of a smear of peripheral blood ▪ bone marrow biopsy can be done, but not usually needed Measure serum and red cell folate and vitamin B12 levels Testing for the presence of neuropathy in B12 deficiency Hematology 4 part 2 Assorted Anemias, interpretation of hematology labs Autoimmune hemolytic anemias Two general mechanisms: ○ “Innocent bystander” damage – antibodies directed to a medication or other foreign substance attack RBCs because the molecule gets “stuck” to the RBC ○ True immunohemolytic anemia “Warm” antibody hemolytic anemia – the antibody binds best at 37 Celsius RBCs are removed in the liver or spleen by macrophages with Fc receptors – usually IgG “Cold” agglutinin disease – autoantibodies react only at lower temperatures (i.e. blood in the extremities at colder temperatures) A clone of B-cells produces IgM Abs that recognize particular common antigens on RBCs AIHA – intravascular vs. extravascular hemolysis This is the type that is more common in cold AIHA – note that complement activation is more Thisprominent is the type that is more common in warm AIHA (splenic or hepatic removal  Comparison – warm vs. cold AIHA Cold AIHA is less severe than warm AIHA Warm AIHA can result in ○ massive hemolysis & life-threatening anemia ○ very rapid development of jaundice ○ Development of splenomegaly Diagnosis – Coombs test Direct Coomb’s test (direct antiglobulin test) ○“Wash” the patient’s RBCs, look for any remaining antibodies that are bound to the RBCs Indirect Coomb’s test (indirect antiglobulin test) ○Take the patient’s patient’s plasma and expose them to a standard sample of RBCs ○Look for antibodies (patient’s) binding to RBCs Coomb’s Test CBC and Diff Complete blood cell count and differential count ○ Test of peripheral blood providing lots of info: Red blood cell (RBC) count Hemoglobin Hematocrit RBC indices Mean corpuscular volume (MCV) Mean corpuscular hemoglobin (MCH) Mean corpuscular hemoglobin concentration (MCHC) RBC distribution width (RDW) White blood cell (WBC) count Blood smear for morphology Platelet count Diff? 🡪 differential ○ Counts for individual WBCs Red Blood Cell Count RBC Count, Erythrocyte count ○A count of the number of circulating RBCs in 1mm of 3 peripheral venous blood Useful for evaluating anemias ○However, the usually parameter used for evaluating anemia is either hematocrit or hemoglobin concentration Red Blood Cell Count / RBC Count / Erythrocyte Count Low RBC counts – any anemia: ○ Anemias of increased RBC destruction Like? ○ Hypoproliferative anemias: Marrow failure Disorders of Hb synthesis Renal failure ○ Hypersplenism High RBC counts: ○ High altitudes ○ Chronic hypoxia due to disease ○ Polycythemia Hemoglobin and Hematocrit Hemoglobin ○ Total hemoglobin concentration in peripheral blood Hematocrit: ○ Measure of the percentage of total blood volume made up by RBCs Abnormal values indicate the same pathologic states as abnormal RBC counts ○ Hemoglobin concentration is the preferred method of diagnosing anemia Can estimate hemoglobin concentration by multiplying hematocrit by 3.3 Hematocrit and hemoglobin concentration will both be decreased with fluid resuscitation ○ Often crystalloid (IV fluid, no blood products) is given 🡪 “dilution” of blood RBC Indices Provides information about: ○ RBC size (MCV, RDW) ○ Mass of hemoglobin per red cell(MCH) ○ Hemoglobin concentration (MCHC) Useful for classifying anemias ○ MCV = Mean Corpuscular Volume ○ MCH: Mean Corpuscular Hemoglobin ○ MCHC: Mean Corpuscular Hemoglobin Concentration ○ RDW: Red blood cell Distribution Width Mean Corpuscular Volume and Red Cell Distribution Width MCV = average volume, or size, of single RBC ○Derived by dividing the hematocrit by the total RBC count – unit is cubic micrometers (µm ) 3 RDW = the variance in RBC size (unit = % variance) ○The higher the RDW, the more variable the size of RBCs = anisocytosis ○Variations in width helpful when classifying anemia IDA classically shows a high degree of anisocytosis Thalassemia typically involves RBCs that are a uniform size MCH + MCHC MCH = Measure of the average amount of hemoglobin within an RBC ○Derived from hemoglobin concentration and red cell count (unit = picograms/cell = pg/cell) MCHC = measure of the average concentration of hemoglobin within a single RBC ○Derived from hemoglobin concentration and hematocrit (unit = pg/µm OR percent hemoglobin) 3 Total Reticulocyte Count Indirect assessment of RBC production ○ Reflects how quickly immature RBCs are produced by bone marrow and released into blood ○ Normal reticulocyte count is 1% ○ With blood loss, reticulocytes should increase 2-3x initially and then 5-7x over the next week Can help differentiate hypoproliferative marrow from a compensatory marrow response to an anemia ○ A lack of reticulocytosis in anemia indicates impaired RBC production Nutritional deficiencies, bone marrow infiltration, aplastic anemias Categorization of Anemia According to RBC Indices Normocytic, normochromic anemia ○ Early iron deficiency ○ Anemia of chronic illness/disease (ACD) ○ Acute blood loss ○ Aplastic anemia or other types of marrow failure ○ Hemolytic anemias Microcytic, hypochromic anemia ○ Late iron deficiency ○ Thalassemia ○ Lead poisoning ○ Sideroblastic anemia ○ ACD can also be mildly microcytic, hypochromic ○ Mnemonic - TAILS Categorization of Anemia According to RBC Indices Microcytic, normochromic anemia ○ Renal disease Macrocytic, normochromic anemia ○ Megaloblastic = Vitamin B12 or folic acid deficiency Chemotherapy ○ Non-megaloblastic: Liver disease, alcohol use Hypothyroidism Myelodysplastic syndromes Coagulation Labs Measure your blood’s ability to clot and how long it takes ○Assess risk of excessive bleeding or thrombosis Include: ○Prothrombin time ○Activated partial thromboplastin time ○D-dimers ○Platelet count Prothrombin Time (PT/iNR) Used to evaluate the adequacy of the extrinsic system and common pathway in the clotting mechanism Measures the clotting abilities of factors I, II, V, VII and X If deficient, then PT is prolonged Prolonged PT ○ Liver disease ○ Hereditary factor deficiency (not usually) ○ Vitamin K deficiency or warfarin administration PT/iNR is usually used to monitor warfarin therapy ○ Bile duct obstruction ○ DIC Activated Partial Thromboplastin Time (aPTT) Used to assess the intrinsic system and the common pathway of clot formation Used to monitor heparin therapy Evaluates factor I, II, V, VIII, IX, XI, XII Increased levels: ○Congenital clotting deficiencies ○Cirrhosis ○DIC ○Vitamin K deficiency or warfarin administration ○Heparin administration D-dimers Sensitive confirmatory test for disseminated intravascular coagulation (DIC) ○D-dimer = fibrin degradation fragment that is made through fibrinolysis ○D-dimer assay is a sensitive measurement of the degree of fibrin degradation Not specific, though 🡪