HYPOTHALAMUS

Craniopharyngiomas:%growth%retardaJon,%visual%disturbances,%DI%
[adamanJnomatousK%kids;%papillaryKelderly]%

ANTERIOR PITUITARY

Sheehans%(postpartum%necrosis%of%anterior%pituitary):%unable%to%breasceed,%
elevaJon%of%all%hypothalamic%hormones%except%dopamine.%
Empty-Sella-Syndrome:%obese,%mulJparous;%hemorrhage%compresses%pituitary%

!BMR!(!O2!consump7on,!RR,!Temperature)!
!Glycogenolysis,!gluconeogenesis,!lipolysis,!!LDLHR!("!serum!cholesterol)!
!B1R!on!heart!(!CO,!HR,!SV,!contrac7lity)!
!:%1%Hypothyroidism/Hashimotos%[anJKTPO,%Hurthle%cells,%risk%BCL],%Goiter[THYROID'HORMONE'SYNTHESES:!!Na/Iodine'Symport'(TSH!sensi7ve).!!Iodine!diuses!to!apices.!!Thyroperoxidase!
uses!H2O2!(IH!#!I+).!!I+!binds!!tyrosine!residues!on!Thyroglobulin!in!colloid/follicle,!forming!MIT/DIT!(2!DITs=thyroxine/
":%1%Hyperthyroidism/Graves%[exophthalmos,%preJbial%myxedema,%scalloped%colloid]%
T4;!1!DIT!&!1!MIT=!triiodothyronine/T3).!!Endocytosis!of!thyroglobulin.!!Lysosomal!diges7on!(MIT!&!DIT!are!
":-Dequervian%[viral%infecJon%"%painful%enlargement%"%transient%thyrotoxicosis%
":%Toxic%Goiter/Plummer(goiterK"%chronic%involuJon/revoluJon%"%toxic%nodule)-%
deiodinated!for!iodine!recycling,!T3!&!T4!diuse!into!capillary).!!Carried!in!blood!by!TBG!(70%),!transthyre9n!(12%),!
":-Subacute-Lymphocy<c-Thyroidi<s-[painless,%anJKTPO,%transient%thyrotoxicosis%then%hypothyroid]% albumin!(15%).!!Only!free!and!albuminHbound!are!ac7ve.!!Autoregula9on:!high!levels!of!iodine!leads!to!decreased!
Neoplasms:%%Follicular-adenoma-[nodule%w/%capsule]transport!into!thyroid!&!inhibi7on!of!thyroid!peroxidase!(WolHChaiko!Eect).!!Type!1!5!deiodinase!in!most!7ssues,!
Papillary-C-[Psammoma,%Orphan%Annie,%LN%spread]%
type!2!in!pituitary,!type!3!converts!T4#!rT3.!!!Type!3!to!conserve!energy!during!a!fast!(rT3!cannot!!metabolism].!
Follicular-C-[vascular%spread],%Anaplas<c,%%
'

TSH!(Gs)%

High%levels%of%TRH%can%inhibit%
DA,%this%is%why%primary%
hypothyroidism%can%lead%to%
elevated%prolacJn%and%
decreased%libido.%

TRH!(Gq)%

Medullary%C-[CKcell%hyperplasia,%Amyloid,%calcitonin;%MEN2]-

ACTH!(Gs)%

CRH!(Gs)%

Pituitary!
Neoplasms!!can!
cause!bitemporal'
hemianopia''

!:-Cushing-Disease-[corJsol%is%suppressed%by%high%dose%dexamethasone]!:-Nelson-Syndrome-[post%adrenalectomy%pituitary%hyperplasia/adenoma]!:Addisons/1-adrenal-insuciency-[hypoTN,%#Na+,%!K+,%!%pigmentaJon.%%May%be%due%to%
autoimmune%destrucJon,%TB]!:-Small-Cell-Lung-Cancer-[corJsol%not%suppressed%by%high%dose%dexamethasone]!:-XLALD,-stress,-Friedrich-Waterhouse-[bilateral%adrenal%hemorrhage,%Neisseria]%
%
#:-2-Adrenal-insuciency-[no%!%pigmentaJon]#:-Hyperplas<c-Adrenal-Gland-[corJsol%not%suppressed%with%HDKDMS]%
#:-Steroid-use-[+%adrenal%atrophy]-

