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Disseminated Intravascular Coagulation
Hematologists Perspective

Dr. Naghmi Asif and Prof. Khalid Hassan

MCH Centre, Pakistan Institute of Medical Sciences, Islamabad

Introduction
Disseminated intravascular coagulation (also called
consumption coagulopathy and defibrination syndrome) is
an acquired condition characterized largely by uncontrolled
activation of the coagulation system, excess thrombin
generation, which results in the intravascular formation of
fibrin and ultimately thrombotic occlusion of small and
midsize vessels.
1, 2
There is also activation of the
fibrinolytic system, and this along with consumption of
coagulation factors and platelets results in bleeding,
particularly when the patients blood vessels have been
damaged by vascular punctures, trauma, or surgery. There is
thus evidence of both thrombin and plasmin activation.
Intravascular coagulation can also compromise the blood
supply to organs leading to hemodynamic and metabolic
derangements and multiple organs failure resulting in
increased mortality and morbidity.
3
Sometimes thrombosis
and hemorrhage may occur almost at the same time and
clinical features are characterized by the variable presence
of both intravascular coagulation and hemorrhage.
Etiological factors (Table 1)
DIC begins with appearance of procoagulant
activity in dynamic or active circulation. It is however not a
primary disease but reflects a complication of one of several
possible underlying illnesses or conditions
4
and sometimes
the features of primary disease are overtaken by sudden
onset of life threatening hemorrhage or hypoperfusion of
vital organs due to microcirculatory obstruction.
5
It has
been proved in various studies that most prevalent
etiological factors include infections, obstetric
complications and malignancies.
6

Pathophysiology
The diagnosis of disseminated intravascular
coagulation is made by laboratory testing. In order to
understand the use of screening and specific tests for this
entity, a brief review of these laboratory tests is needed.
Disseminated intravascular coagulation is mainly due to the
presence of thrombin in the systemic circulation. Thrombin
is generated from prothrombin by activation of either the
intrinsic and/or extrinsic coagulation systems.
Effects of Thrombin
Thrombin plays a key role in coagulation system. Increased
thrombin generation is predominantly mediated by tissue
factor, which enters the circulation as a result of tissue
damage or enhanced expression of tissue factor on cells in
response to endotoxins or cytokines.
7,8
Thrombin itself is
very short lived and difficult to measure. Thus, the effects
of thrombin on the circulating blood are usually used to
Table 1: Etiological Factors associated with DIC
Infections
(Herpes, Rubella, Smallpox, Acute hepatitis, Viral
hemorrhagic fever)
(Septicemia particularly due to gram negative organisms,
Meningococcemia etc)
Rickettsial (Rocky mountain spotted fever, others)
Mycotic (Aspergillosis, Histoplasmosis)
Protozoal (Malaria, Kala-azar, Typanosomiasis)
Obstetrical Complications
Abruptio placenta
Septic abortion
Amniotic fluid embolism
Intrauterine fetal death
Abortions
Degenerating hydatidiform mole
Abdominal pregnancy
Neoplasms
Carcinomas (Prostate, Pancreas, Ovary, Breast, lung, etc)
Miscellaneous (metastatic carcinoid, Rhabdomyosarcoma,
Neuroblastoma, others)
Disorders of Hemopoietic System
Acute Leukemias (Promyelocytic, other types)
Intravascular hemolysis (transfusion reaction, PNH, drug
induced, Sickle cell disease)
Histiocytic Medullary Reticulosis
Vascular Disorders
Malformations (Giant hemangiomas, aneurysms, others)
Collagen vascular disorders
Hypoxia and hypoperfusion
Congestive failure with pulmonary emboli, Myocardial
infarction, shock, hypothermia
Massive tissue injury
Large traumatic injuries and burns, extensive surgical
intervention, fat embolism
Miscellaneous
Snake bite, anaphylaxis, heat stroke, diabetic acidosis,
acute pancreatitis, graft versus host disease.

