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1-28-10 Hemostasis and Thrombosis Part I and II REVIEW LECTURE SUMMARIZING ALL OF PLATELETS (10 HEMOSTASIS) and COAGULATION

(20 HEMOSTASIS) 1. Plat l t !"#d$%t&#n' d&(t"&)$t&#n' and ($"*&*al. Platelet production: Megakaryocyte proli eration and maturation: !"#-$%MM is the pluripotent marro& stem cell that gi'es rise to ("#-Megs and !"#-Megs) ("#-Megs and !"#-Megs are the compartments &here proliferation occurs) Proli eration stops once these cells di erentiate) %ndomitosis allo&s or megakaryocyte maturation* increasing ploidy and 'olume) Proplatelets protrude out o the endothelium into the lumen* gi'ing o platelets) TPO is the main stimulatory hormone or platelet proli eration and maturation) It is made in the li'er +and a little in the kidney,) TP- by itsel is not enough* though. it &orks in con/unction &ith %P-* stem cell actor* I0-1* and $M-!2") IL+, increases production o TP- in the li'er +TP- is normally constituti'ely secreted at a constant le'el,) TP- binds -!l receptor on platelets and megs) 0e'els o TP- 'ary based on platelet and megakaryocyte mass* 3-T due to changes in secretion* but rather due to the a'ailability o mpl receptors) That4s because an increase or decrease in platelets5megs &ill lead to an increase or decrease in mpl receptors* and a subse6uent decrease or increase in ree plasma TP-* respecti'ely) %)g) aplastic anemia: decrease in megs and plateletsdecrease in mpl receptorsincrease in plasma TP %)g) ITP is an e7ception: platelet counts plummet &ith ITP due to autoantibodies* but megs are preser'ed and respond to the thrombocytopenia by increasing in si8e and number* thus increasing the number o mpl receptors that they ha'e) TP- le'els thus usually stay normal &ith ITP) 9 normal platelet count is 1:0*000-;:0*000) Platelet sur'i'al is 10 days) Platelet turno'er daily is 10< %7tra'ascular pool is 10< +mostly in the red pulp o the spleen,) There is not marro& reser'e or platelets +megs don4t count,) 2. A!!"#a%. t# !at& nt /&t. t."#-)#%0t#! n&a (a1a t."#-)#! n&a). %liminate underlying cause) Platelet trans usion) TP- is not used as treatment) 2. Ca$( ( #3 a l#/ and .&4. !lat l t %#$nt !auses o t."#-)#! n&a +=1:0*000,:

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decreased total thrombopoesis: reduction in numbers o megs* decreased ploidy o megs +smaller megs>smaller platelets,* apoptosis or phagocytosis o megs) a) !auses: aplastic anemia* acute leukemia* myelodysplasia +M?2,* chemo* hereditary thrombocytopenia@ b) 0abs: normal MPA* prolonged (T. (M biopsy re'eals in iltration5replacement c) @hereditary disorders o platelet unction include: i) ?isorders o platelet ADHESION: 1) %7trinsic: 'B? a) Type 1: partial quantitative de iciency in 'B" i) !linically: presents &ith bleeding during surgery* menorrhagia* easy bruising. labs re'eal decreased le'els o 'B":9g and "AIII) Patients generally asymptomatic) b) Type 2A: absence o HMB 'B" multimers i) !linically: labs re'eal normal "AIII and 'B":9g* coupled &ith 'ery lo& Cistocetin co actor assay@ c) Type 25: absence o HMB 'B" multimers plus increased a inity or $P 1b5A5ID +gain-o - unction mutation, i) !linically: similar to 29Elabs re'eal normal "AIII and 'B":9g* but lo& Ciscocetin co actor assay ii) Fou cannot treat T( &ith desmopressin due to un&anted platelet aggregation d) Type 2M: abnormal unctioning 'B" 3-T caused by absence o HMB multimers i) !linically: also similar to 29Elabs re'eal normal AIII and 'B":9g* but lo& Cistocetin e) Type 2N (N#"-and0): 6ualitati'e 'ariants &ith decreased a inity or "AIII i) !linically: the only type II 'B? that has reduced "AIII) 'B":9g remains normal) - ten misdiagnosed as Hemophilia 9) 1) +the normal 'B":9g* in the ace o lo& "AIII* can be used to di erentiate 23 rom types 1 and 1,) ) Type 2: complete de iciency o 'B" i) !linically: most se'ere type* &ith se'ere mucosal and possibly some /oint bleeding +hemarthrosis,* no 'B":9g* 'ery lo& "AIII) 1) basically* look or e'en lo&er le'els o 'B":9g and "AIII than in type 1) g) P( $d#-'B?: this is similar to type 2(* e7cept there4s no loss o HMB multimers* only a gain-o - unction mutation to&ards increased a inity or $P 1b5A5ID) It4s considered an intrinsic* rather than e7trinsic* disorder o adhesion)

