BL Unit 4 Flashcards
What is the definition of Osteoarthritis?
- disorder characterized by destruction of articular cartilage and proliferation of contiguous bone
- end stage of all types of arthritis
What are common clinical features of OA?
- joint pain
- decrease joint mobility
- hypertrophic bony spurs (osteophytes)
- infrequent joint inflammation
- lack of systemic involvement
What are the symptoms of OA?
- pain with use
- improvement with rest
- stiffness for 40yo
- no systemic symptoms
What are physical signs of OA?
- localized joint tenderness
- bony enlargement
- crepitance (grating)
- restricted movement
- variable swelling
- doesn’t get better with movement
What are Herberden’s nodes?
bony enlargement in the distal interphalangeal joints (DIPs)
What are Bouchard’s nodes?
bony enlargement in the proximal phalangeal joints (PIPs)
What are typical lab results for OA?
- synovial fluid shows: 200-2000 WBCs, 25% PMNs, no crystals, normal glucose
- cartilage degradation products: hyaluronic acid, aggrecan, type II collagen
What would you see on x-rays of joints affected by OA?
- loss of cartilage space
- bony sclerosis (hardening)
- osteophyte formation
- joint effusion (but not inflammatory)
- cysts in subchondral bone
What are risk factors stats for OA?
- xray prevalence increases with age
- pathologic changes in weight-bearing joints in 100% by 40yrs
- inc. incidence for women if >45yo
- women have more severe disease and more frequent H and B nodes
- trauma/previous injury
- obesity correlates with OA of hands and knees in women
What is the difference between primary and secondary OA?
- primary: idiopathic; no known inciting event
- secondary: as a result of a specific event
Where does OA tend to affect?
- can be seen in knee or hip, esp after trauma
- generalized in DIPs, PIPs, and CMC joints
- weight-bearing joints that are heavily used
- spares ankle, wrist, shoulder, elbow
Describe the pathology of OA
- fissuring of cartilage
- hypertrophy of bone adjacent to joint (periarticular)
- cartilage surface has frayed collagen fibers
- chondrocytes proliferate
- proteoglycan content of ECM dec
- subchondral bone is more dense
- synovium can be inflamed or have infiltrates
Describe normal cartilage
- acts like a sponge (water squeezed out when loading and bring in water when relaxed)
- allows for joint movement without friction and absorbs impact
- no vasculature and no nerves
What are the 5 components of cartilage?
1) Collagen: 50% of weight; mainly type II; forms rigid framework
2) Proteoglycans: charged aggregates of GAGs; make up ECM w/in collagen fibrils; retains water
3) Matrix proteins: MMPs (proteolytic enzymes including collagenase, gelatinase, stromelysin); also TIMP to control these enzymes)
4) Chondrocytes: synthesize all the above EC stuff
5) Water
How does focal mechanical stress affect OA?
- can injure the chondrocyte and cause the release of degenerative enzymes and matrix breakdown
Describe the effect that inflammatory mediators can have on cartilage damage
- IL-1 promotes degradation of type II collagen and proteoglycan by stimulating chondrocytes to make MMPs; also stimulates prostaglandins, NO, and IL-6
- TNFa works with IL-1 to cause cartilage damage
- NO inc MMP production and inhibits proteoglycan synth; NO induces chondrocyte apoptosis
- Prostaglandins can inc MMPs
- IL-4, -10, -13, and IL-1Ra can dec activity of cytokines
- Some complement component –> cell death or inc degradative enzymes
- Cytokines made by adipose tissue can contribute
What happens with water early in OA?
- water content inc in cartilage –> destroys weave network of collage and proteoglycan –> dec proteoglycan –> inc degradative enzymes
What are the pre-disposing factors to OA?
- Genetics: point mutations in type II collagen
- Metabolic problems of cartilage: chondrocyte toxicity; calcium pyrophosphate crystals in ECM
- *Trauma: main predisposing factor; trauma –> chondrocyte injury –> imbalance of anabolism and catabolism –> ECM degradation –> OA
- Inflammation: inflammatory processes can eventually lead to OA secondarily
- Obesity
- Age: 75% of >70yo have OA
How do you treat OA?
