SOLUBLE FIBRIN
MONKEY (E. COLI INJECTION)
HUMAN (ACUTE LEUKEMIA)
CAUSES OF DIC
• Blood exposed to excess tissue factor
Endothelial damage
Tissue factor expression by monocytes
Massive tissue/organ injury
Cancer
Obstetric catastrophe
•
•
Activation of fibrinolysis
Secondary to thrombin formation (t-PA)
Cancer/leukemia (t-PA, u-PA, other)
Cardiopulmonary bypass
Other procoagulant or profibrinolytic substances
Cancer cells
Venoms
TFPI
TFPI
AT3
APC
AT3
APC
TFPI
F. VIII/F. IX
F. VII
Tissue
factor
AT3
APC
Thrombin
PL, Ca++
TFPI
APC
F. II
F. X/F. V
AT3
AT3
TFPI
APC
APC
AT3
TFPI
Thrombin
F. VIII/F. IX
F. VII
Tissue
factor
Thrombin
PL, Ca++
F. II
F. X/F. V
Thrombin
TISSUE FACTOR
• Ubiquitous lipoprotein
• Highest concentrations in mucosa, brain, skin,
•
•
vascular adventitia
 "hemostatic envelope"
Not normally expressed by endothelium or
circulating cells
 Expression induced by inflammatory cytokines
Major physiologic (and pathologic) initiator of
coagulation
TISSUE FACTOR
Am J Pathol 1989; 134:1087-97
LARGE VESSEL
SMALL
VESSEL
MONOCYTE
+
MONOCYTE
ENDOTOXIN
CYTOKINE-INDUCED GAPS IN ENDOTHELIAL MONOLAYER
J Exp Med 1989;169:1977-91
Control
5 nM TNF x 90 min
5 nM TNF x 24h
KINETICS OF MONOCYTE TISSUE FACTOR mRNA
EXPRESSION AND THROMBIN GENERATION AFTER
ADMINISTRATION OF BACTERIAL LIPOPOLYSACCHARIDE TO
HEALTHY VOLUNTEERS
Tissue factor mRNA
Franco et al, Blood 2000;96:554-9
Thrombin
Cancer cells shed procoagulant membrane
vesicles
Fibrin deposits around tumor
cells
Intravascular fibrin
Dvorak et al, 1981
SECRETED PRODUCTS OF MYELOBLASTS
Urokinase
Tissue
factor
Elastase
tPA
Cytokines
PROMOTERS OF DIC
• Inflammation (TNF, IL-1, IL-6, etc)
 Upregulation of procoagulant pathways
 Downregulation of profibrinolytic pathways
 Effects on endothelium
• Liver disease
 Inhibitor deficiency (antithrombin,
antiplasmin, protein C, etc)
 Diminished clotting factor production
 Delayed clearance of FDP
INFLAMMATORY CYTOKINES
TNF
monocyte
IL-1
endothelial
cell
Tissue factor Decreased
expression Thrombomodulin
IL-3/IL-6
liver
megakaryocyte
Increased Increased
Increased
PAI-1
Fibrinogen, Platelets
antiplasmin
Fibrin deposition in kidney in DIC induced by tissue
factor (TF) or bacterial lipopolysaccharide (LPS) in rats
Asakura et al, Crit Care Med 2002;30:161
RELATIONSHIP BETWEEN MORTALITY AND TNF LEVEL IN
CHILDREN WITH INFECTIOUS PURPURA FULMINANS
100
Mortality (%)
80
Under 0.15
0.15-0.50
60
0.50-1.00
40
Over 1.00
20
0
TNF level (ng/ml)
NEJM 1988;319:397-400
COMPLICATIONS OF DIC
•Bleeding
•Thrombosis
•Tissue necrosis
CAUSES OF BLEEDING IN DIC
• Clotting factor consumption
• High levels of FDP (inhibit fibrin
formation)
• Endothelial damage
• Increased fibrinolytic activity
FIBRINOLYSIS
Platelets
Endothelial cell
PAI-1
Plasminogen
Fibroblasts
TPA
UK
Macrophage
Liver
Fibrin
2 PI
Plasmin
FDP
2 PI
Fibrinogen
Bleeding severity vs antiplasmin activity
patients with platelets > 30,000
100
% of patients
80
0-2+ bleeding
60
3-4+ bleeding
40
20
0
< 50%
50-75%
Antiplasmin activity
> 75%
DIC WITH HYPERFIBRINOLYSIS
Examples
• Acute leukemia (particularly
promyelocytic)
• Metastatic cancer (esp. prostate)
• Cardiopulmonary bypass
• Liver disease or transplantation
THROMBOSIS IN DIC
• Large vessel thrombosis uncommon
•
•
 Disordered clotting
 Increased fibrinolysis
More common in "chronic DIC"
 e.g., Trousseau syndrome
Clots may form around intravascular
catheters, etc
TISSUE NECROSIS AND DIC
(PURPURA FULMINANS)
Contributing factors
• Intravascular fibrin
• Endothelial damage
• Downregulated fibrinolysis
• Hypotension
• Pressor administration
• Acquired protein C deficiency
PUPURA FULMINANS
Pneumococcal sepsis in splenectomized patient
High level bacteremia
NEJM 2001;344:1593
NEJM 2004;351:2636
PURPURA FULMINANS IN MENINGOCOCCEMIA
High level bacteremia
Blood 2005;105:11
NEJM 2001;344:1372
TISSUE NECROSIS IN PURPURA FULMINANS
ADRENAL GLAND
(Waterhouse-Friderichsen syndrome)
NEJM 2005;353:1245
RENAL CORTEX
Hum Pathol 1972;3:327
PROTEIN C
• Physiologic anticoagulant
•
•
 Vitamin K-dependent
 Destroys factors Va, VIIIa (Protein S is cofactor)
Activated by thrombin bound to endothelium
 Activation downregulated by inflammatory
cytokines
Protective effect on endothelium?
