How should we diagnose DIC

and other consumptive

coagulopathies?

Pall T. Onundarson, M.D.

Laboratory Hematology and Thrombosis and Hemostasis Unit
National University Hospital
University of Iceland School of Medicine
Iceland

Treasurer of the ISLH

1
 Conflict of interest

• No COI related to this topic

• [Inventor of the patented Fiix-prothrombin time®, a

new modified PT-test that improves vitamin K
antagonists´treatment by stabilizing their
management and is being commercialized in
cooperation with Hart Biologicals Ltd, UK]

2
How should we diagnose DIC
and other consumptive
coagulopathies?

Pall T. Onundarson, M.D.

Laboratory Hematology and Thrombosis and Hemostasis Unit
National University Hospital
University of Iceland School of Medicine
Iceland

Treasurer of the ISLH

3
23 YO ICELANDIC WOMAN

ERRONEOUSLY DIAGNOSED FOR 24 HOURS WITH GASTROENTERITIS WHEN REFERRED TO THE ED

SEPTIC SHOCK AND PURPURA ON PRESENTATION

SHE WAS DEAD WITHIN 90 MINUTES

“I HAVE MENINGITIS AND I WILL DIE”

4
TERMINOLOGY

5
 Consumptive coagulopathies
vs Thrombotic microangiopathies
– TTP
• Highly lethal and manifested by – Thrombotic thrombocytopenic
– microvascular thromboses, purpura
– microangiopathic hemolysis
– thrombocytopenia – HUS
– Hemolytic uremic syndrome

– Consumptive coagulopathy
– Disseminated intravascular
coagulation (DIC)

– Localized intravascular
coagulation

6
 Terminology:
Consumptive coagulopathies
CONSUMPTIVE COAGULOPATHIES Differential diagnosis
• Acute DIC (disseminated intravascular • Septicemic thrombocytopenia
coagulation) • Non-consumptive acute thrombotic
microangiopathies (TMA)
• Subacute DIC – Thrombotic thrombocytopenic purpura
(TTP)
– Hemolytic uremic syndrome (HUS)
• Chronic DIC (Trousseau´s syndrome) – Atypical HUS
– migrating thrombophlebitis (VTE) • HITT
– Non-bacterial endocarditis
• Primary hyperfibrinolysis
• Vitamin K deficiency
• Localised intravascular coagulation
• Liver failure
(“LIC”)

• HELLP syndrome
7
What are they?
CONSUMPTIVE COAGULOPATHIES

8
Biochemical approach
DIC is characterized by
• systemic activation of coagulation,
vessels DIC is a clinical condition, a syndrome but not a disease
• potentially leading to thrombotic obstruction of small and midsize
• thereby contributing to organ dysfunction.
• At the same time, ongoing consumption of platelets and
coagulation proteins results in thrombocytopenia and low
concentrations of clotting factors, which may cause profuse
hemorrhagic complications.
Primarily a thrombotic syndrome
DIC is always secondary to an underlying condition, such as severe
infections, solid or hematologic malignancies, trauma, or obstetric
calamities.
A reliable diagnosis of DIC can be made through simple scoring
algorithms based on readily available routine hemostatic
parameters. (Biochemical confirmation)
The cornerstone of supportive treatment of this coagulopathy is
management of the underlying condition. Additionally,
administration of heparin may be useful, and restoration of
physiological anticoagulants has been suggested, but has not been
proven successful in improving clinically relevant outcomes so far. In
patients with major bleeding or at risk for hemorrhagic
complications, administration of platelet concentrates, plasma, or
coagulation factor concentrates should be considered.
(Levi M, Scully M. Blood. 2018;131(8):845-854)
Clinical approach
Disseminated intravascular coagulation (DIC) is a clinical condition
characterized by
• symptoms and signs of microinfarctions and bleeding
• caused by systemic activation of coagulation which leads to
thrombotic obstructions of small and midsize vessels, which cause
organ dysfunction and secondary ongoing consumption of platelets
and coagulation proteins resulting in thrombocytopenia, low
concentrations of clotting factors and varying degree of
hyperfibrinolysis
DIC is always secondary to an underlying condition, such as severe
infections, solid or hematologic malignancies, trauma, or obstetric
complications.
A reliable diagnosis of DIC cannot be made through simple scoring
algorithms based on routine hemostatic parameters.
The cornerstone of supportive treatment of this coagulopathy is
management of the underlying condition. Additionally,
administration of heparin may be useful, and restoration of
physiological anticoagulants has been suggested, but has not been
proven successful in improving clinically relevant outcomes so far. In
patients with major bleeding or at risk for hemorrhagic
complications, administration of platelet concentrates, plasma, or
coagulation factor concentrates should be considered.
9
 Consumptive
part is missing
from definition

