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 PRIMARYHEMOSTASIS 62+520 !G+31I3)02.5- !,1* W6!!R Rd9ag
 Vascular injury allows platelets to be exposed to subendothelial collagen & vWF. After initial injury, there !G+31I,- !,1* W!!R  *d9RR 6+3?G+31I,- !,1* W6!R **9*d &@A/73& C,A,-H 8?/F,*.
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is transient arteriolar vasoconstriction mediated by reflex neurogenic mechanisms & augmented by local 3/L7 0/ J/2468/7 /J 6 fH2'7 A?/0
• !:;'T7,%3'D+3+&%"K • k$%/ '1 %B*+7*'%( /3$G&673$; #%'A%%& Q*8'10 /%j83%&83%$ *&/
secretion of factors such as endothelin. J@8D9!:9X8&!:cD9!:9 *0%%&/1';%+3&DY *&'*61&3$'$ k$%/ '1 %B*+7*'%(
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@&'03&$38 4*';A*. R 3&;3#3'10
• Bernard Soulier Syndrome- GpIb Deficiency; defective adhesion
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• GbIb can also bind other components of ECM ( fibronectin ) !&/3'>4 A'0260@ A1@?60@& A6?A'>4 673 .2@I@70& Bf\ # "C*8'10 J ` !NSS
2. SECRETION 7&6B"&7:C@<DX $,03.?2\30 3&;3#3' &./7067@/>& A?/e7K$U D/6K>?68/7 '& '7'860@3
•  ADP # ! aggregation [binding to ADP-R # !Ca++# GpIIb/IIIa on surface] 0%74'*9% 1Q */%&1$3&%5 N\c5 "\N? Y%$7+'$ H- 633'7K @G/K@7/>& A6?A'>4 Z 01@ 84@ J/2 6 602?*0*? ;/-453- :..2( W6;:R
• Calcium # coagulation cascade 3& !8"XN *&/ " *660%6*G1&? k$%/ A3';  fH2'7 A?/0 '& 2@A/23@3U • X%*$70%$ */;%$31& R *660%6*G1&
• Phosphatidyl serine and other negatively charged lipids appear on surface # binds calcium; *$4303& '1 40%B%&' ';01,#1%,#1+3$, 3& :N03,*0. =%,1$'*$3$>
serves as nucleation site for IX & X 401$';%G8 ;%*0' B*+B%$? • Z{%& ,10% %^%8GB% ';*& L+%%/3&6
3.  AGGREGATION S3,% '1 /%'%8' Bf\
 ADP, TXA 2 # Gq # Ca++ release # PKC # PLA2 # GpIIb-IIIa conformational change #
• • "#&10,*+ 0%$7+'$ /7% '1(  A#;%,%3K
binds fibrinogen .L0K 2,+&%" N,+3"5 R"%52,+OK 5%.+,
• Glanzmann Thrombasthenia (AR)- GpIIb/IIIa Deficiency; defective aggregation/fibrin bridge $<@6&7@%"D< W)02>,ARX !,403),F,-*  R"%52,+K *5"3[&"33)#K X+3",>W6'25%+,_
• The primary platelet plug is unstable and easily dislodged. Platelet aggregation is followed by 3&;3#3'$ "\ND3&/78%/ %a40%$$31& 1Q
platelet contraction-cytoskeletal remodeling the results in a fused mass of platelets 4+*'%+%' 6+.81401'%3& 0%8%4'10$ :NIn EI>5
 Although this initial wave of aggregation is reversible, concurrent activation of the coagulation cascade generates thrombin, 0%/783&6 *660%6*G1&? ]+143 3$ 6A8I60@3 
#. ]nNI]Ex? S38+1 3$ *$$183*'%/ A3'; !+&';$%5%" A) rE] J6A0/2 s 3@fA'@7A- 3>@ 0/
which stabilizes the platelet plug by: (1) binds to PAR on platelets to further increase aggregation and (2) converts
 fibrinogen to fibrin, cementing the plates together &%7'01 R ';01,#1 z8.'14%&3*$? '7026A12/4/&/46? 2@62267K@4@70 "  '7I@2&'/7
