Clot or Bleed

About th|s gu|de
PemosLasls ls one of Lhose parLs of paLhology LhaL loLs of sLudenLs flnd overwhelmlng. 1here's so
much golng on ln Lhe coagulaLlon cascade alone - so many 8oman numerals, so many arrows Lo
dlfferenL molecules, so many slmllar-soundlng abbrevlaLlons...lL's enough Lo make a person Lhrow
Lhe book aL Lhe wall and go Lake a nap. As one sLudenL puL lL: l don'L know anyone who doesn'L
haLe coag."

1hls gulde ls wrlLLen for Lhose of us who have had a dlfflculL Llme undersLandlng coag. lL breaks
hemosLasls down lnLo reasonably-slzed secLlons, wlLh easy-Lo-undersLand explanaLlons, sllly buL
helpful mnemonlcs, and answers Lo commonly-asked quesLlons. 8y Lhe end of Lhls gulde, you'll
undersLand how cloLs are formed and whaL keeps us from cloLLlng Loo much. ?ou'll also know how
Lo use coag and plaLeleL laboraLory LesLs ln pracLlce, and you'll have a good undersLandlng of mosL
bleedlng and LhromboLlc dlsorders.

Lxtra he|p
lf you are sLuck, or frusLraLed, or lf someLhlng [usL doesn'L make sense, feel free Lo send me an
emall aL paLhology[paLhologysLudenL.com. l'll do my besL Lo geL you unsLuck and back on Lrack.

Acknow|edgements
A blg Lhanks Lo !effrey Lucak for hls meLlculous edlLlng.

2011 aLhology SLudenL

age 3 of 32
Chapter 1: now 1o Make a C|ot
8efore we begln
PemosLasls ls a dellcaLe balanclng acL. LecLures and LexLbooks Lend Lo focus on Lhe mechanlsms of
cloLLlng (and we'll do so ln Lhls sLudy gulde Loo). 8uL Lhere's an equally lmporLanL and robusL anLl-
cloLLlng sysLem LhaL keeps cloLLlng under conLrol. 1here has Lo be, obvlously, or as soon as we goL
a small Lear ln a blood vessel (whlch happens all Lhe Llme ln caplllarles), we'd become one blg cloL.

8oLh sysLems have Lo have all Lhelr parLs lnLacL and be able Lo funcLlon aL Lhe proper level. lf your
pro-cloLLlng sysLem ls overacLlve, or lf your anLl-cloLLlng mechanlsms are less Lhan sLellar, Lhe
balance wlll Llp Lowards Lhe pro-cloLLlng slde, and you'll have an lncreased rlsk of Lhrombosls.
Llkewlse, lf your pro-cloLLlng mechanlsms are slugglsh, or lf your anLl-cloLLlng sysLem ls
hyperacLlve, you'll be more llkely Lo bleed. Causes of such lmbalances can be elLher dlsease-
relaLed (e.g.., Lhe paLlenL has a coagulaLlon facLor deflclency) or drug-relaLed (e.g., Lhe paLlenL ls
on warfarln, whlch lnhlblLs vlLamln k dependenL coagulaLlon facLors).

keeplng LhaL balance ln mlnd, leL's Lalk abouL how Lo make a cloL.
1he Lhree sLeps
1he whole polnL of cloLLlng ls Lo plug holes ln vessels so blood can'L escape. 1here are Lhree sLeps
ln Lhls process:
1. consLrlcL Lhe blood vessel ln Lhe reglon of Lhe hole
2. form a plaLeleL plug
3. seal LhaL plug wlLh flbrln.

lf you llke drawlngs beLLer Lhan words (who doesn'L?), you could summarlze lL llke Lhls:

CloLLlng
lugs up holes
ln blood vessels
AnLl-CloLLlng
keeps cloLLlng
under conLrol

age 4 of 32
LeL's Lake a qulck look aL whaL's golng on ln each sLep (we'll geL lnLo more deLall ln a mlnuLe).

1. 8|ood vesse|s constr|ct
1hls ls a good way Lo qulckly cuL down on blood loss, vessel consLrlcLlon leads Lo decreased
blood flow, reduclng Lhe amounL of blood losL.
lL also helps plaLeleLs and coagulaLlon facLors come lnLo conLacL wlLh each oLher and sLlck
LogeLher when Lhey bump lnLo each oLher (whlch ls necessary for Lhe whole process Lo
proceed). normally, Lhe speed and shear sLress of blood flow breaks" Lhls blndlng afflnlLy.
nobody Lalks much abouL Lhls parL of cloLLlng (and nelLher wlll we) - probably because lL
works preLLy well mosL of Lhe Llme, and Lhere aren'L many dlseases lnvolvlng Lhls sLep of
cloLLlng.

2. |ate|ets form a p|ug
ln Lhls sLep, Lhe plaLeleLs clump LogeLher and form a llLLle mushy plug LhaL covers Lhe hole
ln Lhe vessel. lL's greaL - buL wlLhouL Lhe flnal sLep (flbrln formaLlon), lL would fall aparL and
be useless.
1hls sLep ls ofLen called prlmary hemosLasls" (ln splLe of Lhe facL LhaL lL's noL really Lhe
flrsL Lhlng LhaL happens ln cloLLlng).

3. I|br|n sea|s the p|ug
ln Lhls flnal sLep, flbrlnogen Lurns lnLo flbrln, a long molecule LhaL blnds Lo and solldlfles Lhe
plaLeleL plug.
1here are a bunch of molecules lnvolved ln Lhe process, each acLlvaLlng Lhe nexL ln a
cascade fashlon (hence Lhe name coagulaLlon cascade").
1hls sLep ls ofLen called secondary hemosLasls" (even Lhough Lechnlcally lL's Lhe Lhlrd sLep
ln Lhe process).
1here are several sLeps Lo flbrln formaLlon:
1. 1he lnlLlaLor of Lhe whole process ls a molecule called Llssue facLor (1l).
2. 1he coagulaLlon cascade proceeds, one molecule acLlvaLlng Lhe nexL, all Lhe way down
Lo Lhe lasL sLep (whlch ls Lhe converslon of flbrlnogen Lo flbrln).
3. llbrln superglues Lhe plaLeleLs Lo each oLher, seallng and anchorlng Lhe plug.

age 3 of 32
rlmary hemosLasls
rlmary hemosLasls ls LhaL parL of cloLLlng ln whlch you form a plaLeleL plug. LeL's Lake a look aL
plaLeleLs, and Lhen we'll look aL how Lhey lnLeracL Lo form Lhe plug.

|ate|et morpho|ogy
laLeleLs are noL really cells (Lhey don'L have a nucleus). 1hey're fragmenLs of cyLoplasm shed by
glganLlc precursor cells called megakaryocyLes LhaL llve ln Lhe bone marrow. laLeleLs look llke
Lhls:

Norma| p|ate|et |n b|ood smear

1hey are cuLe llLLle lrregularly-shaped fragmenLs of cyLoplasm wlLh a cenLral reglon of purpllsh
granules (Lhe granulomere") and a perlpheral reglon LhaL ls granule-free (Lhe hyalomere"). MosL
of Lhe plaLeleLs llve ln Lhe blood (and bone marrow), abouL a Lhlrd are sequesLered ln Lhe spleen.

1helr slmple appearance belles an amazlngly complex sLrucLure. 8oLh Lhe membrane and Lhe
granules have a Lon of lmporLanL feaLures.

|ate|et membrane
1he plaLeleL membrane ls crlLlcal Lo Lhe whole process of cloL formaLlon:
lL provldes a speclal phosphollpld surface (hlsLorlcally referred Lo as plaLeleL facLor 3, or
l3) for coagulaLlon facLors Lo blnd Lo. CoagulaLlon facLors need Lhls unlque phosphollpld
surface ln order Lo funcLlon properly, and whaL beLLer place Lhan Lhe surface of Lhe
plaLeleLs Lhemselves?
lL dlsplays a bunch of recepLors LhaL blnd lmporLanL molecules. 1wo lmporLanL ones are
glycoproLeln (C) lb, whlch blnds von Wlllebrand facLor (vWl), and C llb-llla, whlch blnds
flbrlnogen.

|ate|et contents
1here are loLs of Lhlngs lnslde plaLeleLs LhaL help wlLh Lhe process of cloLLlng:
o granules ("speclflc granules") conLaln flbrlnogen, von Wlllebrand facLor (vWl), plaLeleL-
derlved growLh facLor and -selecLln.
granules ("dense granules") conLaln seroLonln, A1, Au, and calclum (whlch ls necessary
for Lhe vlLamln k dependenL coagulaLlon facLors).
ConLracLlle proLelns (llke acLln) LhaL help Lhe plaLeleL change shape durlng adheslon (a sLep
LhaL ls essenLlal for Lhe release of granules).

age 6 of 32
now do p|ate|ets form a p|ug?
1. LndoLhellal damage exposes subendoLhellal proLelns (llke collagen), whlch aLLracL plaLeleLs.
2. laLeleLs sLlck Lo Lhe subendoLhellum (von Wlllebrand facLor ls Lhe glue), a process called
adheslon.
3. 1hey change shape and release Lhelr granule conLenLs, whlch aLLracL more plaLeleLs.
4. 1hey sLlck Lo each oLher and form a Lemporary plug (flbrlnogen ls Lhe glue), a process
called aggregaLlon.
3. AfLer a whlle, Lhe plaLeleLs conLracL, whlch helps reLracL Lhe cloL and seal Lhe vessel wall.
Secondary hemosLasls
Secondary hemosLasls ls LhaL parL of cloLLlng ln whlch you make flbrln, whlch seals up Lhe plaLeleL
plug. LeL's Lake a look aL how flbrln ls made, whlch lnvolves a process called Lhe coagulaLlon
cascade (or, as one sLudenL puL lL, Lhe 8oman numeral cascade of memorlzaLlon hell").

1he coagulaLlon cascade ls a serles of enzymes ("facLors") whlch acLlvaLe each oLher ln a cascade
fashlon (hence Lhe brllllanLly descrlpLlve name). 1he whole polnL of Lhe cascade ls Lo Lurn
flbrlnogen (a blg long precursor molecule whlch ls used as a glue ln early plaLeleL plug formaLlon,
buL whlch ls useless as far as permanenL seallng of a plaLeleL plug goes) lnLo flbrln (Lhe lncredlble
superglue LhaL Lurns a mushy plaLeleL plug lnLo a rock solld blood loss barrler).

Pere's someLhlng LhaL you should LaLLoo on your Lhlgh (okay, maybe [usL wrlLe lL on your hand):
1he Whole olnL of Lhe CoagulaLlon Cascade ls Lo 1urn llbrlnogen lnLo llbrln.

Why would you wrlLe LhaL on your body?

8ecause lL's way Loo easy Lo geL so caughL up ln memorlzlng Lhe names of Lhese enzymes (plus all
Lhelr 8oman numeral deslgnaLlons, plus whlch one acLlvaLes whlch) LhaL you forgeL Lhe seemlngly
obvlous goal of Lhe whole process, whlch ls [usL Lhe formaLlon of flbrln. lL's Lhe old can'L-see-Lhe-
foresL-for-Lhe-Lrees Lhlng. lL's also easy Lo forgeL LhaL flbrln formaLlon ls only one parL of cloL
formaLlon! lL wouldn'L mean anyLhlng lf you dldn'L already have a walLlng plaLeleL plug. 1ry Lo
keep Lhls ln mlnd as we Lalk abouL Lhe deLalls of Lhe coagulaLlon cascade.

Coagu|at|on factors
All Lhe coagulaLlon facLors excepL flbrlnogen are elLher enzymes or cofacLors.

Lnzymes
1hese guys acLlvaLe oLher coagulaLlon facLors.
1hey clrculaLe as lnacLlve enzyme precursors. When Lhe cascade ls lnlLlaLed, Lhey are
hydrolyzed by Lhe precedlng coagulaLlon facLor (Lhough noL always ln numerlcal order),
formlng acLlve enzymes. A llLLle a" afLer Lhe 8oman numeral lndlcaLes Lhe acLlve form of
Lhe enzyme.
MosL of Lhese enzymes are serlne proLeases, whlch means Lhey hydrolyze pepLlde bonds
uslng a serlne resldue aL Lhelr acLlve cenLer. 1he excepLlon ls xlll, a LransgluLamlnase, whlch
crossllnks and sLablllzes flbrln polymers.

age 7 of 32
Lnzyme precursors lnclude: ll, vll, lx, x, xl, xll, and xlll. Lach of Lhese has a regular old
name Loo (you can look Lhese up ln Lhe reference secLlon lf you're lnLo LhaL klnd of Lhlng),
buL by convenLlon, we use 8oman numerals for all of Lhem excepL ll (whlch ls usually
deslgnaLed by lLs regular old name, Lhrombln).

Cofactors
1hese guys ampllfy Lhe coagulaLlon cascade.
Some of Lhem (v and vlll) are lnacLlve unLll cleaved.
CofacLors lnclude: 1l (Llssue facLor), v and vlll.

Intr|ns|c, extr|ns|c and f|na| common pathways
As you'll see ln a scary dlagram ln a mlnuLe, Lhe coagulaLlon cascade ls dlvlded somewhaL
arLlflclally lnLo lnLrlnslc and exLrlnslc paLhways (followed by Lhe flnal common paLhway).
ln vlLro, Lhe lnLrlnslc and exLrlnslc paLhways operaLe separaLely.
ln vlvo, Lhe Lwo paLhways are blg-Llme co-dependenL. We need boLh lnLrlnslc and exLrlnslc
paLhways for cloLLlng. We know Lhls because people wlLh deflclencles of facLors from elLher
paLhway have bleedlng problems!

1hlngs Lo make you look smarL
C. Pow come Lhe lnLrlnslc and exLrlnslc paLhways are named llke LhaL?
A. 1he nomenclaLure arose ouL of laboraLory observaLlons of cloL formaLlon. 1o generaLe a cloL vla
Lhe lnLrlnslc paLhway ln a LesL Lube, you only need Lhlngs LhaL are !"#$!"%!& Lo whole blood. 1o
generaLe a cloL vla Lhe exLrlnslc paLhway ln a LesL Lube, you need Lo add someLhlng ()#$!"%!& Lo
whole blood (LhaL ls, Llssue facLor or some Llssue-facLor-llke subsLance).