detect its presence. Thrombin is a known activator of the
fibrinolytic system. Thrombin also acts on fibrinogen in a
very specific way to release two peptides (fibrino-peptides
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A and B) producing a fibrinogen molecule that is still
soluble in plasma called soluble fibrin monomer (sFM).
Fibrin monomer then polymerizes and is converted to the
insoluble fibrin form by the action of activated factor XIII.
Factor XIII is similarly activated by thrombin. Thrombin
also acts on platelets to induce aggregation and subsequent
thrombocytopenia occurs. Thrombin in small amounts acts
on both the intrinsic and extrinsic coagulation systems by
facilitating increased production of factor V and VIII.
Fibrinolysis
Fibrinolysis is a process in which plasmin, an
active form of plasminogen, cleaves fibrin and fibrinogen to
restore vessel patency following hemostasis. The formation
of plasmin (fibrinolysin) is a very necessary part of the
normal physiologic response to thrombin generation.
Activity of plasmin is regulated by vascular endothelial cells
that secrete both serine protease plasminogen activators and
plasminogen activator inhibitors (PAI-1 and PAI-2). It is
suppressed at the time of maximal activation of coagulation
due to a sustained rise in plasminogen activator inhibitor-1.
Plasmin may degrade fibrin polymer, fibrin monomer, and
fibrinogen. All four of these reactions result in the
formation of what are called fibrinolytic split or degradation
products (FSP, FDP).
Inhibitors of coagulation
Despite potent stimulation of the coagulation
pathway, it cannot be propagated unless there is a problem
with the natural anticoagulation pathways.
9
These pathways
include antithrombin III, protein C, protein S and tissue
factor pathway inhibitor (TFPI). These inhibitors of
coagulation are also very important for development of DIC
particularly in sepsis which leads to suppression of this
system. Activation protein C is induced by a complex
formed thrombin and endothelial cell protein called
Thrombomodulin. Activated protein C causes inhibition of
factor V and factor VIII. Activity of this factor is also
greatly enhanced by Protein S (free protein S)
10
Tumor
necrosis factor (TNF) downregulates thrombomoduhn
expression on endothelial cells, resulting in a decreased
protein C activity, thus further contributing to a
procoagulant state.
11,12

Antithrombin III is a circulating plasma protease
inhibitor that neutralizes mainly thrombin and factor Xa.
Plasma levels of antithrombin III, the most important
inhibitor of thrombin, are markedly reduced during DIC due
to a combination of consumption, degradation by elastase
from activated neutrophils, and impaired synthesis.
13
Tissue
factor pathway inhibitor directly inhibits factor Xa, and it
complexes with factor Xa to inhibit tissue factor. Its
increase in DIC is insufficient in relation to the increase in
tissue factordependent activation of coagulation.
Thus Pathophysiology of DIC is complex. The
mechanisms that activate or trigger DIC act on processes
that are involved in normal Hemostasis. These mechanisms
have in common the capacity in terms of either the
magnitude or the duration of activating stimulus, to exceed
normal compensatory processes. Thrombin is persistently
generated and fibrin is formed in the circulating blood.
Fibrinogen, various coagulation factors and platelets are
consumed. The fibrinolytic mechanism is activated and
large amounts of FDPs are produced, which further impair
the haemostatic function. Normal compensatory processes
become impaired creating a self- perpetuating viscous
cycle.
The 3 major mechanisms underlying DIC are:
1. Excessive generation and circulation of thrombin,
2. Impairment of the natural anticoagulant pathway, and
3. Suppression of fibrinolysis.
Bleeding, shock and vascular occlusion commonly
supervene and produce profound alteration in the function
of various organ systems. The ultimate outcome depends
upon equilibrium between the various pathologic processes
and compensatory mechanisms. Hence coagulopathy may
be compensated or decompensated depending upon the
degree of consumption of the various procoagulants and
platelets. If the consumption of these procoagulants exceeds
production, then the resultant levels may be reduced and
many cases may be reduced below normal hemostatic
levels. In such cases, one would see a decompensated form
of DIC which, by and large, is the predominant variety.
14

Conditions that may be complicated by
disseminated intravascular coagulation (DIC) include:
Infectious Disease
In septic patients, DIC occurs frequently, may
complicate the already complex clinical situation and
contribute to the high mortality. Recent clinical trials for
severe sepsis showed that the mortality in severe sepsis was
about 3545%
15,16
and it was higher in those that experience
DIC than in those without.
17
Although virtually all
microorganisms can cause disseminated intravascular
coagulation including viruses and parasites, bacterial
infection is most frequently related to the development of
this syndrome. Among these bacterial infections gram-
negative bacterial sepsis is the most notable infectious
cause, but DIC may occur with any cause of sepsis.
Clinically overt disseminated intravascular coagulation may
occur in 30-50% of patients with gram-negative sepsis
18

