5/7/2012

Disseminated Intravascular
Coagulation as an Effect of
the Oncologic Process

Christopher A. Tormey, MD
Assistant Professor of Laboratory Medicine
Yale University School of Medicine
VA Connecticut Healthcare System
April 28, 2012

Talk Outline

General pathophysiology of disseminated

intravascular coagulation (DIC)
 Basic mechanisms & diagnosis

DIC as a manifestation of a hematologic or
oncologic malignancy

Therapeutic approaches
 What can we do beyond treating the
underlying disorder

What is DIC and how do

we diagnose it?

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Acute DIC Defined

At its core, acute DIC represents over-activity

of the coagulation system

Independent of the trigger, a patient in DIC
has massive activation of the extrinsic
pathway of the coagulation cascade
 Generation of tissue factor and activation of
Factor VII drive a clot-forming process

This over-activity leads to clot formation and
fibrin-generation

Acute DIC in Diagrams

Inflammatory stimulus
provokes expression
of tissue factor

FVIIa drives the

extrinsic clotting
cascade

Large amount of fibrin

clot are generated

Acute DIC Over Time

If not immediately controlled, activation of the

extrinsic pathway drives forward the clotting
response

A feedback loop ensues whereby the end-
products of the coagulation cascade
propagate additional clot formation via the
activation of the intrinsic cascade pathway

The end result is more fibrin generation

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DIC Propagation

Acute DIC:
Initial Manifestations

In normal hemostasis, fibrin is generated at
the site of a wound to form clot

In the pathologic process of DIC, as there is
no specific wound site, fibrin begins to
deposit throughout the body
 Particular deposition in the microcirculation

This deposition leads to an initial wave of end
organ damage
 Renal and pulmonary systems frequently effected

DIC:
Fibrin Deposition

Microangiopathy

Fibrin Deposition Platelet activation & clearance

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DIC:
Anticoagulants Fight Back

As massive pro-coagulant forces are
underway in the initial stages of DIC, the
bodys natural anti-coagulant system
activates
 This is an attempt to control systematic clot
activation

This system seeks ultimately to degrade
fibrin and fibrin-based clots

Fibrin Degradation

Acute DIC:
Later Stages

As DIC progresses, the pro-coagulant system
becomes exhausted of its supplies
 Fibrinogen and other coagulation factors quickly
become depleted

In addition, the anti-coagulant system remains
fully activated

As such, patients are now subjected to risk for
bleeding due to coagulation factor and platelet
consumption & anti-coagulation activity

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DIC Manifestations

Typically, DIC manifests itself most clearly

in its later stages
 The only signs of early DIC may be subtle

Changes in urine output, rise in BUN/creatinine,
etc

Patients typically present with small
vessel microangiopathy, oozing, and
thrombocytopenia-related bleeding

Bleeding Manifestations

Continuous Oozing

Acute DIC:
Diagnostics

While DIC is a clinical diagnosis, some
laboratory tests can be of use in
establishing a diagnosis

Many of these tests reflect the physiologic
changes occurring in the coagulation
system
 And, their outcome can be used to guide
therapeutic approaches (as discussed later)

Levi M, et al. Blood Rev. 2011; 25:33-7

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Acute DIC Diagnostics

Initial assessment of DIC should be aimed at
evaluating the coagulation cascade

As such, the following are useful:
 Prothrombin time (PT)
 Partial thromboplastin time (PTT)
 Fibrinogen
 Thrombin time (TT)
 Platelet count
 Smear review for RBC schistocytes

Levi M, et al. Blood Rev. 2011; 25:33-7

Typical Results in Acute DIC

PT / PTT
 Prolonged above baseline

Fibrinogen / TT
 Decreased to <100 mg/dL / prolonged

Platelets
 Decreased to <100,000 /uL

Smear review
 Numerous RBC schistocytes

Levi M, et al. Blood Rev. 2011; 25:33-7

Other Laboratory Tests

for Acute DIC

D-dimer and Fibrin-split products
 Tests that measure and quantitate the breakdown
of fibrin