1he extr|ns|c pathway
1lssue facLor ls Lhe acLlvaLor of Lhe exLrlnslc paLhway.
1lssue facLor ls a membrane proLeln LhaL ls found:
1. on cells LhaL are normally noL ln conLacL wlLh blood (llke smooLh muscle cells ln Lhe
subendoLhellum, and flbroblasLs surroundlng blood vessels). vascular ln[ury exposes
Lhls 1l Lo Lhe blood and lnlLlaLes Lhe coagulaLlon cascade.
2. ln mlcroparLlcles" - llLLle fragmenLs of cell membrane found ln normal blood. 1hese
mlcroparLlcles have recepLors for -selecLln. -selecLln ls a cell adheslon molecule LhaL
llves ln plaLeleLs and endoLhellal cells. When lL's acLlvaLed, lL fllps Lo Lhe ouLslde of Lhe
cell membrane, and Lhe mlcroparLlcles sLlck Lo lL, and Llssue facLor accumulaLes ln Lhe
reglon of Lhe formlng cloL, and LhaL's all she wroLe.
3. on endoLhellal cells, and on monocyLes, when Lhere's lnflammaLlon (buL noL under
normal resLlng condlLlons - oLherwlse we'd be coagulaLlng all over Lhe place).
1l blnds Lo vll, acLlvaLes lL, and Lhen Lhls 1l-vlla complex klcks off Lhe coagulaLlon cascade
vla Lhe exLrlnslc paLhway.
AfLer a llLLle xa ls formed, 1ll (Llssue facLor paLhway lnhlblLor) Lurns off 1l, and Lhe
exLrlnslc paLhway ls shuL down, prevenLlng over-cloLLlng and Lhrombosls.

age 8 of 32
1he |ntr|ns|c pathway
1hrombln ls Lhe maln acLlvaLor of Lhe lnLrlnslc paLhway !" *!*+. (WalL a mlnuLe, Lhe dlagram
below shows lL aL Lhe end of Lhe cascade! uon'L worry, we'll geL Lo LhaL laLer.)
?ou'll noLlce LhaL Lhe conLacL facLors" (PMWk, prekalllkreln, xll) are preLLy much absenL
from much of our dlscusslon. 1haL's because alLhough Lechnlcally Lhey are able Lo acLlvaLe
Lhe lnLrlnslc paLhway, Lhey don'L play much of a role !" *!*+. xll, ln parLlcular, ls only
lmporLanL ln formlng cloLs ln LesL Lubes. eople wlLh conLacL facLor deflclencles don'L have
bleedlng dlsorders! 1hese facLors are noL cruclal for acLlvaLlon of Lhe lnLrlnslc paLhway !"
*!*+.

1he f|na| common pathway
1hls ls Lhe lasL leg of Lhe cascade.
lL can be acLlvaLed by elLher Lhe lnLrlnslc or exLrlnslc paLhway.
lL conslsLs of facLors x, v, ll (Lhrombln) and l (flbrlnogen).

Ckay, okay, [ust show me the d|agram.
llne! Pere lL ls:

Scary, lsn'L lL?
AcLually, you can make lL qulLe a blL slmpler. lf you Lake ouL some sLuff aL Lhe Lop lefL (Lhe so-
called conLacL facLors" LhaL you'll hear abouL from Lhe blochemlsLs, buL whlch have baslcally no
real lmporLance !" *!*+) and remove Lhe arrows showlng Lhe acLlvaLlon of each facLor (you know
LhaL each one geLs acLlvaLed from proenzyme Lo enzyme - so you don'L need Lo draw LhaL ouL each
Llme), lL looks a llLLle beLLer:

age 9 of 32

?ou'll need Lo come up wlLh some way Lo make Lhls dlagram memorlzable. l have a llLLle
mnemonlc LhaL l use for my sLudenLs LhaL Lends Lo work. lL's sllly, buL hey, aren'L mosL
mnemonlcs? 1hls one requlres a shorL dlgresslon lnLo Lhe Loplc of women's shoes.

Shoes?
?es, shoes. lor Lhe purposes of Lhls dlscusslon, we'll say LhaL Lhere are Lwo klnds of shoes ln Lhe
world: good ones and bad ones. And we're [usL Lalklng hlgh heels here - forgeL flaLs and booLs and
Lhose dlsgusLlng mld-helghL heels.

A good shoe ls eleganL. lL ls slmple, Llmeless, and clean ln deslgn. lL draws aLLenLlon noL Lo lLself
buL Lo Lhe gorgeous leg lL adorns. Llke Lhls:

age 10 of 32
A bad shoe, on Lhe oLher hand, ls Lacky. lL ls compllcaLed (Lhlnk bows, zlppers, flshlng lures, or - lf
you're Lady Caga - flank sLeak), frlvolous, and busy. lL ls so dlsLracLlng LhaL lL makes lL lmposslble Lo
dlscern Lhe beauLy of Lhe woman, one ls Loo caughL up ln Lrylng Lo vlsually deconsLrucL Lhe
obnoxlous shoe. Llke Lhls:

So lL ls wlLh Lhe coagulaLlon cascade. 1here ls Lhe lnLrlnslc arm of Lhe cascade, whlch ls
unapologeLlcally cluLLered wlLh so many 8oman numerals and arrows LhaL one cannoL flgure ouL
(leL alone remember) whaL ls golng on. And Lhere ls Lhe exLrlnslc arm, whlch ls slmple, unfeLLered,
and easy Lo undersLand.

lnLrlnslc: 8oman numeral hell
LxLrlnslc: 1wo facLors (1l and vll)
Common: AcLlvaLed by boLh Lo produce flbrln

1he blg Lhlng Lo remember abouL Lhe cascade ls whlch facLors consLlLuLe Lhe lnLrlnslc arm and
whlch ones consLlLuLe Lhe exLrlnslc arm. lf you can do LhaL, everyLhlng else follows. lL's easy Lo
remember LhaL one slde has [usL Llssue facLor and vll, and Lhe oLher slde has every oLher facLor ln
lL...buL you need Lo know whlch ls whlch. ?ou mlghL noL Lhlnk Lhls ls lmporLanL now, buL when
your aLLendlng asks you aL Lhree ln Lhe mornlng whlch paLhway Lhe proLhrombln Llme measures,
you'll Lhank me.

8ack Lo Lhe shoes. 1he lnLrlnslc paLhway ls eplLomlzed by Lhe bad shoe. 8oLh are compllcaLed,
cluLLered, and (Lo exaggeraLe a blL) slnful. 8ehold: Lhe SlnLrlnslc paLhway! 1he exLrlnslc paLhway ls
symbollzed by Lhe good shoe. 8oLh are slmple, eleganL, and (wlLh a llLLle sLreLch of Lhe
lmaglnaLlon) sexy. PenceforLh, Lhen, Lhls paLhway shall be known as Lhe SLxLrlnslc paLhway. (As an
aslde, when we geL Lo coag LesLs, we'll see LhaL Lhe LesL names fall rlghL lnLo Lhls
slmple/compllcaLed analogy.)

ALLendlng: Whlch paLhway conLalns facLor vll?"
SLudenL (Lhlnklng quleLly: leL's see...LhaL's Lhe slmple, eleganL paLhway wlLh [usL Llssue facLor and
vll, Lhe one wlLh Lhe good shoe...): 1he sexLrlnslc paLhway."
ALLendlng (eyes opened wlde): WhaL?"
SLudenL (recoverlng qulckly): LxLrlnslc. 1he exLrlnslc paLhway."
ALLendlng (conslderlng a hearlng ald): LxacLly."

age 11 of 32
1he |nteract|on of the pathways |n rea| ||fe
So Lhere are Lwo paLhways, boLh of whlch can be lndependenLly acLlvaLed. Pere's how Lhe
paLhways flL LogeLher !" *!*+:
vascular ln[ury exposes Llssue facLor Lo Lhe bloodsLream.
CoagulaLlon ls sLarLed along Lhe exLrlnslc paLhway (maklng a llLLle xa and Lhrombln along
Lhe way).
xa qulckly Lurns off Lhe exLrlnslc paLhway (Lhrough 1ll, whlch we'll Lalk abouL ln Lhe nexL
chapLer).
1hrombln acLlvaLes Lhe lnLrlnslc paLhway.
1hrombln also acLlvaLes v and vlll, ampllfylng Lhe lnLrlnslc paLhway (and flnal common
paLhway).
WlLhln a few hours, Lhe lnlLlal mushy plaLeleL plug ls Lransformed lnLo a solld mass by
flbrln.

age 12 of 32
Chapter 2: now to Stop C|ott|ng

1here are Lwo maln ways of keeplng cloLLlng under conLrol:
1. ?ou can lnhlblL Lhe coagulaLlon cascade (number 1 ln Lhe fancy dlagram below)
2. ?ou can lyse porLlons of Lhe cloL Lo keep lL down Lo a reasonable slze (number 2 ln Lhe fancy
dlagram), a process whlch forms llLLle flbrln fragmenLs called flbrln degradaLlon producLs, or lus.

LeL's Lake a look aL each of Lhese processes ln a llLLle depLh.
CoagulaLlon cascade lnhlblLlon
Several proLelns keep Lhe coagulaLlon cascade - and Lhus, flbrln formaLlon - under conLrol. 1hese
naLural anLlcoagulanLs lnclude 1ll (Llssue facLor paLhway lnhlblLor), A1lll (anLlLhrombln lll),
proLeln C (8aLman), and proLeln S (8obln). LeL's Lake a look aL where Lhese proLelns acL.

Coagu|at|on cascade |nh|b|tors
1ll (Llssue facLor paLhway lnhlblLor) does whaL lLs name says: lL shuLs off Lhe Llssue facLor
(exLrlnslc) paLhway. lL does Lhls by lnhlblLlng vlla.
AnLlLhrombln lll lnhlblLs Lhe serlne proLeases (lla, vlla, lxa, xa, xla, xlla), shuLLlng off all
Lhree paLhways (lnLrlnslc, exLrlnslc, and common). Who names Lhese Lhlngs? lL's noL [usL
anLl-Lhrombln, lL's anLl-a-whole-bunch-of-Lhlngs. Peparln poLenLlaLes lLs acLlon.
roLeln C ls a serlne proLease whlch desLroys va and vllla (and hence Lhe common and
lnLrlnslc paLhways, respecLlvely), effecLlvely shuLLlng down coagulaLlon. roLeln S ls a
cofacLor LhaL helps proLeln C (lf proLeln C ls 8aLman, proLeln S ls 8obln).

age 13 of 32

C. So whaL Lurns on proLeln C?
A. roLeln C ls Lurned on by Lhrombln. AcLually, Lhrombln blnds Lo Lhrombomodulln (a recepLor on
endoLhellal cells LhaL alLers Lhe Lhrombln molecule), and Lhe resulLlng Lhrombln-Lhrombomodulln
complex acLlvaLes roLeln C. 1haL's preLLy cool: Lhrombln regulaLes lLself by Lurnlng on Lhe Lhlng
LhaL keeps lL ln check.

8y Lhe way, proLeln C does a couple oLher lmporLanL Lhlngs. lL promoLes flbrlnolysls by helplng ouL
Llssue plasmlnogen acLlvaLor (L-A) (see below). lL also helps keep lnflammaLlon ln check by
lnhlblLlng cyLoklne producLlon. 8ecause of lLs effecLs on cloLLlng and lnflammaLlon, glvlng acLual
proLeln C can be useful ln cases of really really bad ulC (dlssemlnaLed lnLravascular coagulaLlon).

age 14 of 32
CloL lysls
When Lhe cloL has done lLs [ob and bleedlng has sLopped, Lhere are several proLelns LhaL help
remodel" Lhe cloL by breaklng down flbrln lnLo llLLle chunks called flbrln degradaLlon producLs
(lus). 1hese cloL-busLlng proLelns lnclude L-A (Llssue plasmlnogen acLlvaLor) and plasmln. L-A ls
acLually used as a drug for LreaLmenL of very recenL lschemlc sLrokes (buL noL hemorrhaglc ones,
obvlously!).

I|br|no|yt|c agents
L-A blnds Lo flbrln (a good ldea, because LhaL keeps lLs acLlon locallzed Lo Lhe cloL!) and
converLs plasmlnogen Lo plasmln.
lasmlnogen ls converLed Lo plasmln, whlch breaks down flbrln lnLo flbrln degradaLlon
producLs (lus), also called spllL producLs, whlch Lhemselves lnhlblL Lhrombln and flbrln
formaLlon (how handy).
8lood conLalns lnhlblLors of L-A (plasmlnogen acLlvaLor lnhlblLor, or Al) and plasmln (o2-
anLlplasmln) so flbrlnolysls doesn'L geL ouL of hand.

age 13 of 32
Chapter 3: Laboratory 1ests
1here are loLs of dlfferenL LesLs LhaL evaluaLe a paLlenL's cloLLlng sLaLus. 1hey can be broadly
dlvlded lnLo Lhose LhaL evaluaLe plaLeleLs and Lhose LhaL evaluaLe Lhe coagulaLlon cascade. We'll
go over Lhe ones LhaL you wlll order very frequenLly, as well as a few LhaL you may encounLer aL
some polnL (on Lhe boards, aL leasL).
laLeleL LesLs
|ate|et count (|t)
laLeleL counLs are usually done by a blg elecLronlc parLlcle counLer.
?ou can also esLlmaLe Lhe counL on a blood smear, you should see beLween 7 and 21
plaLeleLs per hlgh power fleld (x1,000 oll lmmerslon).
1he reference range ls 130 - 430 x 10
9
/L.
1hls LesL does noL evaluaLe plaLeleL funcLlon, lL [usL Lells you Lhe number of plaLeleLs
presenL.

|ate|et morpho|ogy
?ou can look aL a blood smear under a mlcroscope and see lf Lhe plaLeleLs look normal.

Norma| p|ate|et |n b|ood smear

1hey almosL always look llke Lhls (even when Lhey don'L work properly) - buL on occaslon, Lhey wlll
be blgger Lhan usual, or lack granules, or boLh. We'll look aL some plaLeleL dlsorders LhaL have
funny morphology laLer.

8|eed|ng 1|me
What does the b|eed|ng t|me measure?
Pow plaLeleLs respond !" *!*+ Lo vascular ln[ury.
unforLunaLely, Lhe bleedlng Llme ls affecLed by oLher facLors, Loo (hemoglobln, skln quallLy,
whaL klnd of a mood Lhe Lech ls ln LhaL day...).

age 16 of 32
now do you do a b|eed|ng t|me?
uL a blood pressure cuff on Lhe paLlenL's arm and lnflaLe lL Lo 40 mm Pg.
Make a llLLle lnclslon (uslng a dlsposable sprlng-loaded lanceL) on Lhe lnner surface of Lhe
paLlenL's lower arm, noLlng Lhe Llme.
8loL drops of blood as Lhey appear aL Lhe lnclslon slLe.
WalL (Ledlous!). When Lhe lnclslon sLops bleedlng, noLe Lhe Llme.
1he LoLal Llme elapsed beLween lnclslon and bleedlng cessaLlon ls called Lhe bleedlng Llme.
1he reference range ls 2 Lo 9 mlnuLes ln adulLs (longer ln chlldren).

What k|nds of th|ngs cause a pro|onged b|eed|ng t|me?
laLeleL dlsorders, such as von Wlllebrand dlsease.
Severe LhrombocyLopenla.

When shou|d you order a b|eed|ng t|me?
Some experLs order lL Lo screen sympLomaLlc (bleedlng) paLlenLs for lnherlLed plaLeleL
dlsorders.
CLher experLs conslder lL so unrellable LhaL Lhey don'L use lL aL all, and go sLralghL Lo Lhe
fancy, speclflc LesLs for von Wlllebrand dlsease and oLher plaLeleL dlsorders.
?ou can always call your frlendly hosplLal paLhologlsL and ask her whaL she would
recommend.

|ate|et aggregat|on stud|es
What do p|ate|et aggregat|on stud|es measure?
Pow well Lhe plaLeleLs are able Lo aggregaLe (sLlck Lo each oLher).

now do you do a p|ate|et aggregat|on study?
Add varlous aggregaLlng agenLs (llke Au, collagen, rlsLoceLln, arachldonlc acld,
eplnephrlne) Lo llLLle Lubes of Lhe paLlenL's plaLeleLs.
Measure Lhe decrease ln LurbldlLy of Lhe plaLeleL soluLlon.
1he ,-##($" of response Lo each agenL helps narrow down your dlagnosls.
! normal plaLeleLs wlll respond Lo every aggregaLlng agenL.
! ln plaLeleL dlsorders, however, Lhe plaLeleLs do noL respond normally Lo every
aggregaLlng agenL.
Cne dlsorder may show normal aggregaLlon wlLh every agenL excepL rlsLoceLln. AnoLher
may show normal aggregaLlon wlLh rlsLoceLln and arachldonlc acld, buL no response Lo any
oLher aggregaLlng agenL. A Lhlrd dlsorder may show no aggregaLlon wlLh any of Lhe
aggregaLlng agenLs.