- usually diagnosed late because waiting for symptoms and radiographic changes
- reduce risk factors (obesity and avoid repetitive activities)
- DMOADs
- individualize treatment: treating pain or functional limitation?
- NSAIDs
- analgesics
- hyaluronic acid
- surgery
What is RA characterized by?
- systemic, inflammatory, autoimmune
- peripheral, symmetric, inflammation of synovium (usually small joints of hands and feet)
What joints are usually affected in RA?
- small joints of hands and ffet
- cervical spine (C1, C2)
- cricoarytenoid, inner ear, TMJ
- occasionally medium and large joints; DIP spared
What are signs and symptoms indicating RA?
- morning stiffness
- warmth and swelling and pain around joints
- loss of function/limitation of motion
- deformities
What are lab findings for RA?
- RF in 85%
- ESR or CRP elevated
- anemia and hypergammaglobulinemia
- antibodies against cyclic citrullinated peptides (CCPs) in 70%
- cigarette smoking (risk factor for RA) and HLA alleles have a shared epitope
What do you expect to see in the synovial fluid for a patient with RA?
- > 2000 WBC/ul because of inflammation (neutrophils)
- complement and glucose levels low
What would you see in an xray for a patient with RA?
- soft tissue swelling
- symmetric loss of joint space
Outside of the joints, what can happen in RA?
- B symptoms from inflammation (fatigue, malaise, weight loss, fever)
- Rheumatoid nodules: extensor surfaces/tendon sheaths, lung or other internal organs
- scleritis, neuropathy, vasculitis, granulomatous infiltration
What are risk factors for RA?
- Females 2.5x more likely
- Any age but likelier with older age
- HLA-DR4 in >50%
What are early findings of RA pathology?
- microvascular injury and mild inflammation
- synovial fluid is predominantly mononuclear cells
- minimal synovial lining cell prolif
What are the late findings of RA pathology?
- proliferation of synovial lining cells (macrophages and fibroblasts)
- fibroblast prolif, blood vessel growth, T and B cells
- more microvascular injury
- pannus: granulation tissue of macrophages, T and B cells, and fibroblasts formed from cytokines; invades cartilage –> loss of joint space and periarticular erosion
- synovial fluid is mainly PMNs
What are the genetic factors for RA?
- class II MHC (HLA DR): QKRAA shared epitope on 3rd HVR of DRB1 gene; shared epitope surrounds antigen-binding groove and can interact with side chains of bound antigen and T cell receptor; determines susceptibility and severity; have anti-CCP antibodies and citrullination enhances binding to shared epitope
Describe the arthritogenic peptide hypothesis for how genetic factors influence disease process of RA
- different exogenous infectious agents (EBV, HSPs) can be potential antigenic agents to cause RA
- class II MHC binds and presents citrullinated peptides –> production of anti-CCP antibodies
- smoking generates citrullinated peptides
- anti-CCP antibodies target citrullinated proteins in joint (type II immune reaction) or form immune complexes and deposit in joint (type III)
Describe what happens in the synovial fluid in RA
- mainly neutrophils which release PGs, LTs, cytokines, ROS, and enzyme to damage tissue
Describe what happens in the synovial tissue in RA
- pannus formation
- right next to cartilage and bone
- most cells are mononuclear cells (lymphocytes and macrophages) and fibroblasts
- Macrophages: make IL-1, TNFa, and IL-6 and proteolytic enzymes –> tissue destruction becomes self-perpetuating; also produce osteoclasts which destroy bone
- Cytokines: IL-1, TNFa, IL-6, and IL-17 are produced a lot; systemic effects by IL-6 (fever, weight loss, liver produces CRP and serum amyloid A); local effects by IL-1 and TNFa –> induce collagenase and neutral proteinase production by synovial fibroblasts and chondrocytes; TNFa, IL-1, and IL-17 activate osteoclasts through RANK
- Lymphocytes: mainly memory T cells but not activated; Th-17 play a large role; low Th2 and Treg; T cells can recognize citrullinate peptides or proteoglycan or collagen altered by enzymes; B cells make RF and anti-CCP abs –> immune complexes and local inflam
- RF: Igs (usually IgM) that recognize epitopes on Tc portion of IgG; forms immune complexes with IgG –> complement
How do you treat RA?