GHIH'(Gi)%
!Hyperinsulinemia''
"Hyperprolac9nemia''
Absent:!Kallmann!Syndrome'

FSH!(Gs)%
LH!(Gs)%

GnRH!is!low!in!childhood.!!Pulsa7le!
secre7on!begins!preHpuberty!and!is!
regulated!by!the!arcuate!nucleus.!!!
Pulses!#!!GnRH!receptors;!con7nuous!
GnRH!secre7on!downHregulates!receptor.!!
Hyperinsulinemia!!!pulses!(PCOS).!!
Prolac7n!inhibits!secre7on!of!GnRH.!!

!BP!(!1!on!arterioles)!
!Insulin!Resistance!
!Gluconeogenesis,!Lipolysis,!Proteolysis!(!blood!aa)!
"Fibroblast!ac7vity!(striae)!
"Inamma7on/Immune!response!
"Bone!forma7on!
Ac7vates!PNMT!(NE#EPI;!permissive!for!vasoconstric7on)!

Cor9costerone'

GHRH!(Gs)%

21'
PMNT%
Deoxycor9sol' Testosterone'
Epi'

11'
Cor9sol'

Estradiol'

2!(Gs)!Epi>NE!
Dilate!vessels!in!skeletal!muscle!
(1!more!abundant)!
Relax!uterus!
Dilate!bronchus!
!K+!uptake!in!skeletal!muscle!
!glycolysis!in!liver!

GONADS

!:-Prolac<noma,-DA-antagonists-(an<psycho<cs)-

FSH!(Gs)#Granulosa/Sertoli;!Follicle!development/spermatogenesis!(rst!meiosis;!form!2spermatocytes),!aromatase,!
ABP!(keeps!testosterone!in!lumen!of!seminiferous!tubule),!Inhibin!(inhibits!FSH;!FSH!levels!drop!at!end!of!follicular!phase)!
LH!(Gs)#!Theca/Leydig;!Androstendione!&!Testosterone!release!

GH!(JAK2)%

Prolac7n!
!Milk!produc7on!
"ovula7on!&!spermatogenesis!($GnRH)!
"Libido!(excessive!amounts)!

Before'pregnancy:!low!prolac7n!
During'pregnancy:!estrogen!>!prolac7n!>!breast!matura7on!&!lactogenesis!(lacta7on!is!
inhibited!by!!the!high!levels!of!estrogen!&!progesterone!made!by!the!placenta).!
A[er'parturi9on:!estrogen!drops,!prolac7n!will!drop!as!well!unless!s7mulated!by!suckling.!!
May!inhibit!GnRH!leading!to!anovulatory!infer7lity!while!nursing.!!

!:-Acromegaly/Gigan<sm-

[!lipolysis,!"glucose!uptake!(high!GH#!hyperglycema),!!
!gluconeogensis.!!Increases!linear!growth!via!IGFH1!(!aa!uptake)!
(!GH!pulses!during!sleep)]!
MEN2b'(1P,'
2Ms)'GOF%Ret%

POSTERIOR PITUITARY!
Supraop9c:'ADH!(V1%&%V2)%

Pituitary!
Pancreas!
Parathyroid!
Pheochromocytoma!
Medullary!thyroid!carcinoma!
Marfanoid!!
Cynthia'Czawlytko'

Zona%Fasiculata%H#!Cor9sol'(highest%in%morning,%lowest%at%midnight)'

Zona%ReJcularis%#!Androgens'
Medulla!(Chroman!Cells)!#!EPI/NorEPI!(s7m!by!SNS)!