Can be very useful in the assessment of DIC because of
the constant fibrinolysis
 False positives can be seen in post-surgical
patients, post-trauma and in patients with venous
thromboemboli (e.g. DVTs)

Therefore, results should be interpreted with caution

Levi M, et al. Blood Rev. 2011; 25:33-7

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DIC and malignancy

DIC in Malignancy

When approaching DIC in malignancy, one

must first consider the type of malignancy

Hematologic malignancies
 Acute myelogenous / lymphoid leukemia
 Lympomas (e.g. T-, B-cell)
 Myeloproliferative / myelodysplastic disorders

Solid tumors
 For instance, prostate and breast cancer

Why the division?

Hematologic Solid Tumor
Malignancies Malignancies

Tend to present more
Tend to present more

commonly with acute DIC with a low-grade,
picture chronic DIC picture

Biggest threat is  Also referred to as
bleeding complications Trousseaus Syndrome
 Seen in about 15% of new
Biggest threat is clotting
acute leukemia diagnoses or thrombotic
 An important cause of early complications
mortality  Effects about 7% of patients
with solid tumors
Kitchens CS. Hematology Am Soc Hematol Educ Program. 2009:240-6
Levi M. Best Pract Res Clin Haematol. 2009;22:129-36

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Hematologic Malignancies &

Acute DIC

The classic model of acute DIC complicating
hematologic malignancies is acute
promyelocytic leukemia (APML)
 Up to 80% of patients presenting with APML
manifest acute DIC

In this disorder, the granules of circulating
promyelocytic blasts are believed to elaborate
cytokines and other molecules which activate
the coagulation system leading to DIC
Kitchens CS. Hematology Am Soc Hematol Educ Program. 2009:240-6
Levi M. Best Pract Res Clin Haematol. 2009;22:129-36

DIC in APML

Kitchens CS. Hematology Am Soc Hematol Educ Program. 2009:240-6

Levi M. Best Pract Res Clin Haematol. 2009;22:129-36

Acute DIC in Hematologic

Malignancies

The elaboration of pro-coagulant molecules
from leukemia cells initiates the chain of
events described earlier
 Consumptive coagulopathy  bleeding risk

Patients with hematologic malignancies are
at even higher risk for bleeding complications
because they frequently present with low
platelet counts
 Marrow replacement by malignant cells
Kitchens CS. Hematology Am Soc Hematol Educ Program. 2009:240-6
Levi M. Best Pract Res Clin Haematol. 2009;22:129-36

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Solid Tumors & Chronic DIC

In the case of solid tumors, the pathogenesis
of DIC-thrombosis is believed to derive from
the elaboration of pro-coagulant substances
from the tumor cells

Implicated factors include:
 Tissue factor
 Cytokines/chemokines

In these cases, the more striking feature may
be activation of the clotting cascade rather
than fibrinolysis and bleeding
Kitchens CS. Hematology Am Soc Hematol Educ Program. 2009:240-6
Levi M. Best Pract Res Clin Haematol. 2009;22:129-36

DIC in Solid Tumors

TUMOR
CELL

DIC in Solid Tumors

In addition to the tumor cells, patients with
solid tumors may be higher risk for clot
formation than other populations
 Thus, potentially more susceptible to DIC-
thrombosis

Risks include:
 In-dwelling catheters/lines/ports
 Chemotherapy

Causes endothelial cell activation
 Immobilization
Kitchens CS. Hematology Am Soc Hematol Educ Program. 2009:240-6
Levi M. Best Pract Res Clin Haematol. 2009;22:129-36

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Chronic DIC Diagnostics

Unlike acute DIC (in which lab tests can help

confirm a diagnosis), there are no reliable
tests to predict a patients risk for thrombosis

As such, the suspicion for chronic DIC must

be made by frequently examining for clinical
signs of thrombosis

Clinical Signs of Chronic DIC

Kitchens CS. Hematology Am Soc Hematol Educ Program. 2009:240-6

Acute DIC in Solid Tumors

Although the majority of patients with solid
tumors manifest primarily DIC-thrombosis
(i.e. chronic, low-grade DIC), they are still
susceptible to the classic, acute form

