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BL and DD Unit 3 > BL Unit 4 > Flashcards

BL Unit 4 Flashcards

1
Q

What is the definition of Osteoarthritis?

A
  • disorder characterized by destruction of articular cartilage and proliferation of contiguous bone
  • end stage of all types of arthritis
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2
Q

What are common clinical features of OA?

A
  • joint pain
  • decrease joint mobility
  • hypertrophic bony spurs (osteophytes)
  • infrequent joint inflammation
  • lack of systemic involvement
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3
Q

What are the symptoms of OA?

A
  • pain with use
  • improvement with rest
  • stiffness for 40yo
  • no systemic symptoms
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4
Q

What are physical signs of OA?

A
  • localized joint tenderness
  • bony enlargement
  • crepitance (grating)
  • restricted movement
  • variable swelling
  • doesn’t get better with movement
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5
Q

What are Herberden’s nodes?

A

bony enlargement in the distal interphalangeal joints (DIPs)

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6
Q

What are Bouchard’s nodes?

A

bony enlargement in the proximal phalangeal joints (PIPs)

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7
Q

What are typical lab results for OA?

A
  • synovial fluid shows: 200-2000 WBCs, 25% PMNs, no crystals, normal glucose
  • cartilage degradation products: hyaluronic acid, aggrecan, type II collagen
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8
Q

What would you see on x-rays of joints affected by OA?

A
  • loss of cartilage space
  • bony sclerosis (hardening)
  • osteophyte formation
  • joint effusion (but not inflammatory)
  • cysts in subchondral bone
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9
Q

What are risk factors stats for OA?

A
  • 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
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10
Q

What is the difference between primary and secondary OA?

A
  • primary: idiopathic; no known inciting event

- secondary: as a result of a specific event

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11
Q

Where does OA tend to affect?

A
  • 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
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12
Q

Describe the pathology of OA

A
  • 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
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13
Q

Describe normal cartilage

A
  • 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
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14
Q

What are the 5 components of cartilage?

A

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

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15
Q

How does focal mechanical stress affect OA?

A
  • can injure the chondrocyte and cause the release of degenerative enzymes and matrix breakdown
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16
Q

Describe the effect that inflammatory mediators can have on cartilage damage

A
  • 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
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17
Q

What happens with water early in OA?

A
  • water content inc in cartilage –> destroys weave network of collage and proteoglycan –> dec proteoglycan –> inc degradative enzymes
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18
Q

What are the pre-disposing factors to OA?

A
  • 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
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19
Q

How do you treat OA?

A
  • 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
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20
Q

What is RA characterized by?

A
  • systemic, inflammatory, autoimmune

- peripheral, symmetric, inflammation of synovium (usually small joints of hands and feet)

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21
Q

What joints are usually affected in RA?

A
  • small joints of hands and ffet
  • cervical spine (C1, C2)
  • cricoarytenoid, inner ear, TMJ
  • occasionally medium and large joints; DIP spared
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22
Q

What are signs and symptoms indicating RA?

A
  • morning stiffness
  • warmth and swelling and pain around joints
  • loss of function/limitation of motion
  • deformities
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23
Q

What are lab findings for RA?

A
  • 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
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24
Q

What do you expect to see in the synovial fluid for a patient with RA?

A
  • > 2000 WBC/ul because of inflammation (neutrophils)

- complement and glucose levels low

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25
Q

What would you see in an xray for a patient with RA?

A
  • soft tissue swelling

- symmetric loss of joint space

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26
Q

Outside of the joints, what can happen in RA?

A
  • 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
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27
Q

What are risk factors for RA?

A
  • Females 2.5x more likely
  • Any age but likelier with older age
  • HLA-DR4 in >50%
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28
Q

What are early findings of RA pathology?

A
  • microvascular injury and mild inflammation
  • synovial fluid is predominantly mononuclear cells
  • minimal synovial lining cell prolif
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29
Q

What are the late findings of RA pathology?

A
  • 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
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30
Q

What are the genetic factors for RA?