'Prolac9n!(JAK/STAT)%

Tyrosine'
Tyrosine%
Hydroxylase%
DOPA'
Dopa%
Pregnenolone'
Decarboxylase%
3'
Dopamine
Dopamine%
Progesterone'
17' %Khydroxylase%
NorEpi'

Conn-Syndrome:%low%renin%HTN,%hypoK+,%spironolactone%bodies%a^er%HTN%Tx%
Cholesterol'
Hyperaldosteronism%can%also%be%idiopathic%(1-hyperplasia)%or%2%to%!%Renin%(renal-stenosis)%

Dopamine'(Gs/Gi)%

MEN2a'(2Ps,'
1M)'GOF%Ret%

ADRENAL CORTEX

Zona%Glomerulosa#!Aldosterone!(s7mulated!by!Angiotensin!II)!!
!Na/K!pump,!!ENaC!in!principal!cells!of!CT,!!K+!&!H+!excre7on!

Follicular'Phase'(variable):'Pulsa7le!GnRH!s7mulates!FSH!&!LH.!!!LH!
ac7vates!desmolase!on!theca'cells'(cholesterol#!androstendione).!!FSH!
ac7vates!aromatase!in!granulosa!cells!(androstendione!#!estrogen).!
Granulosa!cells!have!no!LDLHR;!androstendione!must!diuse!into!cell.!!
Aldosterone'
Estrogen!is!responsible!for!development!of!genitalia,!breast,!&!female!
fat!distribu7on,!growth!of!follicle,!endometrial!prolifera7on,!
!myometrial!excitability.!!Estrogen!+s!on!granulosa!cells!(!estrogen),!
Pheochromocytoma:-episodic%headache,%sweat,%palpitaJons.%%!VMA.%%Zellballlen.%
Hs!on!GnRH,!FSH!&!LH!un7l!high!levels!#!LH'surge'(ovula9on;!
collagenase!breaks!down!follicle#!WBCs!atracted!#!PGs!#!
contrac7on!#!burst.)!!Fer7liza7on!must!occur!within!24!hours;!implants!
1 (Gq)!NE>Epi!
2!(Gi)!NE>Epi!
1 (Gs)!NE=Epi!
6!days!later.!!FSH!is!not!as!high!as!LH!due!to!Inhibin.''
Luteal'Phase'(14%days):'The!corpus'luteum!expresses!LHHR,!produces!progesterone!(also!
Contract!radial!bers!(dilate/
"presynap7c!NE!release!
+chronotropy!
estrogen!+!inhibin)!which!induces!thick!cervical!secre7ons!to!inhibit!sperm!entry!into!uterus,!!!
mydriais)!
"insulin!release!
+inotropy!
endometrial!vascularity,!!!basal!body!temp.!!If!fer7liza7on!does!not!occur,!
!platelet!aggrega7on!
!!Renin!release!
syncy9otrophoblasts!of!placenta!will!not!secrete!hCG!(which!acts!as!LH)!to!maintain!the!corpus! Constrict!vessels#!!Dias,!BP)!
luteum!(and!thus!progesterone).!!The!corpus!luteum!regresses#!"!progesterone!and!estrogen! (predominant!vasculature!control)!
#!menses!due!to!apoptosis!of!endometrial!cells.!!FSH!&!LH!begin!to!increase!again.!!Menopause! Urinary!reten7on!
is!due!to!loss!of!func7oning!of!ovarian!follicles;!LH!&!FSH!!!due!to!"!Hs.!!
ejacula7on!

GnRH'(Gq)%
PRH'(Gq)'

MEN1'(3Ps)'
LOF%menin%

THYROID

T3>T4!(5Hdeiodinase:!major!product!T4#T3)!

!:-SIADH,-#:-Neurogenic-DI[s7mulated!by!!blood!osmolarity!>280mm,!!
"BV!(atrial!stretch!receptor),!!
"BP!(caro7d/aor7c!baroreceptors]!

Paraventricular:'Oxytocin'(milk!ejec7on!due!