- NSAIDs or aspirin or prednisone to help inflammatory symptoms
- DMARDs (disease modifying anti rheumatic drugs): help prevent tissue destruction by inhibiting macrophage and lymphocyte functions
- some new drugs can inhibit effect of cytokines
- rituximab depletes B cells
What characterizes crystal arthritis?
- deposition of monosodium urate (MSU) crystals due to hyperuricemia (MSU supersaturation of extracellular fluids)
What is gouty arthritis?
- recurrent attacks of severe acute or chronic articular and periarticular inflammation
What are tophi?
- aggregated deposits of MSU occurring in joints, bones, and soft tissue
What is gouty nephropathy?
- renal interstitial, glomerular, and/or tubular deposition of MSU crystals
What is uric acid nephrolithiasis?
Kidney stones
What are the stages of gouty arthritis?
1) Asymptomatic hyperuricemia
2) Acute gouty arthritis
3) Intercritical gout
4) Chronic tophaceous gout
What happens in Asymptomatic hyperuricemia?
- high serum uric acid (>7/0mg/dl at 37C), but not gouty arthritis, tophi, or kidney stones
What happens in Acute gouty arthritis?
- abrupt onset of painful, warm, red, swollen joint at night usually (cooler, peripheral areas where solubility can decrease)
- usually MTP of big toe, but also ankles, heels, wrists, fingers, elbows
- usually resolve over 3-10days
What happens in intercritical gout?
- asymptomatic intervals between acute attacks of gout
What happens during chronic tophaceous gout?
- subcutaneous, synovial, or subchondral bone deposits of MSU crystals
- usually on hands, feet, elbow, extensor surface of forearm, achilles tendon
Describe the risk factors for gout
- usually adult men
- usually >30yo
- in women, gout occurs after menopause
- most common cause of inflammatory arthritis in men >40yo
- associated with alcohol abuse, obesity, insulin resistance, HT
What happens in hyperuricemia?
- either increased production or decreased renal excretion (90%) of urate
- 1) filtered through glomerulus then 2) pre-secretory reabsorption then 3) secretion back into tubule then 4) post secretory reabsorption
- 90% of filtered uric acid is reabsorbed so 10% is excreted in urine
- URAT1 secretes waste to reabsorb uric acid
- If URAT1 activated –> more reabsorption of uric acid –> hyperuricemia
How is uric acid made?
- product of purine metabolism
- ## humans do not have uricase which oxidizes uric acid to allantoin, which is more soluble
What can cause overproduction of uric acid?
- superactivity of PRPP (phosphoribosyl-pyrophosphate) synthetase or deficiency of HGPRT (hypoxanthine-guanine phosphoribosyltransferase)
How are MSU crystals formed?
- supersat synovial fluid of MSU
- temperature dec = decreased solubility = precipitate
- dehydration
- trauma
- proteoglycans usually bind MSU and make it soluble
- low pH = dec solubilit
When uric acid crystals present, what happens?
- uric acid crystals interact with synovial lining –> activate monocytes and mast cells
- TLRs recognize crystals and induce inflammation; bring in PMNs
- can also activate complement and promote PG, LT, and ROS production
- IgG binds to crystals and get phagocytized by PMNs –> PMN lysis and release of proteolytic enzymes
How do you treat gout?
- acute gouty attack treated with NSAIDs, colchicine, or corticosteroids
- chronic: uricosuric to enhance renal excretion of uric acid; xanthine-oxidase inhibitor can decrease production
What is CPDD?
- calcium pyrophosphate dihydrate deposition disease
What is CPDD characterized by?
- arthritis where CPDD crystals released into joint space and cause joint cartilage calcification
- “pseudogout”
What are the clinical features of CPDD?
- sudden onset of pain, swelling, warmth, redness of a joint
- usually large joint, like the knee
- first MTP rarely involved
What are the risk factors for CPDD?
- elderly
- concurrent OA
- younger people, joint trauma or surgery are risk factors
What do you see when you look at fresh synovial fluid from a patient with CPDD?
- CPDD crystals are rhomboid shaped and positively bifringent (blue when parallel to axis of red)
- inflammatory (2k-80k WBCs) with lots of neutrophils
What is the pathophysiology of CPDD?
