failure of c oagula tion
DESCRIPTION
Failure of C oagula tion. MUDr. Tomáš Stopka Ph.D. and colleagues from the Institute of Pathophysiology, Charles University. Pl a n. Coagulation Methods DIC T h erap y Presentation. I. Coagulation. Initiating the Clotting Process - PowerPoint PPT PresentationTRANSCRIPT
Failure ofFailure of CCoagulaoagulationtion
MUDr. Tomáš Stopka Ph.D. MUDr. Tomáš Stopka Ph.D. and colleagues from the and colleagues from the
Institute of Pathophysiology, Institute of Pathophysiology, Charles UniversityCharles University
PlPlaann CoagulationCoagulation MethodsMethods
DICDIC TThheraperapyy
PresentationPresentation
I. CoagulationI. CoagulationInitiating the Clotting Process
1. Damaged cells (extrinsic pathway) display a surface protein called tissue factor (TF) that binds to activated Factor 7 (TF-7) to cleave: Factor 10
2. Factor 10 binds and activates Factor 5 (prothrombinase) convertíng prothrombin (also known as Factor II) to thrombin
3. Thrombin proteolytically cleave fibrinogen (Factor I) to fibrin.
4. Factor 13 forms covalent bonds between the soluble fibrin molecules converting them into an insoluble meshwork — the clot.
I. CI. CoagulaoagulationtionAmplifying the Clotting Process
1. The TF-7 complex also activates Factor 9.
2. Factor 9 binds to Factor 8, a protein that circulates in the blood stabilized by another protein, von Willebrand Factor (vWF).
3. Complex 9-8-vW activates more factors: 5,8,10,11
I. CoagulationI. CoagulationLUMEN
Blood clotWALL
Endothelial demageDamaged
endothelial cells display tissue factor
(TF) that binds to activated
Factor 7 (TF-7) to cleave: Factor 10
The intrinsic
cascade is initiated
when contact is
made between
blood and exposed
endothelial cell
surfaces.
I. CoagulationI. Coagulation Controlling ClottingAntithrombin III inactivates: prothrombin, factor 9,
factor 10
Protein C and its cofactor Protein S together inhibit thrombin formation by inactivating Factor 5 and by inactivating Factor 8. Inherited
deficiency (mutations) of Protein C or Protein S (or FV, Leiden)= thrombophilia
Vitamin K is a cofactor needed for the synthesis (in the liver) of
factors 2 (prothrombin), 7, 9, and 10, proteins C and SDeficiency of Vitamin K predisposes to bleeding.
Conversely, blocking the action of vitamin K helps to prevent inappropriate clotting.
Heparin binds to and enhances antithrombin III.
Warfarin (aka coumadin) is an effective vitamin K antagonist.
I. CI. Coagulaoagulationtion Dissolving clots
Plasma plasminogen to the fibrin molecules in a clot. Nearby healthy cells release tissue plasminogen activator (TPA), which also binds to fibrin and, activates plasminogen forming plasmin. Plasmin (serine protease) proceeds to digest fibrin, thus dissolving the clot.
I. CoagulationI. CoagulationHEMOCOAGULATION is INTEGRAL PART of INFLAMATORY RESPONSE
PLATELETS PLAZMATIC COAGULATION SYSTEM
VASCULAR WALL
ENDOTHELIUM
I. CI. CoagulaoagulationtionDISORDERS OF HEMOCOAGULATION = THROMBOSIS AND EMBOLISM
THROMBOSIS
IN MICROCIRCULATION
ARTERIAL
VENOUS
EMBOLISM
LUNGS SYSTEMICSIGNS
-TISSUE ISCHEMIA
- HEMODYNAMIC FAILURE
I. CI. Coagulaoagulationtion Deep Venous Thrombosis (DVT)
A) asymptomatic : > 50% Lung Embolism.B) symptomatic: pain (Homans’s sign), oedema,
dicoloration and incr. temperature of the skin
Posthrombotic syndromelatent, 3 - 15 y after DVT: distension of superf. veins, lipodermatosclerosis, varices, ulceration.
Lung embolism (LE)Dyspnoe, tachypnoe, tachykardia, pleuritic chest pain, distension of the jugular veins, hemoptysis, hemodynamic instability, hemodynamic failure or death.
I. CI. CoagulaoagulationtionBLEEDING
SURGERY SMALL, TRAUMATIC- sc., im.injections- Easy bruising
DIFUSEMICROVASCULAR- purpura - petechia, ekchymosis (>3 mm)- organ apoplexia
A) trombocytopeniaB) Desintegration of microvascular intima
Failure of coagulationtraumatic
II. LaboratoryII. Laboratory
Bleeding time (Duke, 1910)standard puncture of the ear lobe (Duke, 1910) 2 - 5 min. prolonged in thrombocytopenia (<20 000/uL) OR vonWillebrand disease
Capillary resistance ( Rumpel, Leede)pressure on the arm 10,5 kPa/10 min petechia > 5 = increased fragility of capillaries. (hereditary purpura e.g. Weber-Rendu-Osler).
BLEEDING TIME and RESISTANCE OF CAPILARS
II. LaboratoryII. Laboratory
Thrombin time
-full blood is activated with thrombin to form fibrin fiber
-used for measurement of fibrinogen levels (DIC)
Basic coagulation methods
II. LaboratoryII. Laboratory (PLT) – normal 150 - 300 000/uL, for surgery
optimum > 100 000 /uL. Thrombocytopenia PLT < 20 000/ uL – spontaneous bleeding and purpura.
