Pathology

Hemostasis Lecture
Taught by Dr. Lewis
Important definitions
1. Edema collection of fluid
2. Effusion collection of fluid in a body cavity
3. Hydrothorax/pleural effusion collection of fluid in lungs / alveolar air spaces
4. scites fluid in the peritoneum
!. nasarca s"elling every"here
a. #sually do to lo" plasma proteins
b. Either not making albumin or are peeing it out $glomerulonephritis%
&. Hyperemia and congestion too much blood / fluid
a. Hyperemia is an active process due to altered inflow into a tissue e.g. vasodilation in
s'eletal muscle
b. (ongestion is a passive process altered outflow from a tissue
i. )econdary due to a pathological condition
ii. E.g. (ongestive heart failure blood collects
*. (lot and thrombus
a. (lot is coagulation of blood in a non vascular space e.g. paper cut
b. +hrombus collection and coagulation of blood in a vascular space e.g. heart failure
,. Hematoma
a. -leeding into a tissue / collection of blood
b. E.g. a bruise
Causes of Edema
1. .ncreased hydrostatic pressure/ due to things li'e0
a. Impaired enous flow caused by thrombosis/ heart failure and scarring
i. 1eep vain thrombosis
1. )a" a fe" 2uestions "ith someone sitting on an airplane for a long
time/ get one s"ollen foot 3 deep vain thrombosis in the affected leg
ii. Heart failure
1. )"elling "ont be limited to one foot/ "ill be more systemic
2. 4idney "ill try to compensate 'idney detects lo" flo" 56 rennin
system "ill increase aldosterone 56 retain salt 56 increase plasma
volume but dump it all bac' into a failing heart
a. The increased plasma olume increases hydrostatic
pressure !" edema
b. #rteriolar dilation in inflammation
2. 1ecreased osmotic pressure due to things li'e0
a. $lomerulonephritis pee out all your protein
b. liver disease stop ma'ing albumin
c. nutritional deficiencies
i. more so in third "orld countries
1. no inta'e at all body does "hat it can to retain "hatever protein it has
2. '"ashior'or lo" to no protein inta'e/ "orse than above in regards to
s"elling
d. 'idney "ill try to compensate here too $bc of lo" flo" to the 'idney%/ but all the fluid
that is retained 7ust ends up leaving the vessels again bc haven8t corrected the underlying
problem of lo" plasma protein so "ill actually ma'e the s"elling "orse
3. lymphatic obstruction due to
a. neoplasia actual metastatic cells clog up lymphatic vessels
b. surgery removal of axilary nodes in breast cancer
c. radiation
d. infections
i. microfilaria infection in developing "orld
1
1. elephantiasis of lo"er limbs and genetailia 9 enlarged inguinal nodes
4. salt retention "ater follo"s salt
a. any time renal flo" is lo" get aldosterone secretion and salt retention
b. salt retention can also be due to diet
c. in both cases/ salt retention0
i. increases hydrostatic pressure $more fluid circulating through vessels%
ii. decreases oncotic pressure $"hatever proteins you had are diluted by the extra
fluid%
!. Heart :ailure see slides 13 and 14
a. ;eft sided is more common than right sided
i. ;eft sided is due to atherosclerosis / heart disease 'ill heart tissue bit by bit
ii. Characteri%ed by build up of fluid in lungs $heart can8t pump it so blood
bac's up into lungs%
1. "hat do you see on a slide
a. pin'ish filled air spaces
b. macrophages full of hemosiderin eat red blood cells trapped
in the lung
b. <ight sided failure is usually caused by left sided failure
i. ;eft side fails 56 pressure in lungs increases 56 right side can8t overcome that
pressure 56 right side fails
ii. +his is your most common clinical picture biventricular (H:
c. (or =ulmonale
i. =ure right sided heart failure
ii. 1ue to pulmonary infections or embolisms
d. 1ifferentiating bet"een left sided heart failure and (or =ulmonale
i. .n left sided heart failure main symptoms are due to pulmonary congestion and
