Robbins Essential Pathology PDF - Hemodynamic Disorders, Thromboembolism, and Shock

32 CHAPTER 3 Hemodynamic Disorders, Thromboembolism, and Shock A...

32 CHAPTER 3 Hemodynamic Disorders, Thromboembolism, and Shock A A B Fig. 3.2 Liver with chronic passive congestion and hemorrhagic necrosis. (A) In this autopsy specimen, central areas are red and slightly depressed compared with the surrounding tan viable parenchyma, creating “nutmeg B liver” (so called because it resembles the cut surface of a nutmeg). (B) Fig. 3.3 (A) Punctate petechial hemorrhages of the colonic mucosa, a Microscopic preparation shows centrilobular hepatic necrosis with hemor- consequence of thrombocytopenia. (B) Fatal intracerebral hemorrhage. rhage and scattered inflammatory cells. (Courtesy of Dr. James Crawford, Hofstra/Northwell School of Medicine, Hempstead, NY.) Platelets    P ur pura are 3- o 5-mm be e ds  a may sem  rom d ee c  s n p aee  unc  on,  rauma, v as c u  ar  n   am ma  on , or vas c u  ar Platelets are anucleate fragments derived from megakaryocytes  rag   y. that form the primary hemostatic plug and provide a procoagu-    Eccymoses are 1-2 cm n sze and correspond o “bruses”; ey are lant surface that promotes secondary hemostasis. usuay caused by rauma. Paee uncon depends on surace gycoproen recepors, a con- race cyoskeeon, and cyopasmc granues a conan a number Hemostasis, the clotting of blood following blood vessel trauma, is o procoaguan subsances. In e seng o vascuar njur y, paees essential for life. undergo a seres o sereoypc evens: Under norma crcumsances, bood cong occurs a ses were e    Adeson. Paee adeson s medaed argey by neracons w was o bood vesses ave been pyscay dsruped. he na seps n vWF, wc acs as a brdge beween exposed subendoea coa- co ormaon are wo muuay renorcng processes (Fg. 3.4): gen and paee surace recepor gycoproen 1b (Gp1b).    Prmary emostass s naed by e exposure o subendoea    Actvaton. Paees cange sape rom smoo dscs o spky coagen and von Webrand acor (vWF) wn njured vesse speres and reease e conens o er granues, wc ncude was. hese acors ead o e adeson and acvaon o paees, coaguaon coacors (cacum, acor V) and paee acvaors wc orm a paee-rc pug. suc as adenosne dpospae (ADP), wc recru oer paees    S econdary emostass s rggered by e exposure o ssue acor o e growng paee pug. wn e subendoeum and ssues. Tssue acor acs n con-    Aggregaton. he sape cange assocaed w acvaon exposes juncon w acor VII (descrbed aer) o nae e coaguaon negavey carged pospopds, wc are requred by ceran cascade, wc uses coacors a are presen on e suraces o coaguaon acors (descrbed aer), and aso aers e conorma- acvaed paees and eads o e deposon o brn. Fbrn ren- on o surace gycoproen IIb/IIIa (GpIIb/IIIa), converng GpIIa/ orces and sabzes e paee pug, seang e area o vascuar IIIb o a g-ainy recepor or brnogen. Bvaen brdgng damage and prevenng urer beedng. neracons nvovng GpIIa/IIIb recepors and brnogen en Once a co as ormed, s exen mus be med o e area o cause paees o cump no aggregaes. damage. hs s medaed by counerreguaor y mecansms, wc we Decences o GpIb, GpIIa/IIIb, or vWF are assocaed w abnor- w dscuss aer n s caper. ma beedng (Fg. 3.5).  CHAPTER 3 Hemodynamic Disorders, Thromboembolism, and Shock 33 A. VASOCONSTRICTION Deficiency: Bernard-Soulier Endothelium Basement membrane Arteriole smooth muscle syndrome Deficiency: GpIb Glanzmann Platelet thrombasthenia Site of injury GpIIb-IIIa Fibrinogen complex GpIb Endothelium ADP induces conformational Endothelin release Reflex ECM (collagen) change causes vasoconstriction vasoconstriction von Willebrand factor B. PLATELET ACTIVATION AND AGGREGATION Deficiency: von Willebrand Subendothelium disease Fig. 3.5 Platelet adhesion and aggregation. vWF functions as an adhe- 2 Shape change 4 Recruitment sive bridge between subendothelial collagen and the glycoprotein Ib 3 Granule release (GpIb) platelet receptor. Platelet aggregation is accomplished by fibrin- (ADP, TXA ) 2 1 Platelet adhesion ogen binding to platelet GpIIb-IIIa receptors on different platelets. Con- Aggregation (hemostatic genital deficiencies in the various receptors or bridging molecules lead vWF plug) to the diseases indicated in the colored boxes. ADP, Adenosine diphos- 5 phate. Endothelium Basement Collagen reeased by acvaed paees s romboxane A , a poen agons o 2 membrane paee aggregaon. Asprn’s anpaee efecs are due o s rrevers- be nbon o cycooxygenase, an enzyme requred or romboxane C. ACTIVATION OF CLOTTING FACTORS AND FORMATION A syness. 