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Disseminated Intravascular C oagu la ti on (DIC) Dept of Internal Medicine Univ. of Indonesia /Cipto

Disseminated Intravascular Coagulation (DIC)

Disseminated Intravascular C oagu la ti on (DIC) Dept of Internal Medicine Univ. of Indonesia /Cipto

Dept of Internal Medicine Univ. of Indonesia /Cipto Mangunkusumo Hospital

TERMINOLOGY

Consumptive coagulation

Defibrin(ogen)ation syndrome

Thrombohemorrhagic syndrome Disseminated Intravascular Coagulation

PATHOPHYSIOLOGY

Very complex & high variability

Depends upon the :

Triggering event (s)

Host response (s)

Comorbid conditions

CAUSES OF DIC

Infection Neoplasm

bacterial sepsis, viral infections AML , adenocarcinoma

Obstetrical disorders retained dead fetus, abruption, etc Trauma/surgery brain injury, crush, burns, etc.

Others

acute hemolytic transfusion reaction

Pathophysiology of Severe Sepsis

Pathophysiology of Severe Sepsis

PAI-1 Endothelium LPS / endotoxin n amma ory fl t I Neutrophil to Infection to Infection
PAI-1
Endothelium
LPS / endotoxin
n amma ory
fl
t
I
Neutrophil
to Infection
to Infection
to Infection
Factor VIIIa
Fibrin clot
Factor Va
Suppressed
fibrinolysis
THROMBIN
TAFI
Tissue Factor
IL-6
IL-1
TNF-α
Monocyte
esponse
c
o
rom
l
b
R
R
R
Th
CASCADE
esponse
c
esponse
r no y
ti
ti
Fib i
IL-6
Bacteria
COAGULATION
Fibrin
Tissue Factor

Pathogenesis of DIC

Release of Consumption of coagulation factors; presence of FDPs ↑ aPTT ↑ PT ↑ TT ↓
Release of
Consumption of
coagulation factors;
presence of FDPs
↑ aPTT
↑ PT
↑ TT
↓ Fibrino
(intravascular)
Plasmin
Intravascular clot
↓ Platelets
Presence of plasmin
↑ FDP
Coa ulation
g
Thrombin
thromboplastic
Fibrinogen
Clot
material into
circulation
en
Fibrin
Monomers
Fib i
r n
Degradation
Fibrin(ogen)
Products
Schistocytes
Plasmin
Fibrinol sis
y
g

Underlying disorder

Underlying disorder Systemic activation o f coagulation Widespread intravascular fibrin deposition organ failure Consumption of platelets

Systemic activation of coagulation

Widespread intravascular fibrin deposition

Underlying disorder Systemic activation o f coagulation Widespread intravascular fibrin deposition organ failure Consumption of platelets

Thrombosis and organ failure

Underlying disorder Systemic activation o f coagulation Widespread intravascular fibrin deposition organ failure Consumption of platelets
Underlying disorder Systemic activation o f coagulation Widespread intravascular fibrin deposition organ failure Consumption of platelets

Consumption of platelets and clotting factors

Underlying disorder Systemic activation o f coagulation Widespread intravascular fibrin deposition organ failure Consumption of platelets

(severe) Bleeding

Activation of coagulation
Activation of coagulation
degradation + in the bleeding products thrombosis Fibrinolysis microcirculation Circulating fibrin Events leading to
degradation
+
in the
bleeding
products
thrombosis
Fibrinolysis
microcirculation
Circulating fibrin
Events leading to
Events leading to
Events leading to
Circulating thrombi
Circulating thrombi
Thrombotic occlusion of microcirculation of all organs
Thrombotic occlusion of microcirculation of all organs
Thrombotic occlusion
of microcirculation of
all organs

Consumption of

platelets and

coagulation proteins

•Skin : petechiae, ecchymoses, venipuncture •Neuologic : intracerebral bleeding •Mucous membranes: epistaxis gingival oozing Signs of
•Skin : petechiae, ecchymoses, venipuncture
•Neuologic : intracerebral bleeding
•Mucous membranes: epistaxis gingival oozing
Signs of hemorrhagic diathesis
•GI: massive bleeding
•Renal : hematuria
oozing
,
•Fragmentation hemolytic anemia •GI: acute ulceration Signs of microvascular thrombosis •Pulmonary: acute respiratory distress syndrome •Renal
•Fragmentation hemolytic anemia
•GI: acute ulceration
Signs of microvascular thrombosis
•Pulmonary: acute respiratory distress syndrome
•Renal : oliguria, azotemia, cortical necrosis
•Skin : focal ischemia, superficial gangrene
•Neuologic : multifocal, delirium, coma