Intrinsic: (ernard-2oulier4s 2yndrome +GP 1)6V6I7 de ect > platelets can4t bind 'B" > no adhesion,* pseudo-'B? +$P 1b5A5ID de ect,* collagen receptor de ect +GP 1a6IIa' GP VI de ects,* 1) "yi: in platelet agglutination cur'esE) a) $lansmann4s Thrombasthenia does not agglutinate &ith anything except ristocetin i) Cecall that $lan8mann4s Thrombasthemia is a de iciency in $P IIb5IIIa* &hich means that platelets ha'e di iculty binding fibrinogen and there ore cannot aggregate b) 'B? and (22 &ill agglutinate &ith e'erything e7cept ristocetin i) 8"&(t#% t&n %#3a%t#" a((a0 6uanti ies the adhesi'e activity o 'B") This is in contrast to *WF9A4* &hich simply measures the presence o 'B" protein* not its unction) ii) 9nother &ay to detect 'B? is to measure FVIII le'els* &hich &ill be diminished +'B" is a carrier o "AIII,) ii) ?isorders o platelet AGGREGA ION: 1) e7trinsic: a3&)"&n#4&n -&a: autosomally recessi'e condition in'ol'ing mal unctioning ibrinogen 2) intrinsic: Glan:-ann;( T."#-)a(t. -&a +$P IIb5IIIa > platelets can4t bind ibrinogen > can4t aggregate,* (t#"a4 !##l d&(#"d "( +reduced alpha granules* dense granules* or both,* <$ ) % !lat l t d&(#"d " +autosomal dominant disorder o high uP9 le'els* resulting in high plasmin and ibrinolysis,* abnormal secretion o signal transduction +reduced !-D or TD92,* S%#tt S0nd"#- +de ecti'e P0 translocation* a ecting platelet coagulation, 2) ine ecti'e thrombopoeisis: megaloblastic anemia a) causes: (125 olate de b) 0abs: 'ariable MPA* prolonged (T 1) increased destruction: can be immune or non-immune related. suspect increased destruction &hen you ha'e younger* bigger platelets +increase! "#$, and bigger5larger5higher ploidy megs +(T &ill actually be s%ortene! b5c the platelets are younger and better, a) !auses: i) Immune mediated: auto5alloimmune disease +like ITP@* systemic autoimmune diseases* lymphomas* and in ections by H)pylori5Hep!5HIA, or drug induced@8 1) @@anti-platelet drugs include A(!&"&n +929 is a !-D-1 inhibitor* blocks TD9 production,* 329I?2* t&%l#!&d&n 6%l#!&d#4" l +9?P receptor inhibitors,* GPII)6IIIa &n.&)&t#"( +block plateletibrinogen binding,* ) ta+la%ta- ant&)&#t&%( +-penems, ii) non-immune mediated: ragmentation hemolysis +includes ?I!* endocarditis5'al'ular disease* ITP@* hemolytic uremia syndrome +acute renal ailure,* multi ocal endothelial disease +'asculitis* pre-eclampsia*
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eclampsia,,* endo5e7oto7emia* hemophagocytosis* arti icial sur aces* !P bypass* clonal pluripotent stem cell disorders* dysproteinemia iii) 8ITP comes in t&o orms 1) A%$t ITP occurs in children) 9brupt onset* o ten ollo&ing an in ection) Presents &ith bullae in mouth* lasts 2-G &ks* &ith 80< o cases undergoing spontaneous remission) Platelet count alls =20*000) 0ymphocytosis and eosinophilia are common) 2) C."#n&% ITP occurs in adults) -ccurs more commonly in emales 1:1* no prior in ection) Presents &ith insidious bleeding but not hemorrhagic bullae in mouth) Platelet count ranges rom 1:-80*000) 0asts months to years &ith no spontaneous remission) 1) Treat ITP &ith prednisone* I'I$ or anti-?* splenectomy* and thrombopoietin receptor agonist ;) ITP is the Hposter childI or a decreased (T rom increased destructionJ !ontrast ITP &ith 9spirin* uremia* and 'B?* all o &hich a ect platelet unction and there ore prolong (T) b) 0abs: increased MPA* shortened (T ;) Cedistribution: platelet se6uestration in red pulp* &hich can shi t up to 80< o platelets into the e7tra'ascular pool, a) !auses: splenomegaly b) 0abs: normal MPA. prolonged (T. palpate spleen :) ?ilution: &ashout a) !auses: trans usion rom trauma +gun shots, b) 0abs: normal MPA. prolonged (T. take a good history G) Pseudothrombocytopenia: arti icially reduced platelet count due to platelet aggregation in smear) !an be mistaken or a true thrombocytopenia) a) cause: %?T9 !auses o t."#-)#%0t#(&(: +K;:0*000, E(( nt&al T."#-)#%0t#(&( +myeloproli erati'e disorder &ith o'eracti'e megs, CML* !#l0%0t. -&a * "a +o'erproduction o red cells and platelets, Ceacti'e processes like &n3la--at&#n* surgery* hyposplenism5asplenia +remember that 10< o platelets are normally in e7tra'ascular splenic red pulp,* hemorrhage* iron de iciency Bhen platelet counts hit KL:0*000* there4s a risk or thrombosis) =. . " d&ta"0 and a%>$&" d >$al&tat&* !lat l t d&(#"d "(. 9ll the H%C%?IT9CF de ects are all single factor abnormalities* but each is characteri8ed by a &hole host o genetic mutations) 9ll are autosomally recessi'ely inherited e7cept or the hemophilias* &hich are D-linked H -#!.&l&a A +"AIII de iciency,: most common mutation is an in'ersion o the actor AIII gene +an upstream homologous gene crosses o'er and disrupts the actor AIII gene, I mothers is a carrier :0< o daughters &ill end up being carriers* and :0< sons &ill ha'e hemophilia 9