(MPV) - normal 6 - 9 fL, incr. hereditary trombocytopathy.
Agregometry – photometric, with addition of activator of platelet aggregation - ADP, thrombin, kolagen. Diagnosis of hereditary trombocytopaty
Flow cytometry - imunologic. Anti PLT antibodies – diagnosis of imune-
mediated trombocytopenia vWf - imunologic or functional tests incl.
ristocetin
Methods for measuring platelets and vWf
II. LaboratoryII. Laboratory
PT – prothrombin time PT (Quickův) APTT - activated partial thromboplastin time
Statim FBG - fibrinogenu plasma levels (normal :2 -
4 g/L). ( FBG acute phase protein) FDP - imunologic measurement of
degradation products of fibri(noge)n (normal: < 1000 ug/L), ELISA or aglutination semiq. methods.
Methods for measuring Coagulation factorsBlood drown into citrate is centrifuged to obtain decalcified plasma
II. LaboratoryII. Laboratory D-dimer - imunologic measurement of
FDP specific for stabilized fibrin (normal < 500 ug/L). Increased D-dimer DVT/PE and DIC.
AT - function test to measure antithrombin activity in plasma (normal 80 - 100% activity of the control plasma). With heparin part of the TAT inhibitory complex, deficiency predispose to thrombophilia or DIC.
Methods for measuring Coagulation factors
II. LaboratoryII. Laboratory Ethanol test – FDP anti-polymeration
effect on fibrin fiber is blocked by ethanol
Euglobulin method of measuring fibrinolytic activityEuglobulin fraction of plasma obtained with acetic acid conatins predominantly plasminogen, in DIC there is more plasmin and so the test is quicker (result of increased fibrinolysis).
Methods for measuring Coagulation
II. LaboratoryII. Laboratory proteinu C- Act. Protein C
resistence, mutation of FV, mutation of protein S
fibrinolytic system- tPA , inhibitor PAI-1, plazminogen, inhibitor alfa2AP
Antifosfolipid antibodies - lupus anticoagulans (LA) : modif. APTT
Individual factors hemofilia A (FVIII), B(FIX), C (FXI)
Methods for measuring Coagulation
II. LaboratoryII. Laboratory Principle: extrinsic pathway – tissue factor.
Blood drawn to citrate and TF is added. with CaCl2. Time is measured until the fibrin fiber is formed.
Normal: PTN= 12 - 15 s
Prolonged PT:, deficiency of FV, vit. K dep: FII, VII, X, deficient FBG, high FDPs
International normalized ratio INR= (PTP/ PTN)ISI ISI = international index of used tromboplastin (usu > 1). (max. therapeutic INR = 4,5)
Protrombin time PT (Quick)
II. LaboratoryII. Laboratory Principle : intrinsic pathway. Blood drawn to citrate
and kaolin (activates inner system) is added with CaCl2. Time is measured until the fibrin fiber is formed.
Normal APTTN = 27 - 35 s
Used: hemophilia, lupus anticoagulans, heparin therapy (1,5x - 2,5 x).
Prolonged APTT: deficient FII,V, X, - F XII, PreK, HMWK, - FXI, FIX , FVIII (hemofilia C, B,A), lupus anticoagulans, low FBG, high FDP.
Shortened APTT: thrombophilia
APTT
II. LaboratoryII. Laboratory
Disorder PLT BT APTT PT TT FBGTrombocytopenia L P N N N NHemofilia A N N P N N NHemofilia B N N P N N NHemofilia C N N P N N NvW-disease N P N/P N N NLA N N P N/P N N
II. LaboratoryII. Laboratory
Disorder PLT BT APTT PT TTFBG
FV-def.
FII-def.
FVII-def.
Vit.Kdef./OA
FBG-def.
HeparinN P/N P N/P P N N N P P P L
N N P P N NN N N P N NN N P P N NN N P P N N
III.III. DICDICDefinitionDefinition
SecondarySecondary
Disorder of Coagulation with pro-Disorder of Coagulation with pro-thrombotic phase followed by severe thrombotic phase followed by severe bleeding phase (as a result of bleeding phase (as a result of consumption of coagulation factors).consumption of coagulation factors).
III.III. DICDICEthiopathogenesisEthiopathogenesis
Intravascular coagulationIntravascular coagulation
Conditions Associated with Conditions Associated with DICDIC
Heat strokeHeat stroke SepsisSepsis ViremiaViremia PancreatitisPancreatitis Neoplasia (Diffuse and Neoplasia (Diffuse and
local)local) Parasitic InfectionsParasitic Infections Intravascular HemolysisIntravascular Hemolysis Immune-mediated Immune-mediated
DiseasesDiseases Exposure to venom/toxinsExposure to venom/toxins Massive tissue injury Massive tissue injury
(including burns, crush (including burns, crush trauma, and surgical trauma, and surgical procedures)procedures)
ObstetricObstetric ComplicationsComplications Insufficiency of major Insufficiency of major
organs (Liver, Kidney)organs (Liver, Kidney) Diabetes mellitusDiabetes mellitus AcidosisAcidosis PolycythemiaPolycythemia Severe prolonged Severe prolonged
hypotension (including hypotension (including shock)shock)
Severe volume depletionSevere volume depletion Impaired blood flow to a Impaired blood flow to a
major orgamajor organn
What are FDPs and D-What are FDPs and D-dimers and how do they dimers and how do they
relate to DIC?relate to DIC? Activation of the coagulation Activation of the coagulation
cascade results in cascade results in increased increased levels of circulating thrombin levels of circulating thrombin and plasminand plasmin. .