The mechanisms involved in the onset of DIC
associated with sepsis are different from that associated
with leukemias/solid cancers. Triggers of the activation of
diffuse coagulation in patients with infections include cell-
specific membrane components of the microorganism, such
as lipopolysaccharide or endotoxin, or bacterial exotoxins
leading to activation of the cytokine network and increased
plasma levels of elastase, and C reactive protein (CRP).
Other mechanisms include the release of fat and
phospholipids from tissue into the circulation, hemolysis,
and endothelial damage, all promoting the systemic
activation of coagulation. Tissue factor activity in
peripheral blood is markedly elevated upon tissue injury
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and activation of monocytes and is the main factor
responsible for coagulopathy in patients with polytrauma
and patients with sepsis. Other factors responsible for the
development of DIC in septicaemia are: suppression of
protein C-protein S system and an increase in fibrinolytic
activity. TNF- is supposed to be a mediator of this effect.
Coagulopathy is present in 25% of trauma patients and is
associated with a five-fold increase in mortality.
7
Its
presence may be confused with coagulopathy secondary to
massive blood transfusion. DIC is a rare complication
following severe burn trauma. It complicates the course of
the critically ill burn patient, although appropriate therapy
prevents its fulminant course.
19

Cancer
Both solid tumors and hematologic cancers may be
complicated by disseminated intravascular coagulation. 10-
15 % of patients with metastasized tumors have evidence of
disseminated intravascular coagulation, and the condition is
present in approximately 15 percent of patients with acute
leukemia.
20,21
The mechanism of the derangement of the
coagulation system in patients with cancer is not clear.
Expression of tissue factor by cancer cells (which in
conjunction with factors VIIIX, can activate the intrinsic
pathway)
22
is thought to play an important role in the
pathogenesis of DIC in patients with malignancy.
23,24
Other
factors include release thromboplastin and other attractant
factors from the tumor tissue, with subsequent clot
formation. In one of the studies done by Malik Zeb et al at
D.I. Khan on patients of breast carcinoma found that levels
of fibrinogen degradation products (FDPs) and D-Dimers
were quite high in breast carcinoma, especially in those with
distant metastasis.
25

A distinct form of disseminated intravascular
coagulation is frequently encountered in patients with acute
promyelocytic leukemia, which is characterized by a severe
hyperfibrinolytic state in addition to an activated
coagulation system (by increased expression of tissue
factor). This hyperfibrinolysis is due to increased
expression of Annexin II expression by blast cells which act
as co receptor for plasminogen activator and plasminogen.
In one of the studies done by Hideki Uchiumi it was found
that Leukocyte counts, C-reactive protein, and lactate
dehydrogenase were significantly higher in patients of APL
with DIC.
26
Though DIC is most frequently associated with
AML-M3 it can also be seen in other hematological
malignancies as well. In a study done by Rizwan Qazi et al
on patients of AML they found that DIC was the most
frequent in AML M3 (69 %) followed by in M5 (40 %), M2
(23.1 %), M4 (18.2 %) and M1 (16.6 %), respectively.
Another study was done in J apan to look for prevalence and
clinical characteristics on de novo nonAPL AML, they
observed that DIC was diagnosed in 32% of their patients
and its incidence was the highest in M5 (60%) and lowest in
M6 (0%). They also mentioned that DIC also has
association with high leukocyte count and raised CRP levels
(observed both in infections and malignancies).
27

Similarly Anwar M et al observed deranged
coagulation profile with raised FDPs in 15% their ALL
patients.
37
DIC is thus still a devastating complication of
acute leukemias and early therapeutic intervention for DIC
is warranted. Therefore, efforts to identify the clinical
parameters associated with DIC are important.
28
In a study
done by Kohji Okamoto et al on Frequency and hemostatic
abnormalities in pre-DIC patients, it was found that the
highest absolute number of DIC cases was observed in
patients with infectious disease, solid cancer and
hematopoietic disorders.
29

