病理生理学病理生理学 (4).pdf

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1、Disseminated Intravascular CoagulationBenjamin M.Boral,DO,1Dennis J.Williams,MD,2and Leonard I.Boral,MD,MBA2From the Departments of1Medicine and2Pathology and Laboratory Medicine,University of Kentucky Medical Center,Lexington.Key Words:Coagulopathy;DIC;Thrombi;Hemorrhage;Thrombocytopenia;ThrombinAm

2、 J Clin Pathol December 2016;146:670-680DOI:10.1093/AJCP/AQW195ABSTRACTObjectives:To provide a review of the definition,patho-physiology,differential diagnosis,and treatment of dissemi-nated intravascular coagulation(DIC).Methods:A case scenario and a review of the literaturerelated to the pertinent

3、 facts concerning DIC are provided.Results:DIC is a systemic pathophysiologic process and nota single disease entity,resulting from an overwhelming acti-vation of coagulation that consumes platelets and coagula-tion factors and causes microvascular fibrin thrombi,whichcan result in multiorgan dysfun

4、ction syndrome from tissueischemia.Some conditions associated with acute DIC in-clude septic shock,exsanguinating trauma,burns,or acutepromyelocytic leukemia.Conclusions:The massive tissue factor stimulus results inexcess intravascular thrombin,which overcomes the anti-coagulant systems and leads to

5、 thrombosis.Because of con-sumption of coagulation factors and platelets,DIC also hasa hemorrhagic phase.Treatment of the bleeding patient withDIC is supportive with the use of blood components.Case HistoryA 44-year-old man with a medical history of hepatitis C,cirrhosis,and chronic kidney disease s

6、ought treatment at theemergency room for altered mental status and an ammonialevel over 400 mmol/L(11-51 mmol/L).The patient was givenlactulose;however,his mental status worsened to a pointwhere he required intubation.Vital signs on admission to theintensive care unit(ICU)on October 23 were as follo

7、ws:bloodpressure,120/84mm Hg;heart rate,107 beats/min;respiratoryrate,18/min;and temperature,97.8?F.The following labora-tory results were obtained(reference range is in parentheses)on admission:WBC,20.1?109/L(3.7-10.3?109/L);so-dium,111mmol/L(136-145mmol/L);potassium,5.7mmol/L(3.7-4.8mmol/L);hemogl

8、obin(Hb),13.5g/dL(13.7-17.5g/dLin males);platelet count,253?109/L(155-369?109/L);international normalized ratio(INR),1.4(0.9-1.2);prothrom-bin time(PT),13.5 seconds(9.6-12.5 seconds);activatedthromboplastin time(aPTT),34 seconds(19-30 seconds);andcreatinine,5.8mg/dL(0.8-1.3mg/dL).On October 23,thepa

9、tient was started on vancomycin,piperacillin/tazobactam,and fluids because of concern for sepsis associated with sys-temic inflammatory response syndrome and multiorgan fail-ure,as well as laboratory values showing a high WBC countand an elevated lactate of 8mmol/L(0.5-1.6mmol/L).Hisvital signs wors

10、ened over the next 24hours,and he becamehypotensive,requiring treatment with norepinephrine and 6 Lof normal saline on October 24.His renal function continuedto decline,for which he received continuous renal replacementtherapy on October 25.Laboratory values on October 25 wereconsistent with DIC,sho

11、wing a significant decrease in hemo-globin,fibrinogen,and platelets and an increase in PT,aPTT,INR,and lactate dehydrogenase(LDH)Table 1.Petechiaewere not present.A paracentesis was performed to rule outperitoneal bleeding,and red fluid(shown to be RBCs in the la-boratory)was noted on the tap.It was

12、 felt that the patient had670 Am J Clin Pathol 2016;146:670-680DOI:10.1093/ajcp/aqw195 American Society for Clinical Pathology,2016.All rights reserved.For permissions,please e-mail:AJCP/REVIEWARTICLEDownloaded from https:/ by guest on 15 December 2020developed spontaneous multifocal hemoperitoneum