 Protein C receptor on endothelial cells
 Activated protein C modulates endothelial
response to inflammation and hypoxia
Severe deficiency of protein C can cause tissue
necrosis
THE PROTEIN C SYSTEM
Blood 2007; 109:3161
CYTOPROTECTION BY APC
Blood 2007; 109:3161
PROTEIN C OR S DEFICIENCY STATES
ASSOCIATED WITH THROMBOSIS OR
PURPURA FULMINANS
Situation
Mechanism
Clinical Manifestations
Inherited protein C or S
deficiency (homozygous)
Genetic
Neonatal purpura
fulminans
Inherited protein C or S
deficiency (heterozygous)
Genetic
Increased risk of venous
thromboembolism
Genetic + decreased
protein C synthesis
Warfarin-induced skin
necrosis
? Immune-mediated
protein S consumption
? Protein C and S
consumption (DIC) or
downregulation
? Monoclonal Ig binds
protein C or APC
Post-infectious purpura
fulminans
Heterozygous protein C
(or S?) deficiency +
warfarin Rx
Varicella infection
Meningococcemia
Acquired protein C
inhibitor
Meningococcal purpura
Purpura fulminans
HOMOZYGOUS PROTEIN C DEFICIENCY WITH
NEONATAL PURPURA FULMINANS
WARFARIN-INDUCED SKIN NECROSIS
ACQUIRED PROTEIN C INHIBITOR
PROTEIN C IN BACTERIAL SEPSIS
Baboon model
With normally lethal dose of E. coli:
 Activated protein C prevents DIC, tissue necrosis and
death
 Another inhibitor of thrombin formation blocks DIC
but not tissue necrosis and death
With normally sublethal dose of E. coli:
 Monoclonal antibodies to either protein C or its
endothelial receptor promote DIC, tissue necrosis and
death
F.B. Taylor et al, J Clin Invest 1987; Blood 1991; Blood 2000
TRANSGENIC MICE THAT OVEREXPRESS THE
ENDOTHELIAL APC RECEPTOR HAVE IMPROVED
SURVIVAL AFTER ENDOTOXIN ADMINISTRATION
J Thrombos Haemost 2005;3: 1351–1359
CIRCULATING ACTIVATED PROTEIN C IN
SEVERE SEPSIS
Survivors had higher APC levels and lower F1.2/APC
ratios than non-survivors
Blood 2004;104:3958
ENDOTHELIAL PROTEIN C ACTIVATION
IS REDUCED IN SEPSIS
Normal
Sepsis
Thrombomodulin
NEJM 2001;345:408
Protein C receptor
ANTICOAGULANT PROTEIN LEVELS
IN MENINGOCOCCEMIA
Relationship to multiorgan failure
Mean level (% normal)
ORGAN FAILURE?
Protein C
Antithrombin
Protein S
Yes
18 ± 7
53 ± 16
75 ± 19
No
42 ± 13
81 ± 20
87 ± 14
Blood 2000;96:3719
Protein C levels predict ICU survival as well as the
APACHE II or SAPS II score
Anesthesiology 2007;107:15
DIC PATHOPHYSIOLOGY
Summary
• Excess tissue factor + flowing blood = DIC
• Inflammatory cytokines set the stage for DIC
and contribute to tissue damage
• Excessive fibrinolysis associated with higher
bleeding risk
• Acquired protein C deficiency associated
with high risk of tissue necrosis/purpura
fulminans
DIAGNOSIS OF DIC
DIC is likely when there is
1. A condition known to cause DIC
2. Evidence of accelerated fibrinolysis
and clotting factor consumption
LABORATORY TESTS IN DIC
DIAGNOSIS
ASSESS
SEVERITY
GUIDE
TREATMENT
FDP or D-Dimer
Antithrombin III
PT/INR
Fibrinogen
Alpha2-antiplasmin
Fibrinogen
PT/INR
Protein C
Platelet count
Platelet count
Fibrin monomer
Alpha2-antiplasmin
Death
Is
Coming
OUTCOME IN DIC
• 346 patients
• Incidence of bleeding: 77%
• Mortality
 Overall:
 With bleeding:
 Without bleeding:
68%
72%
63%
• Most deaths from underlying disease, not
bleeding
Thromb Haemost 1980; 43:28-33
TREATMENT OF DIC
• TREAT UNDERLYING DISEASE!