Obstetrical Disorders
DIC is a classic complication of obstetrical
conditions which include obstetric accidents as amniotic
fluid embolism, placental abruptio, placenta previa, pre-
eclampsia, eclampsia, HELLP) syndrome (Hemolysis,
elevated liver enzymes, and low platelet count), retained
fetus syndrome, retained products of conception and
abortion occurring in more than 50 % of patients with these
conditions.
30
It can also be associated with gynecologic
malignancies e.g. ovarian cancer, uterine cancer, breast
cancer and paraneoplastic syndromes.
Amniotic fluid embolism (AFE) is a rare
catastrophic complication of pregnancy; the estimated
incidence is 1 in 8000 to 1 in 80 000 pregnancies.
31
AFE is
associated with a mortality rate of 60% to 86 %.
32,33
DIC is
one of the common potential complications of this
condition, probably because of the presence of direct factor
Xactivating factor and thromboplastin like material (or
tissue factor), which is a potent activator of coagulation in
vitro. AFE remains one of the most devastating
complications of pregnancy. The diagnosis is difficult to
make because it is mostly a diagnosis of exclusion.
Similarly abruptio placentae is another condition
which may end up in DIC and the degree of placental
separation correlates with the extent of disseminated
intravascular coagulation.
34
Although these obstetrical
conditions may cause fulminant disseminated intravascular
coagulation sometimes they are short-lived and self-
limiting. Management is essentially supportive. The
administration of heparin is generally limited to patients
with chronic compensated DIC who have predominantly
thrombotic manifestations
Preeclampsia can also be complicated by
disseminated intravascular coagulation, which occurred in 7
% of consecutive patients with severe preeclampsia in one
study.
35
Similarly another study was done by Tayyab M. et
al in PGMI Lahore on patients of pre-eclampsia. They
found that although various baseline tests like PT, APTT
were normal in these patients FDPs and D-Dimers were
raised in majority of patients with pre-eclamsia, especially
those with severe pre-eclampsia. They also mentioned that
D-Dimers were more sensitive as compared to FDPs for
evaluation of these patients.
36
In another study done by
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Asifa Ghazi et al in Civil Hospital Karachi the frequency of
deranged coagulation profile among obstetric patients was
4.3%, and among them 84% had raised FDPs. However
they did not mentioned frequency of DIC their patients.
37

Likewise HELLP syndrome is an atypical form of
severe preeclampsia, and if not treated is potentially fatal
for both mother and fetus. Mostly presentation of HELLP
syndrome is after 34 weeks of gestation but presentation
may be between 20 weeks of gestation to few days after
delivery. It is estimated that up to 10% of pregnancies are
affected by HELLP syndrome.
38
HELLP Syndrome is also
associated with quite a number of cases of disseminated
intravascular coagulation. In one of the prospective studies
done by BM Sibai, on 442 pregnancies with HELLP
syndrome DIC was observed in 21% patients.
39

Giant Hemangiomas
Giant hemangiomas (the KasabachMerritt
syndrome) and even large aortic aneurysms may result in
local activation of coagulation.
40,41
In patients with these
conditions there is local activation of coagulation factors
can reach the systemic circulation and cause disseminated
intravascular coagulation resulting in the systemic depletion
of locally consumed coagulation factors and platelets.
Clinical features
DIC also called consumption coagulopathy and
defibrination syndrome is a complication of underlying
illness occurring in approximately 1% of hospital
admissions.
42
Factors which influence the clinical course of
DIC include potency of the procoagulant agent and its dose,
the speed with which this enters the body, presence of
coexisting endothelial damage, vasomotor changes (e.g.
DIC due to endotoxin shock) and efficiency of
compensatory mechanisms.
There are 2 clinical forms of DIC:
1.Acute DIC
Acute DIC occurs when a large amount of
procoagulant enters the circulation over a brief period of
time, overwhelming the bodys ability to replenish
coagulation factors and predisposing patients to bleeding.
This presents with life-threatening bleeding from various
sites, often in a patient who is already seriously ill. Shock
and multiple organ failure frequently coexist, making
therapeutic decisions difficult. It can exist in the
compensated and uncompensated forms:
Compensated DIC
When the stimulus for coagulation is mild, the liver
can increase production of clotting factors to up to 5 times
the normal rate, 'in an effort to maintain plasma levels.
43