13、secondaryto his DIC,and he was given packed RBCs,fresh-frozenplasma,cryoprecipitate,platelets,and vitamin K to treat hisperitoneal bleeding,which stopped by October 26.Over thenext few days,he continued to require norepinephrine,buteventually his vital signs and laboratory values stabilized.During t

14、he next few days,he clinically seemed to improve,buthe was found to have multiple infections,including a bloodculture growing vancomycin-resistant enterococcus(VRE),aprotected alveolar lavage growing Stenotrophomonas malto-philia and VRE,a peritoneal fluid growing Acinetobacter,and a urinalysis grow

15、ing Candida glabrata.On October29,he was started on daptomycin,linezolid,trimethoprim/sulfamethoxazole,and fluconazole to treat his current infec-tions,and his vancomycin and piperacillin/tazobactam werediscontinued.He remained hemodynamically stable,so hewas taken off pressors and extubated on Nove

16、mber 1.Hewas in the process of being transferred out of the ICU,butunfortunately overnight the patient became obtunded andhypotensive.The following laboratory values(referencerange)were obtained shortly after midnight on November4:INR,2.6(0.9-1.2);PT,25.9 seconds(9.6-12.5seconds);aPTT,44 seconds(19-

17、30 seconds);Hb,5.8g/dL(13.7-17.5g/dL);platelet count,34?109/L(155-369?109/L);D-dimer,8.6mg/L(1604142-49160Fibrinogen(150-450),mg/dL6617682Lactate(0.5-1.6),mmol/L82.0-2.512pH(7.35-7.45)7.187.027.327.427.487.57.4-7.456.77Lactate dehydrogenase(140-280),U/L412262207Creatinine(0.8-1.30),mg/dL5.86.42.51.7

18、1.161.11.1-4.05.24Blood products,No.RBC units3None0Fresh-frozen plasma units22None2Apheresis platelet units3None1Cryoprecipitate units10None10aNote that the prothrombin time reagent contains a heparin neutralizer.AJCP/REVIEWARTICLE American Society for Clinical PathologyAm J Clin Pathol 2016;146:670

19、-680 671DOI:10.1093/ajcp/aqw195671Downloaded from https:/ by guest on 15 December 2020Today,it is thought that in vivo secondary hemostasistakes place mainly through TF activation of the cell-basedsystem,even where there is breakdown of the endothelium.1Here,TF,considered to be part of most cell mem

20、brane lipo-proteins,is either released upon damage of a cell,includingthe endothelial cells,or secreted into the blood by plateletsand/or monocytes after stimulation.Factor VII is then acti-vated,and through a series of enzyme reactions proceedingon cell membranes involving the activation of several

21、 co-agulation factors(X,IX,XI,and prothrombin),thrombin isformed and subsequently a fibrin clot.Factors V and VIIIare nonenzyme catalysts in this model,and factor XII is notpart of this new coagulation in vivo system.The major rolesof the contact system(factor XII,high molecular weightkininogen HMWK

22、,and prekallikrein PK)are to enhancethe inflammatory response by stimulating chemotaxis inneutrophils and activating C1,C3,and C5 in the comple-ment system and to promote vascular repair.HMWK can beenzymatically altered by factor XIIa,factor XIa,and/or kal-likrein to produce bradykinin,a vasoactive

23、agent causingvascular dilation,increased vascular permeability(as seenin inflammation),and endothelial cells to release tissue plas-minogen activator(TPA).Therefore,the activation of factorXII in vivo is thought to be primarily associated with in-flammation and vascular repair rather than coagulatio

24、n.Onthe other hand,in the test tube(in vitro),the plasma-basedcoagulation test,aPTT,will be very prolonged if there is adeficiency of factor XII.Factor XII is needed in the firststep(contact)of the intrinsic coagulation pathway in vitrobut is thought to play a minor role,if any,in normalphysiologic