Wa|t, what?
Ckay, Lhls ls [umplng ahead, buL l Lhlnk you can handle lL.
As an example: Lhere's a plaLeleL dlsorder called 8ernard-Souller whlch we'll Lalk abouL
laLer. ln Lhls dlsorder, paLlenLs make abnormal C lb (Lhe plaLeleL recepLor LhaL blnds von
Wlllebrand facLor).
When you do a plaLeleL aggregaLlon sLudy on Lhese paLlenLs, Lhelr plaLeleLs respond
normally Lo every aggregaLlng agenL excepL one: rlsLoceLln.
1haL's because rlsLoceLln works by maklng plaLeleLs express Lhelr C lb recepLors.

age 17 of 32
|ate|et-r|ch human p|asma before (L) and after (k) add|t|on of AD
./!(#0(123 4$+5 6!7!5(8!-)
9:( 1(4# *!-1 !% 5;$7< =(&-;%( #:( ,1-#(1(#% -$( %;%,("8(8 !" #:( ,1-%5->
9:( $!?:# *!-1 &+"#-!"% 1!##1( &1;5,% +4 ,1-#(1(#% .#:(< 1++7 1!7( 1!##1( 41-7(%@
A:!&: 4+$5(8 !" $(%,+"%( #+ #:( -88!#!+" +4 B/C> D+#( #:-# #:( $!?:# *!-1 !%
1(%% #;$=!8E #:!% 8(&$(-%( !" #;$=!8!#< !% A:-# !% 5(-%;$(8 !" #:( ,1-#(1(#
-??$(?-#!+" -%%-<> F+#: *!-1% :-*( <(11+A 5-?"(#!& %#!$$($% -# #:( =+##+5>

So you can glve all Lhe rlsLoceLln you wanL Lo plaLeleLs from paLlenLs wlLh 8ernard-Souller,
and Lhe plaLeleLs [usL won'L aggregaLe properly (because Lhey can'L express normal C lb).
von Wlllebrand dlsease, lncldenLally, has Lhe same paLLern, [usL for a dlfferenL reason. ln
vWu, Lhe paLlenL has no vWl (or lL's very abnormal). So you can mlx Lhese plaLeleLs wlLh
rlsLoceLln, and Lhey wlll go ahead and express Lhelr llLLle C lb recepLors, buL Lhere's no
normal vWl around...so Lhe plaLeleLs won'L aggregaLe.
Whew, LhaL's enough. ?ou can come back Lo hls a llLLle laLer, and lL wlll make more sense
Lhen. now back Lo our regularly-scheduled programmlng.

age 18 of 32
CoagulaLlon facLor LesLs
1hese LesLs measure how long lL Lakes Lo make flbrln. 1here are several LesLs, each of whlch sLarL
aL a dlfferenL polnL ln Lhe coagulaLlon cascade (so you can Lell where Lhe problem ls). ?ou'll use
Lhese LesLs a loL when you're on Lhe wards (and ln cllnlc). ?ou'll use Lhe 11 and ln8 so frequenLly
LhaL you'll Lalk abouL Lhem ln your sleep.
Most coagu|at|on tests are done ||ke th|s:
uraw Lhe paLlenL's blood lnLo a speclal Lube (conLalnlng clLraLe, whlch blnds Lhe calclum ln
Lhe blood sample Lo prevenL Lhe blood from cloLLlng).
8ack ln Lhe lab, spln Lhe Lube ln a cenLrlfuge, and decanL Lhe plasma (whlch ls [usL serum
plus coagulaLlon facLors).
uL Lhe paLlenL's plasma ln a LesL Lube and add reagenL.
Measure how long lL Lakes Lhe paLlenL's blood Lo form flbrln.
rothromb|n t|me (or prot|me) (1)
What are the |ngred|ents?
aLlenL plasma
1hromboplasLln (a Llssue-facLor-llke reagenL)
Calclum
What does the 1 measure?
1hls LesL lnlLlaLes coagulaLlon along Lhe exLrlnslc paLhway (Lhrough Lhe addlLlon of a Llssue-
facLor-llke subsLance Lo Lhe LesL Lube).
So, lL measures Lhe exLrlnslc paLhway (baslcally, facLor vll). lL also measures Lhe common
paLhway (facLors x, v, ll and flbrlnogen).
1he 1 doesn'L measure Lhe paLlenL's Llssue facLor! 1haL's why lL's called Lhe exLrlnslc"
paLhway - you have Lo add an exLrlnslc Lhlng (Llssue-facLor-llke subsLance) Lo Lhe LesL Lube
Lo geL Lhe LesL Lo go.
What's the dea| w|th factor VII?
lL's made by Lhe llver
lL needs vlLamln k for acLlvaLlon
lLs synLhesls ls lnhlblLed by coumadln (warfarln)
lL has a %:+$# half-llfe (lL doesn'L Lake long Lo depleLe your facLor vll sLores!)
What makes the 1 go up (or put another way, what "pro|ongs" the 1)?
ueflclency or lnhlblLlon of any of Lhe facLors ln Lhe exLrlnslc paLhway (vll) or Lhe common
paLhway (x, v, ll, and/or flbrlnogen). Some causes: llver dlsease, vlLamln k deflclency, and
lnhlblLors" or anLl-phosphollpld anLlbodles, whlch we'll Lalk abouL ln a mlnuLe.
Coumadln (whlch affecLs facLors ln all Lhree paLhways - ll, vll, lx, x).
Peparln, Lo some exLenL (whlch affecLs facLors ln all Lhree paLhways: lla, vlla, lxa, xa, and
xla).
ulC (whlch screws everyLhlng up).

age 19 of 32
When shou|d you order a 1?
never (Lrlck quesLlon)! lL's obsoleLe! 1here was so much varlablllLy beLween dlfferenL
reagenLs and lnsLrumenLs LhaL Lhe reference range was way Loo dlfferenL from lab Lo lab -
lL's llke Lhere wasn'L any way Lo be conslsLenL and lnLerpreL Lhe resulLs.
8uL.you sLlll need Lo undersLand Lhe 1, so you can undersLand (and order) Lhe ln8.
All LhaL belng sald, you'll sLlll see Lhls LesL ordered as a 1/ln8...even Lhough people only
look aL Lhe ln8 parL (see nexL).
Internat|ona| norma||zed rat|o (INk)
Ckay, so what's an INk?
lL's [usL a 1 LhaL's been maLhemaLlcally correcLed Lo accounL for dlfferences beLween
laboraLorles.
1he 1 ls a preLLy annoylng LesL, because a paLlenL could geL a 1 ln one hosplLal, and Lhen
go Lo anoLher hosplLal down Lhe sLreeL, and Lhe 1 would be LoLally dlfferenL (because Lhe
sLupld LhromboplasLln varles so much beLween manufacLurers). So Lhe resulLs of Lhe 1
were really only useful wlLhln each parLlcular hosplLal.
1o flnd ouL whaL Lhe ln8 ls, you do a 1 (add LhromboplasLln and calclum Lo Lhe paLlenL's
blood), and Lhen you plug Lhe resulL lnLo a formula, whlch splLs ouL Lhe ln8.
1haL's cool, because now everyone ls uslng Lhe same scale of measuremenL. My ln8 aL SL.
Mary's, for example, would be Lhe same as my ln8 done aL SL. Luke's.
now we can use sLandards LhaL apply Lo everyone, no maLLer where Lhey goL Lhelr LesL
done! When someone has a LhromboLlc Lendency, for example, Lhe sLandard of care ls Lo
keep Lhelr ln8 (wherever lL's performed) beLween 2 and 3.
When shou|d you order an INk?
1o assess a paLlenL's coagulaLlon sLaLus (e.g., ln unexplalned bleedlng, ln ulC, or afLer loLs
of Lransfuslons)
1o monlLor coumadln Lherapy. 1he ln8 ls Lhe besL LesL for monlLorlng coumadln (beLLer
Lhan Lhe 11, whlch we'll Lalk abouL nexL). 1haL's because Lhe flrsL facLor Lo become
depleLed afLer coumadln admlnlsLraLlon ls facLor vll. So you wanL a LesL LhaL measures
facLor vll, because LhaL LesL wlll be Lhe mosL senslLlve. A LesL LhaL only measured Lhe oLher
(longer-half-llfe) vlLamln k dependenL coagulaLlon facLors wouldn'L be as useful - because
by Lhe Llme #:-# LesL became abnormal, Lhe paLlenL would be aL greaL rlsk of bleedlng!
When you are assesslng llver funcLlon/damage (acuLe hepaLlLls, aceLamlnophen overdose)
Maybe as an hosplLal admlsslon or pre-operaLlve screen (especlally lf paLlenL ls on
coumadln or has a bleedlng hlsLory)

art|a| thrombop|ast|n t|me (11)
aLlenL plasma
hosphollpld exLracL
Calclum
What's the !"#$%!#&' part|a| thrombop|ast|n t|me (A11)?
1he A11 ls [usL llke Lhe 11, wlLh Lhe addlLlon of an acLlvaLlng agenL. 1hls makes Lhe
reacLlon go fasLer ln Lhe laboraLory lnsLrumenL.
1he Lerms A11" and 11" are ofLen used lnLerchangeably. uon'L worry abouL Lhls.

age 20 of 32
Why |s |t ca||ed the part|a| thrombop|ast|n t|me, when there's no thrombop|ast|n |n |t? Are these
peop|e sad|st|c?
?es, Lhey are sadlsLlc.
lL's called Lhe ,-$#!-1 LhromboplasLln Llme because way back when Lhey were creaLlng Lhls
LesL, Lhey flgured ouL LhaL lf you [usL added a parL of LhromboplasLln Lo a LesL Lube, you
could acLlvaLe flbrln formaLlon. lL Lurns ouL LhaL Lhe parL Lhey were addlng was [usL
phosphollpld, and LhaL LhromboplasLln lLself conslsLs of boLh phosphollpld and Llssue
facLor.
1he 11 lnlLlaLes coagulaLlon along Lhe lnLrlnslc paLhway (Lhrough Lhe addlLlon of [usL
phosphollpld and calclum).
CoagulaLlon won'L occur along Lhe exLrlnslc paLhway ln Lhls LesL, because Lhere's no Llssue
facLor (or Llssue-facLor-llke reagenL) ln Lhe LesL Lube.
So, Lhls LesL measures Lhe lnLrlnslc paLhway (facLors xl, lx, and vlll) and Lhe common
paLhway (facLors x, v, ll, and flbrlnogen)
1haL's why Lhe lnLrlnslc paLhway ls named LhaL way, Lo acLlvaLe Lhe paLhway, you don'L
need Lo add anyLhlng exLrlnslc" Lo Lhe blood! (?eah, you add phosphollpld - buL LhaL's ln
normal blood already, ln plaLeleLs, so you're [usL addlng lL back Lo Lhe LesL Lube.)
What makes the 11 go up (or, what "pro|ongs" the 11)?
ueflclency or lnhlblLlon of facLors ln elLher Lhe lnLrlnslc or Lhe common paLhway (so facLors
xl, lx, vlll, x, v, ll, and/or flbrlnogen). Some causes: hemophllla, von Wlllebrand dlsease
(Lhrough lncreased degradaLlon of facLor vlll - see laLer), llver dlsease, vlLamln k deflclency,
and lnhlblLors" or anLl-phosphollpld anLlbodles (see laLer).
Peparln (whlch affecLs lla, lxa, xa, and xla). 1he 11 ls Lhe besL LesL for heparln monlLorlng,
because alLhough heparln affecLs coagulaLlon facLors on boLh sldes of Lhe paLhway, lL
appears Lo affecL Lhose on Lhe lnLrlnslc slde Lo a greaLer degree.
Coumadln, Lo some exLenL (buL Lhe ln8 ls a beLLer LesL, for Lhe reasons llsLed above. 8y Lhe
Llme Lhe 11 goes up, Lhe paLlenL wlll be very anLlcoagulaLed, and posslbly aL rlsk of
bleedlng).
ulC (whlch screws everyLhlng up).
When you are assesslng a paLlenL's coagulaLlon sLaLus (e.g., ln unexplalned bleedlng, ln ulC,
or afLer loLs of Lransfuslons)
When you are monlLorlng heparln Lherapy
When you are assesslng llver funcLlon/damage (acuLe hepaLlLls, aceLamlnophen overdose)
Maybe as a pre-operaLlve screen (Lo make sure your paLlenL doesn'L have hemophllla or
von Wlllebrand dlsease before you do surgery)

ou sa|d these tests fa|| |nto the shoe ana|ogy.
1hey do (wlLh a llLLle sLreLch of lmaglnaLlon).
1he slmple LesL (Lhe 1) measures Lhe slmple, eleganL, sexLrlnslc paLhway.
1he complex LesL (Lhe 11, whlch ls way more complex Lhan Lhe 1 because lL has Lhree
leLLers lnsLead of Lwo) measures Lhe complex, Lacky, slnLrlnslc paLhway.

age 21 of 32
11 m|x|ng study
aLlenL plasma
ooled human plasma
hosphollpld exLracL (11 reagenL)
Calclum
What's the "m|x|ng" part for?
1hls LesL ls baslcally [usL a regular old 11 LesL - wlLh a bunch of pooled human plasma
Lhrown ln Lhe Lube Loo.
So you're 5!)!"? Lhe paLlenL's (probably abnormal) plasma wlLh some pooled (hopefully
normal) plasma, and Lhen runnlng a 11 LesL, and seelng whaL Lhe new 11 value ls.
Why wou|d you want to do that?
1o dlfferenLlaLe beLween Lhe Lwo maln causes of a prolonged 11 (wlLh a normal 11 - see
below for whaL Lhe 11 measures): facLor deflclency or one of Lhese lnhlblLors" LhaL we
keep menLlonlng.
lf Lhe new 11 value ls wlLhln Lhe normal range (lf Lhe 11 correcLs"), Lhen you know Lhe
pooled human plasma musL have supplled someLhlng Lo Lhe paLlenL's plasma Lo make lL
cloL normally. (1he someLhlng" ls usually a coagulaLlon facLor LhaL Lhe paLlenL ls mlsslng.)
lf Lhe new 11 value ls sLlll abnormal (lf Lhe 11 ls sLlll prolonged, and doesn'L correcL"),
Lhen you know LhaL even Lhough you added a bunch of normal plasma Lo Lhe mlx, Lhe
paLlenL's plasma sLlll couldn'L cloL normally. 1here musL be some oLher problem wlLh Lhe
paLlenL's plasma. (1he oLher problem" ls usually an lnhlblLor.)
When shou|d you order a 11 m|x|ng study?
when Lhe 11 ls prolonged buL Lhe 11 ls normal...
.Lhe 11 mlxlng sLudy wlll help you narrow down your dlagnosls Lo (1) a coagulaLlon facLor
deflclency or (2) an lnhlblLor.