This may manifest itself as:
 Hemorrhagic complications

Bleeding from lines, mucous membrane bleeds, etc

Bleeding into the tumor itself

Difficult to predict when patients with solid
tumors may manifest acute DIC forms

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Factors to Predict Acute vs Chronic

DIC

Kitchens CS. Hematology Am Soc Hematol Educ Program. 2009:240-6

Treatment approaches
to DIC

First Approach

Before determining a treatment approach,
one must first determine what type of DIC the
patient is experiencing
 Acute vs chronic
 Typically obvious from clinical and laboratory
studies

Acute DIC approaches are aimed at
preventing/overcoming bleeding

Chronic DIC approaches are aimed at
preventing/overcoming clotting

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Acute
DIC

Management of Acute DIC:

Transfusion

The approach to management of acute DIC relies upon
transfusion using the bricks and mortar approach:

Platelets
are the
bricks

Fibrinogen
is the
mortar

Platelets and Cryoprecipitate

Since PLTs and fibrinogen are the bricks and
mortar, the therapeutic approach revolves around
PLATELET and CRYOPRECIPITATE transfusion

Many clinicians will want to use FFP as a first line
therapy; this is not the optimal approach
 Initial PT/PTT prolongations are commonly due to the
depletion of fibrinogen
 It is preferable to replace fibrinogen with CRYO since it
has a high concentration in a very small volume

For fibrinogen content, 1 unit of FFP = 2 units of cryo

Volume comparisons are 200 mL (FFP) vs 25-30 mL (cryo)!
Kitchens CS. Hematology Am Soc Hematol Educ Program. 2009:240-6
Tormey CA, Snyder EL. Rossis Principles of Transfusion Medicine 2009; 482-98.

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DIC Case Scenario:

The Bleeding Patient

78 year old man with a new diagnosis of APML,
develops thrombocytopenia (PLTs 33,000 /uL),
prolonged PT and PTT, rare schistocytes on
peripheral smear and a Hct of 22%
 The team suspects a new-onset GI bleed

The clinical and laboratory picture is consistent
with DIC-associated bleeding

His fibrinogen = 70 mg/dL and he weighs 98 kg

How should we proceed?

Cryoprecipitate Dosing:
Fibrinogen for DIC

The formula is:
(Desired baseline fibrinogen) x P.V.
Avg. fibrinogen content / unit cryo
Our typical goal is fibrinogen > 150 mg/dL

The formula is tricky:
 Fibrinogen is measured in mg/dL but P.V. is
generally calculated in mL
 The amount of fibrinogen in a unit of cryo can be
variable
Brecher ME. AABB Technical Manual, 2007

Cryo:
Additional Notes

As a general rule, unless a patient is small
(i.e. a child) or morbidly obese, a 10 unit
CRYO pool is sufficient for quick-and-dirty
fibrinogen replacement to achieve levels of
150 mg/dL or greater

Cryo is also beneficial in DIC because it

replenishes fXIII (a clot stabilizer which is
also rapidly consumed)

Kitchens CS. Hematology Am Soc Hematol Educ Program. 2009:240-6

Tormey CA, Snyder EL. Rossis Principles of Transfusion Medicine 2009; 482-98.

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Platelet Transfusion in DIC

As with any other bleeding problem involving
thrombocytopenia, we should aim to keep
PLTs above 50,000 / uL in the setting of DIC
 Typically, one pool of random donor or apheresis
PLTs should suffice
 Repeated measurements of PLT count and
additional PLT doses are likely needed

If a patient is consuming large amounts of
PLTs in the setting of DIC, then a PLT drip
may be considered
Tormey CA, Snyder EL. Rossis Principles of Transfusion Medicine 2009; 482-98.
Tormey CA et al. Transfusion 2005; 45:140-41.