I a hemophiliac male has kids* all daughters &ill be carriers* and no sons &ill be a ected) L0#n .0!#t. (&(: in emales* one o the D chromosomes can be inacti'ated* resulting in mild e7pression o the actor AIII de iciency phenotype in hetero8ygote emale carriers) Thus* all carriers should ha'e "AIII le'els measured or in'asi'e procedures) H -#!.&l&a 5 +"ID de iciency,: Hemophilia ( is much rarer than Hemophilia 9* so i you suspect hemophilia* al&ays do "AIII:9g irstJ It4s also D-linked recessi'e* so the genetics50yon4s Hypothesis also apply) Eand *W?* &hich is usually autosomal !ominant: it is the most common hereditary platelet disorder. see pre'ious ob/ecti'e or details Eand 3a%t#" 7I: rare e7cept in %uropean &e'is% population. autosomal dominant 9ll others + ibrinogenemias* other actor de iciencies, are rare enough to ignore

There are our path&ays to pathogenesis o bleeding: 1) ailure to generate ade6uate amounts o thrombin: a) includes Hemophilias 9 and (* "DI de iciency +M%B2,* "II* A* AII* and D de iciencies 2) 0ack o substrate or thrombin: a) 9 ribrinoginemia or dy ibrinoginemia 1) "ailure to cross-link ibrin: a) "actor DIII de iciency ;) %7cessi'e ibrinolysis: a) ?iminished inhibition o plasmin +homo8ygote al!.a+2+ant&!la(-&n d 3&%& n%0 is most common, or e7cessi'e plasminogen acti'ator acti'ity +high uP9 and tP9 rom P9I-1 de iciency, ?iagnosing based on frequency and type o bleeding 3o bleeding despite a prolonged aPTT HMW@' !" 1all&1" n' 7II d 3&%& n%& ( -ccurs &hen blood comes in contact &ith glass or sand L$!$( Ant&%#a4$lant also does this +alongside thrombosis, 2e'ere* spontaneous muscle* /oint* and postsurgical bleeding S * " H -#!.&l&a 9 and ( +&ith A1B clotting actor acti'ity,* all other clotting actor de iciencies except ()I !eficiency +includes "DII and alpha-2-plasmin inhibitor de iciencies, (leeding is very di erent rom thrombocytopenic patients &ho get small petechiae) Hemophilia presents &ith 'ery hea'y bleeding &ith /ust minor trauma) Moderate Hemophilia 9 and ( 2+CB clotting actor acti'ity. more mild muscle and /oint bleeding +you only need a little more actor or a less se'ere disease, Mild Hemophilia 9 and ( DCB clotting actor acti'ity* or ( * " F7I d 3&%& n%0 +=1<, -nly bleeding &ith surgery and trauma +not spontaneous, Fou can use prophylactic AIII prior to surgery in hemophiliacs