1hromb|n t|me (11)
aLlenL plasma
1hrombln
1he converslon of flbrlnogen Lo flbrln. 1he lasL polnL ln Lhe common paLhway. 1haL's lL.
When you add Lhrombln Lo plasma, flbrlnogen ls converLed Lo flbrln (bypasslng Lhe lnLrlnslc
and exLrlnslc paLhways).
What makes the 11 go up?
llbrlnogen deflclency (quanLlLaLlve or quallLaLlve)
1he presence of lus (whlch lnhlblL Lhe converslon of flbrlnogen Lo flbrln)
Peparln (whlch wlll lnacLlvaLe Lhe Lhrombln LhaL you add Lo Lhe paLlenL's sample)
When a paLlenL has a prolonged 11, and you wanL Lo look for a flbrlnogen problem
When you are monlLorlng heparln Lherapy

age 22 of 32
I|br|n Degradat|on roducts (ID) Assay
What does an ID assay measure?
llbrln degradaLlon producLs (lus), whlch are Lhe resulL of Lhe breakdown of flbrln (ln a
cloL) by plasmln.
unforLunaLely, Lhe same end producLs (lus) are formed when plasmln clrculaLes ln Lhe
blood and breaks down flbrln+?(" (Lhls happens all Lhe Llme aL a very low raLe, and does
noL mean LhaL Lhe paLlenL has a cloL).
lorLunaLely, Lhere ls a speclal klnd of lu LhaL ls only formed by breaklng down cloLs. lL ls
called a u-dlmer, and lL ls Lhe resulL of Lhe breakdown of &$+%%1!"7(8 flbrln (whlch ls only ln
cloLs!) by plasmln. lf you see u-dlmers floaLlng around, you know LhaL somewhere, Lhere ls
a cloL LhaL ls belng broken down.
What causes IDs to go up?
Any klnd of abnormal LhromboLlc sLaLe, llke dlssemlnaLed lnLravascular coagulaLlon (ulC),
pulmonary embolus (L), or deep venous Lhrombosls (uv1).
unforLunaLely - or maybe forLunaLely - Lhls LesL ls very very senslLlve. lL can deLecL Lhe
mosL mlnuLe levels of flbrln degradaLlon producLs (lncludlng u-dlmers) ln blood.
When shou|d you order an ID assay?
Clad you asked. Slnce Lhls LesL ls sooooo senslLlve, lL's noL a good LesL for provlng LhaL a
paLlenL uCLS have an abnormal cloL (llke a pulmonary embolus or a deep venous
Lhrombosls). lf Lhe LesL ls poslLlve, you can'L be sure LhaL Lhe paLlenL has a cloL (because
even normal, physlologlc cloLLlng can make your lus go up).
8uL, slnce Lhls LesL ls sooooo senslLlve, lL's a greaL LesL for provlng LhaL a paLlenL uCLS nC1
have an abnormal cloL! lf Lhe LesL ls negaLlve, you can be preLLy sure Lhe paLlenL does noL
have a cloL. lL's used qulLe a blL ln L8s Lo rule ouL pulmonary embollsm.

I|br|nogen Assay
What's f|br|nogen aga|n?
llbrlnogen ls Lhe flnal coagulaLlon facLor way aL Lhe boLLom of Lhe cascade. lL's Lhe
precursor Lo flbrln.
lL's made by Lhe llver, and ls rapldly depleLed durlng cloLLlng.
What causes the f|br|nogen |eve| to go down?
ln rlp-roarlng ulC (dlssemlnaLed lnLravascular coagulaLlon), Lhe flbrlnogen level ofLen goes
down (flbrlnogen geLs used up maklng all Lhose cloLs).
Powever, slnce flbrlnogen ls an acuLe phase reacLanL, a paLlenL can be ln florld ulC and sLlll
have a normal flbrlnogen level.

age 23 of 32
When shou|d you order a f|br|nogen assay?
When you're evaluaLlng a paLlenL for ulC (whlle reallzlng LhaL a normal flbrlnogen level
does noL rule ouL ulC).
When you're masslvely Lransfuslng a paLlenL (because when someone comes ln wlLh a
masslve blood loss - say, from a bad car accldenL - you generally don'L use whole blood, you
use a comblnaLlon of blood producLs, sLarLlng wlLh red cells, and addlng fresh frozen
plasma as necessary.
lf you're noL careful wlLh your comblnaLlon of replacemenL producLs, you mlghL upseL Lhe
coagulaLlon/anLl-coagulaLlon balance, and Lhe paLlenL's flbrlnogen could geL dlluLed,
puLLlng hlm/her aL rlsk for bleedlng. So generally you'll order a flbrlnogen level now and
Lhen when you're masslvely Lransfuslng someone.

I'm exhausted. Iust g|ve me a qu|ck summary.
11 = lnLrlnslc paLhway
1/ln8 = exLrlnslc paLhway
11 mlxlng LesL = 11 wlLh paLlenL blood plus pooled plasma
11 = flbrlnogen Lo flbrln
lu/u-dlmer = measures lus/u-dlmers
llbrlnogen = measures flbrlnogen

I'm even more exhausted now. kem|nd me why I wou|d order these tests.
11: 1o measure a paLlenL's general coagulaLlon sLaLus, Lo check Lhe lnLrlnslc paLhway ln
parLlcular, Lo monlLor llver funcLlon, Lo monlLor heparln.
1/ln8: 1o measure a paLlenL's general coagulaLlon sLaLus, Lo check Lhe exLrlnslc paLhway
ln parLlcular, Lo monlLor llver funcLlon, Lo monlLor Coumadln.
11 mlxlng LesL: ln a paLlenL wlLh a prolonged 11 (buL a normal 11), Lo flgure ouL wheLher
Lhe problem ls a facLor deflclency or an lnhlblLor.
11: 1o look for a flbrlnogen problem, Lo monlLor heparln.
lu/u-dlmer: 1o rule ouL a Lhrombus.
llbrlnogen: 1o monlLor flbrlnogen levels durlng masslve Lransfuslon.

age 24 of 32
Chapter 4: 8|eed|ng d|sorders
Ceneral
8efore we get |nto b|eed|ng d|sorders
1here are loLs of Lhlngs LhaL can make you bleed: vascular dlsorders, LhrombocyLopenla, and
problems wlLh Lhe cloLLlng sysLem. Cur dlscusslon wlll be llmlLed Lo Lhose bleedlng dlsorders
lnvolvlng LhrombocyLopenla and Lhe cloLLlng sysLem. ulsorders resulLlng from LhrombocyLopenla
lnclude ldlopaLhlc LhrombocyLopenlc purpura (l1) and Lhe LhromboLlc mlcroanglopaLhles.
ulsorders lnvolvlng Lhe cloLLlng sysLem can resulL from coagulaLlon abnormallLles (e.g.,
hemophllla), plaLeleL abnormallLles (e.g., 8ernard-Souller), or boLh (e.g., von Wlllebrand dlsease
and dlssemlnaLed lnLravascular coagulaLlon).

C||n|ca| features
1o a cerLaln exLenL, Lhe cllnlcal plcLure (Lhe locaLlon and manner of bleedlng) depends on Lhe
underlylng problem. aLlenLs wlLh LhrombocyLopenla Lend Lo presenL wlLh sponLaneous skln and
mucous membrane bleedlng. normally, Lhe plaLeleLs llnlng Lhe vessel walls provlde a blL of
physlcal proLecLlon agalnsL blood seepage beLween endoLhellal cells. lf Lhere are very few
plaLeleLs around, Lhere ls less proLecLlon, and blood seeps from caplllarles, formlng llLLle red doLs
(or peLechlae).

aLlenLs wlLh coagulaLlon dlsorders Lend Lo bleed afLer a LraumaLlc lncldenL - buL noL rlghL away.
lor example, Lhey'll have Lhelr wlsdom LeeLh pulled, and hours laLer Lhey wlll have excesslve
bleedlng from Lhe surglcal slLe. 1hese paLlenLs can form a plaLeleL plug [usL flne, so rlghL afLer an
ln[ury, Lhey are able Lo achleve hemosLasls. 8uL Lhey are noL able Lo make flbrln well, so Lhe
plaLeleL plug lsn'L sealed up, and lL [usL washes away afLer some Llme. aLlenLs wlLh severe facLor
deflclencles (llke severe hemophllla) bleed lnLo [olnLs and sofL Llssue (Lhey geL large lnLramuscular
bleeds).

llnally, paLlenLs wlLh plaLeleL dlsorders Lend Lo bleed from mucous membranes and skln (Lhey geL
nosebleeds, Cl bleeds, and menorrhagla) wlLh llLLle or no apparenL precedlng Lrauma.

1hose are generallzaLlons, however - Lhere's some crossover of sympLoms, so lL's noL enLlrely
black and whlLe. 1he cllnlcal plcLure [usL polnLs you ln a general dlrecLlon (plaLeleLs vs.
coagulaLlon) so you know how Lo sLarL Lhe workup of your paLlenL.
1hrombocytopen|a
l1
11/PuS

rob|ems w|th c|ott|ng
Coag problems (e.g., hemophllla)
laLeleL problems (e.g., 8ernard-Souller)
8oLh coag and plaLeleL problems (vWu, ulC)

age 23 of 32
8|eed|ng d|sorders
We're golng Lo dlvlde Lhe bleedlng dlsorders lnLo Lwo blg groups: Lhose LhaL are heredlLary, and
Lhose LhaL are acqulred. Some of Lhese are preLLy rare (llke Lhe hemophlllas) buL you obvlously sLlll
need Lo know a blL abouL Lhem. Pere's Lhe ouLllne we'll be followlng:
1. nered|tary b|eed|ng d|sorders
von Wlllebrand dlsease (a dlsorder of boLh plaLeleLs and coagulaLlon)
Pemophllla A (coagulaLlon)
Pemophllla 8 (coagulaLlon)
CLher facLor deflclencles (coagulaLlon)
PeredlLary plaLeleL dlsorders (plaLeleLs)
2. Acqu|red b|eed|ng d|sorders
ulssemlnaLed lnLravascular coagulaLlon (ulC) (plaLeleLs and coagulaLlon)
ldlopaLhlc LhromobocyLopenlc purpura (l1) (LhrombocyLopenla)
1hromboLlc mlcroanglopaLhles: LhromboLlc LhrombocyLopenlc purpura (11) and
hemolyLlc-uremlc syndrome (PuS) (LhrombocyLopenla)
8leedlng caused by deflclency of vlLamln k dependenL facLors (coagulaLlon)
8leedlng assoclaLed wlLh llver fallure (plaLeleLs and coagulaLlon)

age 26 of 32
PeredlLary bleedlng dlsorders
PeredlLary bleedlng dlsorders lnclude coagulaLlon facLor deflclencles and plaLeleL abnormallLles. ln
general, Lhey are less common Lhan acqulred bleedlng dlsorders (alLhough as we'll see nexL, von
Wlllebrand dlsease ls preLLy dang common).
CfLen a good hlsLory wlll ellclL some commenLs from Lhe paLlenL wlLh a heredlLary bleedlng
dlsorder: ?eah, now LhaL you menLlon lL, my slsLer geLs Lhe same nosebleeds l do" or well, my
mom says LhaL my grandfaLher dled when he was really young from some klnd of blood problem."
SomeLlmes, of course, Lhere ls no hlsLory LhaL Lhe paLlenL knows abouL - or Lhe paLlenL ls
unconsclous - so lL's someLhlng you wlll wanL Lo conslder when worklng up any paLlenL wlLh
abnormal bleedlng.

von W|||ebrand D|sease (vWD)
Genera|
1he mosL common heredlLary bleedlng dlsorder (1 ln 100 people, by some esLlmaLes).
AuLosomal domlnanL lnherlLance, usually.
?ou need Lo be aware of Lhls dlsease because lL ls so common! ?ou may never see
someone wlLh hemophllla (whlch happens ln 1 ln 10,000 people), buL you'll for sure see
someone wlLh von Wlllebrand dlsease.
CaLchlng and dlagnoslng Lhls dlsease early can reduce unnecessary procedures (llke
hysLerecLomles for heavy mensLrual flow) and lessen rlsks (llke excesslve bleedlng afLer
LooLh exLracLlons).
1he bas|c prob|em
1here's noL enough von Wlllebrand lacLor (vWl), or Lhe vWl doesn'L funcLlon properly.
1ype 1 vWu (70 of paLlenLs): decreased level of vWl
1ype 2 vWu (23 of paLlenLs): quallLaLlvely abnormal vWl
1ype 3 vWu (3 of paLlenLs): compleLe lack of vWl
What's von W|||ebrand factor aga|n?
von Wlllebrand facLor ls a huge proLeln composed of mulLlmers.
lL ls synLheslzed by megakaryocyLes and endoLhellal cells.
lL glues Lhe plaLeleLs Lo Lhe subendoLhellum.
lL ls Lhe carrler molecule for facLor vlll (free facLor vlll ls desLroyed).
C||n|ca| f|nd|ngs
1he severlLy of bleedlng ls varlable from paLlenL Lo paLlenL.
Some paLlenLs (probably qulLe a few) don'L have any sympLoms aL all.
1yplcal vWu bleedlng lncludes:
! plaLeleL-Lype" bleedlng - heavy menses (>24 pads/Lampons a monLh), mucous
membrane bleedlng (e.g., nosebleeds), excesslve blood loss from Llny cuLs, easy
brulslng.
! facLor-Lype" bleedlng - laLe posL-operaLlve hemorrhage, [olnL bleedlng (ln severe
cases).
aLlenLs wlLh very severe (Lype 3) vWu may also show facLor-deflclency-Lype bleedlng, such
as bleedlng lnLo large [olnLs. 1hls ls because vWl ls Lhe carrler molecule for facLor vlll - so lf
you don'L have any vWl around, you're noL golng Lo have much vlable facLor vlll around.

age 27 of 32
Laboratory tests
1he bleedlng Llme ls prolonged (LhaL's Lhe whole polnL: you need vWl Lo blnd plaLeleLs Lo
endoLhellal cells).
1he ln8 ls normal (because Lhe exLrlnslc sysLem ls worklng flne)
1he 11 ls usually prolonged (because of Lhe whole facLor vlll Lhlng), and lL correcLs" when
you do a 11 mlxlng sLudy (because Lhe pooled plasma should have a normal amounL of
facLor vlll ln lL).
1o conflrm your dlagnosls, you can order some fancy LesLs llke:
! a vWl level (low ln Lype 1, absenL ln Lype 3, normal ln Lype 2)
! plaLeleL aggregaLlon sLudles (abnormal)

1reatment
uuAv (desmopressln) - sLlmulaLes vWl (and facLor vlll) release from paLlenL's endoLhellal
cells. 1hls ls a common and easlly-admlnlsLered LreaLmenL (lL's a nasal spray).
CryopreclplLaLe - Lhls ls a creamy whlLe blood producL LhaL comes ln a Llny pouch. lL
conLalns plasma proLelns (lncludlng facLor vlll and vWl) from a slngle human donor. lf you
need a loL, order a 6-pack (serlously).
lacLor vlll concenLraLe - Lhls can be real facLor vlll from pooled human plasma (noL so
good, because you worry abouL lnfecLlous dlseases) or fake facLor vlll from a drug company
(a beLLer ldea, made uslng monoclonal anLlbodles and speclal unA Lechnlques).

nemoph|||a A
Genera|
1he mosL common coagulaLlon facLor deflclency.
x-llnked recesslve lnherlLance, usually (abouL 30 of paLlenLs have a sponLaneous
muLaLlon).
Cueen vlcLorla (8rlLlsh soverelgn from 1837 unLll her deaLh ln 1901) had hemophllla and
passed lL on Lo Lhree of her chlldren: one affecLed son (Leopold) and Lwo carrler daughLers
(Allce and 8eaLrlce). Allce and 8eaLrlce ln Lurn passed Lhe gene on Lo Lhelr chlldren, and
Lhrough Lhese descendanLs, Lhe dlsease proved dlsasLrous for several of Lhe royal houses of
Lurope. Check ouL Lhe sLory of Lhe mad monk" 8aspuLln, who was consulLed by Allx, wlfe
of Lhe 8usslan Czar nlcholas ll, for LreaLmenL of Lhelr affecLed son, Alexls. CerLaln people
dldn'L llke Lhe monk's lnfluence on Lhe 8oyal famlly, and Lhls may have conLrlbuLed Lo Lhe
evenLual murder of Lhe enLlre famlly ln 1917.
Anyway. Cne more lnLeresLlng facL, and Lhen we move on Lo Lhe dlsease. Cueen vlcLorla
had no known famlly hlsLory of Lhe dlsease - so she may have been one of Lhe 30 of
paLlenLs ln whlch a sponLaneous muLaLlon ls Lhe cause of Lhe dlsease.