Thrombin cleaves Thrombin cleaves fibrinopeptides A and B from fibrinopeptides A and B from fibrinogen, leaving soluble fibrinogen, leaving soluble fibrin monomersfibrin monomers as the end as the end product (Figure 1).product (Figure 1).
Activation of factor XIII results Activation of factor XIII results in in polymerization of these polymerization of these fibrin monomersfibrin monomers into insoluble into insoluble cross-linked fibrin clots.cross-linked fibrin clots.
•Increased levels of Increased levels of circulating plasmin causes circulating plasmin causes clot lysis and degradation of clot lysis and degradation of fibrinogenfibrinogen and the soluble and the soluble fibrin monomersfibrin monomers..
•Plasmin cleaves fibrinogen Plasmin cleaves fibrinogen into fragments X,Y,D, and E, into fragments X,Y,D, and E, known as known as fibrinogen fibrinogen degradation products degradation products (FDPs).(FDPs).
•Plasmin also cleaves Plasmin also cleaves insoluble cross-linked fibrin insoluble cross-linked fibrin polymers into x-oligomers. polymers into x-oligomers. The main x-oligomers are The main x-oligomers are known as d-dimers.known as d-dimers.
DIC
What are FDPs and D-What are FDPs and D-dimers and how do they dimers and how do they
relate to DIC?relate to DIC?FIBRIN
Monoclonal antibodies have Monoclonal antibodies have been generated which recognize been generated which recognize the the cross-linked domain of d-cross-linked domain of d-dimers as an antigenic targetdimers as an antigenic target. . These antibodies are used in all These antibodies are used in all available d-dimer assays.available d-dimer assays.
Quantitative tests for d-dimers Quantitative tests for d-dimers are available, including are available, including enzymatic immunoassays enzymatic immunoassays (ELISA) and (ELISA) and immunoturbidometric systems. immunoturbidometric systems.
III.III. DICDICNORM NORM
PLT 150 - 300 000 x 10 exp9 /lPLT 150 - 300 000 x 10 exp9 /l APTT 30 - 35 sAPTT 30 - 35 s AT 80 - 140 %AT 80 - 140 % TT 14 - 16 sTT 14 - 16 s FBG 2.5 - 5 g/lFBG 2.5 - 5 g/l FM (ethanol test) FM (ethanol test) DD < 500 ng/mlDD < 500 ng/ml FDP FDP
III.III. DICDICDIC DIC
PLT lowPLT low APTT short or prolonged APTT short or prolonged AT low AT low TT prolonged TT prolonged FBG lowFBG low FM (etanol test) positive FM (etanol test) positive plasminogen lowplasminogen low DD positiveDD positive FDP positiveFDP positive euglobulin lysis norm. - prolongedeuglobulin lysis norm. - prolonged
III.III. DICDIC PLT PLT FBG FBG DD DD AT AT
Repeat every 3-4h Repeat every 3-4h
III.III. DICDIC11 HypercoagulationHypercoagulation
SilentSilent22 Hypocoagulation Hypocoagulation
Bleeding and thrombosis in Bleeding and thrombosis in microcirculation microcirculation
33 Massive fibrinolysis Massive fibrinolysis Bleeding and multiorgan failure (MOF)Bleeding and multiorgan failure (MOF)
44 Death Death
Thrombotic Thrombocytopenic Thrombotic Thrombocytopenic PurpuraPurpura
von Willebrand factor protein multimer analysis on agarose gel electrophoresis. Lane 1. - normal plasma. Lane 2. - patient plasma when symptomatic. Multimer pattern is similar to the control plasma. Lane 3. - patient plasma after response to pheresis. Note the presence of ultra-large high molecular weight multimers.
Peripheral smear showing microangiopathic hemolytic features with numerous RBC fragments (helmet cells/schistocytes). Marked thrombocytopenia is evident.
Renal biopsy showing hyaline thrombi in the glomerulus and small arterioles.
Researchers Pinpoint Cause of Deadly Blood-Clotting Researchers Pinpoint Cause of Deadly Blood-Clotting DisorderDisorder
Several earlier studies had implicated a Several earlier studies had implicated a clotting-related protein known as clotting-related protein known as von Willebrand factor (VWF) in the disordervon Willebrand factor (VWF) in the disorder. These studies found that the . These studies found that the blood of patients with TTP showed an blood of patients with TTP showed an abnormally large form of the VWF abnormally large form of the VWF proteinprotein that had not been cleaved into two smaller sizes, as is normally the that had not been cleaved into two smaller sizes, as is normally the case. Thus, said case. Thus, said GinsburgGinsburg, many scientists believed that a defect in a protein-, many scientists believed that a defect in a protein-clipping enzyme known as a protease might be responsible for the disorder. clipping enzyme known as a protease might be responsible for the disorder.
One of the keys to identifying the gene mutations that underlie TTP was the development One of the keys to identifying the gene mutations that underlie TTP was the development of a precise assay for detecting VWF protease activity. Han-Mou Tsai, a senior author of the of a precise assay for detecting VWF protease activity. Han-Mou Tsai, a senior author of the NatureNature paper, and colleagues at Montefiore Medical Center and Albert Einstein College of paper, and colleagues at Montefiore Medical Center and Albert Einstein College of Medicine developed the assay and applied it to blood samples that were provided by Medicine developed the assay and applied it to blood samples that were provided by members of members of four families that had an inherited form of TTPfour families that had an inherited form of TTP. The assays clearly revealed . The assays clearly revealed that within these families, those who had TTP showed low VWF protease activity, while that within these families, those who had TTP showed low VWF protease activity, while carriers of the disease showed medium levels of protease activity, and unaffected carriers of the disease showed medium levels of protease activity, and unaffected individuals showed normal levels. individuals showed normal levels.