2pontaneous mucous membrane* skin and post-surgical bleeding Nualitati'e platelet disorders 0ab Tests 9bnormal aPTT Hemophilia 9 +AIII,* Hemophilia ( +ID,* "DI ?e iciency 3ote on aPTT sensiti'ity cur'es: in using aPTT to assess the se'erity o hemophilia* one must take into account that the cur'e or ID de iciency +hemophilia (, is less steep than the cur'e or AIII de iciency +hemophilia 9, Thus* usually the aPTT is grossly prolonged in AIII de ects +like hemophilia 9,* and a prolonged aPTT clearly indicates hemophilia) In ID de ects* it4s likely that the aPTT can be at the upper limit o normal* but the le'els o ID ha'e allen belo& 10< +the general cuto or mild hemophilia,) In such gray situations* do a "ID 6uantitation to make sure the patient doesn4t ha'e a de ieicncy there) 9bnromal PT "AII ?e iciency PT and aPTT both abnormal "A* "D ?e iciencies

Hemophilia 9 'ersus 'B? 1) clinical e7pression: Hemophilia 9 has se'ere /oint bleeding and deep tissue hemorrhage. 'B? is much milder* &ith some spontaneous mucous membrane bleeding and easy bruising. /oint bleed 'ery rare and &ould probably only occur on type 1) 2) inheritance: Hemophilia 9 is se7 linked recessi'e* &hile 'B? is autosomal 1) Cistocetin assay: normal or Hemophilia 9* abnormal or 'B?) That4s because 'B? is the unctional platelet de ect* &hile Hemophilia 9 is a actor AIII de iciency &ith 9--O platelets) ;) "actor AIII clotting: decreased and constant or Hemophilia 9* decreased but 'ariable in 'B?) :) 'B":9g: normal or hemophilia 9* decreased or 'B? Types 1 and 1 +all Type 2 'B?4s are 6ualitati'e de iciencies* so the numbers o 'B" are normal, G) multimer analysis: normal or hemophilia 9* abnormal or 'B? +all types, C. !lat l t 3$n%t&#n. There are three unctions o platelets: Primary hemostasis Maintain endothelial integrity +think endothelial in/uryprimary platelet plug, Pro'ide sur ace or clotting cascade C. Plat l t+* (( l /all &nt "a%t&#n &n t. d * l#!- nt #3 a"t "&al t."#-)#(&(. Aircho&4s Triad %ndothelial damage 9ccidental trauma* surgical trauma

Aenous stasis 2mall thrombi obstructing lo&* immobili8ation +bed-ridden patients* prolonged tra'el in airplanes,. increases 'iscosity o blood Hypercoaguability Three &ays this occurs: increase in ibrinogen 'ia coagulation actor acti'ation. decrease in coagulation inhibitors. decrease in ibrinolysis Markedly ele'ated AIII* ID* and DI le'els ?e iciencies in antithrombin III* Protein !* Protein 2 !an be 'ie&ed as an imbalance bet&een increased pro-coagulant acti'ity and decreased anticoagulant acti'ity