!+&';$%5%" X !?@&& A/44/7$) rE] J6A0/2 l
3@fA'@7A- 3>@ 0/ 4'&&@7&@ 4>068/7U
SECONDARY HEMOSTASIS
_4.6'2@3 012/4H'7 .2/3>A8/7 012/>K1 01@      e     n
Coagulation factors and proteins interact to form f ibrin assembly on negatively charged membrane
     s
"SN V=S
phospholipids of activated platelets. Calcium is a cofactor necessary for the binding of factors '702'7&'A s6(l6 A/4.?@G ! !6
  ;::$U : 1@ @G02'7&'A "\N c43     e
 .601L6- '& 6?&/ >76H?@ 0/ H@ 2@'7J/2A@3 012/>K1      n     g  
(gammma-carboxy residue/gla domain) to the negatively charged surface of platelets.  Vitamin K  is ^:";:"&9 3$ ';% 1&+. ZY"[      e ]* __ X6     o
responsible for the formation of the g amma-carboxylase domain of factors 2, 7, 9, 10, as well as *&G81*67+*&'? S*9%$ TDV /*.$5 $1 012/4H'7t& 6A8I68/7 /J s(lU ] @&>?0& '7
      D     n
      i
3&3G*++. $'*0'%/ A3'; ;%4*03&? L1&% &./7067@/>& H?@@3'7K '70/ b/'70&(&/\ 8&&>@&= ;3$'*,3&%     r :J$&_&C:JX
Protein S, C & Z. Vitamin K is oxidized as it adds a carboxyl group to the glutamate residues. /.$,104;16%&$3$ 3Q 7$%/ 3& 40%6&*&8.  .2/?/7K@3 H?@@3'7K 6\@2 026>46(&>2K@2-U       b D)5`I25F*X!,+3`I2 *0%
 Vitamin K Epoxide Reductase is necessary to recycle/reduce vitamin K to the active form again       fi <4@@#O@@@* 3&;3#3'10$5
:?+("5 L",R",%3 6:3>,'&+>? =36;+.
( 
 Warfarin inhibits this enzyme). 401'%3&D#17&/ : *$4303&5 $7+Q*&*,3/%$5 3&;3#3G&6*660%6*G1&?
• Warfarin-induced skin necrosis/purple toe syndrome occurs in patients taking Warfarin who have a 4;%&.'13& /3$4+*8% A*0Q*03& # "c ';01,#18.'14%&3*
previously occult Protein C Deficiency . !%^%8'$> X%'*#1+3p%/ #. ]nN$ '1 $%%& A3'; *#8? k$%/ Q10
 After the proteolytic cascade, thrombin converts soluble fibrinogen into fibrin monomers that '76A8I@ Q10, :83,%G/3&%5,*801+3/%$5
*p1+%$ 3&;3#3' ]nN$ # !%^%8'$b
Thrombomodulin GpIIb-IIIa *87'% 8101&*0.
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 #*0#3'70*'%$5 8*0#*,*p%43&%5 03Q*,43& " $.&/01,% R $'%&'
3&/78% ]nN$ # "%^%8'$>? 4018%/70%$O8101&*0.
is activated by thrombin. ap-C p-S *&6314+*$'.
INTRINSIC PATHWAY 8 5 ?"8(', ^ 9+%>+3/ PD '7 Q>2/.@67
• Plasma contacts damaged tissue & activates Factor 12 (Hageman Factor; synthesized by the liver 12 # 11 # 9 # 10 # 2 # 1  ./.>?68/7&U ;/'70 4>068/7 '7 ^d
!M2K"  "?7$ '7 01@ .2@J@22@3 A?@6I6K@
& circulates in inactive form). Occurs when vascular permeability increases [via C3a, C5a,
TF      #
&'0@ J/2 6;DO 46B'7K ^d 2@&'&0670 0/
Bradykinin, LTC 4, LTD4, LTE4, PAF, thickening of the BM which alters the charge surrounding 3@6A8I68/7 " ! 012/4H/&'&U
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/
;@97:6:"&9a_
3$ * /30%8' Q*8'10
7 GpIb
TFPI
IC deposition & complement activation]. Factor 12 then undergoes a conformational change to y* 3&;3#3'10?