- abnormal pyrophosphate metabolism
- PPi made from nucleoside triphosphates from articular chondrocytes
- mutations in ANKH that produces a transmembrane PPi transporter protein in chondrocytes –> CPDD crystal formation
- synovial fluid PPi high
- Crystal shedding: CPDD crystals do not form from being supersaturated like MSU; instead released into synovial fluids by shedding or strip-mining of pre-formed crystals in cartilage matrix
How do you treat CPDD (and compare to gout treatment)?
- anti-inflammatory drugs
- no way to remove crystals unlike MSU
- gout: build up of uric acid; can take meds to lower uric acid;
- pseudogout: shedding process; abnormal metabolism of pyrophosphate; wind up binding in cartilage with extracellular Ca; then get strip mined and shed
What are the characteristics of axial arthropathies?
- axial arthritis (spine and SI joints)
- enthesitis
- mucocutaneous lesions
- genetic assoc with HLA class I marker HLA-B27
Describe the risk factors for Ankylosing Spondylitis
- males more than females
- 16-40yo onset
- caucasians mainly
- 9/10 who have AS are positive for HLA-B27
- 1/10 caucasians are HLA-B27 positive
- 1/100 develop AS if HLA-B27 positive (becomes 1/10 if a 1st deg relative with AS)
- 1/1000 have AS in general pop
- not entirely genetic though; probably an environmental component as well (maybe bacterial infection)
What are clinical signs of AS?
- inflammatory back pain last >3mos
- morning stiffness >1hr
- improvement of pain with movement
- no neurologic problems
- SI joint tenderness
- loss of spinal ROM
- back deformities and reduced chest expansion
- 25% have peripheral arthritis of hips and shoulders
- affects enthesis (cartilage with bone)
- uveitis
- osteoporosis
- colitis
What are common lab findings in AS?
- high ESR
- no RF (not RA)
- negative for ANA (not lupus)
- sacroiliitis and bone erosion by age 45
- bamboo spine with syndesmophytes
Describe the risk factors for reactive arthritis
- males more than females
- onset from childhood to 40/50yo
- caucasians mainly
Describe clinical signs of reactive arthritis
- infectious diarrhea or urethritis 2-4wks before onset (due to shigella, salmonella, yersinia, campylobacter, chlamydia)
- abrupt onset of inflammatory peripheral arthritis
- sausage digits
- asymmetric, many jointed arthritis (knees and ankles)
- inflammatory back disease
- conjunctivitis
- mucocutaneous lesions
What are common lab findings in reactive arthritis?
- high ESR
- no RF or ANA
- erosion of feet and ankle and knee joints; usually not hips
- some SI joint abnormalities; usually asymmetric
Describe colitic arthropathy
- inflammatory peripheral arthritis in 10-20% of patients with inflammatory bowel disease
Describe psoriatic arthritis
- 10% of patients with psoriasis have peripheral or axial arthritis
- DIPs, PIPs, MCPs asymmetrically
What is the pathology of spondyloarthropathies?
- happens at enthesis (ligament, tendon, attachment to bone) inflammation
- macrophages, T cells, and cytokines, but not a synovial pannus
- can see calcification of entheses
Describe the genetics of AS
- HLA-B27 gene give 50x higher chance of getting AS
- some environmental component (probably bowel bacteria)
possible theories:
1) arthritogenic peptide: microbial peptides bind to HLA-B27 and presented to T cells
2) molecular mimicry: cross-reaction between epitopes on an infecting organism and a part of the HLA-B27 molecule or other self-peptides
3) free heavy chain hypothesis: heavy chains of HLA-B27 can form homodimers without beta2 microglobulin –> activate NK cells
4) unfolded protein hypothesis: HLA-B27 misfolds often –> unfolded protein stress response –> release of cytokines like IL-23 and activation of Th17 cells
Describe the pathogenesis of reactive arthritis
- environmental/bacterial trigger (chlamydia –> urethral; salmonella, yersinia, shigella, campylobacter –> diarrhea)
- bacteria gets to joints through monocytes
- HLA-B27 not as strong of an indicator of reactive arthritis, but similar mechanisms as in AS
- stronger Th2 response –> bacterial persistence
How do you treat AS and reactive arthritis?