1he bas|c prob|em
lacLor vlll ls decreased or LoLally absenL.
1he facLor vlll gene (aL Lhe end of Lhe long arm of Lhe x chromosome) ls muLaLed.

What's factor VIII good for?
lL's one of Lhe lmporLanL coagulaLlon facLors ln Lhe lnLrlnslc coagulaLlon paLhway (on Lhe
lefL-hand slde of Lhe llLLle coagulaLlon cascade lmprlnLed on your braln).

age 28 of 32
ueen V|ctor|a, r|nce A|bert and the|r ch||dren
C+$#$-!# =< G$-"0 H-*($ 6!"#($:-1#($ !" IJK2>

C||n|ca| f|nd|ngs
ulsease severlLy depends on how much facLor vlll Lhe paLlenL can make.
1yplcal bleedlng ln hemophllla lncludes recurrenL, palnful bleedlng lnLo [olnLs followlng
some sorL of Lrauma, prolonged bleedlng afLer denLal exLracLlons, and sponLaneous
mucosal hemorrhage.
lf dlsease ls severe or unLreaLed, [olnL deformlLy or dlsablllLy can resulL.

Laboratory tests
1he 11 ls prolonged, and lL correcLs" when you do a 11 mlxlng sLudy (Why? lf you need
Lo, go back and read abouL Lhe 11 mlxlng sLudy).
1he ln8, 11, plaLeleL counL, and bleedlng Llme are normal.
Pey walL, Lhe bleedlng Llme ls normal?
?es! 1he bleedlng Llme ls normal. 1haL's because Lhe bleedlng Llme CnL? measures Lhe
plaLeleL response Lo ln[ury, noL Lhe coagulaLlon cascade. Seems welrd, buL lL's Lrue. 1hls ls
llkely because paLlenLs wlLh hemophllla can make a plaLeleL plug [usL flne (so Lhey sLop
bleedlng normally afLer Lhe bleedlng Llme lnclslon) - buL Lhey can'L make flbrln Lo seal up
LhaL plug (so Lhey wlll llkely bleed aL some polnL laLer on, afLer Lhey've lefL Lhe laboraLory).
Same prlnclple as laLe bleedlng followlng Lrauma or surglcal procedures.
1o conflrm your dlagnosls, order quanLlLaLlve and quallLaLlve facLor vlll assays.
ulagnose Lhe carrler sLaLe uslng unA LesLlng.
1reatment
aLlenLs wlLh mlld hemophllla (who can make a llLLle facLor vlll on Lhelr own) can use
uuAv (desmopressln), whlch sLlmulaLes Lhe paLlenL's endoLhellal cells Lo release facLor
vlll (along wlLh vWl).
aLlenLs wlLh severe hemophllla (who can'L make any facLor vlll aL all) need facLor vlll
replacemenL. ?ou wanL Lo glve as llLLle of Lhls as you can, because some paLlenLs wlll sLarL
maklng anLlbodles Lo facLor vlll (and Lhen you have Lo glve a Lon of facLor vlll Lo geL any
response).

age 29 of 32
nemoph|||a 8
Genera|
lnherlLance paLLern ls Lhe same as LhaL of hemophllla A.
Much less common Lhan hemophllla A.

1he bas|c prob|em
lacLor lx ls decreased or LoLally absenL.
lL's klnd of nlce LhaL Lhey named Lhem Lhls way: hemophllla A ls facLor vlll, and hemophllla
8 ls facLor lx.
1he facLor lx gene (locaLed nexL Lo Lhe facLor vlll gene) ls muLaLed.

What's factor Ik good for?
lL's one of Lhe lmporLanL coagulaLlon facLors ln Lhe lnLrlnslc coagulaLlon paLhway (on Lhe
lefL-hand slde of Lhe llLLle coagulaLlon cascade lmprlnLed on your braln).

C||n|ca| f|nd|ngs
Same as Lhose of hemophllla A.
Laboratory tests
Same ln8, 11, 11 and bleedlng Llme resulLs as ln hemophllla A.
1he only way Lo Lell hemophllla A and 8 aparL ls by dolng facLor vlll and lx assays (and
geneLlc LesLs).
1reatment
8ecomblnanL facLor lx concenLraLe.

Cther factor def|c|enc|es
ueflclencles of facLors oLher Lhan vlll and lx are very rare!
Iactor kI deflclency ls seen malnly ln Ashkenazl !ews, and usually causes excess bleedlng
only afLer Lrauma (such as surgery).
Iactor kIII deflclency causes a severe bleedlng Lendency (usually presenLlng wlLh umblllcal
sLump bleedlng). lL has a normal 11! 1haL's because facLor xlll crossllnks flbrln molecules
wlLhln Lhe cloL, lL really has noLhlng Lo do wlLh flbrln formaLlon. So lL's noL measured by Lhe
11 or Lhe ln8.

age 30 of 32
nered|tary p|ate|et d|sorders
1hese are dang rare. So why are we coverlng Lhem? 1wo reasons:
1. 1hey have shown up on n8ML parL 1. l know, rlghL? 8ldlculous.
2. Several Llmes afLer lecLurlng on Lhls, someone has sald, l [usL had a paLlenL wlLh 8ernard-
Souller!" or one of Lhe oLhers. So...wheLher someLhlng ls rare or noL, lL happens (and Lo Lhe
paLlenL who has lL, lL doesn'L maLLer how rare lL ls).
8ernard-Sou||er syndrome
AuLosomal recesslve lnherlLance
aLlenLs have an abnormallLy of glycoproLeln lb (whlch blnds von Wlllebrand facLor), so
Lhelr plaLeleLs can'L blnd Lo Lhe subendoLhellum
ClanL plaLeleLs
Severe bleedlng
G|anzmann thrombasthen|a
AuLosomal recesslve lnherlLance
aLlenLs have an abnormallLy or absence of glycoproLeln ll8-llla (whlch blnds flbrlnogen), so
Lhelr plaLeleLs don'L aggregaLe
Severe bleedlng
Gray p|ate|et syndrome
laLeleLs have few or no o granules (hence Lhey look empLy, or gray)
ClanL plaLeleLs
Mlld bleedlng
granu|e def|c|ency
laLeleLs have few or no granules (Lhese aren'L really vlslble by llghL mlcroscopy anyway)
lsolaLed, or parL of a syndrome (llke Chedlak-Plgashl)

age 31 of 32
Acqulred bleedlng dlsorders
Acqulred bleedlng dlsorders are more common Lhan heredlLary bleedlng dlsorders. unllke
heredlLary bleedlng dlsorders, Lhey lnvolve mulLlple facLor deflclencles.

D|ssem|nated |ntravascu|ar coagu|at|on (DIC)
Genera|
ulC ls a Lhrombo-hemorrhaglc (cloLLlng and bleedlng) dlsorder LhaL occurs as a
compllcaLlon of loLs of dlfferenL condlLlons.
SomeLhlng (see below) Lrlggers Lhe coagulaLlon sysLem, resulLlng ln loLs of llLLle flbrln cloLs
(whlch enLrap plaLeleLs) LhroughouL Lhe body.
1hese llLLle cloLs (or mlcroLhrombl) do bad Lhlngs: Lhey snag and desLroy red blood cells
(causlng a hemolyLlc anemla) and occlude small vessels (causlng Llssue hypoxla and
lnfarcLlon).
All Lhls rampanL cloLLlng uses up Lhe plaLeleLs and coagulaLlon facLors, causlng bleedlng.
1o make maLLers worse, as Lhe body Lrles Lo lyse Lhe cloLs, flbrln ls broken down lnLo flbrln
degradaLlon producLs (whlch Lhemselves lnhlblL cloLLlng and aggravaLe Lhe bleedlng
problem).

What k|nds of th|ngs make a person go |nto DIC?
1. 1hlngs LhaL dump procoagulanL subsLances lnLo Lhe blood
obsLeLrlc compllcaLlons (abrupLlon, amnloLlc fluld embollsm)
adenocarclnoma (especlally really muclnous ones, llke pancreaLlc adenocarclnoma)
venomous snake blLes
acuLe promyelocyLlc leukemla
2. 1hlngs LhaL damage endoLhellum or Llssue
severe, gram-negaLlve, Loxln-produclng bacLerlal lnfecLlon
Lrauma or Lhermal burns
vascullLls (llke sysLemlc lupus eryLhemaLosus)

now am I supposed to remember a|| those th|ngs?
?ou'll do well lf you remember Lhe four Lhlngs LhaL cause mosL cases of ulC (8eally! LlsLed Lhls
way, Lhey spell mosL!"):
mallgnancy
obsLeLrlc compllcaLlons
sepsls
Lrauma

ALLendlng: 1ell me Lhe four mosL common causes of ulC."
SLudenL (leL's see...M.C.S.1...M.C.S.1...): Mallgnancy, C8 compllcaLlons, sepsls, and Lrauma."
ALLendlng: l'm so lmpressed. nlce [ob. Lvery sLudenL should be as smarL as you."

age 32 of 32
C||n|ca| f|nd|ngs
1. CnseL may be fulmlnanL (e.g., sepsls) or lnsldlous (e.g., adenocarclnoma)
2. SympLoms are ofLen ln many organ sysLems:
resplraLory sysLem (dyspnea, cyanosls)
nervous sysLem (selzures, coma)
renal sysLem (ollgurla, acuLe renal fallure)
vascular sysLem (clrculaLory fallure, shock)
3. Slgns of bleedlng and Lhrombosls:
bleedlng from venlpuncLure slLes or surglcal wounds
Cl, lung, or obsLeLrlcal bleedlng
peLechlae
gangrene

Laboratory tests
1. CoagulaLlon LesLs
1he ln8, 11, 11 and flbrlnogen level are prolonged (because all facLors are depleLed)
llbrln degradaLlon producLs are lncreased (because of all Lhe cloLLlng golng on)
2. 8lood smear
1he plaLeleL counL ls low.
lragmenLed red blood cells (schlsLocyLes) are presenL, Lhls ls called a mlcroanglopaLhlc
hemolyLlc anemla (MAPA) because Lhe red cells are desLroyed ln small (mlcro) vessels.
1he severlLy of ulC ls reflecLed ln Lhe blood smear! Cllnlclans ofLen order dally blood
smears Lo see lf Lhe number of schlsLocyLes ls Lrendlng up or down.

ALLendlng: lf Mr. !ones really ls ln ulC, whaL should hls blood smear look llke?"
SLudenL: lL wlll show a low plaLeleL counL and also some fragmenLed red cells, or schlsLocyLes. We
can order a smear every day and see lf Lhe number of schlsLocyLes ls golng up or down."
ALLendlng: ?es, LhaL's Lrue. Man, where dld you Lraln? ?ou're brllllanL! 1he resL of you, Lake
noLe."

1reatment
1. llrsL of all, you need Lo dlagnose and LreaL Lhe underlylng cause of Lhe ulC as besL as you can.
2. Whlle you're dolng LhaL, you can supporL Lhe paLlenL wlLh:
fresh frozen plasma (ll) - Lhls conLalns coagulaLlon facLors
cryopreclplLaLe - Lhls conLalns flbrlnogen
plaLeleLs
red cells

age 33 of 32
Id|opath|c thrombocytopen|c purpura (I1)
Genera|
ldlopaLhlc LhrombocyLopenlc purpura - also called lmmune LhrombocyLopenlc purpura - ls
a dlsorder ln whlch Lhe paLlenL makes anLlbodles agalnsL hls/her plaLeleLs, whlch Lhen geL
eaLen up by macrophages.
lL ls dlvlded lnLo chronlc and acuLe forms, each of whlch has lLs own cllnlcal feaLures.
C||n|ca| f|nd|ngs
1. Chronlc l1
MosL common ln adulL women <40.
rlmary (unrelaLed Lo any known rlsk facLors) or secondary (occurrlng ln Lhe seLLlng of
oLher condlLlons, such as lupus, Plv, or chronlc lymphocyLlc leukemla).
CnseL ofLen lnsldlous. SympLoms lnclude bleedlng lnLo skln and mucosal surfaces
(peLechlae), nosebleeds, easy brulslng, melena, hemaLurla, and excesslve mensLrual flow.
uanger: subarachnold hemorrhage and lnLracerebral hemorrhage (rare ln LreaLed paLlenLs
Lhough).
2. AcuLe l1
MosL common ln chlldren.
AbrupL onseL, usually follows a vlral lllness.
Self-llmlLlng ln mosL cases.
ln abouL 20 of chlldren, Lhough, lL may perslsL and resemble chronlc l1.
athogenes|s
AuLo-anLlbodles Lo plaLeleL membrane glycoproLelns llb-llla, or lb-lx.
1hese anLl-plaLeleL anLlbodles blnd Lo plaLeleLs, maklng Lhe plaLeleLs yummy Lo phagocyLes.
MosL of Lhe eaLlng happens ln Lhe spleen (lf you Lake ouL Lhe spleen, Lhe sympLoms usually
go away).
Laboratory tests
1. llndlngs lndlcaLlng plaLeleL desLrucLlon lnclude:
Low plaLeleL counL.
normal/lncreased megakaryocyLes ln bone marrow.
Large plaLeleLs ln blood (megakaryocyLes are Lrylng so hard Lo make plaLeleLs fasL LhaL Lhey
end up maklng blg ones).
2. ln8/11 are normal! (because Lhls ls [usL a plaLeleL problem)
3. 1here ls no speclflc lab LesL Lo ,$+*( LhaL Lhe paLlenL has l1. lL ls a dlagnosls of excluslon, only
call lL l1 afLer rullng ouL oLher causes of LhrombocyLopenla, such as:
urug effecL
AplasLlc anemla
8one marrow replacemenL (e.g., by Lumor)
8lg spleen
non-lmmune-relaLed plaLeleL desLrucLlon (e.g., ulC, 11, PuS)
1reatment
MosL paLlenLs respond Lo glucocorLlcolds (whlch lnhlblL phagocyLe funcLlon).
ln paLlenLs who relapse, splenecLomy ofLen normallzes Lhe plaLeleL counL. lf LhaL doesn'L
work, Lry lmmunomodulaLory agenLs (llke lv lg or anLl-Cu20).