25、clot formation in vivo.However,because ofprevention of pathologic thrombus formation in factorXIIdeficient mice,factor XII may play a role in thepathologic propagation and stabilization of fibrin thrombi inischemic strokes and pulmonary emboli.2Factor XIIinhibition is under investigation as a possib

26、le anticoagulanttherapy that would not increase the risk of bleeding.3Once a fibrin clot is produced,it is stabilized by cova-lent cross-linking through the actions of factor XIII.The laststep of the healing process is for blood clots to be reorgan-ized and resorbed by fibrinolysis so that unimpeded

27、 bloodflow through the originally damaged vessel can be reestab-lished.The plasma protein plasminogen,the inactive precur-sor to the active fibrinolysis agent plasmin,is bound tofibrinogen and fibrin so that it is incorporated into clots.When endothelial cells are injured,they release TPA,whichcause

28、s the plasminogen in clots to convert to plasmin anddigest the cross-linked fibrin clot to form soluble fibrin deg-radation products.Any free circulating plasmin is rapidlyinactivated by plasma a2-antiplasmin,made in the liver,and plasminogen activator inhibitor 1(PAI-1),from endo-thelial cells,inhi

29、bits TPA activity.1There is a generalized interrelationship between theinitiation of coagulation,complement activation,and the in-flammatory response,so that when one is activated,theothers are stimulated as wellFigure 2.They interactthrough a mechanism known as“crosstalk,”as shown inFigure 3.4Essen

30、tially,primary hemostasis(platelet aggregation)stimulates secondary hemostasis(the coagulation factor cas-cade)through TF/factor VIIa as well as inflammationthrough the factor XIIa/kallikrein/bradykinin/C3a mechan-ism.4Complement can then lyse cells and/or bacteria,whichrelease damage-associated mol

31、ecular patterns(DAMPs)and/or pathogen-associated molecular patterns(PAMPs)aswell as phospholipids,which all can stimulate secondaryhemostasis.DAMPs are warning signals that cell damage hasoccurred,and DAMP receptors,when activated,causecellularIntrinsicKPKHMWKHMWKExtrinsicCommonXIIXIIXaVIITFVIIaTFXI

32、IVaXFibrinIIaXIaXIIaXaVIIIIXFibrinogenFigure 1 The coagulation cascade showing coagulation fac-tor activation in plasma:intrinsic,extrinsic,and commonpathways.a,activated factor;HMWK,high molecular weightkininogen;II,prothrombin;IIa,thrombin;K,kallikrein;PK,pre-kallikrein;TF,tissue factor.Coagulatio

33、nComplement activationFigure 2Generalized interrelationship between the initi-ation of coagulation,complement activation,and the inflam-matory response.Boral et al/DISSEMINATEDINTRAVASCULARCOAGULATION672 Am J Clin Pathol 2016;146:670-680 American Society for Clinical Pathology672DOI:10.1093/ajcp/aqw

34、195Downloaded from https:/ by guest on 15 December 2020signaling pathways to initiate physiologic actions resulting indamage containment and repair,which include inflammatory,immune,and coagulation responses.A subset of DAMPs isPAMPs consisting of microbial molecules that alert multicel-lular animal

35、s to the presence of invading organisms.PAMPsare detected by the immune system through Toll-like recep-tors,which activate signaling cellular pathways,creating bothan inflammatory and an immune response.The immune re-sponse produces specific antibodies and specific T cells todestroy the intruding pa

36、thogens while the inflammatory re-sponse is more general in nature.5Both thrombin and plasmincan stimulate C5a to create more cell lysis.DICDefinition and BackgroundIn 2001,the International Society on Thrombosis andHemostasis(ISTH)proposed a definition of DIC thatincluded microvascular thrombosis:“

37、DIC is an acquiredsyndrome characterized by the intravascular activation ofcoagulation without a specific localization and arising fromdifferent causes.It can originate from and cause damage tothe microvasculature,which if sufficiently severe,canproduce organ dysfunction.”6In response to an injury t

