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Disseminated Intravascular

oagu a on

Dept of Internal Medicine Univ. of Indonesia

/Cipto Mangunkusumo Hospital

• onsump ve coagu a on

• Defibrin(ogen)ation syndrome

• Thrombohemorrhagic syndrome

epen s upon e :

• Triggering event (s)• Host response (s)

• Comorbid conditions

CAUSES OF DIC

Infection ‐ bacterial sepsis, viral infections

Neo lasm ‐ AML, adenocarcinoma

Obstetrical disorders ‐ retained dead fetus, abruption, etc

‐ ra n n ury, crus , urns, e c.

Others ‐ acute hemolytic transfusion reaction

Pathophysiology of Severe SepsisPathophysiology of Severe Sepsis

Endothelium COAGULATION

IL-6IL-1

PAI-1Factor VIIIa

Tissue Factor

Monocyte

Suppressed

Factor Va

Bacteria

Neutrophil

TAFITHROMBIN

Fibrin

LPS / endotoxin

Fibrin clotTissue Factor

to Infection

Patho enesis of DIC

Release ofthromboplastic

material intocirculation

Consumption of coagulation factors;

presence of FDPs

Fibrinogen

Thrombin Plasmin

Fibrin

Presence of plasmin

Fibrin(ogen)Degradation

ProductsIntravascular clot

↓ Platelets

(intravascular) Plasmin

Underlying disorder

Systemic activation o coagu ation

Widespread

intravascular fibrin

Consumption of

platelets and

(severe) Bleeding

organ failure

Activation of coagulation

Events leading to

thrombosis

Events leading to

bleeding

Circulating thrombi

Thrombotic occlusion

of microcirculation of

all organs

Fibrinolysis

in the

microcirculation

Circulating fibrin

degradation

products

Consumption of

platelets and

coagulation proteins

Signs of microvascular thrombosis Signs of hemorrhagic diathesis

•Neuologic : multifocal, delirium, coma•Skin : focal ischemia, superficial gangrene

•Renal : oliguria, azotemia, cortical necrosis

•Pulmonary: acute respiratory distress syndrome

•Neuologic : intracerebral bleeding•Skin : petechiae, ecchymoses, venipuncture

oozing

•Renal : hematuria

• •Fragmentation hemolytic anemia

•GI: massive bleeding

Marder VJ. Hemost and Thromb. 5edt. 2006.1571‐1600

CLINICAL PHASES OF DIC

c va on o e coagu a on

Preci itation of soluble fibrin with

consumption of coagulation factors

c va on an or n on o r no ys s

with microthrombosis, embolism and

emorr age

End‐or an failure and hemorrha eIV

v ence o procoagu a on

• Elevated prothrombin fragment 1+2• Elevated fibrinopeptide A

• Elevated fibrinopeptide B

• ‐

• Elevated D‐dimer

• Elevated FDP

• Elevated plasmin

• Elevated plasmin antiplasmin complex

• ‐

• Decreased alpha‐2‐antiplasmin

• Decrease eparin co actor II

• Decreased protein C or S• Elevated TAT complex

• Elevated creatinine

• Decrease pH

• Decreased paO2

Needs 2 out of 4 above items for diagnosis

Features Affected Patients

• Renal dysfunction 25%

• Hepatic ys unction 19%

• Respiratory dysfunction 16%• Shock 14%

Platelet count ↓

sMF (soluble fibrin

aPTT ↑

D‐dimer ↑ TT ↑

FDP (fibrin degradation

product) ↑

antithrombin ↓

National consensus of DIC in sepsis 2001

Taylor, FB, et al. Thromb Haemost 2001;86:1327

Vitamin K deficiency

Liver disease

Thrombotic thromboc to enic ur ura

Congenital abnormalities of fibrinogen

Treat the underlying disease

Restore the circulation Re lacement thera

Cryoprecipitate/FFP

Packed red cells

controversial or investigational agents

, , , ,

Treatment of acute, severe DIC (1)ModalityModality RationaleRationale DetailsDetails ExpectationsExpectations

Life supportLife support Self Self--evidentevident Fluids, blood, respiratoryFluids, blood, respiratory Maintain cardiac output, gasMaintain cardiac output, gas

measuresmeasures care,care, etcetc exchange, electrolyteexchange, electrolyte

balance, etcbalance, etc

Treating theTreating the Correct theCorrect the Dependent on theDependent on the Inhibit or block theInhibit or block the

un er y ngun er y ng

disorder disorder

cause ocause o pr mary agnos spr mary agnos s comp ca ng pa o og ccomp ca ng pa o og c

mechanism of DICmechanism of DIC inparallelinparallel

with the response (if any) ofwith the response (if any) of

the disorder the disorder

Antithrombotic Antithrombotic

agentsagents

BlockBlock

microthrombusmicrothrombus

formationformation

Heparin by continuous IVHeparin by continuous IV

infusion, monitor withinfusion, monitor with

fibrinogen and plateletfibrinogen and platelet

levels; continue as longlevels; continue as long

Prevent fibrin formation; tipPrevent fibrin formation; tip

the balance within thethe balance within the

microcirculation towardmicrocirculation toward

physiologicphysiologic fibrinolysisfibrinolysis; allow; allow

as the predisposingas the predisposingclinical state persists; ATclinical state persists; AT