E. P.a"-a%#l#4&% &nt "* nt&#n &n t. t" at- nt #3 a"t "&al t."#-)#(&(. Cl#!&d#4" l +blocks 9?P receptor on platets* reducing $P IIb5IIIa acti'ity and thus reducing platelet binding to ibrinogen,* A(!&"&n* l#/ -#l %$la" / &4.t H !a"&n +dri'es antithrombin III to degrade actor D. must monitor paitent closely &ith aPTT,* thrombolytics F. H " d&ta"0 d&(#"d "( !" d&(!#(&n4 t# t."#-)#(&(. 9 e& notes o AT%: V n#$( t."#-)#(&( occurs in 151000 patients per year* more common in males and higher recurrence in males o'er ;:) Ho&e'er* under ;:* it is more common in emales due to estrogen +pregnancy and (!Ts,) High morbidity and mortality* usually due to pulmonary embolism) +1 or more prothrombic mutations* i)e actor A leiden or prothrombin mutation, P +ac6uired prothrombic stimuli* like surgery or a cast, > AT% %)g) emale &ith actor A leiden &ho takes (!T* gets pregnant* and is immobili8ed &ill be at 'ery high risk or AT%) Thus* one should take into account age* genetic mutations* and acquire! prot%rombic stimuli &hen assessing AT% risk) Things to consider: hereditary thrombophilia* ac6uired thrombophilia* surgery5trauma* estrogens* malignancy* in lammation* immobility The ollo&ing disorders predispose to 'enous thrombotic disease +AT%, only) Most are due to a ailure to inhibit acti'ated clotting actors +'ia de iciencies in serine proteases,: ant&t."#-)&n III d 3&%& n%09 predisposes to AT% only* 3-T arterial disease b5c you need a slo& lo& system. antithrombin normally degrades thrombin +IIa,* IDa* Da* DIa* and DIIa . !a"&n %#3a%t#" II d 3&%& n%0: normally inhibits IIa* so de iciency allo&s thrombin production to go unchecked. rare* antithrombin III de iciency is much more common "ailure to inhibit acti'ated coagulation co actors +namely Aa* AIIIa,: !"#t &n C or !"#t &n S d 3&%& n%0: normally inacti'ate Aa and AIIIa 3a%t#" V L &d n: produces a Aa resistant to 9P! degradation. common* in :< !aucasian population "ailure to achie'e ade6uate ibrinolysis: !la(-&n#4 n d 3&%& n%0: !la(-&n#4 n a%t&*at#" d 3&%& n%0

d0(3&)"&n#4 n -&a: ibrinogen is resistant to ibrinolysis Increased coagulation actors: G20210A -$tat&#n: results in a 'ery ele'ated prothrombin le'el +%le'ated II,. 'ery common* 2< !aucasian population El *at d VIII' I7' and 7I

Hereditary disorders associated &ith (-TH arterial and 'enous thrombosis El *at d .#-#%0(t &n S&%1l % ll d&( a( ?0(l&!&d -&a(: 0P9inhibits ibrinolytic system Plat l t all#t0! ( G. A%>$&" d and . " d&ta"0 d&(#"d "( #3 )l##d %#a4$lat&#n and 3&)"&n#l0(&( %a$(&n4 H% ((&* )l d&n4. V&ta-&n @ d 3&%& n%0: leads to drop in the Hbig si7 coagulation actors II* AII* ID* D* Protein !* Protein 2) Ceduced Ait O acts as a co actor or carbo7ypeptidase* &hich adds gamma*carboxy glutamic aci! to 'it O-dependent proteins so that they can bind metal ions and ha'e an a inity or P0 membranes 9 ter acting as a co actor* Ait O con'erts into its o7idi8ed state* and it re6uires t&o reductases +one o them* 'it O epo7ide reductase* is inhibited by Wa"3a"&n. thus* gi'ing Bar arin can cause ac6uired protein ! de iciency and lead to HBar arin necrosisI, "actor AII and Protein ! &ill drop most rapidly &ith Bar arin Patients predisposed to protein ! de iciency should be treated &ith %eparin bri!ging t%erapy prior to administration to Bar arin) It is con'entional to monitor patients on !oumadin &ith PT* rather than aPTT* since AII and Protein ! both decrease rapidly together) Oeep in mind* though* that both aPTT and PT &ill be prolonged &ith Ait O de iciency or Bar arin therapy Physiology o Ait O and its absorption: ?ietary source: lea y plants. 'egetable oil. synthesi8ed by the $I bacteria "at soluble* so re6uires bile salt emulsi ication. mostly absorbed in small bo&el (ody stores: despite being at soluble* 'ery limited to /ust a e& days. a concern or hospitali8ed patients &hose antibiotics ha'e depleted the $I lora !auses o de iciency: ?ecreased intake: &atch out or post-op patients on broad-spectrum antibiotics Pancreatic e7ocrine insu iciency ?i use small bo&el disease (ile duct obstruction Bar arin5rat poison Hemorrhagic ?isease o the 3e&born: caused by a combination o immature hepatic proein synthesis and Ait O de iciency