38、o the blood vessel wall,clotting occurs only as a localized phenomenon,as part ofnormal healing,because there are many checks and balancesto prevent extension of the hemostatic plug mechanism tothe whole intravascular system.The pathophysiology ofDIC,in simple terms,is that the underlying disease st

39、imu-lates such a strong procoagulant activity that it results in anexcess of thrombin,which then overcomes the anticoagulantcontrol mechanisms of protein C(PrC),antithrombin(AT),and the tissue factor pathway inhibitor(TFPI),allowingthrombosis to freely take place throughout the vasculature.1In DIC,t

40、here is a battle between the excess thrombin state,which clinically manifests itself as thrombosis,embolism,and microvascular occlusion by fibrin thrombi,leading tomultiorgan dysfunction syndrome(MODS)from tissue is-chemia,and a hemorrhagic disorder from depletion of plate-lets,consumption of coagul

41、ation factors,and/or acceleratedplasmin formation.7Both thrombosis and bleeding can bepresent in the same patient.DIC is a manifestation/symp-tom/sign of an underlying pathologic process,as is fever,and is not a specific disease entity.If the causative diseaseor condition is successfully treated,the

42、 DIC will disappear.Laboratoryabnormalitiesinthis“consumptioncoagulopathy”include prolonged aPTT and PT/INR,a de-crease in platelet count and in fibrinogen,and an increase infibrin degradation products,including D-dimers(plasmindegradation of cross-linked fibrin).In the older literature,DIC was also

43、 known as defibri-nation syndrome,acquired afibrinogenemia,consumptivecoagulopathy,and thrombohemorrhagic disorder.1Maladies resulting in both thrombosis and hemorrhagehave been recognized for centuries,the foremost of whichwere the“black plague”of the Middle Ages with symptomsof gangrene of the fin

44、gers as well as generalized hemorrhagein organs.It remains controversial as to whether the cause ofthis plague was from Yersinia pestis,spread by the bites ofthe rat flea,or from an Ebola-like hemorrhagic virus.8DIC was first experimentally induced by M.Dupuy in1834 when he intravenously injected br

45、ain tissue intoanimals,resulting in clots seen throughout the vasculature.In1873,B.Naunyn intravenously injected dissolved RBCs andobserved disseminated thrombosis.A.Trousseau in 1865described in patients with advanced malignancy,the multiplethromboses,and tendency of blood to clot.In 1961,Lasch eta

46、l introduced the concept of consumption coagulopathy asthe mechanism leading to hemorrhage in DIC.1DIC is relatively uncommon in the general hospitalizedpatient but accounts for 9%to 19%of ICU admissions andhas a high mortality rate of 45%to 78%.9Acute vs Chronic DICAcute DIC is a consumption coagul

47、opathy state whereexcess thrombin is generated to such a high degree that itPrimary hemostasis(platelet aggregation)Tissue factor/FVIIaC3aC5aC6-C9(membrane attack complex)Recruitment and activation of WBCsMinimalActivated coagulation factorsFXIIaKallikreinBradykinin(vascular integrity)ThrombinSecond

48、ary hemostasis(coagulation factor cascade)Complement(host defense)Cell/Bacterial lysisDAMPS and PAMPSFigure 3 Crosstalk between coagulation,complement acti-vation,and inflammation.Modified from Kurosawa S andStearns-Kurosawa DJ.4a,activated factor;DAMPS,damage-associated molecular patterns;PAMPS,pat

49、hogen-associatedmolecular patterns.AJCP/REVIEWARTICLE American Society for Clinical PathologyAm J Clin Pathol 2016;146:670-680 673DOI:10.1093/ajcp/aqw195673Downloaded from https:/ by guest on 15 December 2020overcomes the large amounts of natural anticoagulants nor-mally present in the plasma.10Acut

50、e DIC is usually trig-gered by large amounts of tissue factor released into theintravascular space,leading to generalized deposition of fi-brin thrombi in the microvasculature contributing to multi-organ dysfunction.10,11MODS most frequently involves thelungs and kidneys followed by brain,heart,live