Using results from the assay as a guide, Gallia G. Levy, lead author of the Using results from the assay as a guide, Gallia G. Levy, lead author of the NatureNature article, article, performed performed linkage analyses of the family members and determined which of known linkage analyses of the family members and determined which of known genomic markers were inherited with the disease genegenomic markers were inherited with the disease gene. These studies enabled her to . These studies enabled her to narrow down the region containing the disease gene to a specific region of chromosome 9. narrow down the region containing the disease gene to a specific region of chromosome 9.
Levy then obtained the full gene sequence and proceeded to test the other patients for Levy then obtained the full gene sequence and proceeded to test the other patients for mutations in the gene, which they named mutations in the gene, which they named ADAMTS13ADAMTS13. Levy subsequently identified a dozen . Levy subsequently identified a dozen mutations in the gene among the patients, accounting for nearly all the cases of TTP. mutations in the gene among the patients, accounting for nearly all the cases of TTP. According to Ginsburg, Levy’s findings open the way to understanding how and why the According to Ginsburg, Levy’s findings open the way to understanding how and why the ADAMTS13ADAMTS13 protease cleaves VWF and how the failure to cleave the protein causes disease protease cleaves VWF and how the failure to cleave the protein causes disease. .
III.III. DICDICTherapy: Therapy:
Blockade of activated coagulation Blockade of activated coagulation
1 Heparin1 Heparin 5-105-10 IU/kg/h IU/kg/h bolus 2500 IU, inf. Up to 10 000 IU/24h bolus 2500 IU, inf. Up to 10 000 IU/24h
LMWH LMWH
III.III. DICDICTherapy: Therapy:
Blockade of activated coagulation Blockade of activated coagulation
2 AT (Antitrombin III, Kybernin P) 2 AT (Antitrombin III, Kybernin P) If less 60%, target~ 100 - 150% If less 60%, target~ 100 - 150% 500 - 1000 bolus 500 - 1000 bolus KI unknown KI unknown Half life 3-4 d, during sepsis hours Half life 3-4 d, during sepsis hours
III.III. DICDICTherapy: Therapy:
SubstitutionSubstitution
3 Fresh frozen plasma3 Fresh frozen plasma 15 ml/kg if APTT more than 1.5 R 15 ml/kg if APTT more than 1.5 R
4 Fibrinogen4 Fibrinogen If less than 1.0 g/l (maximally 2g/24h) If less than 1.0 g/l (maximally 2g/24h) 2 - 4 g in infusion2 - 4 g in infusion
III.III. DICDICTherapy: Therapy:
SubstitutionSubstitution
5 5 ErythrocytesErythrocytes
6 PLT6 PLT 1 unit/10kg 1 unit/10kg
III.III. DICDICTherapy: Therapy:
OTHEROTHER
1 shock1 shock 2 volume2 volume 3 acidobasic and ionts3 acidobasic and ionts 4 ATB4 ATB 5 Surgical5 Surgical
III.III. DICDIC
Acute DICAcute DIC DIAGNOSISDIAGNOSIS
Clinical findingsClinical findings Multiple bleeding sites Multiple bleeding sites Ecchymoses of skin, mucous membranes Ecchymoses of skin, mucous membranes Visceral hemorrhage Visceral hemorrhage Ischemic tissue Ischemic tissue
Laboratory abnormalitiesLaboratory abnormalities Coagulation abnormalities: prolonged prothrombin Coagulation abnormalities: prolonged prothrombin
time, activated partial thromboplastin time, thrombin time, activated partial thromboplastin time, thrombin time; decreased fibrinogen levels; increased levels of time; decreased fibrinogen levels; increased levels of FDP (eg, on testing for FDP, D dimer) FDP (eg, on testing for FDP, D dimer)
Platelet count decreased as a rule but may be falling Platelet count decreased as a rule but may be falling from a higher level yet still be normal from a higher level yet still be normal
Schistocytes on peripheral smear Schistocytes on peripheral smear
Chronic DIC Chronic DIC DIAGNOSISDIAGNOSIS
Clinical findings Clinical findings Signs of deep venous or arterial thrombosis Signs of deep venous or arterial thrombosis
or embolismor embolism Superficial venous thrombosis, especially Superficial venous thrombosis, especially
without varicose veins without varicose veins
Multiple thrombotic sites at the same time Multiple thrombotic sites at the same time Serial thrombotic episodes Serial thrombotic episodes
Chronic DICChronic DIC Laboratory abnormalitiesLaboratory abnormalities
Modestly increased prothrombin time in some patients Modestly increased prothrombin time in some patients Shortened or lengthened partial thromboplastin time Shortened or lengthened partial thromboplastin time Normal thrombin time in most patients Normal thrombin time in most patients High, normal, or low fibrinogen level High, normal, or low fibrinogen level High, normal, or low platelet count High, normal, or low platelet count Increased levels of FDP (eg, on testing for FDP, D Increased levels of FDP (eg, on testing for FDP, D
dimer) dimer) Evidence of molecular markers* (eg, thrombin-Evidence of molecular markers* (eg, thrombin-
antithrombin complexes, activation markers on antithrombin complexes, activation markers on platelet membranes, prothrombin fragment F1+2) platelet membranes, prothrombin fragment F1+2)
Current Management of Current Management of DICDIC
At present, diagnosis requires a set At present, diagnosis requires a set of blood tests; therapy focuses on of blood tests; therapy focuses on reversing the underlying disorder reversing the underlying disorder and providing supportive treatment. and providing supportive treatment.