L&* " ?&( a( : leads to decreased synthesis o coagulation actor proteins +keep in mind li'er makes pretty much all the actors except $III,) Thus* depending on the se'erity o li'er disease* you may ha'e 'ariable e7pression o all clotting actors e7cept or actor AIII Parado7ically* actor AIII le'els CI2% in patients &ith cirrhotic li'er disease because their li'ers cannot clear actor AIII e ecti'ely Bill see t%rombocytopenia due to splenomegaly +caused by portal hypertension,. platelets &ill be depressed to a count o about L:*0005ul Accelerate! fibrinolysis occurs in :0< o patients &ith chronic li'er disease. labs &ith sho& shortened dilute blood clot lysis time) It is caused by ailure o li'er to clear plasminogen acti'ators produced by endothelium tP9 is normally cleared by li'er* so it4s high in patients &ith li'er disease underproduction o ibrinogen inhibitors such as alpha-2 antiplasmin and plasminogen acti'ator inhibitor +both made in the li'er, Dysfibrinogenemia: not kno&n &hy this occurs &ith li'er disease* but abnormal ibrinogen inhibits normal ibrin polymeri8ation and prolongs thrombin time thus* PT* aPTT* and TT &ill all be prolonged DI+ due to in ection +endoto7emia or e7oto7emia, ,ualitative platelet !efects: cause unsure* but this &ill prolong bleeding time $itamin - Deficiency: underlying cause is alcoholism* &hich has decreased Ait O intake. this is 3-T re'ersible &ith Ait O* unlike con'entional or Bar arin Ait O de iciency +parenteral Ait O administration can be used to distinguish obstructi'e /aundice* &hich &ill reco'er* rom hepatocellular /aundice* &hich &ill not reco'er), ?IC:

2ine 6uin non is generation o too much thrombin acti'ity ?e ense mechs: depletion o ibrinogen substrate* solubility o e7cess ibrin monomer* P9I-1* antithrombin III* T"PI* Protein !52 0ab diagnosis: ?-dimer le'els* thrombopenia* positi'e protamine test* prolonged PT and aPTT* lo& ibrinogen* increased "?P !linical mani estations: bleeding tendency* ischemic tissue damage* macro-thrombosis* and ragmentation hemolysishemolytic anemia !omes in acute and chronic orms* disseminated and locali8ed Must get rid o underlying causeJJ In addition* replacement therapy o platelet concentrates* cryoprecpitate* and resh ro8en plasma are indicated) Trigger mechs: generation of too muc% TF. e7ception is snake 'enom

Pat.#l#4&% 3&)"&n#l0(&(: H2econdaryI ibrinolysis: ibrinolysis that occurs secon!ary to DI+) The process is &ell regulated and is a protecti'e mechanism against tissue ischemia5in arction by lysing intra'ascular ibrin) This can cause the bleeding seen in ?I!) HPrimaryI ibrinolysis: abnormal accelerated ibrinolysis due to abnormalities in ibrinolytic actors) HPrimary ibrinogenolysisI: degradation o circulating ibrinogen by plasmin or nonplasmin ibrinogenolytic en8yme)

Thrombin causes an increase in tissue plasminogen acti'ator release rom endothelium into the clot) 2) The acti'ator then binds plasminogen and then binds to ibrin 1) lysine residues are e7posed and plasminogen and tP9 binds to ibrin* lysing the clot) 3ote that tP9 is ibrin speci ic* &hile uP9 is not) Most lytic acti'ity that occurs pathologically +and therapeutically, re ers to the ibrin speci icity to tP9J
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!auses o increase ibrinolysis or ibrinogenolysis: Hereditary +rare,: %7cess plasminogen acti'ator acti'ity +too much tP9, ?ecreased plasminogen acti'ator inhibitor acti'ity +P9I-1 de iciency, 9lpha-2 plasmin inhibitor de iciency 9c6uired: 0i'er cirrhosis +!-MM-3J, 9myloidosis Malignancy +tumor makes something analogous to plasminogen acti'ators, Iatrogenic: doctor gi'es too much uP9 or tP9 intra'enously ?iagnosis o abnormalities in ibrinolysis or ibrinogenolysis: 2ine 6uin none o diagnosis is (.#"t n d d&l$t /.#l )l##d %l#t l0(&( t&- +=1 Q hrs, Bhat this is: Take blood and clotting it &ith thrombin in 'itro %le'ated ibrin degradation products Platelet number is usually normal. e7ception is that plasmin can cause $P 1b5A5ID abnormalities. also &atch or splenomegaly in cirrhosis PT and aPTT 'ariable: plasmin can degrade both A and AIII* but sometimes only partially* so can4t rely on them Treatment: EACA (A-&%a") binds lysine residues on plasmin* preventing plasminogen activators an! plasminogen from bin!ing to fibrin) Fou must e7clude ?I! be ore using %9!9* or thrombotic complications &ill result) I the patient has ?I! &ith secondary ibrinolysis* you a combination of %eparin an! EA+A +&hich is 6uite dangerous,) C&"%$lat&n4 ant&%#a4$lant(: T&o types: %7ogenous H !a"&n* 0MB Heparin* Hirudin 9ccidental heparin o'erdoses in hospitals are an issue Treatment: neutrali8e heparin &ith protamine sul ate %ndogenous -ccasional monoclonal Ig that &ill inhibit ibrin polymeri8ation 9ntibodies to any o the coagulation proteins that appear de no'o +autoantibodies, or in patients &ith pre-e7isting clotting actor de ects a ter trans usion +alloantibodies,)