2 OF FIBRIN Coagulation Cascade he coaguaon cascade s a seres o enzymac reacons a cum- nae n e deposon o brn. In e aboraor y, e cascade as wo 2 Phospholipid naon pons, one nvovng acor XII (conac acor) and e sec- 3 Thrombin activation complex expression ond one nvovng acor VII (Fg. 3.6). 4 Fibrin polymerization    e ntrnsc patway sars w acor XII and s naed n e 1 Tissue factor Tissue factor aboraor y by e addon o negavey carged maera suc as 1 gass beads, aong w cacum and pospopds, o pasma. he me un e ormaon o a brn co s recorded as e para rombopasn me (PT T).    e extrnsc patway sars w acor VII and s naed by e Fibrin addon o ssue acor, cacum, and pospopds o pasma. Ca- Fig. 3.4 Normal hemostasis. (A) After vascular injury, local neurohumoral cum s a coacor or prorombn and acors VII, IX, and X, a o factors induce a transient vasoconstriction. (B) Platelets bind via glyco- protein Ib (GpIb) receptors to von Willebrand factor (vWF) on exposed wc conan specay moded guamae resdues a bnd ca- extracellular matrix and are activated, undergoing a shape change and cum, wereas pospopds (provded by paees n e body) are a granule release. Released adenosine diphosphate (ADP) and throm- requred by acor IX and acor X compexes. he me un e or- boxane A (TxA ) induce additional platelet aggregation through platelet 2 2 maon o a brn co s recorded as e prorombn me (PT). he GpIIb-IIIa receptor binding to fibrinogen, and form the primary hemo- key seps n e coaguaon cascade, common o bo paways are: static plug. (C) Local activation of the coagulation cascade (involving    converson o acor X o acvaed acor X (Xa), wc s med- tissue factor and platelet phospholipids) results in fibrin polymerization, aed by a compex o acor IXa and acor VIIIa “cementing” the platelets into a definitive secondary hemostatic plug.    converson o prorombn o rombn by a compex o acor ECM, extracellular matrix. Xa and Va    converson o brnogen o brn medaed by rombn Paee aggregaon occurs n parae w coaguaon acor    he eemens sared by e exrnsc and nrnsc paways (ac- acvaon, and e wo sysems work ogeer. Mos noaby, rom- or X, coacor acor V, prorombn, and brnogen) comprse e bn, e proease a ceaves brnogen o creae brn, aso ceaves a common paway. proease-acvaed recepor on e surace o paees, rggerng sg- he PT and e PT T are useu or evauang e coaguaon acor nas a augmen paee acvaon and aggregaon. Anoer acor uncon bu do no recapuae e evens a ead o cong nvvo. 34 CHAPTER 3 Hemodynamic Disorders, Thromboembolism, and Shock CLOTTING IN THE LABORATORY CLOTTING IN VIVO Intrinsic pathway Vascular damage Exposure of tissue factor Negatively charged surface (e.g., glass beads) TF Extrinsic pathway TF Tissue factor XII XIIa X* VII* VIIa TF XI XIa VII* IX* IXa X* VIIIa TF Va IX* IXa VIIa Xa XI Xla VIIIa Va Prothrombin* Thrombin Xa Prothrombin* Thrombin Fibrin Fibrinogen Fibrin clot Fibrinogen A clot B Fig. 3.6 The coagulation cascade in the laboratory and in vivo. (A) Clotting is initiated in the laboratory by add- ing phospholipids, calcium, and either a negative charged substance such as glass beads (intrinsic pathway) or a source of tissue factor (extrinsic pathway). (B) In vivo, tissue factor is the major initiator of coagulation, which is amplified by feedback loops involving thrombin (dotted lines). The red polypeptides are inactive fac- tors, the dark green polypeptides are active factors, and the light green polypeptides correspond to cofactors. Factors marked with an asterisk (*) are vitamin K dependent, as are proteins C and S (not depicted). Warfarin acts as an anticoagulant by inhibiting the -carboxylation of the vitamin K–dependent coagulation factors. Vita- min K is an essential cofactor for the synthesis of all of these vitamin K–dependent clotting factors. For exampe, rare paens w acor XII decency do no beed, consequences. hs nvoves a number o negave reguaors, e mos wereas paens w acor XI decency ave a md beedng dsor- mporan o wc are consuvey produced by nac norma endo- der. In conras, decences o oer acors are assocaed w severe eum ces near e se o njur y. hese endoeum-derved an- beedng dsorders (e emopas [see Caper 9]) or are ncom- coaguans ncude surace moecues a nb or nacvae varous pabe w e. hs suggess a e major naor o coaguaon cong acors, as we as paee nbors and soube acors a n vvo s ssue acor, and a ssue acor/acor VII compexes ac promoe e dssouon o co (Fg. 3.7). nvvo by acvang acor IX raer an acor X (Fg. 3.6). R e ma rk aby, s e ve r a  o  e mo s  mp or  an c ou ne r- re g u  a - or y me can s ms  nvov  ng nor m a  e nd o e u m are a c  v ae d by Coagulation Control   romb n , w   c b e c ome s an an  c o ag u  an as  s w ase d w ay Once e acvaon o coaguaon acors and paees commences,  rom are as o v as c u  ar d amage. O ne w ay   a   s o c c u rs s   rou g   mus be conned o e mmedae se o njur y o preven serous b nd  ng o   romb n o a su r  a c e proe  n on e nd o e u m caed INHIBIT Heparin-like Tissue factor Thrombomodulin THROMBOSIS molecule pathway inhibitor Endothelial effects t-PA PGI and NO 2 Antithrombin Thrombin III Inactivates tissue factor-VIIa complexes Thrombin Inhibits platelet Protein C Active protein C aggregation Inactivates thrombin (also factors IXa and Xa) (requires protein S) Activates Inactivates factors Va and VIIIa fibrinolysis Fig. 3.7 Anticoagulant properties of normal endothelium. Highlighted are multiple inhibitors of the coagula- tion cascade that are expressed on (heparin-like molecules, thrombomodulin) or secreted from (tissue factor pathway inhibitor) endothelium, as well as secreted inhibitors of platelets (PGI and NO) and t-PA (tissue 2 plasminogen activator), which stimulates the breakdown of fibrin clot.  CHAPTER 3 Hemodynamic Disorders, Thromboembolism, and Shock 35 trombomodun. B ou nd   romb n no  onge r s ab e o c e ave  br  n - wasou o acvaed coaguaon acors and mpedes e nlow o o ge n and  nse a d a c qu  re s  e ab   y o c e ave proe  n C. Proe  n cong acor nbors. C and  s c o a c or, proe  n S, n u r n  n a c  v ae  a c or V, a c r   c a  Numerous abnormaes afecng e ear and e vesses can c o a c or or  a c or X. T e  mp or  anc e o   s re a c   on s ma d e e v - ead o sass or urbuen bood low : aneurysma daons o e d e n by  e  nc re as e d r  sk o deep ve nous   romb o s  s ( DV T )   a ear oowng myocarda narcon, or o aerosceroc areres; s s een n p a  e n s w   a v ar  an o  a c or V caed  a c or V L eden, et ara daon due o mra senoss; and ara braon. w   c s re s s an o  n a c  v a  on by proe  n C. We w re u r n o    Hypercoaguabty. Hypercoaguaby s any aeraon a ren- r sk  a c ors or DV T  ae r. T  romb n a s o c e ave s and a c  v ae s  e ders e bood more prone o romboss an norma. he causes   romb n re c e por on e nd o e u m , s  mu  a  ng  e re e a s e o  s- may be nered or acqured (Tabe 3.2). he mos common ner- su e p as m  no ge n a c  v a  on (  - PA ) , an  mp or  an a c  v aor o  e ed rsk acors ncude actor V Leden (aready menoned), wc bre a kd ow n o  br  n c o s (  br  noy s s ). s ound n 2% o 15% o peope o Norern European descen, and a genec varan a ncreases pasma eves o prorombn. Inered rsk acors are assocaed w romboss a a young age; THROMBOSIS n genera, e occurrence o a romboc even n an ndvdua ess an 50 years o age s an ndcaon or a genec workup. Even Thrombosis, the abnormal clotting of blood within intact vessels, is more common are acqured rsk acors: age over 50 years, mae sex, associated with a serious risk of