!to!contrac7on!of!myoepithelial!cells!&!uterine!contrac7on)'

MAMMARY GLANDS

LIVER

!IGFH1#!Linear!growth!(RTK/MAPK)%%
[inhibits%GHRH,%induced%GHIH],%
%!AA!uptake!
!Insulin!resistance!

KIDNEY TUBULES
!urine!osmolarity!via!V2R!!!

VESSELS

!vasoconstric7on!via!V1R!

Parathyroid Glands
Calcium!binds!GPCR!(Gi!&!Gq)!
Gi#!inhibit!secre7on!of!PTH!
Gq!#!PLC#!IP3!#!Calcium!channels,!calcium!enters!chief!cells!#!!!
cleavage!of!CHterminal!fragment!of!PTH!which!is!necessary!for!the!PTH!
secretory!process!
Very'low/very'high'magnesium!and!calcitriol!also!inhibit!PTH!secre7on!!
As!calcium!falls,!cAMP!rises!&!more!PTH!is!secreted!
Hyperphosphatemia!can!lead!to!hypocalcemia!via!this!rxn:!!!!!!!!!!!!!!!!!
!!!!!!!(Ca++!+!HPO4H!#!CaHPO4),!thus!sJmulaJng!PTH!release!
Acidemia!#!!!!ionized!calcium!as!more!H+!binds!albumin!(hyperCa+:!
tetany,!prolonged!QT,!abdominal!pain,!anxiety,!stones)!
Alkalemia!#!"ionized!calcium!(hypoCa+:!cramps,!pain,!paresthesia,!
carpopedal!spasm)!!
Squamous%Cell%Carcinoma%of%the%Lung%may%
secrete%PTHrp%"%%hypercalcemia%
PTH'
Gut:!!Calcium!reabsorp7on!from!intes7nes!
Kidney:!!Ca!reabsorp7on!from!DCT,!"Phosphate!reabsorp7on,!ac7vate!1W
Whydroxylase!in!Proximal!Tubules!'
Bone:!s7mulates!osteoblasts!to!make!RANKHL!#!ac7va7on!of!osteoclasts!#!
degrada7on!of!bone!matrix!
Calcitriol!!!calcium!and!phosphate!absorp7on!from!gut!and!resorp7on!
from!bone!(promo7ng!proper!remineraliza7on)!
Calcitonin!is!released!from!parafollicular!C!cells!of!thyroid.!!It!is!s7mulared!
by!high!serum!Ca2+;!"bone!resorp7on.!!

FONDAPARINUX'
is!a!direct!factor!
Xa!inhibitor.!!

FIBRINOLYTIC CASCADE
Activation of the coagulation cascade leads to activation of the fibrinolytic cascade which moderates the size of the
clot. Plasmin breaks down fibrin & interferes with its polymerization. FSPs act as weak anticoagulants. FSPs can
also be diagnostic of abnormal clotting states like DVT, DIC, PE. Fragments of cross-linked insoluble fibrin
monomers are called D-dimers. Plasmin also inactivates Factors 5 & 8. tPA must be bound to fibrin in order to
activate plasminogen to plasmin (this why drugs like alteplase and reteplace are useful; the site of action is
confined to clots). PAI inhibits tPA from binding to fibrin.
2-antiplasmin (made by liver) inactivates plasmin. Prevents excess free plasmin from lysing thrombi
indiscriminately elsewhere in the body (plasmin scavenger).
STREPTOKINASE'&'ANISTREPLASE'
ac7vates!plasminogen!(nonselec7vely),!so!
may!lead!to!bleeding.!!An7genic,!may!
develop!allergic!reac7on.!!UROKINASE'is!
also!a!nonselec7ve!plasmin!ac7vator,!but!
it!is!nonHan7genic.'

