disseminated intravascular coagulation dic doç.dr. tiraje celkan
TRANSCRIPT
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DDisseminated isseminated IIntravascular ntravascular CCoagulationoagulation
DICDIC
Doç.Dr. Tiraje Celkan Doç.Dr. Tiraje Celkan
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DIC DIC DEATH is COMINGDEATH is COMING
• An acquired syndrome characterized by systemic intravascular coagulation
• Coagulation is always the initial event.
• Most morbidity and mortality depends on extent of intravascular thrombosis
• Multiple causes
6
ThrombosisThrombosis
FibrinFibrin
Red Blood CellRed Blood Cell
PlateletPlatelet
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Diseases……DIC 2 mechanism • Cytokines ….activated….coagulation activation • (sepsis and major traumas• Procoagulants ….. ın the blood stream • (malignancy and obstetric cases)
DICDIC
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DIC pathogenesis
DICDIC
UYARAN
TF Salınımı Sitokinler
Monosit ve Makrofajlar
Endotel
TF+ FVIIa
Tenaz
Protrombinaz
Trombin
TFPI
Trombomodulin Aktive Protein C Protein S ATIII
Trombomodulin ATIII HCII
Fibrin monomerleri Trombosit agregasyonu
Endotelyel prostasiklin Plazmin
t-PA
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HemostaHemostasissis
• Vascular Endothelium• Blood Flow Dynamics• Platelets • Coagulation cascade
• Anticlotting Mechanisms
• Fibrinolytic System
3
HemostasisHemostasisSubendothelialSubendothelial matrix matrix
PlateletsPlatelets
HemostaticHemostatic plug plug
FibrinFibrin
Endothelial cellEndothelial cell
RBCRBCWBCWBC
WBCWBC
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DICDIC
• An acquired syndrome characterized by systemic intravascular coagulation
• Coagulation is always the initial event
SYSTEMIC ACTIVATION OF COAGULATION
Intravascular deposition
of fibrin
Depletion of platelets and coagulation
factors
Thrombosis in small and
midsize vesselsBleeding
Organ failure DEATHDEATH
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Thrombotic Probblems
Bleeding
OrganFailure
Bleeding
Disease
Activation of coagulation
Plt and factor decrease
Fibrin in the blood stream
Thrombus in capillers
Fibrin FDP formation
activation of fibrinolizis
inhibition of fibrinolizis
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Thrombus in capillers
Decreased anticoagulatıon
trombin formation(DF)
Fibrin formation
• AT-III level decrease • Sürekli trombin oluşumuna bağlı tüketim• Aktive nötrofillerden salınan elastaza bağlı yıkım• AT sentezinin bozulması
• Protein C • Endotelde trombomodulin sunumunda azalma
• PC sentezinde bozulma• Serbest PS düzeyinde azalma
• TFPI decrease• TFPI düzeyi normal
Fibrinogen Fibrin
Thrombin
DF + FVIIa
FIXa + (FVIII) FXa + (FV)
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Küçük ve orta çaplı damarlarda trombüs
Fibrinolitik sistemin baskılanması (PAI-1 ile)
Antikoagülan sistemdeyetersizlik
trombin oluşumu (DF aracılığı ile)
Fibrin oluşumuFibrin uzaklaştırılmasında
yetersizlik
AT-III düzeyinde düşüklük Protein C sisteminde bozulmaTFPI yetersizliği
Plazminojen
Plazmin
Fibrin FYÜ
Plazminojenaktivatörleri
PAI-1
Fibrinojen Fibrin
Trombin
DF + FVIIa
FIXa + (FVIII) FXa + (FV)
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Hemostatic BalanceHemostatic Balance
ATIIIClotting Factors
Tissue factor*
PAI-1
AntiplasminTFPI
Prot. C
Prot. S
ProcoagulantProcoagulant AnticoagulantAnticoagulant
Fibrinolytic System
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Pathophysiology of DICPathophysiology of DIC
• Activation of Blood Coagulation• Suppression of Physiologic
Anticoagulant Pathways• Impaired Fibrinolysis• Cytokines
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Pathophysiology of DICPathophysiology of DIC
• Activation of Blood Coagulation– Tissue factor/factor VIIa mediated thrombin
generation via the extrinsic pathway• complex activates factor IX and X
– TF • endothelial cells• monocytes• Extravascular:
– lung– kidney– epithelial cells
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Pathophysiology of DICPathophysiology of DIC
• Suppression of Physiologic Anticoagulant Pathways– reduced antithrombin III levels – reduced activity of the protein C-protein
S system– Insufficient regulation of tissue factor