III concentrate if AT IIIIII concentrate if AT III

level < 70%level < 70%

reperfusion of the skin,reperfusion of the skin,kidneys, and brainkidneys, and brain

Treatment of acute, severe DIC (2)

Modality Rationale Details Expectations

Tranfusion Reestablish normal

hemostastic potential

Infuse platelets and

fibrinogen

Platelet count and

fibrinogen should increase

(cryoprecipitate); repeat

as indicated bylaboratory and clinical

observation

significantly; bleeding

should diminish and stopduring an interval of hours

to several days

Transfusion

+ heparin

Restore normal

hemostasis if

transfusion of

hemostasis factors

Infuse platelets and

cryoprecipitate 2 h after

starting continous

heparin infusion (7.5

Platelet count and and

fibrinogen should increase

significantly if consumption

is blocked; bleeding should

fails to achieve

significant increment in

factor levels

U/kg/h); repeat as

indicated by laboratory

and clinical observation

diminish; if bleeding

increases, discontinue

heparin

Fibrinolytic Block excessive For adults ε- Bleeding ceases rapidly but

inhibitors fibrinolysis and theaccumulation of

degradation products

in blood; protect

aminocaproic acid;loading dose, 46 g, then

1 g q12h for a limited

duration (up to 48 h)

keeps vascular channelsoccluded with thrombus;

dangerous if the thrombotic

process was not previously

hemostatic plugs treated with heparin

Disorder Treatment approach

Purpura fulminants Heparin by continous infusion

cra or erma sc em a epar n y cont nous n us on

Venous thromboembolism Heparin by continous infusion

Bacteremia (associated with Heparin by continous infusion

dermal ischemia or necrosis)

Organ ischemia Heparin not indicated unless there is evidence or fibrin

deposition elsewhere (dermal or acral ischemia)

Retained dead fetus syndrome Heparin IV or cryoprecipitate alone if labor in progress

Giant hemangioma Thrombose with EACA and possibly cryoprecipitate;

before elective surgery, heparin, cryoprecipitate (or

both), and platelets

Aorta aneurysm without Heparin preceding elective repair

ruptureSolid tumors Heparin by continous infusion; if effective, then

adjusted‐dose or low‐molecular weight heparin s.c.

Promyelotic leukemia Acute promyelocytic leukemia

Disorder Treatment approach

Relative contraindication

Aortic aneurysm, leaking Cryoprecipitate and platelets preceding emergency repair

Hemorrhage in a closed spase

compromising vital function

Heparin a possible option but only with external drainage

Septicemia Heparin only with specific indications; high doses; high

oses o - concen ra e - eve

Abruptio placentae without significantbleeding

Blood volume replacement, prompt delivery, cryoprecipitateif needed

hemostatic factors if bleeding is present

Saline-induced abortion Correct excessive bleeding during delivery by replacing

fibrinogen and platelets

Septic abortion Consider heparin therapy early in course when DIC is

present

Severe liver disease with refractory Discontinue shunt

Acute fatty liver of pregnancy AT-III replacement, preferably by concentrate

Intracranial gunshot wound or severe

brain in ur

Cryoprecipitate and platelets

Anticoa ulation TheraRationale :

1. Septic process reveals with coagulationabnormality DIC.

2. Antithrombin, protein C, protein S and

tissue factor athwa inhibitor TFPI werenatural anticoagulant found to be reduced

‐. ,

indicate that coagulation pathway were

The Role of Activated Protein C in Severe SepsisThe Role of Activated Protein C in Severe Sepsis

Endothelium Activated Protein CActivated Protein C

COAGULATION

IL-6IL-1

Inactivation n

PAI-1Factor VIIIaTissue Factor

Monocyte

Inactivation

e v e n

t i o n

o f a c t i v a t i

SuppressedActivated h i b i t i o n

Factor Va

Neutrophil

Protein C I n

THROMBIN

Fibrin

I n h i b

i t i o

Activated Protein CFibrin clot

Tissue Factor

to Infection

The evidence concernin use of rhAPC in adults is

primarily based on two RCTs:

• PROWESS (1,690 adult patients, stopped early forefficacy)

• s oppe ear y or u y

• Additional safety information comes from an open‐ , .

trial also suggested that early administration ofrhAPC was associated with better outcomes.

PROWESS Survival Rates

RRR: 19.4% (95% CI 6.6 ‐ 30.5)

ARR: 6.1% => NNT=17

N Engl J Med. 2001; 344: 699‐709

The KyberCept (High Dose Antithrombin in Sepsis)

Trial : 90 Da Survival Rates

Primary Outcome

Increased bleeding

risk in those whoreceived heparin+AT

(not shown)

*p = 03

Post Hoc Analysis

Warren, B. L. et al. JAMA

2001;286:1869‐1878.

• DIC is a syndrome characterized systemic

intravascular coagulation.•

of intravascular thrombosis has the greatest

im act on morbidit and mortalit .

• The treatment of DIC is reversal or control of

and replacement therapy as indicated.

an you

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