#PLATELET'PRODUCTION'
Aplas<c-Anemia-[radiaJon,%
chemo,%HIV,%viral%hepaJJs,%
ParvoB19%infecJon%in%paJents%
with%underlying%anemia:%naked,%
linear%ssDNA%(req.%host%cells%
undergoing%division)%with%tropism%
for%erythroid%precursor%via%P%
globoside%anJgen]%
Bone-Marrow-Inltra<on-[acute%
leukemia,%metastaJc%carcinoma]%
Megakaryocyte-Destruc<on[B12/folate%deciency,%
Alcoholism]-Cynthia'Czawlytko'

ALTEPLASE'Reteplase,'
Tenecteplase'are!tPA!analogs!that!
selec7vely!ac7vate!plasminogen!
when!bound!to!brin!(clot!
specic).!!Shorter!HL,!less!
allergenicity,!and!less!bleeding.!

ATP!
5HT!
ADP!
Epi!
Ca++!
Mg!
histamine!!

GpIIb-IIIa!

Thrombomodulin!
"!
ap-C p-S!

8!
5!
12 # 11 # 9 # 10 # 2 # 1!
TF!
7!

Factor-5-Leiden:-MC%in%European%
populaJons.%%Point%mutaJon%in%F5%
(Arg"%Gln)%in%the%preferred%cleavage%
site%for%aPC;%making%F5%resistant%to%
deacJvaJon%"%!thrombosis.%%

HEPARIN''(parenteral,%short%acJing)%enhances!
ac7vity!of!endogenous!an7thrombin!III![binds!ATIII!
&!inac7vates!factors!2a!&!10a].!DoC!for!ab,!
pregnancy.!!PROTAMINE'SULFATE'is!an7dote/
antagonist.!!Enoxa,!Dalte,!&!Tinza!Hparin!are!LMWH!
which!selec7vely!inhibit!factor!10a.!!LMWH!has!a!
longer!halfHlife!&!lower!risk!of!thrombocytopenia;!
DoC!prophylaxis!of!DVT!(hospital,!bedridden),!
unstable!angina,!acute!MI!

Antithrombin !
+ Heparin!
tPA

PHselec7n! PDGF,!
brinogen,! TGFB,!BH
bronec7n,!thromboglo
Factor!5!&! bulin,!VEGF!
8,!pf4,!

Gray-Platelet-Syndrome:-absent%
alpha%granules.%%Giant%platelets,%
thrombocytopenia,%myelobrosis%in%
some%paJents.%

AGRATROBAN,'Lepiruden'
(IV),'Bivaliruden'(SC)'are!
Direct!Thrombin!Inhibitors.!!
DoC!prophylaxis!and!Tx!
thrombosis!in!pa7ents!with!
HITT!

EPOPROSTENOL,'ILOPROST'are!
PGI2!deriva7ves!
An9W
platelet'

Fibrin !

PAI!

HeparinWInduced-Thrombo<c-Thrombocytopenia-occurs%
following%administraJon%of%unfracJonated%heparin%which%
induces%the%appearance%of%%anJbodies%that%recognize%heparainK
pf4%complexes.%%When%the%anJbodies%bind%to%platelets%"%
acJvaJon,%aggregaJon%&%consumpJon%(prothromboJc%state%
but%thrombocytopenia).%%Must%be%suspected%when%platelets%
drop%(>50%)%in%a%paJent%being%treated%with%heparin%(4K10%days%
post%administraJon)%