activity by tissue factor pathway inhibitor (TFPI)• inhibits TF/FVIIa/Fxa complex activity
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Pathophysiology of DICPathophysiology of DIC
• Impaired Fibrinolysis– relatively suppressed at time of maximal
activation of coagulation due to increased plasminogen activator inhibitor type 1
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Pathophysiology of DIC - Pathophysiology of DIC - CytokinesCytokines
• Cytokines– IL-6, and IL-1 mediates coagulation activation in DIC
– TNF- • mediates dysregulation of physiologic anticoagulant
pathways and fibrinolysis• modulates IL-6 activity
– IL-10 may modulate the activation of coagulation
CoagulationInflamation
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Diagnosis of DICDiagnosis of DIC
Presence of disease associated with DIC
Appropriate clinical setting– Clinical evidence of thrombosis,
hemorrhage or both. Laboratory studies
– no single test is accurate– serial test are more helpful than single
test
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Conditions Associated With Conditions Associated With DICDIC
• Malignancy– Leukemia– Metastatic disease
• Cardiovascular– Post cardiac arrest– Acute MI– Prosthetic devices
• Hypothermia/Hyperthermia
• Pulmonary– ARDS/RDS– Pulmonary
embolism
• Severe acidosis• Severe anoxia• Collagen vascular
disease• Anaphylaxis
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Conditions Associated With Conditions Associated With DICDIC
• Infectious/Septicemia– Bacterial
• Gm - / Gm +
– Viral• CMV• Varicella• Hepatitis
– Fungal
• Intravascular hemolysis
• Acute Liver Disease
• Tissue Injury– trauma– extensive surgery– tissue necrosis– head trauma
• Obstetric– Amniotic fluid emboli– Placental abruption– Eclampsia– Missed abortion
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Clinical Manifestations of Clinical Manifestations of DICDIC
ORGAN ISCHEMIC HEMOR.Skin Pur. Fulminans
GangreneAcral cyanosis
PetechiaeEchymosisOozing
CNS Delirium/ComaInfarcts
Intracranialbleeding
Renal Oliguria/AzotemiaCortical Necrosis
Hematuria
Cardiovascular MyocardialDysfxn
Pulmonary Dyspnea/HypoxiaInfarct
Hemorrhagiclung
GIEndocrine
Ulcers, InfarctsAdrenal infarcts
Massivehemorrhage.
Ischemic Findingsare earliest!
Bleeding is the most obvious
clinical finding
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Clinical Manifestations of Clinical Manifestations of DICDIC
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Microscopic findings in DICMicroscopic findings in DIC
• Fragments• Schistocytes• Paucity of platelets
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Laboratory Tests Used in Laboratory Tests Used in DICDIC
• D-dimer*• Antithrombin III*
• F. 1+2*• Fibrinopeptide A*• Platelet factor 4*• Fibrin Degradation
Prod• Platelet count• Protamine test
• Thrombin time• Fibrinogen• Prothrombin time• Activated PTT• Protamine test• Reptilase time• Coagulation factor
levels
*Most reliable test
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Laboratory diagnosisLaboratory diagnosis• Thrombocytopenia
– plat count <100,000 or rapidly declining
• Prolonged clotting times (PT, APTT)• Presence of Fibrin degradation products
or positive D-dimer• Low levels of coagulation inhibitors
– AT III, protein C
• Low levels of coagulation factors– Factors V,VIII,X,XIII
• Fibrinogen levels not useful diagnostically
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Differential DiagnosisDifferential Diagnosis
• Severe liver failure• Vitamin K deficiency• Liver disease• Thrombotic thrombocytopenic
purpura• Congenital abnormalities of
fibrinogen• HELLP syndrome
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Treatment of DICTreatment of DIC
• Stop the triggering process .– The only proven treatment!
• Supportive therapy• No specific treatments
– Plasma and platelet substitution therapy– Anticoagulants– Physiologic coagulation inhibitors
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Plasma therapyPlasma therapy
• Indications– Active bleeding– Patient requiring invasive procedures– Patient at high risk for bleeding complications
• Prophylactic therapy has no proven benefit.
• Cons:• Fresh frozen plasma(FFP):
– provides clotting factors, fibrinogen, inhibitors, and platelets in balanced amounts.