age 34 of 32
11
MAPA
1hrombocyLopenla
lever
1ranslenL neurologlc deflclLs
8enal fallure

nUS
MAPA
1hrombocyLopenla
More common ln chlldren

1hrombot|c m|croang|opath|es
Genera|
1hromboLlc mlcroanglopaLhy" encompasses a bunch of cllnlcal syndromes, Lhe mosL
common of whlch are LhromboLlc LhrombocyLopenlc purpura (11) and hemolyLlc-uremlc
syndrome (PuS).
1he def|n|t|on for these d|seases are sh|ft|ng
1. Crlglnal deflnlLlons:

2. lL's noL so sLralghLforward Lhough. We now know:
11: paLlenLs may lack one or more of Lhe flve crlLerla.
PuS: some paLlenLs have fever, neurologlc dysfuncLlon, and/or renal fallure.
3. lL's someLlmes hard Lo Lell wheLher a paLlenL has 11 or PuS!
Cause
1hromboLlc mlcroanglopaLhy ls caused by Lhlngs (see Lrlggers," below) LhaL acLlvaLe
plaLeleLs.
1he plaLeleLs clump LogeLher formlng Lhrombl LhaL geL sLuck ln Llny vessels. 1hls leads Lo
MAPA and wldespread organ dysfuncLlon. 1o make maLLers worse, consumpLlon of
plaLeleLs leads Lo LhrombocyLopenla.
noLe: LhromboLlc mlcroanglopaLhy has a dlfferenL paLhogenesls Lhan ulC! Whlle boLh have
slmllar feaLures (mlcroLhrombl and MAPA), ln ulC Lhe problem ls acLlvaLlon of coagulaLlon
(so Lhe ln8 and 11 are prolonged), buL ln LhromboLlc mlcroanglopaLhles, Lhe problem ls
plaLeleL clumplng (so Lhe ln8 and 11 are normal!). Pere's a llLLle summary of Lhe lab LesLs
ln 11/PuS and ulC (leL's Lhrow ln l1, hemophllla and vWu [usL for Lhe hell of lL):

ALLendlng: Can anyone Lell me how you would use Lhe ln8 and 11 Lo evaluaLe paLlenLs wlLh a
mlcroanglopaLhlc hemolyLlc anemla?"
SLudenL: Well, ln ulC, Lhe paLlenL ls consumlng coagulaLlon facLors, so Lhe ln8 and 11 are boLh
prolonged. 8uL Lhere are also oLher causes of mlcroanglopaLhlc hemolyLlc anemla. ln 11 and PuS,
for example, Lhe problem ls noL really a coagulaLlon problem, buL a plaLeleL problem...so Lhe ln8
and 11 are normal."
ALLendlng: Wlll you marry me?"
SLudenL: l'll Lhlnk abouL lL. LeL's flnlsh roundlng flrsL."

age 33 of 32
1r|ggers
1. 11
ueflclency of a plasma enzyme called AuAM1S13 ( also called vWl meLalloproLease).
PeredlLary (paLlenLs lnherlL an lnacLlvaLlng muLaLlon ln AuAM1S13) or acqulred (paLlenLs
develop an AuAM1S13-lnhlblLlng auLoanLlbody).
AuAM1S13 normally degrades very hlgh-molecular-welghL mulLlmers of von Wlllebrand
facLor.
1hese are acLually called MulLlmers of ulLra-large Slze, or MCuS. 8emember rlncess
8rlde? Wesley ls aLLacked by menaclng rodenLs of unusual slze, or 8CuS, ln Lhe flre swamp.
klnda slmllar Lo Lhe MCuS ln 11 - blg, honklng, dangerous Lhlngs Lo be avolded aL all cosLs.
WlLhouL AuAM1S13, mulLlmers accumulaLe and Lrlgger plaLeleL acLlvaLlon and aggregaLlon.
?ou probably need some oLher, addlLlonal endoLhellal ln[ury for 11 Lo occur (because
people wlLh heredlLary AuAM1S13 deflclency don'L always geL 11).

2. PuS
Lpldemlc, Lyplcal" PuS
! AssoclaLed wlLh gasLroenLerlLls caused by L. coll C137:P7.
! L. coll C137:P7 makes a nasLy Loxln LhaL ls absorbed from guL lnLo blood.
! 1oxln ln[ures endoLhellal cells and Lrlggers plaLeleL acLlvaLlon.
non-epldemlc, aLyplcal" PuS
! AssoclaLed wlLh defecLs ln complemenL facLor P, membrane cofacLor proLeln (Cu46) or
facLor l (proLelns LhaL normally keep Lhe alLernaLlve complemenL paLhway ln check).
! lnherlLed (varlous defecLs) or acqulred (lnhlblLory auLoanLlbodles).
! unclear how Lhese defecLs Lrlgger plaLeleL acLlvaLlon.

k.C.U.S from r|ncess 8r|de
B =!?L %&-$< #:!"? #+ =( -*+!8(8 -# -11 &+%#%>

age 36 of 32
Don't eat th|s!
M(=-"(%( %#(-7 #-$#-$( =< %#;N%,!*-&7L 4$+5 41!&7$

C||n|ca| f|nd|ngs
1. 11
1he classlc penLad of flndlngs ls llsLed above. Pere are Lhe sympLoms:
1. blood ln urlne, [aundlce (from Lhe MAPA)
2. bleedlng, brulslng (from severe LhrombocyLopenla)
3. fever (Pere's a llLLle secreL: you can always say cyLoklne release" or lnflammaLlon"
when you don'L know Lhe exacL cause of someLhlng)
4. blzarre behavlor, alLered menLal sLaLus, headache (from mlcroLhrombl ln Lhe CnS)
3. decreased urlne ouLpuL (from renal fallure)
aLlenLs may also have oLher sympLoms (besldes Lhose ln Lhe CnS and kldney) relaLed Lo
Lhe deposlLlon of mlcroLhrombl, any organ (hearL, Cl, oLhers) can be affecLed.
aLlenLs do nC1 have Lo have Lhe enLlre penLad Lo be dlagnosed wlLh 11! ln facL, mosL
paLlenLs are mlsslng one or more of Lhe flndlngs.
2. PuS
Lpldemlc PuS
! Chlldren and elderly are aL hlghesL rlsk.
! ConLamlnaLed food (raw hamburger, splnach) ls usually Lhe culprlL.
! Classlc sympLoms: bloody dlarrhea, followed a few days laLer by renal fallure. neurologlc
sympLoms and fever are rare.
! aLlenLs can recover wlLh supporLlve care, buL lrreverslble renal damage and deaLh
occur ln more severe cases.

f

non-epldemlc PuS
! SympLoms are Lhe same as ln epldemlc PuS, buL wlLhouL Lhe dlarrhea.
! 1he dlsease course ls relapslng-remlLLlng.

1reatment
1. 11
lasmapheresls (Lo geL rld of Lhe anLlbodles) ls useful ln cases of acqulred 11.
CLher lmmunosuppresslve drugs (llke sLerolds) can help Loo.
aLlenLs wlLh heredlLary 11 are ofLen glven plasma every few weeks Lo replace Lhelr
AuAM1S13.
2. PuS
aLlenLs wlLh PuS are LreaLed supporLlvely (dlalysls, eLc.).
lf you're noL sure wheLher lL's PuS or 11 (ofLen, lL's hard Lo Lell Lhe dlfference!) you can do
plasmapheresls for a whlle unLll you flgure lL ouL.

age 37 of 32
Lat th|s!
9;"- 5;1#! ?$(("% %-1-8 =< O-$< B""( P"$!Q;(0L 4$+5 41!&7$

Cther acqu|red b|eed|ng d|sorders
8|eed|ng caused by def|c|ency or abnorma||ty of v|tam|n k dependent factors
1. vlLamln k dependenL facLors: ll, vll, lx, x, and proLelns C and S (Lhese guys all need Lo be
y-carboxylaLed by vlLamln k ln order Lo funcLlon).
2. Causes:
Coumadln (Lhls causes a 4;"&#!+"-1 abnormallLy of vlLamln k dependenL facLors. 1he
Q;-"#!#< of ll, vll, lx, x, and proLeln C and S ls normal - buL Lhe quallLy ls abnormal).
oor dleL (?ou geL vlLamln k from green leafy veggles and bacLerlal synLhesls of vlLamln k ln
Lhe guL. LaL your veggles.).
MalabsorpLlon (Lhlngs affecLlng absorpLlon: blllary obsLrucLlon, pancreaLlc dlsease, small
bowel dlsease).
rolonged LreaLmenL wlLh anLlbloLlcs (much of our vlLamln k ls synLheslzed by our guL
bacLerla!)
Pemorrhaglc dlsease of Lhe newborn (newborns lack colonlzaLlon of Lhe bowel - so Lhey geL
a shoL of vlLamln k aL blrLh Lo Llde Lhem over. WlLhouL Lhe shoL, Lhey can bleed durlng Lhls
perlod of Llme.)

8|eed|ng assoc|ated w|th ||ver fa||ure
1here are 1+#% of reasons LhaL paLlenLs ln llver fallure bleed!
8lllary obsLrucLlon causes lmpalred absorpLlon of vlLamln k, and Lherefore decreased
synLhesls of vlLamln k-dependenL coagulaLlon facLors.
1he llver makes mosL of Lhe coagulaLlon facLors. lf llver dlsease ls really severe, Lhe
hepaLocyLes wlll make less - or dysfuncLlonal - coagulaLlon facLors.
orLal hyperLenslon causes hypersplenlsm. WlLh splenlc sequesLraLlon of plaLeleLs, Lhe
plaLeleL counL decreases.
uecreased LhrombopoleLln producLlon by Lhe llver conLrlbuLes Lo Lhe low plaLeleL counL.

age 38 of 32
kudo|f V|rchow
/$-A!"? =< M(%1!( 6-$8 !" R-"!#< G-!$L IJST>

Chapter S: 1hrombot|c d|sorders
Ceneral
8efore we get |nto thrombot|c d|sorders
?ou'll be seelng loLs of paLlenLs wlLh Lhromboembollc evenLs. usually Lhese Lake Lhe form of deep
venous Lhrombl (ln Lhe velns of Lhe leg) or pulmonary emboll. 1he lncldence of Lhrombosls goes up
wlLh age, and wlLh Lhe presence of cerLaln rlsk facLors (whlch we'll Lalk abouL). Cne of Lhose rlsk
facLors ls Lhe presence of a LhromboLlc dlsorder (of whlch Lhere are several Lypes, as you'll see ln a
mlnuLe).

!usL Lo glve you some perspecLlve: mosL paLlenLs who develop Lhrombl do "+# have a LhromboLlc
dlsorder. usually, Lhe Lhrombus ls due Lo a consLellaLlon of rlsk facLors (for example, obeslLy plus
smoklng plus oral conLracepLlve use). So when a paLlenL comes ln wlLh a Lhrombus, you wouldn'L
wanL Lo sLarL worklng Lhem up by looklng for rare LhromboLlc dlsorders rlghL away, you'd sLarL by
looklng for common rlsk facLors. lf Lhere aren'L any, Lhough, or lf Lhere are oLher welrd flndlngs
(see below), LhaL's when you should sLarL looklng for a LhromboLlc dlsorder.

kudo|f V|rchow
lf you haven'L already read abouL 8udolf vlrchow, you should sLop readlng Lhls sLudy gulde
lmmedlaLely and go look hlm up ln Wlklpedla. l'm noL klddlng. 8udy (l llke Lo call hlm 8udy) was
one of Lhose people ln Lhe 1800s LhaL seemed Lo be able Lo do everyLhlng - and do lL well. Pe was
lnLo anLhropology, hlsLory, blology, pollLlcs, and on Lop of lL all, he was a physlclan. Pe has a
speclal place ln Lhe hearLs of paLhologlsLs as he ls consldered Lhe faLher of paLhology."

age 39 of 32
?ou'll hear hls name a loL as you go Lhrough your Lralnlng: vlrchow's angle, vlrchow's cell Lheory
(whlch dlsproved sponLaneous generaLlon), vlrchow's node, vlrchow's auLopsy meLhod (whlch ls a
nlce meLhod, way beLLer Lhan LhaL ldloL 8oklLansky's), vlrchow-8obln spaces, Lhe llsL goes on and
on.

V|rchow's 1r|ad
Cne of hls areas of dlscovery ls parLlcularly perLlnenL Lo our currenL dlscusslon. 8udy colned Lhe
Lerm embollsm" and Lhen wenL on Lo deflne Lhe causes Lhereof. Pe summarlzed Lhem ln a Lrlad:
1. Lndothe||a| damage
AnyLhlng LhaL rlps up Lhe endoLhellum, as we've dlscussed before, wlll lncrease Lhe chances
of cloL formaLlon.
ALherosclerosls falls lnLo Lhls caLegory, by Lhe way, due Lo Lhe damage LhaL Lhe plaques do
Lo Lhe endoLhellum
2. Abnorma| b|ood f|ow
normally, blood should flow ln a nlce, lamlnar, smooLh fashlon. 1hls keeps Lhe cloLLlng
facLors away from each oLher and from plaLeleLs.
1here are Lwo Lypes of abnormal blood flow LhaL dlsrupL Lhls process: sLasls and
Lurbulence.
ln sLasls, Lhe veloclLy of flow drops Lo a polnL where coagulaLlon facLors can aLLach Lo each
oLher and plaLeleLs, lnlLlaLlng Lhe coagulaLlon cascade.
ln Lurbulence, flow ls chaoLlc, and llLLle eddles form. 8lood ls more sLaLlc ln Lhese areas,
allowlng Lhe facLors and plaLeleLs Lo come lnLo conLacL wlLh each oLher as descrlbed above.
Lxamples of sLasls lnclude varlcose velns, aLrlal flbrlllaLlon (blood collecLs ln Lhe hearL
because lL's noL pumplng unlformly), and prolonged lmmoblllzaLlon (llke ln a plane rlde, or
afLer surgery). 1urbulenL blood flow can occur when Lhere's a congenlLal hearL defecL (e.g.,
cardlac valve sLenosls).
3. nypercoagu|ab|||ty
1here are a bunch of seemlngly unrelaLed rlsk facLors LhaL fall lnLo Lhls caLegory, such as
smoklng, oral conLracepLlve use and adenocarclnoma (because Lhe mucln ln Lhe Lumor cells
ls a pro-coagulanL).
1hromboLlc dlsorders (llke we're Lalklng abouL ln Lhls chapLer) also fall lnLo Lhls parL of
vlrchow's Lrlad.