A
    • 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
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31
Q

Describe the arthritogenic peptide hypothesis for how genetic factors influence disease process of RA

A
  • 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)
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32
Q

Describe what happens in the synovial fluid in RA

A
  • mainly neutrophils which release PGs, LTs, cytokines, ROS, and enzyme to damage tissue
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33
Q

Describe what happens in the synovial tissue in RA

A
  • 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
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34
Q

How do you treat RA?

A
  • 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
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35
Q

What characterizes crystal arthritis?

A
  • deposition of monosodium urate (MSU) crystals due to hyperuricemia (MSU supersaturation of extracellular fluids)
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36
Q

What is gouty arthritis?

A
  • recurrent attacks of severe acute or chronic articular and periarticular inflammation
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37
Q

What are tophi?

A
  • aggregated deposits of MSU occurring in joints, bones, and soft tissue
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38
Q

What is gouty nephropathy?

A
  • renal interstitial, glomerular, and/or tubular deposition of MSU crystals
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39
Q

What is uric acid nephrolithiasis?

A

Kidney stones

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40
Q

What are the stages of gouty arthritis?

A

1) Asymptomatic hyperuricemia
2) Acute gouty arthritis
3) Intercritical gout
4) Chronic tophaceous gout

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41
Q

What happens in Asymptomatic hyperuricemia?

A
  • high serum uric acid (>7/0mg/dl at 37C), but not gouty arthritis, tophi, or kidney stones
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42
Q

What happens in Acute gouty arthritis?

A
  • 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
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43
Q

What happens in intercritical gout?

A
  • asymptomatic intervals between acute attacks of gout
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44
Q

What happens during chronic tophaceous gout?

A
  • subcutaneous, synovial, or subchondral bone deposits of MSU crystals
  • usually on hands, feet, elbow, extensor surface of forearm, achilles tendon
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45
Q

Describe the risk factors for gout

A
  • 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
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46
Q

What happens in hyperuricemia?

A
  • 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
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47
Q

How is uric acid made?

A
  • product of purine metabolism
  • ## humans do not have uricase which oxidizes uric acid to allantoin, which is more soluble
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48
Q

What can cause overproduction of uric acid?

A
  • superactivity of PRPP (phosphoribosyl-pyrophosphate) synthetase or deficiency of HGPRT (hypoxanthine-guanine phosphoribosyltransferase)
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49
Q

How are MSU crystals formed?

A
  • supersat synovial fluid of MSU
  • temperature dec = decreased solubility = precipitate
  • dehydration
  • trauma
  • proteoglycans usually bind MSU and make it soluble
  • low pH = dec solubilit
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50
Q

When uric acid crystals present, what happens?

A
  • 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
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51
Q

How do you treat gout?

A
  • acute gouty attack treated with NSAIDs, colchicine, or corticosteroids
  • chronic: uricosuric to enhance renal excretion of uric acid; xanthine-oxidase inhibitor can decrease production
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52
Q

What is CPDD?

A
  • calcium pyrophosphate dihydrate deposition disease
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53
Q

What is CPDD characterized by?

A
  • arthritis where CPDD crystals released into joint space and cause joint cartilage calcification
  • “pseudogout”
54
Q

What are the clinical features of CPDD?

A
  • sudden onset of pain, swelling, warmth, redness of a joint
  • usually large joint, like the knee
  • first MTP rarely involved
55
Q

What are the risk factors for CPDD?

A
  • elderly
  • concurrent OA
  • younger people, joint trauma or surgery are risk factors
56
Q

What do you see when you look at fresh synovial fluid from a patient with CPDD?

A
  • CPDD crystals are rhomboid shaped and positively bifringent (blue when parallel to axis of red)
  • inflammatory (2k-80k WBCs) with lots of neutrophils
57
Q

What is the pathophysiology of CPDD?

A
  • 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
58
Q

How do you treat CPDD (and compare to gout treatment)?

A
  • 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
59
Q

What are the characteristics of axial arthropathies?

A
  • axial arthritis (spine and SI joints)
  • enthesitis
  • mucocutaneous lesions
  • genetic assoc with HLA class I marker HLA-B27
60
Q

Describe the risk factors for Ankylosing Spondylitis

A
  • 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)
61
Q

What are clinical signs of AS?

A
  • 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
62
Q

What are common lab findings in AS?