mortality. mmobzaon, yperesrogenc saes (e.g., pregnancy and use o Pathogeness. hromboss relecs some abnormay nvovng e ora conracepves), and smokng. Esrogens ncrease syness o vesse wa, e low o bood (speccay, sass or urbuen low), procoaguan proens and reduce ormaon o ancoaguan pro- or bood coaguaby, an aeraon reerred o as ypercoaguaby ens n e ver. hese ree acors make up e Vrcow trad (Fg. 3.8), named or e Among oer causes o ypercoaguabe saes, wo deser ve amous 18 cenur y paoogs Rudo Vrcow. bre menon because o er unque paogeness and cnca    Abnormates of te vesse wa (endotea njur y). In vesses car- mporance: r yng bood a g pressures and under g sear orces, suc    Heparn-nduced thrombocytopena (HIT) syndrome occurs n up as e aora and s major brances, e coronar y areres, and o 5% o paens reaed w unraconaed eparn and a ower e areres suppyng e CNS, co ormaon s mos commony racon o paens reaed w ow-moecuar-weg eparn. due o aerosceroc esons (see Caper 7). Rupure o aero- HIT s caused by anbodes a bnd o compexes composed o sceroc paques exposes coagen and ssue acor and eads o eparn and paee acor 4. hroug uncear mecansms, s acvaon o paees and coaguaon acors. he endoea eads o paee acvaon, paee consumpon, and deposon abnormaes assocaed w aerosceross ead o e ncreased o paee-rc cos n e arera and venous crcuaon. hese expresson o procoaguan acors and e decreased expresson o ancoaguan acors by endoea ces, wc may conrbue o e proromboc sae seen n aerosceross. Trauma or nlam- maor y processes suc as vascus a damage vesses aso may Table 3.2 Hypercoagulable States ead o rombus ormaon.    Abnorma bood ow. Turbuence and sass conrbue o rombo- Primary (Genetic) ss n e ear and e arera sde o e crcuaon, wereas sass s e major acor n e deveopmen o venous romb. Sass and Common (>1% of the Population) urbuen bood low cause canges n endoea ce gene expres- Factor V mutation (factor V Leiden) son a avor romboss. Stass aows paees exended con- Prothrombin mutation ac w e vesse wa, were ey may encouner dysuncona Rare endoeum or areas denuded o endoeum; sass aso sows e Antithrombin III deficiency Protein C deficiency Protein S deficiency ENDOTHELIAL INJURY Secondary (Acquired) Higher Risk for Thrombosis Prolonged bed rest or immobilization Cardiac dysmotility (myocardial infarction, atrial fibrillation) Tissue injury (surgery, fracture, burn) THROMBOSIS Disseminated cancer Prosthetic cardiac valves Disseminated intravascular coagulation Heparin-induced thrombocytopenia ABNORMAL Antiphospholipid antibody syndrome HYPERCOAGULABILITY BLOOD FLOW Lower Risk for Thrombosis Nephrotic syndrome (due to loss of antithrombin III) Fig. 3.8 Virchow triad in thrombosis. Endothelial integrity is the most Hyperestrogenic states (during pregnancy and following delivery) important factor. Abnormalities of procoagulants or anticoagulants can Oral contraceptive use tip the balance in favor of thrombosis. Abnormal blood flow (stasis or Sickle cell anemia turbulence) can lead to hypercoagulability directly and also indirectly Smoking through endothelial dysfunction. 36 CHAPTER 3 Hemodynamic Disorders, Thromboembolism, and Shock cos may ead o oss o mbs or e, and recognon o e HIT syndrome and cessaon o eparn erapy are ereore crca.    Antpospopd antbody syndrome, assocaed w recurren romboss, repeaed mscarrages, and cardac vave vegea- ons, may be an soaed anomay or secondar y o an auom- mune dsorder (e.g., sysemc upus er yemaosus). he name o s dsorder came rom e deecon o crcuang anbodes a bnd o pospopds n e ab. I s beeved a e mos mporan paoogc efecs n paens are medaed roug bndng o ese anbodes o epopes on proens a are some- ow nduced or “unveed” by pospopds. In vvo,  s sus- peced a ese anbodes bnd o varous proens and nduce a ypercoaguabe sae roug unceran mecansms. How- A ever, n vro, e anbodes nerere w pospopds and us nb coaguaon (ence e name upus antcoaguant s a msnomer). he anbodes oten cross-reac w cardopn, a componen o e es or syps, producng a ase-posve resu. Morphology. Arera romb ypcay overe