Case 1 Presentation Case 1 Presentation A 56-year-old man was admitted to the A 56-year-old man was admitted to the
emergency department after a car accident. emergency department after a car accident.
•He had several bone fractures, a cerebral contusion, and He had several bone fractures, a cerebral contusion, and hemodynamic instability caused by a ruptured spleen. hemodynamic instability caused by a ruptured spleen. •Emergency splenectomy and aggressive administration of fluids Emergency splenectomy and aggressive administration of fluids restored hemodynamic stability, and the patient was transferred to restored hemodynamic stability, and the patient was transferred to the intensive care unit (ICU). the intensive care unit (ICU).
A few hours later, A few hours later, profuse extravasationprofuse extravasation was noted from was noted from the abdominal drains, the abdominal drains, endotracheal tube, endotracheal tube, and puncture sites of all intravascular linesand puncture sites of all intravascular lines..
Case 1 PresentationCase 1 Presentation Laboratory tests showed a rapidly falling Laboratory tests showed a rapidly falling
hemoglobin level and a platelet count of hemoglobin level and a platelet count of 25,000/µL. 25,000/µL.
The activated partial thromboplastin time The activated partial thromboplastin time (aPTT) was 44 sec (normal, <28) and the (aPTT) was 44 sec (normal, <28) and the prothrombin time (PT) was 29 sec prothrombin time (PT) was 29 sec (normal, <12.5). (normal, <12.5).
The level of fibrinogen degradation The level of fibrinogen degradation products was 360-520 g/L (normal, <40) products was 360-520 g/L (normal, <40) and the plasma antithrombin III level was and the plasma antithrombin III level was 28% (normal, 80-120). 28% (normal, 80-120).
Case 1 PresentationCase 1 Presentation Based on these findings, the diagnosis was DIC Based on these findings, the diagnosis was DIC
secondary to severe trauma. Surgical exploration secondary to severe trauma. Surgical exploration revealed diffuse oozing of blood at the site of the revealed diffuse oozing of blood at the site of the operation, but only partial surgical hemostasis operation, but only partial surgical hemostasis could be achieved. could be achieved.
The patient was given supportive treatment withThe patient was given supportive treatment with::
large infusions of fresh frozen plasma large infusions of fresh frozen plasma platelet concentrates. platelet concentrates.
The bleeding stopped 48 hours later. The bleeding stopped 48 hours later. Coagulation parameters eventually returned to Coagulation parameters eventually returned to normal and the subsequent clinical course was normal and the subsequent clinical course was uneventful. uneventful.
The pathogenesis of DIC The pathogenesis of DIC
Selected Disorders ThatSelected Disorders ThatMay Be Associated with DIC May Be Associated with DIC Malignancy (solid tumors, myeloproliferative, Malignancy (solid tumors, myeloproliferative,
lymphoproliferative) Obstetric emergencies lymphoproliferative) Obstetric emergencies (amniotic fluid embolism, abruptio placentae) (amniotic fluid embolism, abruptio placentae)
Organ destruction (severe pancreatitis) Organ destruction (severe pancreatitis) Sepsis/severe infection (any microorganism) Sepsis/severe infection (any microorganism) Severe hepatic failure Severe hepatic failure Severe toxic or immunologic reactions (snake bites, Severe toxic or immunologic reactions (snake bites,
recreational drugs, transfusion reactions, transplant recreational drugs, transfusion reactions, transplant rejection) rejection)
Trauma (polytrauma, neurotrauma, trauma resulting Trauma (polytrauma, neurotrauma, trauma resulting in fat embolism) in fat embolism)
Vascular abnormalities (Kasabach-Merritt syndrome, Vascular abnormalities (Kasabach-Merritt syndrome, large vascular aneurysms)large vascular aneurysms)
Infection.Infection. Bacterial infection, in particular septicemia, is Bacterial infection, in particular septicemia, is
commonly associated with DIC. However, commonly associated with DIC. However, systemic infections with other microorganisms, systemic infections with other microorganisms, such as viruses and parasites, also may lead to such as viruses and parasites, also may lead to DIC. DIC.
Components of the microorganism's cell Components of the microorganism's cell membrane (lipopolysaccharide, or membrane (lipopolysaccharide, or endotoxinendotoxin) or ) or bacterial exotoxins (e.g. bacterial exotoxins (e.g. staphylococcal alpha-staphylococcal alpha-toxintoxin) may cause a generalized inflammatory ) may cause a generalized inflammatory response characterized by systemic production of response characterized by systemic production of cytokines, mainly by activated mononuclear cells cytokines, mainly by activated mononuclear cells and endothelial cells. and endothelial cells.
The cytokines are responsible for the The cytokines are responsible for the derangement of the coagulation system in DIC. derangement of the coagulation system in DIC.
Trauma Trauma Head trauma in particular is strongly Head trauma in particular is strongly
associated with DIC; both local and associated with DIC; both local and systemic activation of coagulation may systemic activation of coagulation may be detected after such an event.be detected after such an event.
The increased risk of DIC after head The increased risk of DIC after head
trauma is understandable in view of trauma is understandable in view of the relatively large amount of the relatively large amount of tissue tissue factorfactor in the cerebral compartment. in the cerebral compartment.