– Usual dose is 10-15 ml/kg
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Platelet therapyPlatelet therapy
• Indications– Active bleeding– Patient requiring invasive procedures– Patient at high risk for bleeding complications
• Platelets– approximate dose 1 unit/10kg
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BloodBlood
• Replaced as needed to maintain adequate oxygen delivery.– Blood loss due to bleeding– RBC destruction (hemolysis)
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Coagulation Inhibitor Coagulation Inhibitor TherapyTherapy
• Antithrombin III• Protein C concentrate• Tissue Factor Pathway Inhibitor (TFPI)• Heparin
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• The major inhibitor of the coagulation cascade– Levels are decreased in DIC.– Anticoagulant and antiinflammatory properties
• Therapeutic goal is to achieve supranormal levels of ATIII (>125-150%).– Experimental data indicated a beneficial effect in preventing or
attenuating DIC in septic shock• reduced DIC scores, DIC duration, and some improvement in organ function
– Clinical trials have shown laboratory evidence of attenuation of DIC and trends toward improved outcomes.
– A clear benefit has not been established in clinical trials.
Antithrombin IIIAntithrombin III
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Protein C ConcentratesProtein C Concentrates
• Inhibits Factor Va, VIIa and PAI-1 in conjunction with thrombomodulin.
• Protein S is a cofactor• Therapeutic use in DIC is experimental and is
based on studies that show:– Patients with congenital deficiency are prone to
thromboembolic disease.– Protein C levels are low in DIC due to sepsis.– Levels correlate with outcome.– Clinical trials show significantly decreased
morbidity and mortality in DIC due to sepsis.
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Tissue Factor Pathway Tissue Factor Pathway InhibitorInhibitor
• Tissue factor is expressed on endothelial cells and macrophages
• TFPI complexes with TF, Factor VIIa,and Factor Xa to inhibit generation of thrombin from prothrombin
• TF inhibition may also have antiinflammatory effects
• Clinical studies using recombinant TFPI are promising.
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HeparinHeparin
• Use is very controversial. Data is mixed.• May be indicated in patients with clinical
evidence of fibrin deposition or significant thrombosis.
• Generally contraindicated in patients with significant bleeding and CNS insults.
• Dosing and route of administration varies.• Requires normal levels of ATIII.
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Antifibrinolytic TherapyAntifibrinolytic Therapy
• Rarely indicated in DIC– Fibrinolysis is needed to clear thrombi from the
micro circulation.– Use can lead to fatal disseminated thrombosis.
• May be indicated for life threatening bleeding under the following conditions:– bleeding has not responded to other therapies and:– laboratory evidence of overwhelming fibrinolysis.– evidence that the intravascular coagulation has
ceased.
• Agents: tranexamic acid, EACA
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SummarySummary
• DIC is a syndrome characterized systemic intravascular coagulation.
• Coagulation is the initial event and the extent of intravascular thrombosis has the greatest impact on morbidity and mortality.
• Important link between inflammation and coagulation.
• Morbidity and mortality remain high.• The only proven treatment is reversal or
control of the underlying cause.
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In Normal conditions In Normal conditions
• Thrombin....endotelium....TM....TM+ thrombin ....Pr. C act....act FV and FVIII inact
• TM+ thrombin.......fibrin formation decresed
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SepsisSepsis
Coagulation activation
Inhibition of Fibrinolizis
Anticoagulation act. decrease
IL-6
TNF
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sepsissepsis
• Plazminogen decreased• fibrin deposition in tissues • fibrinolitic act. İnsufficient • multi system involvement
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Sepsis Sepsis
• Endotelium …. TM decreased• TM dec……… Pr C activation
decreased• Pr C decreased in blood• Fibrinolizis decreased• Thrombus increased (APC FV, FVIII
protrombinaz and tenaz inhibition)
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• Bleeding 70-90 % of patients skin (petechia, echimozis , hematomas)GIS GUS (hematuria, vaginal) Pulmoner catheter and from surgery lesions
• Thromboembolic complications 10-40 % of patients especially in cancer patients tissue and organ disfunction
ClinicsClinics
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• Screening tests
platelet count
Protrombin timeaPTTTrombin time Fibrinogen level
easy , cheap could be done every where
Laboratory 1Laboratory 1
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• Tests to evaluate Thrombin formationD-dimerFibrin Monomers Fibrinopeptide AProthrombin fragment 1-2Trombin-Antitrombin
complicated could not be done in every lab more spesific for diagnosis
Laboratory 2Laboratory 2
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New txNew tx
• rTFPI ( Tifacogin ) • APC ( Drotecogin ) • Recombinant TM• AT3 ( Atenativ and Kybernin)• C1 inhibitor : C1 PK, and FXII inhibitor
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Summary Summary
• DIC systemic intravaskular coagulation• coagulation …..vascular thrombosis • Enflamation….. coagulation• Morbidity and mortality
• The best treatment to treat the basic reason