pulmonary edema
ii. .n (or =ulmonale/ despite the name/ pulmonary symptoms are minimal
1. =t present "ith &ystemic and portal enous congestion syndrome
a. Hepato and spleenomegally $blood bac'ed up in portal system
bc right atrium is full%
b. ;ots of peripheral edema and ascites
e. :or"ard effects of heart failure effect on the 'idneys
i. 'idney detects lo" flo" 56 rennin system "ill increase aldosterone 56 retain salt
56 increased plasma volume but dump it all bac' into a failing heart
'orphology and Distribution of edema
1. ;ocali>ed vs nasarca
2. 1ependant edema sign of heart failure/ particularly right sided
a. )"elling of dependant places in the body
b. ?ediated by gravity "hich pools blood in certain areas of the body resulting in increased
hydrostatic pressure
i. E.g. legs "hen standing
ii. )acrum "hen recumbent hospital bed
3. =ulmonary edema sign of left sided heart failure
a. :luid fills alveolar air spaces/ hindering gas exchange
4. =eriorbital edema usually sign of head trauma
a. )pace around the eyes allo"s for fluid to accumulate
!. -rain edema medical emergency
a. @ive high dose steroids to reduce inflammation
b. :luid is poorly drained bc of lac' of lymphatic drainage in brain
&. =itting edema standard increased hydrostatic pressure / decreased osmotic pressure edema
a. :luid filled "ith transudate
*. Aon pitting edema
a. (aused by obstructed lymphatics
2
,. Hemorrhage/ in increasing si>e
a. =etechiae $small pin point%/ purpura/ 62cm 3 ecchymosis
b. Hemothorax
c. Hematoma bruise / collection of coagulated blood
B. .mportance of blood volume
a. <apidly lose 2CD or slo"ly lose more/ its o' any more loss and might go into shoc'
b. ;ocation is very important
i. -leeding into a body cavity might be less severe than bleeding out
1. -leed in reabsorb all the iron and heme
2. -leed out get anemia
ii. () year old man in hospital with anemia
1. chec' for carcinoma of the colon might be losing a lot of blood in shit
iii. *) year old female with anemia
1. give her some iron supplements

Hemostasis
1. ?aintenance of flo" and generation of plugs at bleeding sites
a. ?ost of the "or' is on flo" maintenance/ if it "asn8t "e "ould clot to death
2. =ro flo" factors
a. Endothelial =@.2 and AE
b. ntithrombin 3
i. .nactivates thrombin $..a% generation of thrombin is the rate limiting step in
the clotting cascade/ converts fibrinogen to fibrin
ii. Heparin li'e molecules increase activity of antithrombin 3
c. +hrombomodulin
i. -inds to thrombin and facilitates activation of protein (
d. =rotein c
i. 1egrades actiated clotting factors Fa and F...a
ii. <e2uires protein ) from the endothelial cells
e. +5= $tissue plasminogen activatorGG%
i. ?a'es plasmin
ii. =lasmin splits fibrin
iii. Enly effective up to a certain point/ once factor 13 is involved fibrin cannot be
split by plasmin $extensive cross lin'ing has occurred due to actions of 13%
3. =ro clotting factors
a. .n7ured endothelium becomes pro clot
b. +, facilitates platelet adhesion and aggregation
i. exposure of underlying E(? $especially collagen% is the strongest clotting
activator
-. allo"s vH: to bind to collagen/ platelets then bind to vH:
*. note that vH: is al"ays around/ not produced upon in7ury
c. bacterial endotoxin $;=)% and cyto'ines li'e +A: and .;1 get the endothelium to ma'e
Tissue ,actor ! activates the e.trinsic pathway
4. platelet function
a. first the platelet has to bind to the E(? +,
b. once bound/ platelet "ill secrete the contents of its granules
i. alpha granules
-. fibrinogen/ =1@:/ +@:b/ vH:/ platelet factor 0 1heparin binding
chemokine binds heparin so that it can8t increase antithrombin 32
ii. 1ense bodies
-. #DP/ Ca33/ histamine/ seratonin/ epinephrine and T4#*
$vasoconstriction%/ phospholipid comple.