Cancer Cancer Both solid tumors and hematologic malignancies Both solid tumors and hematologic malignancies
may be complicated by DIC. may be complicated by DIC. The mechanism by which the coagulation The mechanism by which the coagulation
system becomes deranged is poorly understood. system becomes deranged is poorly understood. However, most studies implicate However, most studies implicate tissue factortissue factor, , perhaps expressed on the surface of tumor cells. perhaps expressed on the surface of tumor cells.
A distinct form of DIC is frequently encountered A distinct form of DIC is frequently encountered in patients with acute promyelocytic leukemia; it in patients with acute promyelocytic leukemia; it is characterized by a severe is characterized by a severe hyperfibrinolysishyperfibrinolysis superimposed on an activated coagulation superimposed on an activated coagulation system.system.
Although clinical bleeding predominates in such Although clinical bleeding predominates in such cases, disseminated thrombosis is found at cases, disseminated thrombosis is found at autopsy in a considerable number of patients. autopsy in a considerable number of patients.
Obstetric Emergencies Obstetric Emergencies Acute DIC occurs in obstetric complications such as Acute DIC occurs in obstetric complications such as
amniotic fluid embolism and abruptio placentae. amniotic fluid embolism and abruptio placentae. Amniotic fluid can activate coagulation in vitroAmniotic fluid can activate coagulation in vitro, and , and
in abruptio placentae, the degree of placental separation in abruptio placentae, the degree of placental separation correlates with the severity of DIC, suggesting that correlates with the severity of DIC, suggesting that leakage of thromboplastinlike material from the placental leakage of thromboplastinlike material from the placental system triggers DIC in these patients. system triggers DIC in these patients.
The most common obstetric complication associated with The most common obstetric complication associated with activation of coagulation is preeclampsia. Severe activation of coagulation is preeclampsia. Severe preeclampsia may also be complicated by :preeclampsia may also be complicated by :
HELLP syndromeHELLP syndrome ( (hhemolysis, emolysis, eelevated levated liliver enzymes, ver enzymes, and and llow ow pplatelets). The latter, however, is characterized latelets). The latter, however, is characterized by a microangiopathic hemolytic anemia with secondary by a microangiopathic hemolytic anemia with secondary changes in the coagulation system. It is related to, but changes in the coagulation system. It is related to, but clearly distinct from, DIC. clearly distinct from, DIC.
Vascular Disorders Vascular Disorders Large aortic aneurysms or giant Large aortic aneurysms or giant
hemangiomas (Kasabach-Merritt syndrome) hemangiomas (Kasabach-Merritt syndrome) may result in local activation of coagulation may result in local activation of coagulation factors. factors.
The activated local factors can ultimately The activated local factors can ultimately overflow to the systemic circulation and cause overflow to the systemic circulation and cause DIC; more commonly, systemic depletion of DIC; more commonly, systemic depletion of coagulation factors and platelets results from coagulation factors and platelets results from local consumption. local consumption.
The ensuing clinical condition may be difficult The ensuing clinical condition may be difficult to distinguish from DIC. to distinguish from DIC.
Microangiopathic hemolytic Microangiopathic hemolytic anemia anemia
Microangiopathic hemolytic anemiaMicroangiopathic hemolytic anemia is a group of is a group of disorders that includes:disorders that includes:
thrombotic thrombocytopenic purpura, hemolytic uremic thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, chemotherapy-induced microangiopathic syndrome, chemotherapy-induced microangiopathic hemolytic anemia, malignant hypertension, and hemolytic anemia, malignant hypertension, and HELLP HELLP syndromesyndrome. .
A common pathogenetic feature appears to be endothelial A common pathogenetic feature appears to be endothelial damage, which promotes platelet adhesion and aggregation, damage, which promotes platelet adhesion and aggregation, thrombin formation, and impaired fibrinolysis. thrombin formation, and impaired fibrinolysis.
Although some characteristics of microangiopathic hemolytic Although some characteristics of microangiopathic hemolytic anemia and the resulting thrombotic occlusion of small and anemia and the resulting thrombotic occlusion of small and mid-size vessels (leading to organ failure) may mimic the mid-size vessels (leading to organ failure) may mimic the clinical presentation of DIC, these disorders in fact represent clinical presentation of DIC, these disorders in fact represent a distinct group of diseases. a distinct group of diseases.
Early events in sepsis Early events in sepsis 1) The intital toxic stimuli, such as endotoxin (LPS), triggers production of proinflammatory cytokines (TNF, IL-1) and monocyte adherence to endothelial cells.
2) TNF and IL-1 also activates neutrophils and endothelial cells for increased adherence. All activated cells release secondary inflammatory mediators, including cytokines.
3) Activation of platelets and increased production of procoagulants by endothelial cells may trigger microthrombosis. In some cases, disseminated intravascular coagulation (DIC) may occur with life-threatening tissue ischemia.
4) Vessel dilation caused by free radicals, histamine, prostaglandins, prostacyclin, and the kinin and tachykinin family of molecules, combined with the effects of cytokines on the endothelial cells, contribute to increased vascular permeability for fluids and low-molecular weight substances, causing oedema. If the process is wide-spread, a capillary leak syndrome may result.
Case 2 Presentation Case 2 Presentation A 71-year-old woman was admitted to the ICU with A 71-year-old woman was admitted to the ICU with
sepsis complicated by hemodynamic and sepsis complicated by hemodynamic and respiratory instability. respiratory instability.