ISTH SSC definition of DIC Hmmm… Pall´s private definition

“DIC is an acquired syndrome “DIC is an acquired syndrome arising from

characterized by the intravascular
activation of coagulation without a
specific localization
and arising from different causes.
It can originate from and cause damage
to the microvasculature, which if
sufficiently severe, can produce
organ dysfunction.”
Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M, Scientific
Subcommittee on Disseminated Intravascular Coagulation (DIC)
of the International Society on Thrombosis and Haemostasis
(ISTH).
different causes that is characterized by
–intravascular fibrin formation without a specific
localization and
– secondary consumption of platelets and coagulation
factors
It can originate from and cause damage to the
microvasculature, which if sufficiently severe,
can produce organ dysfunction from necrosis
and secondary hemorrhage.”

10
Thromb Haemost 2001; 86( 5):1327-30.
It always occurs in association with severe illness

WHEN DOES IT HAPPEN?

11
Diseases associated with DIC

In DIC there is always an underlying cause

Diseases associated with DIC
WHAT IS HAPPENING?

14
 Coagulation runs amok
In this order:

1. Widespread clotting occurs in the vasculature leads to thrombotic occlusions

in microvasculature with consequent and gangrene.
• Tissue factor in blood
• Tissue factor expressed on endothelium or monocytes

Coagulation runs amok

• Endotoxin suppress thrombomodulin expression on endothelium
• Suppressed natural anticoagulants and fibrinolysis
• functional protein C deficiency

2. Clotting factors, natural anticoagulants and platelets are consumed and red
cells are sliced on fibrin strands in small vessels
• Microangiopathic hemolytic anemia (MHA; fragmentation hemolysis, schistocytes)
• Thrombocytopenia
• Prolonged global clotting tests
• Reduced antithrombin and protein C

3. Secondary bleeding due to

• Thrombocytopenia and clotting factor deficiency
 Pathogenesis of DIC

Cells expressing tissue factor

but alien to blood get into circulation
•Tissue trauma
•Burns
•Amniotic fluid etc

VIIa*TF

Thrombin
Clotting
Fibrin factor and
platelet
consumption
BLEEDING

Modified from: Levi M, van der Poll T.

Intern Emerg Med: 2013;8:23-32

16
 PATHOGENESIS OF TMA [TTP and HUS] :
No TF expression, no clotting factor consumption

Pure platelet thrombi

TTP HUS
• Deficiency of ADAMTS13* • Endothelial cell damage in the
– <10% activity kidney alters adhesive property of
– Normal coags the EC
– Initiated by Shigella toxin
– (from enterotoxic E. Coli or
enterotoxic Shigella)
– ADAMTS-13 is >10%
– Normal coags

* A VWF cleaving metalloprotease

17
Seek and you will find

HOW TO RECOGNIZE DIC?