AS:
- back exercises
- no smoking
- NSAIDs limit bone formation and protect against functional disability
- immunosuppressants for peripheral arthritis (sulfasalazine, methotrexate)
Reactive arthritis:
- tetracycline for chlamydia-induced
- anti-biotics uncertain if they help
- anti-TNF
What is the difference between organ specific AI and systemic AI?
Organ specific:
- against a single autoantigen in a given organ (e.g. myasthenia gravis of AchRs, Goodpasture of BM type IV collage in kidneys and lungs)
Systemic:
- multiple autoantigens –> multiple organs affected
What is Systemic Lupus Erythematosus characterized by?
- chronic, systemic, AI disease affecting many organs
- type II or type II reactions
What are the clinical signs of SLE?
need 4/11 criteria of MDSOAPBRAIN: M - Malar rash D - Discoid rash S - Serositis O - Oral ulcers A - Arthritis P - Photosensitivity B - Blood disorders R - Renal insufficiency A - ANA presence I - immunologic disorders N - Nervous system involvement
What are common risk factors for SLE?
- young women 9x more
- after puberty and peak during childbearing years
- genetic component: HLA-DR3 and C4A null alleles
- sex hormones (estrogen)
- sun exposure
Describe type II reactions that occur in SLE
1) Hemolytic anemia:
- usually anemic, but 10% show hemolysis
- IgG and complement bind to RBCs –> destroyed in liver and spleen
2) Anti-phospholipid Antibodies (aPLs):
- antibodies to phospholipids –> interfere with clotting cascade
- inc PTT
- inc clotting (?)
- beta2-glycoprotein I binds to platelets so aPL can bind –> platelet agg and thrombotic events
3) CNS problems:
- auto antibodies bind to neurons
- 66% of SLE cases
- vasculitis, thrombosis, embolic disease may lead to stroke
Describe type III reactions that occur in SLE
1) Lupus nephritis:
- immune complex and complement deposition in glomerulus
- antibodies to dsDNA of IgGs –> complement activation –> damage
What are antinuclear antibodies?
- ANAs are hallmark of abnormal antibody production in SLE
- antibodies against DNA, RNA, histone, etc. –> systemic AI
- detect with indirect immunofluorescent assay
- specific ANAs: abs to dsDNA, abs to histones, abs to non-histone, non-DNA nuclear antigens
What is the pathophysiology of SLE?
- usually immature autoreactive B cells that bind to self-antigens and activated by T cells to make stronger affinity IgG antibodies; in SLE, mechanisms that suppress these autoreactive B cells are defective
- defective clearance of immune complexes, apoptotic cells, and debris
- NFkB and IFN-1 production/activation by dendritic cells by binding of DNA/RNA containing immune complexes
- Neutrophils activated –> NETs produced when die, which causes dendritic cells to activate again
- LPS can stimulate immature autoreactive B cells
- cross reaction with outside antigen
- outside antigen combines with autoantigen and presented to T cell
- autoantigens sequestered in areas and trauma can dislodge (like in eye)
- complement deficiencies
How do you treat SLE?
- dec sun exposure
- NSAIDs and corticosteroids
- immunosuppression
PT and aPTT vs. extrinsic and intrinsic
PT = extrinsic aPTT = intrinsic
Extrinsic pathway summary
- needs tissue factor
- tissue factor binds to factor 7a –> activates factor 10 –> factor 10a and factor 5a (as a cofactor) activate factor 2 –> factor 2a converts fibrinogen to fibrin
- TF, 7a, 10, 2, fibrinogen
Intrinsic pathway summary
- everything in plasma (don’t need tissue factor)
- contact factors/surface contact activates factor 12 –> factor 12a activates factor 11 –> factor 11a activates factor 9 –> factor 9a and factor 8a (as a cofactor) activate factor 10 –> factor 10a and factor 5a (as a cofactor) activate factor 2 –> factor 2a converts fibrinogen to fibrin
- SC, 12, 11, 9, 10, 2, fibrinogen
Where are most of the proteins in the coagulation cascade made?
- in the liver
- exceptions: tissue factor is on the surface of many cells; vWF is in the endo cells and megakaryocytes; factor 8 can also be produced by spleen, lung, and kidneys
Which factors are vitamin k dependent?