expose a serine center responsible for cleaving & activating protein substrates. Antithrombin
• F12 also cleaves prekallikrein # kallikrein which cleaves HMWK to bradykinin [ ! vascular Plasmin + Heparin ND$%+%8G& N\<C5
permeability, vasodilation, pain; inactivated by kininase & ACE]. Kallikrein amplifies the j#03&16%&5 S<CL5 LD
signal by further activating factor 12, directly converting C5 # C5a, & !  chemotaxis. tPA binds Fibrin   " j#01&%8G&5';01,#16+1
EXTRINSIC PATHWAY #D6:"&9 !.62@70@26?= &1/20 6A8'7K$ %&;*&8%$ C*8'10 V R #7+3&5 Mc<C
• Damaged Tissue releases Factor 3 (Tissue Factor/Thromboplastin/CD142) present on *8GB3'. 1Q %&/16%&17$ *&G';01,#3& @@@ 2#3&/$ "S@@@ PAI J5 4QU5
subendothelial tissue and leukocytes. R 3&*8GB*'%$ Q*8'10$ I* R EK*F? \1] Q10 *j#5
40%6&*&8.? 6"@!:C&9D 8a<;:!D 3$ *&G/1'%O *,": 45"(+5+( 6:3>,'&+/ 6H&@70
FIBRINOLYTIC CASCADE 6?.16 K267>?@&U "'670 .?60@?@0&=
*&'*61&3$'? c&1a*5 \*+'%5 R S3&p* D4*03& *0% [Xf=
012/4H/A-0/.@7'6=4-@?/fH2/&'& '7
 Activation of the coagulation cascade leads to activation of the fibrinolytic cascade which moderates the size of the A;38; $%+%8GB%+. 3&;3#3' Q*8'10 EK*? [Xf= ;*$ * &/4@ .68@70&U
clot. Plasmin breaks down fibrin & interferes with its polymerization. FSPs act as weak anticoagulants. FSPs can +1&6%0 ;*+QD+3Q% R +1A%0 03$9 1Q ';01,#18.'14%&3*b
also be diagnostic of abnormal clotting states like DVT, DIC, PE. Fragments of cross-linked insoluble fibrin \1] 4014;.+*a3$ 1Q \MS :;1$43'*+5 #%/03//%&>5
monomers are called D-dimers. Plasmin also inactivates Factors 5 & 8. tPA  must be bound to fibrin in order to 7&$'*#+% *&63&*5 *87'% X@
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. !+;",%3WP3>28+>=$,'&7'<8 =$,'&7'8:(';+3%" /AA>2&
 J/??/L'7K 634'7'&0268/7 /J >7J26A8/760@3 1@.62'7 L1'A1
!2-antiplasmin (made by liver) inactivates plasmin. Prevents excess free plasmin from lysing thrombi
'73>A@& 01@ 6..@6267A@ /J 678H/3'@& 0160 2@A/K7'h@ 1@.626'79
indiscriminately elsewhere in the body (plasmin scavenger). :86&"&9 300%B%0$3#+. 3&;3#3'$ ]Zy #
 .Ja A/4.?@G@&U i1@7 01@ 678H/3'@& H'73 0/ .?60@?@0& "  :%":!"@J:9X <*),+/F*- "Sy"I? [1A /1$% :tKDItK ,6> $4*0%$
6A8I68/7= 6KK2@K68/7 Z A/7&>4.8/7 !.2/012/4H/8A &060@ W&TRX J,>20,+/F*- W8$R *0%
8!"D6!@b&9:8D S :9&8!"D6<:8D :<!D6<:8D"*?*)02.*X !":98D_:C&$ :$&7X :1,-342)+3,4 :4,F %&/1';%+3*+ $.&';%$3$ 1Q N<@DI 0%$7+G&6
H>0 012/4H/A-0/.@7'6$U P>&0 H@ &>&.@A0@3 L1@7 .?60@?@0& \30%8' S;01,#3& @&;3#3'10$?
*8GB*'%$ 4+*$,3&16%& :&1&$%+%8GB%+.>5 $1 !*-*4?*)02.* *0% 'N" *&*+16$ ';*' *0% +.$3&% *&*+16$ ';*' #3&/ 4+*$,3&16%& 3& #%s%0 *&G4+*'%+%' *8GB3'.
32/. !jdgk$ '7 6 .68@70 H@'7K 02@60@3 L'01 1@.62'7 !a9*g 36-& \1] 4014;.+*a3$ *&/ Sa