18
TEMPO
SEVERITY

DIAGNOSIS OF DIC:
A. CLINICAL SCENARIO

19
 Clinical presentation of D.I.C.
Varying tempo and severity
ACUTE DIC
“Purpura fulminans”
• Evident life threatening
disease and:
– Poor circulation, evidence of
tissue necrosis and organ
failure
• Rapidly forming thrombotic
occlusions in small vessels
causing organ failure
• Acute renal failure
• ARDS
– Purpura and serious
bleeding
Chronic DIC
(Trousseau´s syndrome)
– Microangiopathic
hemolysis,
thrombocytopenia and
coagulation test evidence
of DIC
– Recurrent VTE and
superficial phlebitis
(“migrating
thrombophlebitis”)
– Aseptic vegetations on
heart valves (“marantic
endocarditis”)
– Bleeding is rare
 Symptoms and signs of acute DIC
Widespread microvascular thrombi Platelets and coag. factors are
consumed. Fibrinolysis is usually not
increased:
SPREAD MICROVASCULAR CONSEQUENCES OF CONSUMPTION:
THROMBOSES:
Neurological: Neurological
Multifocal symptoms; delerium, coma Focal symptoms: intracerebral bleeding
Skin: Skin:
end- artery gangrene skin + puncture sites
Renal: Renal:
cortical necrosis, ARF hematuria

Gastrointestinal: Gastrointestinal:
Bleeding due to necrosis
massive bleeding
Adrenal gland bleeding
Pulmonary:
Waterhouse-Friedrichsen syndrome
ARDS
Without an underlying disease
the diagnosis cannot be made!

22
Fibrin deposition and consumption

DIAGNOSIS OF DIC:
B. LABORATORY CONFIRMATORY EVIDENCE

23
 The typical DIC panel*

• CBC/platelet count and blood smear (MHA)

• APTT
• PT
• Fibrinogen
• D-dimer

* Tests can only be assessed for DIC if a relevant underlying disease is identified 24
 Markers of increased fibrin formation

Increased thrombin formation

• Increased TAT
• Prothrombin fragment 1+2

Increased fibrin formation

• Soluble fibrin
• D-dimer
• a crosslinked fibrin degradation
product
• Indicates fibrin formation
• Negative predictive value high
NEJM
2003
Bick RL. Thromb Res. 1992 Mar 15;65(6):785-90.
Singh; N et al . Clin Appl Thromb Hemost 2015 23,
460-465. 25
Figure 1. Box plots of the plasma concentration of d-dimer and fibrin monomer.

Singh; N et al . Clin Appl Thromb Hemost 2015 23, 460-465.

 Markers of consumption

Building material used up Inhibitors of fibrin formation used up

• Thrombocytopenia • Reduced natural
anticoagulants
– Antithrombin
• Prolonged APTT and PT
– Protein C
– Reduced coagulation factors
(multifactor deficiency)

• [Hypofibrinogenemia]

27
Protein C, antithrombin and protein S
in meningococcemia
(White B et al, Blood 2000;96:3719-3724)
 Markers of fibrinolytic activity

Normal or suppressed fibrinolysis Hyperfibrinolysis:

• Normal antiplasmin • Reduced antiplasmin

activity

• High PAP complexes

• (High D-dimer)

29
 Markers of microvascular thrombi
A THROMBOTIC MICROANGIOPATHY
(TMA) IS PRESENT:

• Thrombocytopenia
• Hemolysis with schistocytes
– High LD,
– high bilirubin,
– low haptoglobin
– Fragmented/“sliced”
erythrocytes

30
 Confirming acute DIC
1 D-dimer 2 AT
3 APTT or PT
4 Platelet count

5 Fibrinogen

Li W et al. Int J Lab Hematol 2016;38:151-9.

31
SO WHAT SHOULD OUR
LABORATORY PANEL LOOK LIKE?

32
 Rapid laboratory approach*:
Is there evidence of increased fibrin formation, consumption of platelets, microvascular thrombi,
consumption of coagulation factors and consumption of natural anticoagulants?
Can we exlude vitamin K deficiency at the same time?

Classical DIC screening panel: Reykjavik DIC screening panel:

• CBC and blood smear (MHA) • D-dimer
• APTT • Coagulation inhibitors
• Antithrombin
• PT • Protein C 3 minute spin in
• Fibrinogen • APTT or PT microcentrifuge

• D-dimer • CBC/platelet count Results of all tests

are reported in LIS
• Fibrinogen within 15 minutes of
• Antiplasmin sample receival in
laboratory

• [Blood smear]

* Tests can only be assessed for DIC if a relevant underlying disease is identified 33
 Differential diagnosis
Condition Test:
• Septicemic thrombocytopenia without • D-dimer not very “high”
• APTT and PT normal. No schistocytes.
DIC [or ITP]