Similarly, platelet production too can increase up to 10
times. Thus, although coagulation and fibrinolysis are in
progress, platelet counts and fibrinogen levels may be
normal or only marginally reduced although levels of FDPs
are elevated.
44,45
These patients rarely bleed spontaneously
or from minor trauma, but have severe hemorrhage if
subjected to surgery.
Decompensated DIC
Hemorrhage from multiple sites is the dominant
manifestation of DIC. It commonly starts as bleeding from
puncture sites after intravenous or intramuscular injections,
and from the postpartum uterus or surgical wounds.
Bleeding from mucosal sites follows particularly in obstetric
patients. In severe cases, DIC is invariably accompanied by
shock, either due to the underlying disorder or due to
massive blood loss. Hypotension if prolonged can result in
organ ischemia and dysfunction and acute tubular necrosis.
The thrombotic manifestations of DIC may worsen organ
hypoperfusion and severe renal insufficiency with acute
cortical necrosis may result
2.Chronic DIC
In chronic DIC, smaller amounts of tissue factor
are involved, resulting in much less intense stimulation of
the coagulation system and allowing the body to
compensate for the consumption of coagulation proteins and
platelets.
46
This refers to the conditions where mild bleeding
and abnormal coagulation tests suggestive of low grade DIC
persist for many weeks. Though the pathophysiology is
identical to acute DIC, clinical picture and laboratory
findings in chronic DIC may be wavering. Here, nearly all
of the baseline tests like platelet count, fibrinogen, PT and
APTT may be normal. FDP, fibrinopeptide A and D dimer
however are usually raised and diagnostic.

Malignancy is
the major cause of this syndrome. Other causes include
retained dead fetus, liver disease, aneurysm or
hemangiomas.

Sepsis usually causes acute DIC but nonovert
chronic DIC may also be observed.


Prognosis
The prognosis of DIC depends mainly on the
underlying condition. Nevertheless, very low fibrinogen
levels, post-operative DIC, coexisting hypotension, multiple
organ failure, and systemic sepsis carry a poor prognosis.
The overall mortality varies from 50 to 80 %.
47,48

It is even more in obstetric cases than in non-
obstetric cases.
Diagnosis
The diagnosis of disseminated intravascular
coagulation relies on clinical signs and symptoms,
identification of the underlying disease, the results of
laboratory testing, and differentiation from other
pathologies. In general, the pathogenesis of DIC is
characterized by simultaneous and ongoing activation of
both hemostasis and fibrinolysis, resulting in extensive and
persistent generation of thrombin and plasmin,
49
as well as
progressive consumption of coagulation factors and
platelets, production of fibrin, and consequent fibrin(ogen)
degradation products (FDPs). Levels of plasminogen
activator inhibitor type 1 may also be elevated, suggesting
some imbalance between the procoagulant and fibrinolytic
process.
50
A reduction in antithrombin levels, a depression
of the protein C pathway, and inhibition of the tissue factor
pathway inhibitor may also occur and aggravate the clinical
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course.
51
The laboratory diagnosis of DIC thus uses a
combination of these tests because no single test result
alone can firmly establish or rule out the diagnosis.
The tests commonly used for assessment of DIC
are platelet count, prothrombin time (PT), activated partial
thromboplastin time, fibrinogen level, fibrin degradation
product (FDP) assay and D-dimer assay, Because DIC is a
dynamic process, repeat measurement is necessary. Baseline
tests of hemostasis may initially provide evidence of
coagulation activation and later in the process provide
evidence of consumption of coagulation factors, but their
individual diagnostic efficiency is limited.
Both PT and APTT are simple, rapid and
inexpensive tests that are used for initial screening and
assessment of coagulation pathway. Both these tests can be
prolonged in patients being evaluated for reasons other than
DIC. For example, trauma or other hemorrhage can lead to
loss of blood and plasma components, so that prolonged
coagulation tests may simply reflect this phenomenon rather
than a pathological DIC process.
52
Prolonged coagulation
tests can also occur with hematologic malignancies
unrelated to DIC. Because significant prolongations often
occur at a late stage in DIC, this also compromises the
overall efficiency of this test for an early diagnosis.
Moreover, abnormal values may reflect pathology other
than DIC,
53
and normal values cannot be used to rule out the
diagnosis.
54