9utantibodies can de'elop against any clotting actor* but &hen it occurs* it only de'elops against -3%) The most common is against " AIII) Treatment: immunosuppressi'e therapy. may disappear spontaneously Heparin-like anticoagulants +rare, 3ote on lab diagnosis o inhibitors using :0::0 mi7: 0upus anticoagulant &ill a ect the aPTT and cause thrombosis) To di erentiate* it &ill not correct &ith the addition o :0::0 mi7 o normal plasma because it is an inhibitor)

Ma((&* t"an(3$(&#n > the administration o blood products greater than 1):7 the patient4s blood 'olume* or the replacement o 1 blood 'olume o'er a 2; hour period) Cesults in a !ilution coagulopat%y &ith decreased platelets and coagulation actors Parado7ically* there can also be hypoper usion in some areas o the body resulting in ?I! +10< cases,) Cenal and li'er dys unction can be additional complications) ?iagnosis is usually easy based on blood replacement history 10. H " d&ta"0 and a%>$&" d . -#(tat&% d&(#"d "( a((#%&at d /&t. H% ((&* )l d&n4. ac6uired hemostatic de ects: L$!$( Ant&%#a4$lant: inhibits phospholipid dependent in 'itro coagulation tests* particularly aPTT +thus* the prolonge! a# is an arti act* since none o the clotting actors are de icient. aPTT &ill not correct &ith :0::0 mi7,) The condition is composed o autoantibodies directed at hemostatic proteins that de'elop an a inity or phospholipid) 9lthough the condition blocks coagulation* it also parado7ically causes venous t%rombosis and etal death N !."#t&% S0nd"#- : massive proteinuria) In the proteinuria* patients lose antithrombin III and protein 2* thus compromising ibrinolysis and predisposing to 'enous thrombosis) These actors are Hlo& molecular &eightI and are easily lost &ith nephrosis In addition* patients &ill ha'e increased 'iscosity rom increased ibrinogen le'els ?IC: secondary ibrinolysis T."#-)#t&%+t."#-)#%0t#! n&% !$"!$"a (TTP): platelet plugs in micro'asculature H -#l0t&% U" -&% S0nd"#- : heparin binds to " IA H !a"&n+&nd$% d t."#-)#%0t#! n&a M0 l#!"#l&3 "at&* d&(#"d "( Pa"#H0(-al n#%t$"al . -#4l#)&n$"&a A$t#ant&)#d0 t# nat$"al ant&%#a4$lant: antibodies to Protein ! and 2) - course* there are a &hole host o ac6uired hypercoaguable states that are not o'ert hemostatic de ects) They include 'enous stasis rom surgery5immobili8ation* cancer5chemo* oral contracepti'es* hyper'iscosity* 'asculitis* I(?* arti icial 'al'es* atherosclerosis* ac6uired dyslipidemia* increased 0Pa* ac6uired homocysteinemia* cocaine addiction* hypereosinophilic syndrome* smoking* and diabetes) Hereditary disorders not associated &ith hemostatic de ects include hyperhomocystenemia* dyslipidemia* sickle cell disease* and platelet receptor allotypes) Cecall that these predispose to both arterial and 'enous thrombosis)