1he Lrlad ls sLlll a useful and correcL concepL Loday. lf you look aL all Lhe known rlsk facLors for
Lhrombosls (see below), Lhey all fall lnLo one of Lhese Lhree caLegorles. lf you can'L remember all
Lhose rlsk facLors, you can probably remember vlrchow's Lrlad - and from Lhere, you can llsL off a
bunch of Lhlngs LhaL would lncrease your rlsk. 1hanks, 8udy.

age 40 of 32
k|sk factors for thrombos|s
1here are loLs of rlsk facLors for Lhrombosls. MosL of Lhese ln and of Lhemselves are noL Loo
dangerous...buL lf you sLarL Lo geL Lwo or Lhree or more, waLch ouL: Lhe rlsk goes way up.
aLherosclerosls
Lrauma
obeslLy
prolonged lmmoblllzaLlon
varlcose velns
pregnancy
oral conLracepLlve use
myocardlal lnfarcLlon
aLrlal flbrlllaLlon
carclnoma (especlally adenocarclnoma)
smoklng

When shou|d you start worry|ng about a thrombot|c d|sorder?
MosL of Lhe Llme, Lhrombosls ls caused by Lhe presence of Loo many rlsk facLors. SomeLlmes,
Lhough, Lhere ls an underlylng LhromboLlc dlsorder LhaL ls conLrlbuLlng Lo Lhrombosls. ?ou should
conslder Lhe posslblllLy of a LhromboLlc dlsorder ln your paLlenL lf:
oLher famlly members have venous Lhrombosls
Lhe Lhrombosls ls ln a welrd place (normal" places = leg veln, lungs)
your paLlenL has had recurrenL Lhromboses
your paLlenL ls young (<30)
your paLlenL has had mlscarrlages (feLal losses)

1hrombot|c d|sorders
We're golng Lo dlvlde Lhe LhromboLlc dlsorders lnLo Lwo blg groups, [usL llke we dld for bleedlng
dlsorders: Lhose LhaL are heredlLary, and Lhose LhaL are acqulred. MosL of Lhese are preLLy rare,
buL for Lhe reasons we Lalked abouL earller, we sLlll need Lo dlscuss Lhem. 1he one excepLlon ls
lacLor v Lelden, whlch ls surprlslngly common. Pere's Lhe ouLllne we'll be followlng:
1. nered|tary thrombot|c d|sorders
lacLor v Lelden
AnLlLhrombln lll deflclency
roLeln C (Lhe anLl-cloLLlng 8aLman) deflclency
roLeln S (Lhe anLl-cloLLlng 8obln) deflclency
lacLor ll (proLhrombln) gene muLaLlon
PyperhomocysLelnemla
2. Acqu|red thrombot|c d|sorders
AnLlphosphollpld anLlbody syndrome

age 41 of 32
1he Cude k|[n ("C|d kh|ne") w|th drawbr|dge
M(!8("L D(#:($1-"8%
PeredlLary LhromboLlc dlsorders
SomeLlmes, as menLloned before, paLlenLs have Lhromboses LhaL seem Lo come ouL of Lhe blue. ln
Lhe pasL, paLlenLs llke Lhls would undergo Lons of dlfferenL LesLs - buL a slgnlflcanL number would
noL be dlagnosed wlLh any LhromboLlc dlsorder aL all. 1haL's frusLraLlng. 1hen a new dlsorder
called lacLor v Lelden was dlscovered, and lL Lurned ouL Lo be responslble for a loL of Lhese
prevlously-unexplalned Lhromboses. lf you could only learn abouL one heredlLary LhromboLlc
dlsorder, lacLor v Lelden would be Lhe one.
Iactor V Le|den
What's factor V Le|den?
lL's a sllghLly dlfferenL facLor v molecule, whlch ls Lhe producL of a facLor v gene wlLh a
slngle polnL muLaLlon.
lacLor v Lelden ls almosL ldenLlcal Lo normal facLor v. 1he only dlfference ls LhaL Lhere ls a
gluLamlne lnsLead of an arglnlne aL poslLlon 306 (vlrLually all paLlenLs wlLh Lhe dlsease have
Lhls muLaLlon - a few oLher muLaLlons have been descrlbed buL Lhey are rare).
lL's close enough ln sLrucLure Lo normal facLor v LhaL lL can parLlclpaLe ln Lhe coagulaLlon
cascade.
.buL dlfferenL enough LhaL ,$+#(!" U &-"V# &1(-*( !# (and Lurn lL off)!
So, coagulaLlon proceeds along lLs merry way wlLh one less naLural anLl-coagulanL Lo keep lL
ln check.
Lelden" ls for Lhe clLy ln Lhe neLherlands where Lhe muLaLlon was flrsL dlscovered.

C. WhaL's acLlvaLed proLeln C reslsLance?
A. lL's when proLeln C (afLer belng acLlvaLed) ls unable Lo cleave facLor v. 1here are loLs of causes
of acLlvaLed proLeln C reslsLance - buL lacLor v Lelden ls by far Lhe mosL common.

age 42 of 32
now common |s the factor V Le|den mutat|on?
AbouL half of Lhe paLlenLs wlLh unexplalned" Lhrombosls - LhaL ls, Lhrombosls occurrlng ln
Lhe absence of known rlsk facLors - Lurn ouL Lo have facLor v Lelden.
AbouL 3 of Caucaslans carry Lhe muLaLlon. no, LhaL's noL a Lypo: lL's really 3. eople of
Aslan, naLlve Amerlcan, or Afrlcan descenL are very unllkely Lo carry lL.
What |s the r|sk of gett|ng a bad c|ot |f you have the mutat|on?
PeLerozygoLes have a Lhrombosls rlsk LhaL ls 7 Llmes normal.
PomozygoLes have a Lhrombosls rlsk LhaL ls 80 Llmes normal.
1he lncldence of deep venous Lhrombosls ln Lhe general populaLlon ls acLually preLLy small. lf you
ad[usL for age and sex, Lhe annual lncldence ls somewhere around 120 people per 100,000. 1haL
number lncreases wlLh age, and overall lL's sllghLly hlgher ln men Lhan ln women. SLlll: LhaL puLs
Lhlngs lnLo perspecLlve. lf you have a rlsk of Lhrombosls LhaL's double Lhe normal rlsk, LhaL sounds
really scary - buL ln reallLy, your rlsk ls sLlll very low, slnce Lhe normal rlsk ls very very low.
now do you d|agnose factor V Le|den?
1he ln8 and 11 are normal ln Lhese paLlenLs (Can you explaln why? lf noL, drop us an
emall aL paLhology[aLhologySLudenL.com.), so Lhese LesLs don'L help you.
?ou need Lo order geneLlc LesLlng (sounds compllcaLed, buL lL's noL. lL's a cheap C8 LesL
LhaL's becomlng more and more common Lhese days). 1hls wlll Lell you lf your paLlenL has
Lhe facLor v Lelden muLaLlon, and as a bonus, you'll flnd ouL wheLher your paLlenL ls
homozygous or heLerozygous.
now do you treat pat|ents w|th the factor V Le|den mutat|on?
ln general, paLlenLs wlLh facLor v Lelden (even homozygoLes!) should "+# be LreaLed unless
Lhey have had a Lhrombosls.
Coumadln ls Lhe only Lhlng you can really glve Lhese paLlenLs. 1haL, and Lell Lhem Lo avold
all Lhe rlsk facLors Lhey can.

Ant|thromb|n III def|c|ency
What |s ant|thromb|n III aga|n?
lL's a naLural anLlcoagulanL LhaL lnhlblLs Lhe serlne proLeases (lla, vlla, lxa, xa, xla, xlla), Lhus
lnhlblLlng all Lhree paLhways. Peparln poLenLlaLes lLs acLlon.

What |s wrong w|th the ant|thromb|n gene |n th|s d|sorder?
LoLs of dlfferenL muLaLlons have been descrlbed, each wlLh lLs own rlsk of Lhrombosls (compare
Lhls Lo facLor v Lelden, ln whlch vlrLually all paLlenLs have Lhe exacL same muLaLlon).

now common |s ant|thromb|n III def|c|ency?
lL's a $-$- -*!%. AbouL 0.03 of Lhe general populaLlon has anLlLhrombln lll deflclency.

age 43 of 32
What |s the r|sk of gett|ng a bad c|ot |f you have |t?
8lg! AbouL half of heLerozygous paLlenLs wlLh Lhls dlsorder wlll develop a Lhrombus - and
many have recurrenL Lhromboses. PomozygoslLy ls lncompaLlble wlLh llfe.
Peparln doesn'L work ln Lhese paLlenLs (why?) - so anLlLhrombln concenLraLes are used
lnsLead.

now do you d|agnose ant|thromb|n III def|c|ency?
1he besL meLhod ls funcLlonal LesLlng - whlch Lells you lf Lhe paLlenL's anLlLhrombln lll ls
worklng (and wheLher Lhere's enough of lL around).
AnLlLhrombln lll funcLlonal LesLlng ls done by addlng a known amounL of Lhrombln Lo Lhe
paLlenL's plasma, and Lhen measurlng Lhe Lhrombln acLlvlLy. ln normal paLlenLs, Lhe
Lhrombln acLlvlLy decreases. ln paLlenLs wlLh anLlLhrombln lll deflclency, Lhe Lhrombln
acLlvlLy remalns Lhe same (because Lhere's noL enough anLlLhrombln lll Lo lnhlblL
Lhrombln).
lL's besL Lo do Lhls LesL when Lhe paLlenL ls noL acLlvely cloLLlng or on anLlcoagulanL Lherapy,
because Lhese Lhlngs can Lemporarlly change Lhe level of anLlLhrombln lll. Whlch makes lL
klnda hard Lo flnd a good Llme Lo schedule Lhls LesL.

rote|n C def|c|ency
What |s prote|n C aga|n?
lL's a naLural anLlcoagulanL LhaL lnacLlvaLes facLors v and vlll, Lhereby shuLLlng down cloLLlng. lL
works wlLh proLeln S Lo do Lhls.

What's wrong w|th the prote|n C gene |n th|s d|sorder?
Llke anLlLhrombln lll deflclency, proLeln C deflclency can be caused by many dlfferenL muLaLlons ln
Lhe proLeln C gene.

now common |s prote|n C def|c|ency?
lL's anoLher $-$- -*!%. AbouL 0.2 of Lhe general populaLlon ls heLerozygous for Lhe proLeln C
muLaLlon.

Pomozygous humans have noL been reporLed. 1hey llkely aborL sponLaneously durlng
gesLaLlon.
ln addlLlon Lo Lhe rlsk of Lhrombosls, paLlenLs also have a rlsk of skln manlfesLaLlons:
warfarln (coumadln)-lnduced skln necrosls and purpura fulmlnans.

C. WhaL's warfarln-lnduced skln necrosls?
A. Warfarln-lnduced skln necrosls ls a nasLy problem LhaL happens Lo people wlLh prevlously-
undlagnosed proLeln C deflclency. Pere's how lL happens:
ln addlLlon Lo maklng facLors ll, vll, lx and x nonfuncLlonal (by lnhlblLlng Lhelr acLlvaLlon by
epoxlde reducLase), warfarln (Coumadln) also lnhlblLs proLelns C and S acLlvaLlon.
lL Lurns ouL LhaL proLeln C has a super shorL half-llfe (shorLer Lhan any of Lhe oLher facLors -
even facLor vll). So proLeln C becomes non-funcLlonal flrsL, before any of Lhe oLher facLors.

age 44 of 32
Whlch means LhaL rlghL afLer Coumadln admlnlsLraLlon, paLlenLs are acLually a blL
hypercoagulable.
WlLhln a few days, Lhe oLher facLors are lnhlblLed, Llpplng Lhe balance ln favor of
anLlcoagulaLlon.
lor mosL paLlenLs, Lhe lnlLlal hypercoagulable sLaLe doesn'L manlfesL cllnlcally (glvlng a llLLle
heparln ln Lhe beglnnlng ls noL a bad ldea, Lhough, because LhaL should Lake care of any
hypercoagulablllLy durlng Lhose flrsL few days).
lor paLlenLs wlLh proLeln C deflclency, however, LhaL lnlLlal proLeln C lnhlblLlon ls
dangerous (slnce Lhelr proLeln C levels are already really low). lL can manlfesL as
wldespread cloLLlng LhaL for some reason shows up mosL ln Lhe skln (wlLh purpura and
necrosls).
C. WhaL's purpura fulmlnans?
A. lL's a slmllar slLuaLlon - wldespread coagulaLlon wlLh purpura and skln necrosls. lL ls mosL
common ln bables and small chlldren, and lL ls usually assoclaLed wlLh severe lnfecLlon (ofLen
wlLh a gram-negaLlve organlsm). lL ls an acuLe and llfe-LhreaLenlng condlLlon LhaL requlres
aggresslve LreaLmenL.
now do you d|agnose prote|n C def|c|ency?
1he besL meLhod ls funcLlonal LesLlng - whlch Lells you lf Lhe paLlenL's proLeln C ls worklng
(and wheLher Lhere's enough of lL around).
lL's besL Lo do Lhls LesL when Lhe paLlenL ls noL acLlvely cloLLlng or on anLlcoagulanL Lherapy,
because Lhese Lhlngs can Lemporarlly change Lhe level of proLeln C. So llke anLlLhrombln lll
LesLlng, lL can be a llLLle Lrlcky Lo geL Lhe paLlenL ln Lhe rlghL condlLlon for Lhe LesL.

rote|n S def|c|ency
What |s prote|n S aga|n?
lL's a cofacLor for proLeln C. lL helps proLeln C lnacLlvaLe facLors v and vlll, Lhereby shuLLlng down
cloLLlng.
What's wrong w|th the prote|n S gene |n th|s d|sorder?
1here are many dlfferenL muLaLlons ln Lhe proLeln S gene LhaL can lead Lo proLeln S deflclency.
now common |s prote|n S def|c|ency?
roLeln S deflclency ls an W=($ $-$- -*!% (how's LhaL for mlxlng languages?). lL's even more rare
Lhan proLeln C deflclency - buL Lhe exacL lncldence ln Lhe general populaLlon ls noL known.
Pomozygous lnfanLs are aL rlsk for geLLlng purpura fulmlnans.
now do you d|agnose prote|n S def|c|ency?
Same sLory as for anLlLhrombln lll and proLeln C: funcLlonal LesLlng.
Same caveaLs apply: you can'L be sure of LesL resulLs when Lhe paLlenL ls acLlvely cloLLlng or
on anLlcoagulanL meds.