Thrombocytopenia is the hallmark of DIC, and its
presence should prompt consideration of DIC. A low
platelet count on initial testing and, in particular, a
progressive drop in the platelet count are sensitive signs of
DIC and may indicate ongoing thrombin-induced activation
and use of platelets. The platelet count is considered a
useful test in the diagnosis of DIC because it strongly
correlates with markers of thrombin generation and because
thrombin induced platelet aggregation advances platelet
consumption. Moreover, the platelet count is not influenced
by the acute-phase response. A single estimation of platelet
count however might not reliably identify DIC, and serial
estimations will provide more value in DIC diagnostics.
One should also keep the possibility of many other
underlying conditions associated with DIC (e.g., infections,
malignancy, or anticancer therapy) as well as other life
threatening pathologies (e.g., heparin-induced
thrombocytopenia) can cause a low platelet count in the
absence of DIC. Conversely, a stable platelet count suggests
that intravascular platelet aggregation (and thrombin
formation) is not occurring or has ceased
Fibrinogen levels often decline in patients with
DIC, due to ongoing consumption. However, the overall
sensitivity of plasma fibrinogen levels for the diagnosis of
DIC is also low because this protein is a well-recognized
acute-phase reactant, and levels may therefore be normal
(particularly in the early developing phase of DIC and in
patients with sepsis). Thus hypofibrinogenemia is usually
detected only in very severe cases of DIC or in the
advanced stages of the disease. Similarly, like routine
coagulation test times, depending on the clinical context,
low fibrinogen levels can also reflect inherited or acquired
pathologies other than DIC (e.g., afibrinogenemia, liver
failure). However sudden or dramatic drop in fibrinogen
level which may reflect massive consumption classically is
characteristic of DIC.
Markers of Fibrin Production and Breakdown
Elevated fibrin or FDPs (including D-dimer) and
elevated soluble fibrin monomers are known to be highly
sensitive for the diagnosis of DIC, and elevations of their
values often precede overt DIC by several days.
55,56
FDP
consists of both fibrin and fibrinogen degradation products.
Elevated levels of FDP reflect accelerated fibrinolysis due
to plasmin and are found in 85% to 100% of patients with
DIC. However, FDP is also elevated in various other
conditions, including use of oral contraceptives, pulmonary
emboli, myocardial infarction, renal disease, and arterial or
venous thrombotic or thromboembolic events. Moreover, it
may also be negative when measured using the latex
agglutination assay when there is only a minimal
consumptive process.
D-dimer is formed during fibrinolysis as a result of
degradation of cross-linked fibrin by plasmin. D-dimer
levels are elevated in almost all cases of DIC. In fact D-
dimer testing has largely replaced most other markers of
fibrinolysis in general clinical and laboratory practice, for
both DIC and the diagnosis of other thrombotic disorders.
The natural anticoagulants, especially antithrombin
and protein C, are frequently reduced in patients with DIC,
and these reductions may also have prognostic significance.
66, 67
For example, a decrease in plasma antithrombin levels
<50% of normal is strongly associated with increased
mortality in patients with DIC due to sepsis,
57
and in
surgical patients with sepsis antithrombin levels <70% and
65%, are associated with a 90% and 100% mortality,
respectively.
58
Moreover, lower initial antithrombin levels
in neonatal sepsis are associated with a severe disease and
increased mortality. Antithrombin levels are found to
provide the best prognostic value for prediction of
subsequent death in patients affected by septic shock.
Similarly low levels of activated protein C concentrations in
neutropenic patients affected by septic shock has also been
reported to provide a significant prognostic value.
59

Although a significant decrease in the level of
these natural inhibitors may provide valuable information
for establishing a diagnosis of DIC and monitoring the
clinical course of the disease, these tests are not commonly
available in all laboratories, nor are they always available as
an urgent test procedure. Moreover, the ISTH SSC on DIC
recently concluded there is no added value in including their
tests within the conventional scoring system.
60
Nevertheless,
their measurement might be helpful in selected situations, in
assessing for non-overt DIC or the severity of DIC, in
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131
monitoring of therapy, and in an assessment of the
prognosis.
61

Serial coagulation tests are usually more helpful
than single laboratory results in establishing the diagnosis of
DIC (Table 2 and 3). Following are the tests that can help in
diagnosis of DIC and assessing its clinical course. Among
these the most widely used are complete blood picture and
peripheral blood smear, PT, APTT, fibrinogen levels, FDPs
and D-Dimers.
Baseline laboratory tests/Screening Tests
Prothrombin time activated partial thromboplastin
time, (which are dependent on the conversion of fibrinogen
to fibrin polymer), are prolonged. Schistocytes may be seen
in 50% of patients with fulminant DIC as a result of passage
of red cells through fibrin strands. Likewise
thrombocytopenia may be an initial finding in many of the
patients.
62