Marder VJ. Hemost and Thromb. 5edt. 2006.15711600

CLINICAL PHASES OF DIC

  • I Activation of the coagulation

  • II Precipitation of soluble fibrin with

consumption of coagulation factors

  • III Activation and/or inhibition of fibrinolysis with microthrombosis, embolism and

hemorrhage

IV

Endorgan failure and hemorrhage

Evidence of procoagulation

Elevated prothrombin fragment 1+2

Elevated fibrinopeptide A

Elevated fibrinopeptide B

Elevated thrombinantithrombin com pl ex

Elevated Ddimer

Evidence of fibrinoly tic activation

Elevated Ddimer

Elevated FDP

Elevated plasmin

Elevated plasmin antiplasmin complex

Evidence for inhibitor consumption

Decreased ATIII

Decreased alpha2antiplasmin

Decreased heparin cofactor II

Decreased protein C or S

Elevated TAT complex

Elevated PAP complex

Evidence for endorgan damage

Elevated LDH

Elevated creatinine

Decreased pH

Decreased paO 2

Needs 2 out of 4 above items for diagnosis
Needs 2 out of 4 above items for diagnosis

Features

Affected Patients

Bleeding

64%

Renal dysfunction

25%

Hepatic dysfunction

1 9%

Respiratory dysfunction

16%

Shock

14%

Central nervous system dysfunction

2%

Diagnosis of DIC

Screening tests:

Platelet count

PT

aPTT

TT

Fibrinogen

Confirmatory tests :

sMF (soluble fibrin

monomer)

Ddimer

FDP (fibrin degradation

 

product)

antithrombin

National consensus of DIC in sepsis 2001

Diagnosis of DIC: ISTH score (2001)

Diagnosis of DIC: ISTH score (2001) Taylor, FB, et al. Thromb Haemost 2001;86:1327
Diagnosis of DIC: ISTH score (2001) Taylor, FB, et al. Thromb Haemost 2001;86:1327
Diagnosis of DIC: ISTH score (2001) Taylor, FB, et al. Thromb Haemost 2001;86:1327
Diagnosis of DIC: ISTH score (2001) Taylor, FB, et al. Thromb Haemost 2001;86:1327
Diagnosis of DIC: ISTH score (2001) Taylor, FB, et al. Thromb Haemost 2001;86:1327
Diagnosis of DIC: ISTH score (2001) Taylor, FB, et al. Thromb Haemost 2001;86:1327
Diagnosis of DIC: ISTH score (2001) Taylor, FB, et al. Thromb Haemost 2001;86:1327
Diagnosis of DIC: ISTH score (2001) Taylor, FB, et al. Thromb Haemost 2001;86:1327
Diagnosis of DIC: ISTH score (2001) Taylor, FB, et al. Thromb Haemost 2001;86:1327

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

Differential Diagnosis

Severe liver failure

Vitamin K deficiency

Liver disease

Thrombotic thrombocy topenic purpura

Congenital abnormalities of fibrinogen

HELLP syndrome

TREATMENT OF DIC

Treat the underlying disease Restore the circulation Replacement therapy Cryoprecipitate/FFP Platelet concentrate Packed red cells Consider additional pharma col ogi c th era py controversial or investigational agents AT, APC, heparin, antifibrinolytic agents, others

Treatment of acute, severe DIC (1)

Modality

Modality

Rationale

Rationale

Details

Details

Expectations

Expectations

Life support

Life support

measures

measures

Self--evident

evident

Self

blood, respiratory

Fluids, blood,

respiratory

care, etc

Fluids,

care,

etc

exchange, electrolyte

Maintain cardiac

cardiac output,

balance, etc

balance, etc

output, gas

exchange,

electrolyte

Maintain

gas

Treating the

Treating the

disorder

disorder

erllyyiingng

unundder

cause ooff DIC

Correct the

Correct the

cause

DIC

Dependent onon the

Dependent

diagnos

agnosiiss

priimary

mary di

the

pr

complilicacati tingng papaththoollogogiicc

response (if any) of

Inhibit or block the

Inhibit or block the

with the response

mechanism of

DIC inparallel

the disorder

the disorder

mechanism

inparallel

with the

(if any)

of DIC

comp

of

Antithrombotic

Antithrombotic

agents

agents

microthrombus

microthrombus

formation

formation

Block

Block

concentrate

III

III

III

longg

70%

level

as lon

as the

levels;

Heparin

fibrinogen

continue as

level << 70%

Heparin by continuous IVIV

persists; ATAT

and platelet

clinical state

predisposing

by continuous

levels; continue

concentrate ifif ATAT III

as the predisposing

infusion, monitor with

infusion, monitor with

clinical state persists;

fibrinogen and platelet

balance within the

the

allow

pphhyysiolo

sis;; allow

fibrinolyysis

reperfusion

of the skin,

siologgicic fibrinol

Prevent fibrin formation; tiptip

kidneys, and brain

kidneys, and brain

the balance within the

reperfusion of the skin,

microcirculation toward

microcirculation toward

Prevent fibrin formation;

Marder VJ. Hemost and Thromb. 5edt. 2006.15711600

Treatment of acute, severe DIC (2)

Modality

Rationale

Details

Expectations

Tranfusion

Reestablish normal hemostastic potential

Infuse platelets and fibrinogen (cryoprecipitate); repeat as indicated by laboratory and clinical observation