iii. Expression of the phospholipid complexes is important
-. )erve as binding sites for (a99 and clotting factors
c. the granular contents no" facilitate aggregation
i. primary hemostatic plug formation induced by #DP and T4#* 1D. granules2
3
-. side note formation of the primary hemostatic plug 3 bleeding time
ii. to strengthen the plug/ thrombin interacts "ith 1= and +I2 to ma'e
secondary hemostatic plug
iii. thrombin is initially around in only small amounts/ after secondary plug
formation it is secreted in larger amounts "hich cleaves fibrinogen $from alpha
granules% into fibrin "hich JcementsK the mass
d. ho" is clotting limited to sites of damageG
i. vH: only binds to sites "here E(? is exposed
ii. tissue factor and the phospholipids comple. are only at the site of in7ury
the clotting cascade
-. goal is to ma'e thrombin 5 look at slide 67
*. have en>ymes $the factors themselves%/ substrates $the next factor in the path"ay%/ cofactors $can
be chelators these speed up the reaction e.g. (itrate bdta "hich grabs (a99/ other cofactors 3 ,a
and !a% and phospholipid surface $assembly site%
a. (a99 helps stic' the thing together carboxylation reactions 'ey
6. -asic outline
a. Extrinsic 3/*/1C
b. .ntrinsic 12/11/B/1C
c. (ommon starts at 1C/ 2/ 1/ 13
d. (rosstal' 1C/*/B
0. E.trinsic pathway
a. 6 1tissue factor2 is released upon endothelial in7ury or exposure to ;=)
b. as a cofactor/ 3 complexes "ith 8 to form 698a
c. 3/*a activates -7 to -7a 5 generates a 2uic' burst of thrombin $needed every"here%
i. 3/*a also crosses over to intrinsic and activates :a
). intrinsic pathway
a. e.posure of collagen causes formation of a complex composed of0
i. pre 'alli'rien/ H?H 'ininogen/ 11 and 12
b. pre 'alli'rien converted to kallikrien
c. 'alli'rien activates -* into -*a
d. 12a
i. activates -- to --a
ii. activates more kallikrien from pre 'alli'rein $'eeps rnx going%
e. 11a activates : to :a
f. B activates -7 to -7a on the surface of platelets 9 phospholipids comple.
i. for this last step/ have to form the tenase comple. on the phospholipid surface
-. small amount of thrombin from the extrinsic path activated ;a
*. ;a serves as a receptor for :a/ -7/ Ca33
a. once it is all together have the tenase complex/ -7 !" -7a
ii. (a99 and Fit4
-. (alcium is a cofactor/ Fit 4 is needed in carboxylation rxns
a. ctivation of factors */8/: and -7 so they can bind calcium
*. Fit 4 deficiency/ eerything is present but can<t actiate -7a
iii. Harfarin / coumidin ho" does it "or'G
-. Harfarin is a vitamin 4 antagonist 5 anticoagulant
*. .t inhibits carboxylation reactions in the clotting cascade
a. activation of 2/*/B/1C
6. .f someone has overdosed on "arfarin give Fit4
(. Common pathway
a. )tarts "ith formation of a complex similar to the tenase complex above this is also on
the phoshpholipid surface0
i. )mall amounts of thrombin from extrinsic actiaed )a
ii. !a serves as a cofactor/receptor 1Ca/ 2 $prothrombin% and (a99
-. once the complex is formed * 5=conerted to *a 1TH>?'@IA2
*. thrombin
4
a. "ill activate - 5 -a 1fibrin2
b. "ill also activate -6 5 -6a 1fibrinase2
i. transglutaminase that cross lin's fibrin $stable%
8. summary notes on thrombin
a. most important for activating 1a $fibrin%
b. also activates 11 and the cofactors ,a $for activating 1Ca% and !a $for activating 2a%
c. "hen combined "ith thrombomodulin it can activate Protein C $in the presence of
protein )%
i. "ill cleave !a and ,a anticoagulant action
d. ma7or endogenous inhibitor of thrombin formation3 antithrombin 3
i. also inhibits ..a/ Ba/ 1Ca/ 11a/ 12a
e. can be inhibited pharmaceutically by Heparin 56 ups antithrombin 3 1CCCI
;. summary of cofactors
a. (a99 is needed all across the intrinsic path
i. $12a 56 11/ 11a56B/ Ba561C/ 1Ca562%
b. need 3 to activate *
c. need ,a to get 1Ca $also need the phospholipid layer%
d. need !a to get 2a $also need the phospholipids layer%
:. le"is8s JrealK se2uence
a. not really separate path"ays bc of the crossover $*/B and 1C%
b. extrinsic gives you a 2uic' burst of thrombin and then intrinsic amplifies the response
c. deficiency in 12 or 11
i. no big deal 56 from * can get to B

-7. managing pts "ith clotting problems
a. acute treatment someone is over clotting give .F heparin/ fast to ta'e effect/ long
recovery
!