Four days earlier, she had undergone a Four days earlier, she had undergone a duodenopancreatectomy for pancreatic carcinoma. duodenopancreatectomy for pancreatic carcinoma.
Fever, chills, and abdominal pain developed on the Fever, chills, and abdominal pain developed on the fourth day, and a computed tomographic scan fourth day, and a computed tomographic scan showed an intra-abdominal abscess. showed an intra-abdominal abscess.
The diagnosis was septic shock complicated by The diagnosis was septic shock complicated by respiratory failure, which was caused by adult respiratory failure, which was caused by adult respiratory distress syndrome. respiratory distress syndrome.
Case 2 PresentationCase 2 Presentation The patient was treated with intravenous fluids and The patient was treated with intravenous fluids and
vasopressors, intubation and mechanical ventilation, vasopressors, intubation and mechanical ventilation, surgical drainage of the abscess, and intravenous surgical drainage of the abscess, and intravenous antibiotics. antibiotics.
Acute renal failure and hepatic insufficiency Acute renal failure and hepatic insufficiency supervened during the next several days. Moreover, supervened during the next several days. Moreover, the patient's respiratory status deteriorated; the cause the patient's respiratory status deteriorated; the cause was determined to be a large pulmonary embolism. was determined to be a large pulmonary embolism.
Laboratory tests showed persistent thrombocytopenia Laboratory tests showed persistent thrombocytopenia (platelet count, 30,000-40,000/µL) and prolonged (platelet count, 30,000-40,000/µL) and prolonged global clotting times: aPTT, 40-45 sec; PT, 20-25 sec. global clotting times: aPTT, 40-45 sec; PT, 20-25 sec. Fibrin degradation product levels were very high Fibrin degradation product levels were very high (>1600 µg/L; normal <40), and the antithrombin III (>1600 µg/L; normal <40), and the antithrombin III level was 30%. level was 30%.
Case 2 PresentationCase 2 Presentation Based on those findings, DIC secondary to Based on those findings, DIC secondary to
sepsis was diagnosed. sepsis was diagnosed. The patient received supportive treatment The patient received supportive treatment
with intravenous with intravenous heparin and antithrombin heparin and antithrombin IIIIII concentrate (50-70 U/kg), with a goal of concentrate (50-70 U/kg), with a goal of producing greater than normal plasma producing greater than normal plasma concentrations. concentrations.
After 10 days in the ICU, the patient gradually After 10 days in the ICU, the patient gradually recovered and all organ function normalized. recovered and all organ function normalized. One month after her operation, she was One month after her operation, she was discharged from the hospital in good discharged from the hospital in good condition. condition.
Diagnosis of DICDiagnosis of DICTest Result
Platelet count Markedly decreased
Prothrombin time Increased
Activated partial thromboplastin time Increased
Fibrin degradation products Markedly increased
Fibrinogen Normal or decreased
Antithrombin III Markedly decreased
Protein C Markedly decreased
Specific Therapies Specific Therapies Platelet and Coagulation Factor Platelet and Coagulation Factor
InfusionInfusion HeparinHeparin
Platelet and Coagulation Platelet and Coagulation Factor InfusionFactor Infusion
Although low levels of platelets and coagulation factors Although low levels of platelets and coagulation factors may increase the risk of bleeding in patients with DIC, may increase the risk of bleeding in patients with DIC, plasma or platelet transfusions should not be given on plasma or platelet transfusions should not be given on the basis of laboratory test results alone; the basis of laboratory test results alone; they are they are indicated only in patients with active bleeding and in indicated only in patients with active bleeding and in those who require an invasive procedure or are those who require an invasive procedure or are otherwise at risk for bleedingotherwise at risk for bleeding. .
The suggestion that administration of blood components The suggestion that administration of blood components might exacerbate DIC has never been proved in clinical might exacerbate DIC has never been proved in clinical or experimental studies. The efficacy of treatment with or experimental studies. The efficacy of treatment with plasma or platelets has not been confirmed in plasma or platelets has not been confirmed in randomized controlled trials; however, it appears to be randomized controlled trials; however, it appears to be a rational therapy in patients who are bleeding or at risk a rational therapy in patients who are bleeding or at risk for bleeding because of significant depletion of these for bleeding because of significant depletion of these elements. elements.
Heparin Heparin Experimental studies have shown that Experimental studies have shown that heparin can at least heparin can at least
partly inhibit the activation of coagulation in DIC secondary partly inhibit the activation of coagulation in DIC secondary to sepsis and other causesto sepsis and other causes. .
In addition, patients with DIC need prophylaxis against In addition, patients with DIC need prophylaxis against venous thromboembolism. venous thromboembolism.
The benefit of heparin has been shown in a small, The benefit of heparin has been shown in a small, uncontrolled series of patients with DIC but has never been uncontrolled series of patients with DIC but has never been demonstrated in controlled clinical trials. The safety of demonstrated in controlled clinical trials. The safety of heparin in patients with DIC who are prone to bleeding is heparin in patients with DIC who are prone to bleeding is often debated, but clinical studies have not shown that often debated, but clinical studies have not shown that heparin significantly worsens bleeding complications in this heparin significantly worsens bleeding complications in this group. group.
Altogether, heparin is probably useful in Altogether, heparin is probably useful in patients with DIC, patients with DIC, particularly in thoseparticularly in those with clinically overt thromboembolism with clinically overt thromboembolism or extensive fibrin deposition, such as purpura fulminans or or extensive fibrin deposition, such as purpura fulminans or ischemia in the extremities. ischemia in the extremities.