- 2, 7, 9, and 10
- also anticoagulant protein C
- Vitamin K is required for the precursor of gamma-carboxylation of GIa residues; these residues bind calcium and allow for binding to an anionic phospholipid surface
What does Factor 13 do?
- covalently links fibrin molecules together
What are cofactors in the coagulation cascade?
- Tissue factor: found in fibroblasts and smooth muscle cells surrounding blood vessels (reacts with factor 5a when endo cell damaged –> extrinsic pathway)
- Factor 5 and 8: cleaved by thrombin to get activated
- HMWK
How does fibrinogen clot making work?
- fibrinogen is a symmetric molecule of 3 pairs of polypeptide chains; has a central E domain and two D domains
- thrombin cleaves fibrinopeptide A which allows the E domain to noncovalently bond with D domains to produce overlapping fibrils
- Factor 13a cleaves fibrinopeptide B and crosslinks adjacent D domains
What factor does vWF bind to and protect, extending the half-life?
Factor 8
- def of vWF can lead to factor 8 def which causes hemophilia A
What is extrinsic tenase?
Tissue factor (cofactor) + factor 7a (serine protease) + phospholipid surface + calcium –> activates factor 9 or 10 (part of extrinisic pathway)
What is intrinsic tenase?
Factor 8a (cofactor) + Factor 9a (serine protease) + phospholipid surface + calcium –> activate factor 10
What is prothrombinase complex?
Factor 5a (cofactor) + factor 10/10a (serine protease) + phospholipid surface + calcium –> activated prothrombin (factor 2) to thrombin (factor 2a)
Describe the initiation phase of coagulation
- vascular disruption exposes plasma to TF
- TF binds factor 7a with calcium –> extrinsic tenase then binds factor 10 –> production of factor 10a (and same with factor 9/9a); also produces even more factor 7a
- Factor 5 slowly activated by factor 10a –> factor 5a and factor 10a form prothrombinase complex and make thrombin
Describe the amplification phase of coagulation
- platelets have adhered to exposed subendothelium and have been activated
- thrombin activates factor 5 and 8 to 5a and 8a –> 5a and 8a bind to platelet surface
- factor 10a binds with 5a to form prothrombinase complex and generate more smaller amounts of thrombin
Describe the propagation phase of coagulation
- intrinsic tenase (8a and 9a) activate factor 10 on platelet surface
- intrinsic tenase activates factor 10 a lot faster than extrinsic tenase
- 10a binds to 5a (from amp phase) to make more thrombin in a “burst” for fibrin-clot formation
- thrombin cleaves fibrinogen to make fibrin and activates factor 13, which covalently cross links fibrin
What is vasculitis characterized by?
- inflammation of blood vessels
- variety of sizes of blood vessels categorized
What are the clinical features of vasculitis?
- skin lesions
- B symptoms
- MSK symptoms (arthralgias, arthritis, myalgias, neuropathy)
What are common lab findings in vasculitis?
- inflammation findings
- anemia, thrombocytosis, low albumin, high ESR and CRP, clonal gammopathy
How do you diagnose vasculitis?
- extent of organ involvement
- serum antibodies (RF, ANA, ANCA)
- biopsy
- smooth arterial stenosis alternating with normal artery
What are risk factors for vasculitis?
- onset usually in 50s
- equal male and female
- Takayasu’s in asian and Japanese pops
- Giant cell in north Europe
Describe the pathology of vasculitis
Large and medium vessel vasculitis:
- inflammation of entire vessel wall (all tissue layers) with lymphocytes, monocytes, histiocytes, eosinophils, PMNs
- disruption of elastic lamina –> thickening leads to narrowing of lumen
Small vessel:
- fibrinoid necrosis of vessel wall
- PMN-derived nuclear debris
- Igs and complement deposit in lesions
Describe the pathophysiology of vasculitis
- deposition of ICs in endothelium –> activation of complement –> attraction of PMNs
- ANCA; cytokines activated PMNs and express PR3 and MPO; ANCA binds to neutrophil surface and activates it –> enhanced binding to endo cells –> vascular damage
- antiendothelial antibodies; damage endo cells by ADCC and complement
- T cell dep mediated endo cell injury; HLA-DR4 –> antigen driven vascular inflam
- infection of endo cells –> ICs and PMNs to endothelium
How do you treat vasculitis?