b. chronic treatment can ta'e "arfarin / coumidin orally/ short to ts'e effect but "ith
Fitsmin 4 can 2uic'ly recover
i. e.g. valve replacement pts
c. monitor pts =+ time to ma'e sure drugs are in balance
Thrombosis
--. Fircho"s triad three factors that promote thrombosis 1endothelial damage/ &tasis and
hypercoagulability2
a. Endothelial damage
i. +hings li'e0 trauma/ ischemia/ atherosclerosis/ endotoxins/ cig smo'e/ type 3
H)< $compliment mediated damage%
ii. Ence damaged
-. E(? gets exposed to plasma $start the "hole cascade%
*. =henotypic changes to endothelium $go pro clot 5 stop ma'ing pro flo"
factors =@.2 and AE%
b. &tasis 9 turbulence
i. .n stasis/ anticoagulants diminished/ procoagulants become concentrated
-. -lood is not moving 56 inhibitors are normally around in small
amounts and "ith no movement these all get used up 56 pro coagulants
can no" act "ithout interference
*. Hhy trail :ibrilation is so scary causes stasis stasis leads to
thrombis thrombis out the heart and into your brain
ii. +urbulence very bad shit
-. (an lead to stasis $"hirlpools of blood that don8t follo" normal flo"%
*. -c of the stasis/ endothelium is not being ade2uately supplied "ith C2
56 ischemic damage
6. +he turbulence itself is physically damaging to the endothelium
Example 1eep vain thrombosis $lo"er limbs%
0. lready have stasis bc this area is slo" flo"
). +he valves create areas of turbulence right underneath them
(. =erfect place for thrombosis
a. .s "hy pts have to "al' around after surgery 1F+ can lead
to pulmonary emboli and sudden death
iii. -aby asprin a day
-. 1oes AE+ brea' up clots
*. -ut prevents thrombus formation
c. Hypercoagulability ! dehydration
i. Heparin induced thrombocytopenia
-. Heparin is supposed to be an anticoagulant but in some cases antibodies
are developed to heparin/=:4 complex that cross react "ith platelets
*. (auses the platelets to agglutinate and stic' to endothelium
6. +hrombocytopenia blood analysis sho"s lo" platelets bc are all stuc'
to endothelium or destroyed
0. )mall molecular "eight heparin decrease this ris' of this reaction
ii. ntiphospholipid antibodies e.g. cardiolipin
-. (ross react "ith platelets
*. 1ue to lupus secondary anti phopsholipid antibody syndrome $apas%
6. Er non autoimmune primary apas
0. )ymptoms
a. <ecurrent arterial and venous thrombosis
b. (ardiac valve vegetations
c. +hrombocytopenia
d. ?iscarriages antibodies developed inhibit t= "hich the
trophoblast needs to lodge into the uterus
iii. =rosthesis mechanical valves
i. )ic'le cell disease red cells clog up arteries
&
. Inherited states not very common/ suspect it in pts under !C "ith no other
reason for their hypercoagulability
-. Leiden mutation in factor )a 5 most common inherited mutation
a. ?a'es it resistant to =rotein ( degradation
*. @ain of function mutations in prothrombin
6. Homocysteinemia
a. Homocystein inhibits anti thrombin 3 and thrombomodulin
b. +reatment 3 vit b12
i. ?ther causes
-. ;o" fibrinolytic capacity $plasmin can8t split fibrin%
a. Ene of the factors that predisposes "omen on the pill to clot
$others include ;eiden mutation/ protein c and s deficiencies%
-*. ?orphology of thrombi
a. =ostmortem vs antemortem
i. ntemortem blood moving around is "ell mixed $cellular elements and fluid%
thrombus is dar' in color 3 current Belly
ii. =ostmortem cellular elements and fluid separate thrombi "ill have light and
dar' regions light 3 chicken fat
b. rterial vs Fenous
i. rterial high pressure/ hard to form thrombus/ red cells are moving 2uic'ly so
many 1E AE+ get stuc' thrombus is lighter in color
-. Lines of %aun