Platelet count and fibrinogen should increase significantly; bleeding should diminish and stop during an interval of hours to several days

Transfusion

Restore normal

Infuse platelets and

Platelet count and and

+ heparin

hemostasis if transfusion of hemostasis factors fails to achieve significant increment in factor levels

cryoprecipitate 2 h after starting continous heparin infusion (7.5 U/kg/h); repeat as indicated by laboratory and clinical observation

fibrinogen should increase significantly if consumption is blocked; bleeding should diminish; if bleeding increases, discontinue heparin

Fibrinolytic

Block excessive

For adults ε-

Bleeding ceases rapidly but

inhibitors

fibrinolysis and the accumulation of degradation products in blood; protect hemostatic plugs

aminocaproic acid; loading dose, 46 g, then 1 g q12h for a limited duration (up to 48 h)

keeps vascular channels occluded with thrombus; dangerous if the thrombotic process was not previously treated with heparin

Marder VJ. Hemost and Thromb. 5edt. 2006.15711600

Disorder

Treatment approach

Purpura fulminants

Heparin by continous infusion

Acral or dermal ischemia

Heparin by continous infusion

Venous thromboembolism

Heparin by continous infusion

Bacteremia (associated with dermal ischemia or necrosis)

Heparin by continous infusion

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 rupture

Heparin preceding elective repair

Solid tumors

Heparin by continous infusion; if effective, then adjusteddose or lowmolecular weight heparin s.c.

Promyelotic leukemia

Acute promyelocytic leukemia

Marder VJ. Hemost and Thromb. 5edt. 2006.15711600

 

Disorder

 

Treatment approach

Relative contraindication

   

Aortic aneurysm, leaking

 

Cryoprecipitate and platelets preceding emergency repair

Hemorrhage in a closed spase

 

Heparin a possible option but only with external drainage

compromising vital function

Septicemia

Heparin only with specific indications; high doses; high

doses of AT-III concentrate if AT-III level < 70%

 

Abruptio placentae without significant

Blood volume replacement, prompt delivery, cryoprecipitate

bleeding

if needed

Amniotic fluid embolism

 

Consider he arin before hemostatic failure re lace

 

p

hemostatic factors if bleeding is present

;

p

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

 

i

i

h

asc tes and per toneo venous s unt

 

Acute fatty liver of pregnancy

 

AT-III replacement, preferably by concentrate

 

Intracranial gunshot wound or severe

Cryoprecipitate and platelets

 

brain injury

 
 

Marder VJ. Hemost and Thromb. 5edt. 2006.15711600

Anticoagulation Therapy

Rationale :

  • 1. Septic process reveals with coagulation abnormality DIC.

    • 2. Antithrombin, protein C, protein S and

tissue factor pathway inhibitor (TFPI) were

natural anticoagulant found to be reduced

  • 3. Ddimers or FDP were elevated, they

indicate that coagulation pathway were

activated

The Role of Activated Protein CC inin Severe Sepsis

The Role of Activated Protein

Severe Sepsis

Inactivation Tissue Factor n amma ory fl t I Neutrophil to Infection to Infection to Infection
Inactivation
Tissue Factor
n amma ory
fl
t
I
Neutrophil
to Infection
to Infection
to Infection
Suppressed
fibrinolysis
Inhibitio n
Factor VIIIa
Fibrin
Factor Va
Inactivation
THROMBIN
Tissue Factor
IL-6
IL-1
TNF-α
Monocyte
In hibition
Activated
Protein C
IL-6
Pr evention of activati on
esponse
c
c
o
l
Th
R
R
R
b
Organisms
CASCADE
esponse
esponse
rom
r no y
ti
ti
Fib i
PAI-1
TAFI
Activated Protein C
Activated Protein C
Inactivation
Activated Protein C
COAGULATION
Fibrin clot
Endothelium

Rationale for rhAPC

The evidence concerning use of rhAPC in adults is primarily based on two RCTs:

PROWESS (1,690 adult patients, stopped early for efficacy)

ADDRESS (stopped early for futility)

Additional safety information comes from an openlabel observational study, ENHANCE. The ENHANCE trial also suggested that early administration of rhAPC was associated with better outcomes.

PROWESS Survival Rates

RRR: 19.4% (95% CI 6.6 ‐ 30.5) ARR: 6.1% => NNT=17
RRR: 19.4% (95% CI 6.6 ‐ 30.5)
ARR: 6.1% => NNT=17

N Engl J Med. 2001; 344: 699709

The KyberCept (High Dose Antithrombin in Sepsis)

Trial : 90 Day Survival Rates

Primary Outcome Post Hoc Analysis
Primary Outcome
Post Hoc Analysis

*

Increased bleeding

risk in those who

received heparin+AT

(not shown)

*p = 03

Warren, B. L. et al. JAMA

2001;286:18691878.

SUMMARY

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.

The treatment of DIC is reversal or control of

the underlying cause, maintain the circulation

and replacement therapy as indicated.

Thank you