!PLATELET'LOSS/DESTRUCTION'
ImmuneKmediated%
ITP:%IgG%against%GpIIb/IIIa%
Neonatal-Alloimmune-Thrombocytopenia:-HPAK1b+%mother%makes%anJbodies%to%HPAK1a%
Alloimmuniza<on:%Red%cell/platelet%transfusions%
Drugs%[Penicillin%(haptenKdep],%Sulfas/Quinine%(haptenKindep),%Amphoterin%
HIV-thrombocytopenia:%HIV%can%infect%megakaryocytes%leading%to%apoptosis.%%HIV%also%causes%BKcell%hyperplasia%
and%prdisposes%to%the%development%of%autoanJbodies.%
NonKimmune%
TTP:%%anJKADAMTS13;%anJbodies%to%this%metalloproteinase%that%is%responsible%for%cleaving%vWF.%vWF%remains%as%
large%mulJmers%which%induce%the%aggregaJon%of%platelets,%leading%to%platelet%consumpJon,%occlusion%of%the%
microvasculature"%thrombocytopenia%(with%purpura),%MAHA,%neurological-dysfunc<on,%renal%failure,%fever.%%
Normal%coag,%PT%&%PTT,%!BUN/CR,%lipase,%BNP/ANP,%LDH,%Bilirubin,%le^Kshirt%RBCs.%%
HUS:%aects%very%young%&%old.%%Follows%URI,%or,%more%commonly%in%the%US,%infecJous%gastroenteriJs%[E.coli%0157:H7%
or%Shigella%dysenteriae%serotype%I].%%Bloody%diarrhea%followed%by%kidney%failure.%%Shiga%toxin%binds%to%Gb3%on%
glomerular%endothelium,%also%inacJvaJon%of%ADAMST13.%%Similar%to%TTP%but%no%neuro%symptoms,%prominent%acute%
renal%failure%
DIC:-widespread%brin%thrombi%in%the%microvasculature.%%Tissue%hypoxia/infarcJon%due%to%thrombi.%%Hemorrhage%
due%to%depleJon%of%cloeng%factors.%Causes%(many)K%sespsis%(MC;%endotoxins"%TNF%"%endothelial%expression%of%TF%
&%adhesion%molecules,%#thrombomodulin)),%APL%(promyelocytes%release%granules),%massive-<ssue-injury-(release%
of%TF,%esp.%brain%injury),%adenocarcinomas%of%the%lung,%pancreas,%colon,%stomach,%%anything%that%may%cause%
thromboJc%diathesis%(consumpJon%and%exhausJon%of%coagulaJon%proteins%and%platelets).%!PT,%PTT,%#Platelets%

binds

ABCIXIMAB,'
Ep9ba9de,'Tiroba'are!
GpIIb/IIIa!inhibitors,!
inhibi7ng!aggrega7on.!!
AE!thrombocytopenia!
seen!with!abc.!!Used!for!
acute!coronary!
syndrome!&!stent!
procedures/coronary!
angioplasty!

GpIb!

TFPI!

Plasmin!

TRANSEXAMIC'ACID,'Aminocaproic'Acid'
are!lysine!analogs!that!bind!plasminogen!
and!inhibits!its!ac7va7on!(compe77ve).!!
DoC!Antedote!for!brinoly7c!overdose!
(excessive!menstrual,!postHdelivery,!lifeH
threatening!bleeds)!

Dense!

WARFARIN'is!the!only!ORAL!
an7coagulant.!Takes!3H5!days,!so!
ini7ally!started!with!heparin.!!Bone!
dysmorphogensis!if!used!in!pregnancy!
(Fetal-Warfarin-Syndrome).!!Highly!
proteinHbound!(aspirin,!sulfanamides,!
phenytoin!displace!warfarin!#!
!eects)!!Metabolized!by!CYPs!to!
inacJve!form!(cime7dine,!macrolides,!
azoles!inhibit!CYPs#!!eects;!
barbiturates,!carbamazepine,!rifampin!
induce!CYPs#!"eects).!!

Hemophilia-A:%XLR%factor%8%deciency%due%to%
intrachromosomal%rearrangement"%inversion%
Hemophilia-B-(less%common):%XLR%factor%9%
deciency%due%to%missense%mutaJon.%%
Impaired%thrombin%producJon%through%the%
intrinsic%8a/9a%complex%(!aPTT).%%The%extrinsic%
pathway%is%also%unable%to%be%reinforced%through%
thrombins%acJvaJon%of%8/9.%%Results%in%
spontaneous%bleeding%into%joints/so^%Jssues,%
prolonged%bleeding%a^er%trauma/surgery.%%
%

Platelet'Func9on'Assay'(PFA)'
Measures!adhesion!&!aggrega7on!
(Primary!Hemostasis)!
O|en!more!eec7ve!than!Bleeding!
Time!to!detect!vWD!
Abnormal!results!due!to:!Aspirin,vWD,-uremia-(renal-failure),-liverfailure,-Glanzmanns,-BenardWSoulier.--

gen!