a. )uggest arterial thrombi
b. (an see lines "here red cells are not part of the clot and lines
"here red cells are part of the clot called lamination
ii. Fenous lo"er pressure/ easier to form thrombi/ red cells get lodged in the
thrombi thrombus is darker
c. ?ural thrombi "all thrombi
i. re formed in the "alls of the heart chambers or aorta can cause stro'es
-6. :ate of thrombi
a. =ropagation the clot gro"s
i. Heparin/ "arfarin / coumadin/ baby asprin can all prevent this
b. 1issolution
i. :ibrinolytic / plasmin activity
c. Ergani>ation and recanali>ation 2454,hours
d. Emboli>ation
i. =iece brea's off and gets stuc' some"here else
Emboli
-. =ulmonary emboli see pics slide )0 ! (8
a. :re2uent cause of sudden death
b. ?a7ority stem from 1F+
c. ?ay or may not cause infarction of tissue
i. ;ung has a dual blood supply same "ith liver
d. Horst type is a saddle embolism
i. )tarts in lo"er leg
ii. ?assive embolus that travels up/ at the bifurcation of pulmonary artery one end
goes to the right and the other goes to the left both lungs done
*. :at emboli pics (; and (:
a. Eccur due to crushing in7uries
b. :at enters circulation/ activates platelets and in7ures the endothelium
c. :at is stained "ith sudan blac'
*
6. mniotic :luid Emboli pic 8-
a. (omplication that can occur "hen mothers blood is exposed to amniotic fluid
b. :indings s2uamous cells and hair cells $both from amnion% in lung arterioles
c. 1amage is caused by the biochemical rxns that induce shoc' in the mother 5 asodilation
d. .f the mother survives the initial shoc'/ often die from 1.( $see belo" for def8n% due to
release of thrombogenic substances from the amnion
0. @as embolism
a. ?ost fre2uent cause decompression sic'ness in divers and casson "or'ers $AE2%
b. (an occur during orthopedic surgery
i. Fessels in bone matrix are not collapsible so "hen you cut bone air can get
suc'ed into the vessels
1. (an be prevented / minimi>ed if pts heart is above the operating site
ii. 1oesn8t occur in soft tissue bc vessels are collapsible
c. .n7ections almost impossible need 1CCcc of air to do some damage
). &ee slide 86
(. rterial emboli
a. 'ost arise from mural thrombi in the "all of the left heart
i. ;eft heart 56 aorta 56 any"here in the body
b. (an be caused by abdominal aortic aneurism
i. .n aneurisms get stasis/ turbulence and thrombosis
ii. ?ostly belo" the origin of renal arteries and so emboli tend to 7ust lodge in the
lo"er leg some"here might have to cut off the toe
c. therosclerotic pla2ue
i. (an brea' off and lodge some"here
ii. ?ost dangerous is in the common carotid travel to the brain
d. 1amaged valves
i. -ad shit gro"s on them that can emboli>e can end up any"here
ii. ?itral and aortic are under more stress and so more prone to damage
Disseminated intraascular coagulation 1DIC2
1. (onsumptive coagulopathy
a. :ibrin thrombi all over the microvasculature that use up all of the platelets and
coagulation factors
b. ;eaves you prone to massive bleeding in other areas of the body
2. :ibrinolytic system "ill be activated
a. Diagnostic sign 5 eleated fibrin split products CCC
i. Hill also have lo" platelets and clotting factors on blood test
ii. =t might have massive @. bleeding
iii. )H.)+E(L+E) $fragmented <-(s..cut up by clotting factors/fibers/split
products%
3. Fery sic' ppl get this and mortality rate is high
a. complication of anything that uses up all your thrombin
Tests for bleeding disorders
1. -leeding time
a. measure of platelet function
b. ?easures the time re2uired to ma'e the primary hemostatic plug 1#DP and T4#*2
c. =rolonged if deficienct in vH: or have lo" / poorly functioning platelets