Platelet Drip in DIC

A PLT drip entails the slow infusion (drip) of 0.5-

0.75 units of random PLTs over 4 hours
 Random pools preferred over apheresis, however not as
important for DIC-related bleeding

PLT Drip Advantages:
 Inventory saving measure for the blood bank
 May promote vascular integrity via continuous infusion
(theory not proven)
 Gives clinicians an option when nothing else exists

Tormey CA, Snyder EL. Rossis Principles of Transfusion Medicine 2009; 482-98.
Tormey CA et al. Transfusion 2005; 45:140-41.

Plasma Transfusion in DIC

Plasma transfusion in DIC should only be

considered for patients with continued bleeding who:
 Have fibrinogen levels > 150 mg/dL post-cryo dosing
 Have received PLT transfusion
 Continue to demonstrate prolonged PT / PTT studies
indicative of consumption of other coagulation factors

As with most plasma, we should use a weight-based
dose of 10-15 mL / kg
 Most DIC doses are between 2-4 units of FFP
 Repeated dosing might be needed depending on lab
studies; repeat cryo and PLTs should be tried first though!

Kitchens CS. Hematology Am Soc Hematol Educ Program. 2009:240-6

Tormey CA, Snyder EL. Rossis Principles of Transfusion Medicine 2009; 482-98.

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Red Blood Cell (RBC) Transfusions in

DIC

RBCs should primarily be used to increase
oxygen carrying capacity in anemic patients

However, RBCs can also be used to promote
clotting
 Increasing a Hct to greater than 25% can promote
increased blood viscosity and clotting in the micro-
vascular space
 This is particularly relevant for DIC

Kitchens CS. Hematology Am Soc Hematol Educ Program. 2009:240-6

Tormey CA, Snyder EL. Rossis Principles of Transfusion Medicine 2009; 482-98.

Back to Our Patient

The patient should receive:

 An initial 10 unit pool of CRYO
 One pool (i.e. 5 units) of PLTs
 1 unit of RBCs (should raise his Hct above 25%)
 Clinical and laboratory follow-up every 4-6 hours to measure his
response

If his counts do not recover, or his bleeding is worse,
then he should be re-dosed with an additional pool of
CRYO, a pool of PLTs, and RBCs
 FFP should be considered if his PT/PTT dont correct with the
above approach

Novoseven:
A Role in DIC?

According to the Novoseven package insert:
Patients with DIC may have an increased risk of
developing thrombotic events

The cause of increased risk is unclear, but has been
attributed to increases in circulating tissue factor
seen in DIC which could lead to systemic
thrombosis

As such, use of fVIIa is generally (but not
absolutely) contraindicated in bleeding associated
with DIC

A low-dose (20-40 mcg / kg) may be considered with
intractable, refractory bleeds (no evidence based
dosing available)
Shander A, et al. Pharmacy and Therapeutics 2005; 30:644-58.

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Chronic
DIC

Chronic DIC:
Treatment Approach

Given the general risk for thrombosis in solid
tumors in general, and the added risk for
chronic DIC, patients demonstrating a
tendency toward clotting should be
anticoagulated

Treatments used typically include:
 Unfractionated heparin
 Low-molecular weight heparin
 Warfarin
Kitchens CS. Hematology Am Soc Hematol Educ Program. 2009:240-6
Levi M. Best Pract Res Clin Haematol. 2009;22:129-36

Thrombosis in DIC

For patients manifesting ongoing or life-

threatening thrombo-emboli, natural
anticoagulants can be given to better
enhance protection

Such agents include:
 Antithrombin III concentrates
 Activated protein C formulations

These therapies may be useful in reducing acute
mortality

Kitchens CS. Hematology Am Soc Hematol Educ Program. 2009:240-6

Levi M. Best Pract Res Clin Haematol. 2009;22:129-36

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Summary

DIC is a complex, life-threatening coagulation

disorder that frequently complicates both
hematologic and solid tumor malignancies

Clinical and laboratory criteria can be used to
establish diagnoses of acute or chronic DIC

Transfusion and/or anticoagulation regimens
can be used to manage DIC until underlying
disorders can be addressed

Thanks for your attention!

Questions?

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