A
  • high ESR
  • no RF (not RA)
  • negative for ANA (not lupus)
  • sacroiliitis and bone erosion by age 45
  • bamboo spine with syndesmophytes
63
Q

Describe the risk factors for reactive arthritis

A
  • males more than females
  • onset from childhood to 40/50yo
  • caucasians mainly
64
Q

Describe clinical signs of reactive arthritis

A
  • 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
65
Q

What are common lab findings in reactive arthritis?

A
  • high ESR
  • no RF or ANA
  • erosion of feet and ankle and knee joints; usually not hips
  • some SI joint abnormalities; usually asymmetric
66
Q

Describe colitic arthropathy

A
  • inflammatory peripheral arthritis in 10-20% of patients with inflammatory bowel disease
67
Q

Describe psoriatic arthritis

A
  • 10% of patients with psoriasis have peripheral or axial arthritis
  • DIPs, PIPs, MCPs asymmetrically
68
Q

What is the pathology of spondyloarthropathies?

A
  • happens at enthesis (ligament, tendon, attachment to bone) inflammation
  • macrophages, T cells, and cytokines, but not a synovial pannus
  • can see calcification of entheses
69
Q

Describe the genetics of AS

A
  • 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

70
Q

Describe the pathogenesis of reactive arthritis

A
  • 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
71
Q

How do you treat AS and reactive arthritis?

A

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
72
Q

What is the difference between organ specific AI and systemic AI?

A

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

73
Q

What is Systemic Lupus Erythematosus characterized by?

A
  • chronic, systemic, AI disease affecting many organs

- type II or type II reactions

74
Q

What are the clinical signs of SLE?

A 
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
75
Q

What are common risk factors for SLE?

A
  • young women 9x more
  • after puberty and peak during childbearing years
  • genetic component: HLA-DR3 and C4A null alleles
  • sex hormones (estrogen)
  • sun exposure
76
Q

Describe type II reactions that occur in SLE

A

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

77
Q

Describe type III reactions that occur in SLE

A

1) Lupus nephritis:
- immune complex and complement deposition in glomerulus
- antibodies to dsDNA of IgGs –> complement activation –> damage

78
Q

What are antinuclear antibodies?

A
  • 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
79
Q

What is the pathophysiology of SLE?

A
  • 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
80
Q

How do you treat SLE?

A
  • dec sun exposure
  • NSAIDs and corticosteroids
  • immunosuppression
81
Q

PT and aPTT vs. extrinsic and intrinsic

A 
PT = extrinsic
aPTT = intrinsic
82
Q

Extrinsic pathway summary

A
  • 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
83
Q

Intrinsic pathway summary

A
  • 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
84
Q

Where are most of the proteins in the coagulation cascade made?

A
  • 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
85
Q

Which factors are vitamin k dependent?

A
  • 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
86
Q

What does Factor 13 do?

A
  • covalently links fibrin molecules together
87
Q

What are cofactors in the coagulation cascade?

A
  • 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
88
Q

How does fibrinogen clot making work?

A
  • 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
89
Q

What factor does vWF bind to and protect, extending the half-life?

A

Factor 8

- def of vWF can lead to factor 8 def which causes hemophilia A

90
Q

What is extrinsic tenase?

A

Tissue factor (cofactor) + factor 7a (serine protease) + phospholipid surface + calcium –> activates factor 9 or 10 (part of extrinisic pathway)

91
Q

What is intrinsic tenase?

A

Factor 8a (cofactor) + Factor 9a (serine protease) + phospholipid surface + calcium –> activate factor 10

92
Q

What is prothrombinase complex?

A

Factor 5a (cofactor) + factor 10/10a (serine protease) + phospholipid surface + calcium –> activated prothrombin (factor 2) to thrombin (factor 2a)

93
Q

Describe the initiation phase of coagulation

A
  • 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
94
Q

Describe the amplification phase of coagulation

A
  • 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
95
Q

Describe the propagation phase of coagulation

A
  • 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
96
Q

What is vasculitis characterized by?

A
  • inflammation of blood vessels

- variety of sizes of blood vessels categorized

97
Q

What are the clinical features of vasculitis?