age 43 of 32
Iactor II (prothromb|n) gene mutat|on
What's wrong w|th the factor II gene |n th|s d|sorder?
ln Lhls dlsorder, Lhere ls a gene muLaLlon LhaL causes Lhe producLlon of ()&(%% proLhrombln! 1he
proLhrombln lLself ls normal ln sLrucLure and funcLlon, Lhough. lL's [usL LhaL Lhere's Loo much of lL.
now common |s the factor II mutat|on?
AbouL 3 of Caucaslans carry Lhe muLaLlon.
eople of Aslan, naLlve Amerlcan, or Afrlcan descenL are very unllkely Lo carry lL.
What |s the r|sk of gett|ng a bad c|ot |f you have the mutat|on?
PomozygoLes have a Lhrombosls rlsk LhaL ls 20 Llmes normal.
now do you d|agnose the factor II gene mutat|on?
1here ls a C8 LesL, llke ln facLor v Lelden.
nyperhomocyste|nem|a
What's homocyste|ne aga|n?
PomocysLelne ls made from dleLary meLhlonlne. lL's lmporLanL ln malnLalnlng myelln, and lL ls
essenLlal for Lhe converslon of dleLary folaLe lnLo Lhe form of folaLe LhaL parLlclpaLes ln unA
synLhesls. Check ouL Lhe 812/folaLe/homocysLelne/meLhlonlne dlagram below. ?ou've seen before
ln blochem (shudder) and wlll no doubL see agaln, ln dlfferenL lLeraLlons, ln oLher courses. lL shows
how meLhlonlne (whlch comes from your dleL) ls Lurned lnLo homocysLelne, some of whlch geLs
meLabollzed lnLo cysLaLhlonlne and some of whlch geLs recycled lnLo meLhlonlne (wlLh Lhe help of
812 and folaLe).

age 46 of 32
So how do you get hyperhomocyste|nem|a?
Classlc homocysLeln;$!- ls a rare auLosomal recesslve dlsorder caused by a deflclency ln Lhe
cysLaLhlonlne beLa synLhase (so homocysLelne doesn'L geL broken down lnLo
cysLaLhlonlne). lL Lurns ouL LhaL Lhese paLlenLs geL vascular dlsease and Lhrombosls aL a
much earller age, and Lo a greaLer exLenL, Lhan paLlenLs wlLhouL homocysLelnurla. lL's
LhoughL LhaL Lhe vascular dlsease/Lhrombosls ls caused by Lhe hlgh homocysLelne levels -
buL lL hasn'L been deflnlLlvely proven.
8uL you can geL elevaLed levels of homocysLelne by oLher means:
! Some people have muLaLed meLhyl LeLrahydrofolaLe reducLase gene (Lhe gene LhaL
produces Lhe enzyme wlLh Lhe unforLunaLe abbrevlaLlon M1Pl8). Luropeans, Mlddle
LasLerners, and !apanese paLlenLs have Lhe hlghesL carrler raLes. 1hls muLaLlon can
obsLrucL Lhe normal folaLe cycle, leadlng Lo mlld homocysLelnemla.
! uleLary deflclencles of folaLe, 812, and 86 can also lead Lo mlld homocysLelnemla.

What's so bad about hav|ng hyperhomocyste|nem|a?
PyperhomocysLelnemla appears Lo be assoclaLed wlLh a greaLer rlsk of Lhrombosls and
aLherosclerosls (leadlng Lo arLerlal and venous Lhromboses, myocardlal lnfarcLlon, and
sLroke).
LxacL mechanlsms are noL clear, buL lL ls known LhaL Loo much homocysLelne can have bad
effecLs on hemosLasls (by causlng Llssue facLor expresslon) and vessel walls (by causlng
lnLlmal Lhlckenlng).

What |s the r|sk for gett|ng a bad c|ot |f you have |t?
1he rlsk for venous Lhrombosls ls 2.3 Llmes normal.
1he rlsk for myocardlal lnfarcLlon ls 10 Llmes normal.

now do you d|agnose hyperhomocyste|nem|a?
Measure Lhe plasma level of homocysLelne (homozygoLes have very hlgh levels, buL
heLerozygoLes or paLlenLs wlLh dleLary deflclencles may have only sllghLly elevaLed or even
normal levels).
1here ls a C8 LesL for Lhe M1Pl8 gene muLaLlon (expenslve, buL dlagnosLlc).
?ou mlghL also wanL Lo look for folaLe deflclency (uslng serum and red cell folaLe levels)
and 812 deflclency (uslng meLhylmalonlc acld levels).

age 47 of 32
Acqulred LhromboLlc dlsorders
1he mosL lmporLanL acqulred LhromboLlc dlsorder ls Lhe anLlphosphollpld anLlbody syndrome.
Ant|phospho||p|d ant|body syndrome
What are ant|phospho||p|d ant|bod|es?
AuLoanLlbodles ln Lhe paLlenL's plasma LhaL are dlrecLed agalnsL varlous phosphollplds.
1hese auLoanLlbodles also [usL happen Lo blnd Lo Lhe phosphollpld parL of Lhe 11 reagenL
(and, someLlmes, Lhe 1 reagenL). 1hen Lhere's noL enough usable reagenL ln Lhe LesL Lube,
and Lhe paLlenL's speclmen doesn'L cloL. 1he reacLlon ls Lherefore 4-1%(1< prolonged, maklng
one Lhlnk Lhe paLlenL has a bleedlng Lendency (Lhough Lhls would noL flL Lhe cllnlcal
plcLure). 8emember: LreaL Lhe paLlenL, noL Lhe laboraLory values!
8y Lhe way, Lhese anLlbodles can also blnd Lo Lhe reagenL ln Lhe syphllls LesL, causlng a false
poslLlve resulL.
1hey are someLlmes called lnhlblLors" because Lhey appear Lo !":!=!# coagulaLlon ln Lhe
LesL Lube.
1he welrd Lhlng ls LhaL !" *!*+, Lhese anLlphosphollpld anLlbodles can acLually cause
Lhrombosls (Lhrough a bunch of dlfferenL proposed mechanlsms). 1haL's a welrd paradox:
paLlenLs look llke Lhey should bleed more easlly (lf you look aL Lhelr 11), buL acLually, Lhey
may be aL lncreased rlsk of Lhrombosls.
1here are a bunch of dlfferenL Lypes of anLlphosphollpld anLlbodles, lncludlng
anLlcardlollpln anLlbodles, anLl-2-glycoproLeln anLlbodles, and lupus anLlcoagulanLs (whlch
were dlscovered ln paLlenLs wlLh lupus).
now do you get these ant|phospho||p|d ant|bod|es? Are they dangerous?
Chlldren someLlmes develop Lhem afLer an lnfecLlon. ln Lhls seLLlng, Lhe rlsk of Lhrombosls
ls only sllghLly lncreased.
AdulLs someLlmes develop Lhem as parL of an auLolmmune dlsorder, llke lupus (ln facL,
anLlphosphollpld anLlbodles ln whaLever cllnlcal seLLlng are ofLen called lupus lnhlblLors"
or lupus anLlcoagulanLs" because of Lhls assoclaLlon). ln Lhls seLLlng, Lhe rlsk of Lhrombosls
ls moderaLely lncreased.
Llderly adulLs may develop Lhem ln assoclaLlon wlLh drugs. ln Lhls seLLlng, Lhe rlsk of
Lhrombosls ls noL lncreased.
When a paLlenL wlLh an anLlphosphollpld anLlbody has severe consequences, llke recurrenL
mlscarrlage and renal fallure, lL's called anLlphosphollpld anLlbody syndrome.
What do you do |f you th|nk your pat|ent m|ght have an ant|phospho||p|d ant|body?
Crder a 11. lf lL's prolonged, lL should "+# correcL lf you do a 11 mlxlng sLudy (Why? lf
you need a refresher, go back and look aL Lhe 11 mlxlng sLudy ln chapLer 3.)
1he Lrlcky parL ls Lhls: even lf Lhe 11 ls normal, your paLlenL sLlll may have an
anLlphosphollpld anLlbody! 1haL's because Lhe prolongaLlon of Lhe 11 depends on Lhe
parLlcular 11 reagenL your lab ls uslng.
1here are a bunch of oLher, fancy LesLs you can do Lo deLecL anLlphosphollpld anLlbodles.
!usL call Lhe laboraLory and ask Lhem Lo do whaLever LesL Lhey offer.

age 48 of 32
keference
8lood producLs

CoagulaLlon facLors: common names and funcLlons

age 49 of 32
Common abbrevlaLlons

Sources
Pere are some good reference sources for furLher readlng and explanaLlons.
1. Poffbrand A.v. P%%("#!-1 X-(5-#+1+?<. llfLh edlLlon 2006: 8lackwell Sclence, Lngland
2. 8obblns pages 113 - 121 (normal hemosLasls)
3. 8obblns pages 121 - 129 (Lhrombosls and consequences)
4. 8obblns page 666 (lab LesLs)
3. 8obblns pages 667 -674 (bleedlng dlsorders)
lun acLlvlLles
1. uraw ouL your own llLLle map of Lhe coagulaLlon cascade, lncludlng Lhe naLural anLlcoagulanLs,
ln whaLever way makes sense Lo you. lnclude shoes lf you llke. rompLly forgeL Lhls afLer boards.
8edraw lL as an lnLern and puL lL ln Lhe llLLle book you carry ln your whlLe coaL.

age 30 of 32

2. llll ln Lhe followlng Lables:

3. WrlLe down as many rlsk facLors for Lhrombosls as you can Lhlnk of. Co back Lo 8obblns p. 122,
Lable 4-2, and flll ln Lhe ones you mlssed.

age 31 of 32
4. LaL mapo doufu, an anclenL Chlnese longevlLy dlsh LhaL Lurns ouL Lo be an excellenL source of
anLlcoagulanLs (see PammerschmldL u, Szechwan urpura, nL!M 1980, 302(21):1191-3). use as
excuse Lo go unshaven for a week.

Mapo Doufu
x cup drled Lree ear mushrooms plus 1 cup bolllng waLer
3" plece of fresh glnger
8 or more cloves garllc (for a yleld of 2 1bsp. chopped garllc)
3 scalllons
6 fresh waLer chesLnuLs (can subsLlLuLe [lcama)
x lb. ground pork or beef
2 lbs. fresh bean curd, cuL lnLo x" cubes
2 1bsp. soy sauce
1 Lsp. sesame oll
1 1bsp Chlnese rlce wlne or cooklng sherry
2 Lsp. cornsLarch plus x cup waLer, comblned ln a small bowl
6 1bsp. peanuL oll
1 x Lsp. hoL pepper flakes ln oll
1 1bsp. hoL pepper pasLe
2 1bsp. oysLer sauce (opLlonal)
1 Lsp. sugar
anoLher 3 1bsp. soy sauce, plus 1/3 cup waLer
x Lsp. ground, roasLed Szechwan peppercorns
anoLher 1 Lsp. sesame oll
1 Lsp. salL, or Lo LasLe
uL Lhe Lree ears ln a small bowl and pour Lhe bolllng waLer over Lhem. LeL Lhem soak for abouL 13
mlnuLes, unLll Lhey become sofL and gelaLlnous. eel Lhe glnger, Lhen chop lL lnLo Llny pleces,
abouL Lhe slze of a maLch head. Clean Lhe scalllons, Lhen chop Lhem, boLh Lhe whlLe parL and
abouL one-Lhlrd of Lhe green, lnLo pleces sllghLly larger Lhan Lhe glnger, abouL 1/4" ln dlameLer. lf
a food processor ls noL avallable, march-chop Lhe ground meaL for a flner LexLure. Add 1 1bsp. of
Lhe chopped glnger and one scalllon's worLh of Lhe chopped scalllons Lo Lhe ground meaL, along
wlLh Lhe soy sauce, sesame oll, and wlne, and mlx Lhoroughly. lf a food processor ls avallable,
process Lhe glnger, scalllon, ground meaL, soy sauce, sesame oll, and wlne all LogeLher. SeL aslde
Lhe meaL mlxLure for abouL 30 mlnuLes.
eel Lhe garllc, Lhen chop lL coarsely. Comblne lL wlLh Lhe resL of Lhe chopped glnger and mlnce
Lhem LogeLher unLll Lhey reach Lhe conslsLency of a Lhlck pasLe (or use a food processor). Mrs.
Chlang lnslsLs LhaL Lhe flner you chop Lhe garllc and glnger Lhe more lnLeresLlng Lhe flnlshed dlsh
wlll be.
CuL Lhe dark skln off Lhe ouLslde of Lhe waLer chesLnuLs, Lhen chop Lhem lnLo pleces abouL Lhe slze
of a maLch head. uraln Lhe Lree ears, Lhen rlnse Lhem and plck Lhem over carefully Lo remove Lhe
Llny lmpurlLles, llke llLLle pleces of wood, LhaL mlghL sLlll be embedded ln Lhem. 1hen mlnce Lhem
lnLo llLLle pleces Lhe slze of a maLch head.
!usL before you are ready Lo begln cooklng, add Lhe cornsLarch Lo Lhe meaL mlxLure and blend
Lhoroughly. PeaL your wok or pan over a moderaLely hlgh flame for abouL 13 seconds, Lhen add

age 32 of 32
Lhe peanuL oll. lL should be hoL enough Lo cook wlLh when Lhe flrsL small bubbles begln Lo form
and a few small wlsps of smoke appear.

When Lhe oll ls ready, qulckly Lhrow ln Lhe garllc and glnger and vlgorously sLlr-fry Lhem over a
medlum flame for abouL 30 seconds, uslng your cooklng shovel or spoon Lo scoop Lhe lngredlenLs
from Lhe sldes of Lhe pan and Lhen sLlr Lhem around ln Lhe mlddle, so Lhey won'L burn or sLlck.
ConLlnue Lo sLlr-fry whlle you add Lhe hoL pepper flakes ln oll, hoL pepper pasLe, waLer chesLnuLs,
Lree ears, and oysLer sauce. 1hen sLlr-fry for anoLher 30 seconds.
Add Lhe meaL mlxLure and keep sLlrrlng lL as lL cooks, Laklng speclal care Lo break up any large
chunks of meaL LhaL sLlck LogeLher. AfLer Lhe meaL has cooked for abouL 1 mlnuLe and has losL lLs
plnklsh color, Lhrow ln Lhe bean curd and Lhe remalnlng chopped scalllons and sLlr-fry everyLhlng
LogeLher. 1hen add Lhe sugar and sLlr-fry for anoLher 30 seconds.
our ln Lhe 3 1bsp. soy sauce and Lhe 1/3 cup waLer and walL for Lhe llquld Lo boll, Lhen leL Lhe
conLenLs of Lhe pan cook over a moderaLe flame for 2 mlnuLes more. Add Lhe peppercorns and sLlr
Lhoroughly. AL Lhls polnL, deLermlne how much sauce Lhere ls ln Lhe pan. lf Lhe dlsh seems waLery,
you should geL ready Lo add Lhe cornsLarch and waLer mlxLure LhaL you have already prepared. 8uL
lf Lhere does noL seem Lo be much llquld, you won'L need Lhe cornsLarch.
Make sure LhaL you sLlr up Lhe cornsLarch mlxLure before you pour lL lnLo Lhe pan, Lhen sLlr-fry
everyLhlng over a medlum flame for a few seconds unLll Lhe sauce becomes clear and sllghLly
Lhlckened. Add Lhe 1 Lsp. sesame oll and sLlr lL ln Lhoroughly, Lhen, [usL before servlng, LasLe Lhe
dlsh for salL. lL should LasLe sharp and clear, wlLh [usL a hlnL of sweeLness. SLlr ln Lhe 1 Lsp. salL, lf
you wanL, and serve.

net nu Nu (tree ear mushroom)
.&1-<!$*!"? +" G1!&7$@

Clot or Bleed

Încărcat de

Informații document

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

Clot or Bleed

Încărcat de

Drepturi de autor:

Formate disponibile

About th|s gu|de

S-ar putea să vă placă și