,*. +%*/ '1 #+%%/3&6? "&G6%&385 ,*. $%+%8GB%+. *8GB*'% 4+*$,3&16%& *&/ 3&;3#3'$ 3'$ *8GB*G1& :81,4%GGB%>?  ./&0 634'7'&0268/7$ ';01,#1$3$ 3& 4*G%&'$ A3';
/%B%+14 *++%0638 0%*8G1&? a"@b&9:8D 3$ A;%& #17&/ '1 j#03& :8+1' \1] "&'%/1'% Q10 j#03&1+.G8 1B%0/1$%
$4%83j8>? -;10'%0 =[5 +%$$ =@SS
*+$1 * &1&$%+%8GB% 4+*$,3& *8GB*'105 #7' :%a8%$$3B% ,%&$'07*+5 41$'D/%+3B%0.5 +3Q%D
3' 3$ &1&D*&G6%&38? *++%06%&383'.5 *&/ +%$$ #+%%/3&6? ';0%*'%&3&6#+%%/$>

# 6<:!D<D! 6"@7a$!&@9 ! 6<:!D<D! <@88E7D8!"a$!&@9

_44>7@94@3'60@3
 A;5"#<8 A3+&%" 5263'68/7= • P=4 ) _K" 6K6'7&0 ".__H(___6 D6@6"@8!D9@<X &<@6"@8! *0%
E+'3"("5A55'%&&23+ =$,'&7'8:(';+3%"/ ,;M9*HS 4/01@2 46B@& 678H/3'@& 0/ ,;M9*6 N<@I /%03B*GB%$ D97@!#D<&:< $D<<8
A1@4/= ,_Y= I'26? 1@.688&= •

•  A55'%&&23%["<'3) ]@3 A@??(.?60@?@0 0267&J>&'/7&

;62I/C*l '7J@A8/7 '7 .68@70&
L'01 >73@2?-'7K 67@4'6) 76B@3=
?'7@62 &&VNM !2@#U 1/&0 A@??&
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?@>B@4'6= 4@06&068A A62A'7/46F
B+D"Z",:'8:(+ 0+#(,28<'3
• 0,2D# 5;@7'A'??'7 !16.0@793@.F= W>?J6&(m>'7'7@ !16.0@79'73@.$= M4.1/0@2'7 8&<7D9:;&<X!:7:<:;&<X
• !PU ($,'&7'8:(';+3%") ,_Y A67 '7J@A0 4@K6B62-/A-0@& ?@63'7K 0/ 6./.0/&'&U ,_Y 6?&/ A6>&@& C9A@?? 1-.@2.?6&'6 :-5V 6%&MX 9@ 2!8<XN # B*$1/3+*G1&b N\@ V 3&*8GB*'%$ 8<XNF
T:"7D9:;&< 3&;3#3' N\@ V 2"c( 6+3V >^Z WQ01, f%3#+% N*++*/% #1/3%$> X
673 .23'&./&@& 0/ 01@ 3@I@?/.4@70 /J 6>0/678H/3'@&U )02?*0*? 403*43$,F )02?*0*? 43002H*-
N/79'44>7@
• ==4 ) 6789MVMP:W*nO 678H/3'@& 0/ 01'& 4@06??/.2/0@'76&@ 0160 '& 2@&./7&'H?@ J/2 A?@6I'7K Ii^U Ii^ 2@46'7& 6& :-5V :762.* 6+3V !9; X &<VL5 #*8'%03*+ *-F3?3A,- 8*7$%
?62K@ 4>?84@2& L1'A1 '73>A@ 01@ 6KK2@K68/7 /J .?60@?@0&= ?@63'7K 0/ .?60@?@0 A/7&>4.8/7= /AA?>&'/7 /J 01@ 432H/02-? =%4*0*&D+39% ,1+%87+% : G*)2+2- ./0Z2?*>( 3&*8GB*'%$ ';01,#3& 432H/02-? %&/1';%+3*+ 8%++$ '1 $.&';%$3p% !; WZ24?3+
4'A2/I6&A>?60>2@"  012/4H/A-0/.@7'6 !L'01 .>2.>26$= PM,M= 3+2,'5'D%8"5>:#R238<'3 = 2@76? J6'?>2@= J@I@2U
N/246? A/6K= ;: Z ;::= ! CoN(D]= ?'.6&@= CN;(MN;= EV,= C'?'2>H'7= ?@\9&1'20 ]CD&U !G+31I313F/0,-( #3&/$ ';01,#3& *&/ 81&B%0'$ 3' '1 *& *&G81*67+*&' ';*' PR A;38; *8GB*'%$ ';% %a'03&$38 8*$8*/%
• !\6) 6p@A0& I@2- -/>7K Z /?3U ^/??/L& o]_= /2= 4/2@ A/44/7?- '7 01@ oW= '7J@A8/>& K6&02/@70@2'8& 5QUA/?' g*dq),q *8GB*'%$ N01'%3& ]
/2 W1'K@??6 3-&@70@2'6@ &@2/0-.@ _FU C?//3- 3'6221@6 J/??/L@3 H- B'37@- J6'?>2@U W1'K6 0/G'7 H'73& 0/ "Hn /7 6+3?*,- 8( 81Q*8'10 Q10 401'%3& ] *&/ !;6&  :8%++ $70Q*8% 401'%3& ';*' 3&;3#3'$ SC5 M@@*5
K?/4@2>?62 @73/01@?'>4= 6?&/ '76A8I68/7 /J MVMPW:*nU W'4'?62 0/ ::; H>0 7/ 7@>2/ &-4.0/4&= .2/4'7@70 6A>0@
y*b %a'03&$38 4*';A*.>
2@76? J6'?>2@
• 0P@/ L'3@&.2@63 fH2'7 012/4H' '7 01@ 4'A2/I6&A>?60>2@U :'&&>@ 1-./G'6('7J62A8/7 3>@ 0/ 012/4H'U ,@4/2216K@