- remove inciting drug or infection
- glucocorticoids
- rituximab
What is PM and DM characterized by?
- chronic muscle weakness
- muscle tissue infiltrated by inflammatory cells
- DM has skin rashes
What are the clinical features of PM/DM?
- muscle weakness
- low endurance
- skin disease: erythematous papular rash over hand joints; blue upper eyelid; shawl rash; cracked hands; subcut calc
- B symptoms
- dysphagia, intestinal
- pulmonary fibrosis
- myocarditis
- inflam arthritis
- vasculitis
What are the risk factors for PM/DM?
- females slightly more
- childhood and 50s onset
- AfAms 2-3x
What are the lab findings for PM/DM?
- CPK elevated
- myositis specific antibodies:
What is the life span of a platelet?
9-10 days
What do dense granules contain in platelets?
ATP, ADP, serotonin, and calcium
What do alpha granules contain in platelets?
fibrinogen, factor 5, vWF, platelet activation factors, platelet growth factors
What do lysosomal granules contain in platelets?
Acid hydrolases
What are the functions of platelets?
Adhesion
Activation
Aggregation
Thrombin generation by acting as a phospholipid surface
Von Willebrand Disease
- qualitative
- adhesion problem
- lack of vWF –> bleeding due to abnormal platelet/endothelium interaction
- can also see factor 8 def
- tests show long PFA-100, vW antigen, factor 8 level, ristocetin activity
- treat with DDAVP to release vWF from endo
- type 1 (quantitative def), type 2 (qual defects), type 3 (absence)
Bernard Soulier syndrome
- AR inheritance
- reduced GP1b receptor
- adhesion disorder
Storage pool deficiencies
- def of alpha (gray platelet syndrome) or dense granules
- when crossing vascular surfaces, can degranulate
- activation disorder
Afibrogenemia
- def of fibrogen –> lack of binding to GP2b3a so dec platelet agg AND lack of cross-linking
Glanzmann thrombasthenia
- AR inheritance
- absent/defective GP2b3a –> platelets can adhere but can’t aggregate
Adhesion disorders
vWD
Bernard Soulier syndrome
Activation disorders
Storage pool deficiencies (granules)
Aggregation disorders
Afibrogenemia
Glanzmann thrombasthenia
Drugs
Immune thrombocytopenic purpura
- autoantibodies to platelets
- acute: in children and self resolving
- chronic: in adults and don’t usually remiss
- treat with corticosteroids (dec B cell antibody prod), IVIG (block splenic Fc receptors to prevent them from binding to antibodies on platelets), splenectomy
Alloimmune thrombocytopenia
- antibodies to platelets of other people
- platelet transfusions
- maternal IgG across placentaa
Thrombotic thrombocytopenic purpura
- fever, renal insuff, microangiopathic hemolytic anemia, thrombocytopenia
- endo damage –> release of vWF –> lots of platelet adhesion and aggregation
- ADAMTS13 which normally digests vWF into smaller units is absent b/c of autoantibodies
- treat with plasmapheresis to remove large vWF and replace ADAMTS13
Hemolytic uremic syndrome
- similar to TTP but more renal failure and in children
- endo damage by bacterial toxin –> adhesion and activation and microthrombi
- self-limiting
Antithrombin
- inactivates thrombin and factor 10a
Heparin
- cofactor for antithrombin
- short version accelerates inact of factor 10a
- long version accelerates inact of factor 10a and thrombin
Heparin cofactor II
- inhibits thrombin only
- heparin is a cofactor
Protein C
- Vitamin K dep
- thrombin binds to thrombomodulin on endo cells –> thrombin neutralized but together bind and activate protein C
- APC inactivates 5a and 8a –> dec thrombin
Factor V Leiden
- Factor 5 has a mutation so that 5a is resistant to protein C degradation –> stays longer than usual –> pro-thombotic risk
Tissue factor pathway inhibitor
- inhibits factor 7a
- TFPI binds to 10a and inactivates 7a+TF
Plasmin
- breaks down fibrin to make fibrin degradation products
- plasminogen mainly activated by t-PA (converts plasminogen to plasmin readily when bound to fibrin)
- u-PA also converts plasminogen to plasmin