DIPYRIDAMOLE,'Cilostazol'inhibit!
reuptake!of!adenosine,!PDE,!ADP.!!Results!
in!!cAMP!and!"!aggrega7on.!!Used!with!
aspirin!to!prevent!thromboembolism!in!
prosthe7c!heart!valves.!

Mixing'Studies'
Mix!pa7ents!plasma!with!normal!plasma!to!
dis7nguish!between!factor!deciencies!and!
coagula7on!inhibitors!
Corrected!#!factor!deciency!
Par7ally/uncorrected!#!inhibitor!is!
present!(an<cardiolipin,!an7bodies!to!
factorHcan!be!seen!in!hemophilia).!!

fibrin
o

Add%thrombin%and%measure%the%Jme%required%for%thrombin%to%
convert%brinogen%to%brin%

CLOPIDOGREL'(plavix),'Ticlopidine!
inhibits!ADPHinduced!expression!of!
platelet!glycoprotein!receptors!!(P2Y12),!
reducing!aggrega7on.!!Clopi!is!acJvated!
by!CYP2C19.!!Ticlo!is!associated!with!
neutro!&!thrombo!cytopenias.!

Par9al'Thromboplas9n'Time'(PTT)%25K40%
Evaluates%intrinsic%&%common%system%
down%to%formaJon%of%a%brin%clot%
Used!to!evaluate:!
Heparin!therapy!
Intrinsic!pathway!&!inhibitor!
deciencies!
vWD:!vWD!binds!Factor!8!and!
inhibits!rapid!inac7va7on!in!blood;!
vWD!#!"Factor!8!=!!PTT!

Prothrombin'Time'(PT)%11K15%seconds'
Measures!extrinsic!&!common!pathway!!
Used!to!evaluate:!
Warfarin'
Liver!synthe7c!func7on!
Detect!factor-7-deciency-(prolonged!PT!
with!normal!aPTT)!
Vitamin-K-deciency-(2,!7,!9!,10)!
Adds%TF%&%phospholipids%to%citrated%plasma%
(sodium%citrate%chelates%calcium%and%prevents%
spontaneous%cloeng).%%CoagulaJon%is%iniJated%
by%adding%exogenous%calcium%&%the%Jme%for%a%
brin%clot%is%recorded.%%

#!

SECONDARY HEMOSTASIS
Coagulation factors and proteins interact to form fibrin assembly on negatively charged membrane
phospholipids of activated platelets. Calcium is a cofactor necessary for the binding of factors
(gammma-carboxy residue/gla domain) to the negatively charged surface of platelets. Vitamin K is
responsible for the formation of the gamma-carboxylase domain of factors 2, 7, 9, 10, as well as
Protein S, C & Z. Vitamin K is oxidized as it adds a carboxyl group to the glutamate residues.
Vitamin K Epoxide Reductase is necessary to recycle/reduce vitamin K to the active form again
(Warfarin inhibits this enzyme).
Warfarin-induced skin necrosis/purple toe syndrome occurs in patients taking Warfarin who have a
previously occult Protein C Deficiency .
After the proteolytic cascade, thrombin converts soluble fibrinogen into fibrin monomers that
polymerize into an insoluble gel. The gel encases platelets and other circulating cells in the definitive
secondary hemostatic plug. The fibrin monomers are cross-linked and stabilized by factor 13, which
is activated by thrombin.
INTRINSIC PATHWAY
Plasma contacts damaged tissue & activates Factor 12 (Hageman Factor; synthesized by the liver
& circulates in inactive form). Occurs when vascular permeability increases [via C3a, C5a,
Bradykinin, LTC4, LTD4, LTE4, PAF, thickening of the BM which alters the charge surrounding
the pores between endothelial cells] and plasma proteins contact collagen, or when plasma
proteins contact the basement membrane exposed as a result of endothelial damage [antibody/
IC deposition & complement activation]. Factor 12 then undergoes a conformational change to
expose a serine center responsible for cleaving & activating protein substrates.
F12 also cleaves prekallikrein # kallikrein which cleaves HMWK to bradykinin [! vascular
permeability, vasodilation, pain; inactivated by kininase & ACE]. Kallikrein amplifies the
signal by further activating factor 12, directly converting C5# C5a, & ! chemotaxis.
EXTRINSIC PATHWAY
Damaged Tissue releases Factor 3 (Tissue Factor/Thromboplastin/CD142) present on
subendothelial tissue and leukocytes.