aerosceroc esons, wereas venous and cardac romb caracerscay occur a ses o sass. A ses o naon, romb are aaced o e underyng vesse or cardac wa. Wen ocaed n paray obsruced vesses and exposed o lowng bood, romb end o propagae oward e ear (even arera romb, wc grow n a rerograde drecon). Venous romb are parcuary key o propagae some dsance, ormng ong cass wn e vesse umen. he propagang porons are no aaced o vesse was B and are prone o ragmenaon and embozaon. Fig. 3.9 Mural thrombi. (A) Thrombus in the left and right ventricular Mcroscopcay, romb ave amnaons caed nes of Zan, apices, overlying white fibrous scar. (B) Laminated thrombus in a dilated wc represen aernang pae ayers rc n paees and brn, abdominal aortic aneurysm. Numerous friable mural thrombi are also and darker ayers rc n red ces. Layered romb ony orm n superimposed on advanced atherosclerotic lesions of the more proxi- lowng bood, and e presence o ese ayers, as we as e rm mal aorta (left side of photograph). aacmen o e co o e vesse wa, dsngus anemorem romb rom posmorem cos. Venous romb conan a ger racon o red ces enrapped n brn (red cos) an arera skn o necon and varcose ucers. By conras, deep venous rom- romb. In e days and weeks oowng an na romboc or boses (DVTs) n arge eg vens a or above e eve o e knee oten emboc even, vascuar romb may undergo dssouon; connue emboze. DVTs aso may cause pan and edema, bu coaera venous o sed embo; or undergo organzaon (Suppemena eFg. 3.1). In cannes requeny crcumven e obsrucon. Consequeny, organzng romb, e ngrow o sroma ces and e depos- approxmaey 50% o DVTs are asympomac and are recognzed ony on o exraceuar marx are accompaned by var yng degrees o ater ey ave embozed o e ungs. recanazaon. he cnca mporance o romboemboc dsease canno be Nonobsrucve romb occurrng n e ear or aora bear oversaed. he greaes o s aken by coronar y arer y romboss speca desgnaons. hromb occurrng n e ear and e aorc secondar y o aerosceross, wc s e major cause o myocarda umen (Fg. 3.9) are reerred o as mural thromb, wereas romb narcon (ear aack) n e Wesern word. Embo sed rom e on ear vaves are caed vegetatons. Some vegeaons occur n ear and romboemboc dsease due o aerosceross o e carod ypercoaguabe saes and are sere, bu oers are caused by bac- areres and oer grea vesses suppyng e cenra ner vous sysem era or unga necons (necve endocards; see Caper 8) (CNS) are an mporan cause o sroke. Pumonar y embozaon o and may ead o e deveopmen o arge romboc masses. DVTs s aa n approxmaey 3% o afeced paens. EMBOLISM Clncal Features. Cnca sympoms caused by romb are due o e obsrucon o vesses and co embozaon and var y accordng o e An embolus is a detached intravascular solid, liquid, or gaseous vesses and organs a are afeced. he mos eared compcaon o mass that is carried by the blood from its point of origin to a dis- romb s embozaon (dscussed aer), wereas romb n smaer tant site, where it may cause vascular obstruction and organ dys- areres are occusve and ence more key o cause a oca narcon function or infarction. due o obsrucon o e bood suppy o organs suc as e ear and he vas majory o embo are derved rom dsodged romb; e bran. he reaonsp beween arera romboss, aeroscero- ence, e erm tromboembosm. Less common ypes o embo ss, and cardac dsease s dscussed n dea n Caper 8 ncude a dropes, bubbes o ar or nrogen, aerosceroc debrs More an 90% o venous romboses occur n e ower exrem- (.e., coesero embo), umor ragmens, bs o bone marrow, and es. hromb n superca vens rarey emboze, bu ey may be amnoc lud. Embo are ranspored roug e bood rom er panu and cause congeson and edema, predsposng e overyng se o orgn un ey odge n e rs vesse a s oo narrow o  CHAPTER 3 Hemodynamic Disorders, Thromboembolism, and Shock 36.e1 Supplemental eFig. 3.1 Low-power view of a thrombosed artery stained for elastic tissue. The original lumen is delineated by the internal elastic lamina (arrows) and is totally filled with organized thrombus, now punctuated by several recanalized endothelium-lined channels (white spaces).