A
  • skin lesions
  • B symptoms
  • MSK symptoms (arthralgias, arthritis, myalgias, neuropathy)
98
Q

What are common lab findings in vasculitis?

A
  • inflammation findings

- anemia, thrombocytosis, low albumin, high ESR and CRP, clonal gammopathy

99
Q

How do you diagnose vasculitis?

A
  • extent of organ involvement
  • serum antibodies (RF, ANA, ANCA)
  • biopsy
  • smooth arterial stenosis alternating with normal artery
100
Q

What are risk factors for vasculitis?

A
  • onset usually in 50s
  • equal male and female
  • Takayasu’s in asian and Japanese pops
  • Giant cell in north Europe
101
Q

Describe the pathology of vasculitis

A

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
102
Q

Describe the pathophysiology of vasculitis

A
  • 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
103
Q

How do you treat vasculitis?

A
  • remove inciting drug or infection
  • glucocorticoids
  • rituximab
104
Q

What is PM and DM characterized by?

A
  • chronic muscle weakness
  • muscle tissue infiltrated by inflammatory cells
  • DM has skin rashes
105
Q

What are the clinical features of PM/DM?

A
  • 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
106
Q

What are the risk factors for PM/DM?

A
  • females slightly more
  • childhood and 50s onset
  • AfAms 2-3x
107
Q

What are the lab findings for PM/DM?

A
  • CPK elevated

- myositis specific antibodies:

108
Q

What is the life span of a platelet?

A

9-10 days

109
Q

What do dense granules contain in platelets?

A

ATP, ADP, serotonin, and calcium

110
Q

What do alpha granules contain in platelets?

A

fibrinogen, factor 5, vWF, platelet activation factors, platelet growth factors

111
Q

What do lysosomal granules contain in platelets?

A

Acid hydrolases

112
Q

What are the functions of platelets?

A

Adhesion
Activation
Aggregation
Thrombin generation by acting as a phospholipid surface

113
Q

Von Willebrand Disease

A
  • 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)
114
Q

Bernard Soulier syndrome

A
  • AR inheritance
  • reduced GP1b receptor
  • adhesion disorder
115
Q

Storage pool deficiencies

A
  • def of alpha (gray platelet syndrome) or dense granules
  • when crossing vascular surfaces, can degranulate
  • activation disorder
116
Q

Afibrogenemia

A
  • def of fibrogen –> lack of binding to GP2b3a so dec platelet agg AND lack of cross-linking
117
Q

Glanzmann thrombasthenia

A
  • AR inheritance

- absent/defective GP2b3a –> platelets can adhere but can’t aggregate

118
Q

Adhesion disorders

A

vWD

Bernard Soulier syndrome

119
Q

Activation disorders

A

Storage pool deficiencies (granules)

120
Q

Aggregation disorders

A

Afibrogenemia
Glanzmann thrombasthenia
Drugs

121
Q

Immune thrombocytopenic purpura

A
  • 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
122
Q

Alloimmune thrombocytopenia

A
  • antibodies to platelets of other people
  • platelet transfusions
  • maternal IgG across placentaa
123
Q

Thrombotic thrombocytopenic purpura

A
  • 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
124
Q

Hemolytic uremic syndrome

A
  • similar to TTP but more renal failure and in children
  • endo damage by bacterial toxin –> adhesion and activation and microthrombi
  • self-limiting
125
Q

Antithrombin

A
  • inactivates thrombin and factor 10a
126
Q

Heparin

A
  • cofactor for antithrombin
  • short version accelerates inact of factor 10a
  • long version accelerates inact of factor 10a and thrombin
127
Q

Heparin cofactor II

A
  • inhibits thrombin only

- heparin is a cofactor

128
Q

Protein C

A
  • 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
129
Q

Factor V Leiden

A
  • Factor 5 has a mutation so that 5a is resistant to protein C degradation –> stays longer than usual –> pro-thombotic risk
130
Q

Tissue factor pathway inhibitor

A
  • inhibits factor 7a

- TFPI binds to 10a and inactivates 7a+TF

131
Q

Plasmin

A
  • 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

BL and DD Unit 3 (11 decks)

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