Thrombin'Time'(TT)%%15K22'
Specically!asses!the!status!of!bringen!
Hypobrinogenemia,dysbrinogenemia-

PRIMARY HEMOSTASIS
Vascular injury allows platelets to be exposed to subendothelial collagen & vWF. After initial injury, there
is transient arteriolar vasoconstriction mediated by reflex neurogenic mechanisms & augmented by local
secretion of factors such as endothelin. BOSENTAN,'SITAZENTAN'are!endothelinHR!antagonists!
1. ADHESION
vWF binds GbIb (necessary to overcome sheer forces)
Bernard Soulier Syndrome- GpIb Deficiency; defective adhesion
vWD is clinically similar to Hemophilia A, but vWD also have !bleeding time
Collagen binds GpIb
GbIb can also bind other components of ECM (fibronectin)
2. SECRETION
ADP # ! aggregation [binding to ADP-R # !Ca++# GpIIb/IIIa on surface]
Calcium # coagulation cascade
Phosphatidyl serine and other negatively charged lipids appear on surface# binds calcium;
serves as nucleation site for IX & X
3. AGGREGATION
ADP, TXA2 # Gq # Ca++ release # PKC # PLA2 # GpIIb-IIIa conformational change #
binds fibrinogen
Glanzmann Thrombasthenia (AR)- GpIIb/IIIa Deficiency; defective aggregation/fibrin bridge
The primary platelet plug is unstable and easily dislodged. Platelet aggregation is followed by
platelet contraction-cytoskeletal remodeling the results in a fused mass of platelets
Although this initial wave of aggregation is reversible, concurrent activation of the coagulation cascade generates thrombin,
which stabilizes the platelet plug by: (1) binds to PAR on platelets to further increase aggregation and (2) converts
fibrinogen to fibrin, cementing the plates together

ASPIRIN!irreversibly!inhibits!COX!#!
"TXA2.!!Low!dose!(60H260!mg)!spares!
endothelial!synthesis!of!PGIH2!resul7ng!
in!beter!an7platelet!ac7vity!!

ENDOTHELIAL'CELLS'

SILDENAFIL,'TADALAFIL,'
PGI2,'NO'![!cGMP!#!vasodila7on;!PDI5!inac7vates!cGMP]!'
VARDENAFIL''inhibit!PDI5![AE:!
priapism]!

ProW
platelet'

vWf'(from!Weible!Pallade!bodies),'
collagen'

An9W
coagulant'

ADPase'
HeparanHlike!molecule!(heparan'sulfate):!inac7vates!thrombin!
Thrombomodulin:!binds!thrombin!and!converts!it!to!an!an7coagulant!that!
ac7vates!Protein!C!
Protein'S:!cofactor!for!protein!C!and!TFPI!(cell!surface!protein!that!inhibits!TF,!VIIa,!
Xa;!extrinsic!pathway)!

ProW
coagulant'

TNF!,'ILW1,!bacterial!endotoxin!cause!
endothelial!cells!to!synthesize!TF'(factor'
3)!which!ac7vates!the!extrinsic!cascade!

Fibrinoly9c'

tWPA'(protease!which!cleaves!plasminogen!to!plasmin!which!will!cleave!brin!and!
degrade!thrombi)!
!

An9W
Fibrinolu9c'

PAIs!inhibit!brinolysis!by!inhibi7ng!
plasminogen!ac7vatos!(tPA)r;!favoring!
thrombosis!