• Vitamin K deficiency • PT prolonged > APTT, AT normal, PC low

• Primary hyperfibrinolysis • Antiplasmin very low, not thrombocytopenic

• HIT(T) • Anti PF-4 antibodies positive

• Non-consumptive acute thrombotic

microangiopathies (TMA)
– Thrombotic thrombocytopenic purpura (TTP) • Thrombocytopenia and MAHA, normal coags and D-dimer,
ADAMTS13 activity <10%

– Hemolytic uremic syndrome (HUS)

• Enterotoxic e.coli/shiga toxin (STEC infection)

– [Atypical HUS]
• Biochemically similar to DIC.
• Cirrhosis • but high FVIII and VWF.
34
Severe ADAMTS13 deficiency in
patients with thrombotic Anti PF-4 antibodies in HIT
microangiopathies: The Harvard
TMA Research Collaborative

2015, DOI: (10.1111/bjh.13658)

Answer: I don´t think so…but the scores may be helpful still the same!

DOES DIC-SCORING HELP

DIAGNOSING DIC?

36
 ISTH DIC scoring for “overt” DIC
• No single laboratory test • The ISTH DIC score is
calculated based on
routinely available
laboratory tests

– platelet count,
– prothrombin time,
– a fibrin-related marker
[usually D-dimer]
– fibrinogen.

37
Overt DIC scoring?

Levi M, Scully M. Blood 2018;131:845-54

Score initially published in year 2001
DIC scores

39
 DIC
in severe sepsis

Gando et al. Critical Care 2013, 17:R111 40

CAN WE PROGNOSTICATE PATIENTS
SUSPECTED OF DIC?

41
 Prediction of survival in 1814 patients suspected of disseminated intravascular coagulation
ISTH score

Fullfill ISTH DIC criteria

Survival of patients not fulfilling criteria (non-DIC group; ISTH score 1-4) and matched non-DIC subgroup.

Panel A shows that the one-year survival of patients in the DIC group was 37% compared to 75% in the non-DIC group (P > 0.001). No
statistical difference was found in the survival of the non-DIC group and the matched non-DIC subgroup.

Panel B shows the one-year survival of all patients suspected of DIC in relation to their highest ISTH score. As evident, the higher the
ISTH score, the higher is lower the survival (P < 0.001).
The number of analyzable patients at risk with each ISTH score is shown adjacent to the relevant curve.

Hjörleifsson E. Sigurdsson M, Gudmundsdottir BR, Sigurdsson GH, Önundarson PT.

Acta Anaesth Scand 2015; 59: 870–880
Protein C, antithrombin and protein S
in meningococcemia
(White B et al, Blood 2000;96:3719-3724)
Can ISTH DIC score be predicted based on antithrombin or protein C?

Einar Hjörleifsson et al. Acta Anaesthesiologica Scandinavica

Volume 59, Issue 7, pages 870-880, 24 APR 2015 DOI: 10.1111/aas.12537
http://onlinelibrary.wiley.com/doi/10.1111/aas.12537/full#aas12537-fig-0003
Can prognosis of patients suspected of acute DIC be assessed from
initial antithrombin, protein C and antiplasmin

< 54-70% activity

< 53% activity

Einar Hjörleifsson et al, Acta Anaesth Scand 2015 45

Conclusions: Diagnosis of acute DIC
Diagnosis
• The D-dimer, antithrombin, protein C and
the APTT/PT are the most sensitive tests
– The acute DIC panel should include protein C,
antithrombin and possibly antiplasmin
• ISTH score of 5 or more misses many DIC
cases
– The score results should probably not be
considered as an all or none score but used for
grading severity
• All DIC panel results can be provided
within 15 minutes of sample receival in
laboratory
Syndrome severity
• DIC occurs across a spectrum of
severity.
• The ISTH score across its spectrum
can be used to assess prognosis of
severly ill patients
• The degree of reductions in
antithrombin and in particular
protein C are highly predictive of
mortality
– May substitute need for scoring
46
THE END
47