2. =rothrombin time $=+%
a. ?easures extrinsic path"ay 9 common
b. =rolonged if factors0
i. !/ 1C/ 2 $prothrombin% or 1 $fibrinogen% are messed ;; (E??EA
ii. * 3 pure extrinsic
3. =artial thromboplastin time $=++%
a. ?easures intrinsic path"ay 9 common
b. =rolonged if factors0
,
i. !/ 1C/ 2 or 1 3 all common
ii. 12/ 11/ B/ , 3 pure intrinsic
4. Aote that the above t"o tests are done in tests tubes/ inhibitors are put in so that the path"ays can
be isolated
a. -oth =+ and =++ are elevated 3 problem "ith the common path"ay
b. ll the times are o' according to test tube but pt is still bleeding 3 vit 4 deficiency G
Infarction 5 slides ;7 ! ;0
-. 1eath of tissue due to ischemic necrosis
*. lmost all caused by thrombotic or embolic eents
6. <ed or pale but wedged shaped infarct
0. ,actorsD
a. natomy of blood supply most important factor
i. ;iver and lung have dual blood supply so infarct usually less severe
1. )ame for hand and forearm
ii. 4idney and spleen have end arterial systems only one artery going in most
damage if occluded
b. <ate of occlusion
i. +he 2uic'er it develops the more severe the infarct
ii. Hith slo"er forming bloc's/ body can adapt via collateral vasculari>ation
c. Ergan dependence on aerobic metabolism
i. -rain and heart "ill die fast/ neurons "ill die the fastest
d. Exygen content of the blood
i. nemic pts and heart failure pts
&hock 5 6 forms
1. (ardiogenic )hoc'
a. +his is pump failure/ but not due to heart failure $chronic condition%/ more acute stuff0
i. ?uscle damage due to infarction
ii. (ardiomyopathies
iii. Extrinsic compression
i. rrhythmias
. Eutflo" obstruction $pulmonary embolism%
2. Hypovolumic )hoc'
a. -lood or fluid loss $hemorrhage/ burns/ vomiting/ diarrhea%
3. )eptic )hoc'
a. High mortality rate
b. #sually caused by endotoxin from gram negative bacteria $organisms don8t have to be
alive%
c. +he se2uence for endotoxic shoc'
i. -acterial "all product ;=) $endotoxin% is released "hen bacterial "all is
degraded during normal inflammatory response
1. .n7ection of massive amount of ;=) alone can cause shoc'
ii. ;=) attaches to circulating LP& binding proteins
iii. ;=) protein complexes bind to cell surface receptor 1CD-02
i. +hen activate toll li'e receptors 4 1TL>02
1. +;<4 activated on endothelial cells become pro clot
a. 1ecreases synthesis of tissue factor path"ay inhibitor
i. )o factor 3 of the extrinsic path"ay is easily
activated
b. 1ecreases synthesis of thrombomodulin
i. )o have less activity of =rotein (
2. +;<4 activated on macrophages
a. <elease of +A:/ .;1 and then .;& $in that order%
b. ;ots of this shit leads to0
B
i. )ystemic vasodilation $hypotension%
ii. 1iminished myocardial contractility
iii. Endothelial in7ury and thrombosis 1DIC2
i. lveolar capillary damage 1#>D&2
4. )tages of )hoc'
a. Aonprogressive body can handle the situation compensatory mechanisms activated
b. =rogressive tissue hypoperfusion and shit starting to hit the fan $acidosis 'ic'ing in%
c. .rreversible ischemic damage to the point that reperfusion can8t rescue the tissue
!. +he JnightmareK or shoc'
a. .nitially body does its best to maintain fluid volume and output to the tissue
i. +achycardia/ vasoconstriction/ 'idney starts retaining fluid
b. Hypoxia though induces anaerobic metabolism and lactic acid production increases
i. ;actic acid induces vasodlation $adding to effects of +A:/ .;1 and .;&%
c. -ody starts to shut do"n
i. ;o" cardiac output/ hypoxia gets "orse/ hypoxic heart lo"ers output even more
ii. +A acute tubular necrosis
1. 4idney is damaged and can8t retain fluid 56 eventually no flo" 56
1E1
1C