Heparin is usually given in a relatively low-dose, continuous Heparin is usually given in a relatively low-dose, continuous infusion (300-500 U/hr). infusion (300-500 U/hr).
Recent studies show that low-molecular-weight heparin can Recent studies show that low-molecular-weight heparin can be used as an alternative to unfractionated heparin. be used as an alternative to unfractionated heparin.
Experimental Therapies Experimental Therapies Theoretically, the most logical Theoretically, the most logical
anticoagulation therapy in patients anticoagulation therapy in patients with DIC is an agent that is directed with DIC is an agent that is directed against tissue factor activity. against tissue factor activity.
Indeed, inhibitors of the tissue factor Indeed, inhibitors of the tissue factor pathway have been developed and pathway have been developed and ongoing clinical studies are ongoing clinical studies are evaluating their efficacy and safety in evaluating their efficacy and safety in DIC. DIC.
Experimental TherapiesExperimental Therapies Restoration of physiologic anticoagulation pathways might Restoration of physiologic anticoagulation pathways might
be an appropriate therapeutic option in DIC. Antithrombin be an appropriate therapeutic option in DIC. Antithrombin III is one of the most important natural inhibitors of III is one of the most important natural inhibitors of coagulation; patients with DIC almost invariably have an coagulation; patients with DIC almost invariably have an acquired deficiency of the substance. acquired deficiency of the substance.
Administration of supraphysiologic concentrations of Administration of supraphysiologic concentrations of antithrombin III has produced promising results in clinical antithrombin III has produced promising results in clinical trials involving patients with sepsis or septic shock, with or trials involving patients with sepsis or septic shock, with or without DIC. Some trials showed a modestly (but without DIC. Some trials showed a modestly (but statistically insignificant) reduced mortality in patients statistically insignificant) reduced mortality in patients treated with antithrombin III. A metaanalysis of the trials treated with antithrombin III. A metaanalysis of the trials showed that mortality decreased from 56% to 44% (odds showed that mortality decreased from 56% to 44% (odds ratio, 0.63; 95% confidence interval, 0.39 to 1.0). A large, ratio, 0.63; 95% confidence interval, 0.39 to 1.0). A large, randomized, controlled multicenter trial of supraphysiologic randomized, controlled multicenter trial of supraphysiologic doses of antithrombin III in patients with sepsis is currently doses of antithrombin III in patients with sepsis is currently under way, and its outcome will more definitively determine under way, and its outcome will more definitively determine the place of antithrombin III treatment in sepsis and DIC. the place of antithrombin III treatment in sepsis and DIC.
Experimental TherapiesExperimental Therapies Another promising treatment is recombinant Another promising treatment is recombinant
activated protein C. activated protein C. This compound is now being evaluated in This compound is now being evaluated in
large multicenter trials in patients with large multicenter trials in patients with sepsis, DIC, or both. In view of the pivotal sepsis, DIC, or both. In view of the pivotal role of protein C as inhibitor of the role of protein C as inhibitor of the coagulation cascade and its postulated role as coagulation cascade and its postulated role as an important mediator of inflammation, an important mediator of inflammation, activated protein C may be a good candidate activated protein C may be a good candidate for supportive treatment of patients with DIC. for supportive treatment of patients with DIC.
Treatment options for Treatment options for DIC DIC
Acute DICAcute DIC Without bleeding or evidence of ischemia Without bleeding or evidence of ischemia No treatment No treatment With bleeding With bleeding Blood components as needed Blood components as needed Fresh frozen plasma Fresh frozen plasma Cryoprecipitate Cryoprecipitate Platelet transfusions Platelet transfusions With ischemia With ischemia Anticoagulants (see "with thromboembolism" Anticoagulants (see "with thromboembolism" below) afterbelow) after bleeding risk is corrected with blood products bleeding risk is corrected with blood products
Treatment options for Treatment options for DICDIC
Chronic DICChronic DIC Without thromboembolism Without thromboembolism No specific therapy needed but prophylactic No specific therapy needed but prophylactic drugsdrugs (eg, low-dose heparin, low-molecular-weight (eg, low-dose heparin, low-molecular-weight heparin)heparin) may be used for patients at high risk of may be used for patients at high risk of thrombosisthrombosis With thromboembolism With thromboembolism Heparin or low-molecular-weight heparin, Heparin or low-molecular-weight heparin, trial of warfarintrial of warfarin sodium (Coumadin). (If warfarin is sodium (Coumadin). (If warfarin is unsuccessful, long-term useunsuccessful, long-term use of low-molecular-weight heparin may be of low-molecular-weight heparin may be helpful.)* helpful.)*
DICDIC
DIC - Gangrene in patient with meningococcal sepsis
Schistocytes on the Peripheral Blood Smear
DICDIC
Subdermal bleeding at IV site following a bite by Hoplocephalus stephensi
Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC).(DIC).
Patient with Postvaricella purpura fulminans showing extent of necrotic lesions Leg after skin grafting
14 year old otherwise healthy male who three weeks after primary varicella infection developed large painful lesions on his leg. (Fig 1). Laboratories evaluation showed evidence of disseminated intravascular coagulation (DIC). Plasma free protein S level was below 5% with other factors only mildly decreased (consistent with his DIC).
Patient was treated with heparin and plasma infusion which resulted in stabilization of his lesions. For his presumed autoimmune protein S deficiency he received immunoglobulin. Over the course of the next several months his protein S levels increased back into the normal range but his skin lesions required extensive grafting (fig 2 and 3).
The E N DThe E N D