• Clotting factor & inhibitor replacement
Fresh frozen plasma
Cryoprecipitate
Platelets
?Antithrombin III, protein C concentrate
• Pharmacologic inhibitors
Heparin
Antifibrinolytics
REPLACEMENT THERAPY IN DIC
Product
Content
Indication
Risk
FFP
All clotting factors
and inhibitors
INR > 1.6
Volume, virus
transmission
Cryoprecipitate
Fibrinogen, VIII,
VWF
Fibrinogen < 50-100
(?)
"Feed the fire"?
Platelets
Platelets < 30-50K
Antithrombin
Purified
antithrombin
Low antithrombin?
?
Activated protein C
Purified APC
Purpura fulminans?
Low protein C?
Bleeding
PHARMACOLOGIC INHIBITORS IN DIC
•
•
•
•
Anticoagulant:
 Unfractionated Heparin
 Little experience with LMWHs
Antifibrinolytic:
 Epsilon aminocaproic acid (Amicar)
 Tranexamic acid (?availability)
No controlled trials showing benefit
Convincing anecdotal evidence of benefit in individual
patients
HEPARIN IN DIC
Rationale:
Prevent thrombin/fibrin formation
and secondary fibrinolysis
Indications:
Cancer-associated DIC
Acute leukemia and DIC
Chronic DIC with aneurysm, etc
Overt thrombosis
Purpura fulminans?
Concomitant antifibrinolytic Rx
Risks:
Exacerbate bleeding
Drug-induced thrombocytopenia
Low dose (eg, 500 U/hr) usually adequate
ANTIFIBRINOLYTIC DRUGS
H N
2
LYSINE
H N CH CH CH
CH CH COOH
AMICAR
(EACA)
H N CH CH CH
CH CH COOH
2
2
2
2
2
2
2
2
CH
2
TRANEXAMIC
ACID
2
2
CH
2
H N CH CH
2
2
CH
2
CH
2
CH
2
COOH
FIBRINOLYSIS
Antifibrinolytic drug effects
EACA
Plasminogen
TPA
EACA
Fibrin
UK
Plasmin
FDP
EACA
Fibrinogen
ANTIFIBRINOLYTIC THERAPY IN DIC
Rationale:
Inhibit activation of plasminogen/clot lysis
Prevent bleeding
Indications:
DIC in promyelocytic leukemia
DIC with severe bleeding, low antiplasmin?
Risk:
Thrombosis
Amicar, 1 gram/hour i.v. with low dose heparin
SPINAL ARTERY THROMBOSIS AFTER AMICAR TREATMENT
Hum Pathol 1972;3:327
ANTIFIBRINOLYTIC THERAPY IN
PROMYELOCYTIC LEUKEMIA
•
•
•
•
APML often associated with DIC and hyperfibrinolysis, high
risk of fatal intracranial hemorrhage
In seven patients with APML, bleeding occurred only in
those with severe alpha2-antiplasmin deficiency (<30%)
Patients with low antiplasmin levels were treated with EACA
plus low-dose heparin
EACA treatment was associated with prompt cessation of
bleeding, reversal of laboratory evidence of
hyperfibrinolysis, and decreased need for blood product
support
Ann Intern Med 1986;105:873-7
62 yo man with
spontaneous
intracranial bleed
PT 20.4 sec
Plts 69K
Fibrinogen 163
Antiplasmin < 25%
Antithrombin 116%
PSA > 10,000
DIC AND PROSTATE CARCINOMA
60 yo man post XRT for spine mets with diffuse bleeding
250
250
200
200
150
150
100
100
50
50
0
0
1
2
3
4
5
DAY
6
7
8
Pla te le ts
F ib rin o g e n , m g /d l
300
PROTEIN C REPLACEMENT IN PURPURA
FULMINANS
A prospective, open-label clinical trial
• Subjects: 36 patients with meningococcemia, shock and purpura
fulminans
 Mean age = 12 (3 months-72 yrs)
 Mean protein C activity 18%
• Intervention: Protein C concentrate, 100 IU/kg loading dose and 10
IU/kg/hr, adjusted to keep protein C activity in 80-120% range
 Two patients also received antithrombin concentrate
OUTCOME
OBSERVED
PREDICTED
Death
8%
50%
Amputation
12%
30%
Blood 2000;96:3719
RECOMBINANT ACTIVATED PROTEIN C
INFUSION IN SEVERE SEPSIS
NEJM 2001;344:699
• Subjects: 1690 patients with severe sepsis
• Method: randomized, double-blind, placebo-controlled
multicenter trial
• Intervention: rAPC infusion vs placebo
• Outcomes:
Mortality lower in treated pts (24.7% vs 30.8%,
p=.005)
Serious bleeding more common in treated pts (3.5%
vs 2%, p=.06)
EFFECT OF rAPC INFUSION ON SURVIVAL IN
SEVERE SEPSIS
NEJM 2001;344:699
EFFECT OF rAPC INFUSION ON D-DIMER
LEVELS
NEJM 2001;344:699