The derangements observed in above laboratory
tests in DIC are as follows
Specific Tests
Fibrin(ogen) degradation products (FDPs) are
determined using latex agglutination test and thrombin clot
tubes are used to remove any fibrinogen so that these latex
particles do not falsely measure the fibrinogen as FDPs.
However, the thrombin clot tubes remove not only
fibrinogen, but also the early fragments X and Y, and so if
fibrinolysis is in the early phase of activation wherein the
lysis has not progressed beyond this stage, the FDPs would
be falsely negative.
Table 2: Diagnostic Tests for DIC
Screening Tests
Peripheral smear Schistocytes
Thrombocytopenia with large platelets
Prolongation of PT, aPTT, TT
Specific Tests
Elevated D-dimer & soluble fibrin monomer (sFM)
Elevated fibrinogen degradation products (FDPs)
Elevated fibrinopeptide A & fibrinopeptide B
Decreased protein C and S
Decreased antithrombin
Elevated plasmin
Decreased antiplasmin
Elevated PAP complex
Elevated TAT complex
Tests for end organ damage
Elevated LDH
Elevated creatinine
Moreover the available test method detects the D and E
fragments only and so if the plasmin digestion has gone
beyond this stage, then again the FDPs may not be detected
inspite of profound fibrinolytic activity. Hence, a negative
test for FDPs does not rule out DIC The measurement of D-
dimer is the most sensitive and cost effective test and could
possibly replace the need to measure FDPs particularly in
chronic DIC, most of the baseline laboratory tests such as
PT, PTT, fibrinogen and platelets may be normal but D-
dimer are always abnormal. D-Dimer is the only test that
directly addresses both thrombin and plasmin generation.
This is estimated most reliably by latex agglutination test
using the monoclonal antibody against the D-dimer neo-
antigen, that are specific for the cross-linked fibrin
derivatives containing the D-dimer configuration. Tests for
fibrin-degradation products or D-dimers are also helpful to
differentiate disseminated intravascular coagulation from
other conditions that are associated with a low platelet count
or prolonged clotting times.
More specialized laboratory tests that are useful
in the diagnosis of DIC include the measurement of soluble
fibrin and sensitive assays that can measure the generation
of thrombin, such as assays for the detection of prothrombin
activation fragment F1+2 or thrombinantithrombin
complexes (TAT). Prothrombin fragments 1+2, fibrino-
peptide A and thrombin-antithrombin (TAT) complex can
all be reliably measured by enzyme linked immunosorbent
assay (ELISA). The decrease in antithrombin is related to
outcome, and plasma levels are significantly lower in non-
survivors than in survivors. The soluble fibrin monomer
(sFM), like the D-dimer, serves as a marker for both
procoagulant and plasmin activation, and is measured by
ELISA It is difficult to measure plasmin level in plasma
since it is rapidly inactivated by anti plasmin and slowly by
alpha-2-macroglobulin. PAP serves as a marker of
fibrinolytic activation as well as inhibitor consumption.
Plasmin-antiplasmin (PAP) complex can be measured by
crossed immunoelectro-phoresis, ELISA and radioimmuno-
assays. PAP is elevated early in DIC and changes in parallel
with the course of DIC, with levels decreasing in clinical
remission. A lower ratio of PAP/TAT points towards a poor
prognosis and is associated with organ failure. Both TAT
and PAP are more useful for diagnosing pre-DIC. Recently,
tests have been developed to measure tissue plasminogen
activator and tissue plasminogen activator inhibitor (PAI).
62
.
Although they may be helpful in complicated clinical
situations, they are usually not essential in general clinical
practice

Table 3:Laboratory Features of Chronic DIC
Platelet count: usually normal or borderline
Fibrinogen: normal/increased
PT: normal/prolonged
PTT: normal/prolonged
Schistocytes: 90% patients
FDP: usually increased
Fibrinopeptide A: usually increased
D dimer: usually increased
Antithrombin III measurement is of paramount
importance not only for diagnosis but also for prognosis and
therapy. It has been proved that no single test can make or
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refute the diagnosis of DIC. We have to look for multiple
parameters carefully; particularly cases of chronic DIC have
to be dealt with very cautiously before ruling out DIC.
A scoring systems have been developed by the
subcommittee on DIC of the International Society of
Thrombosis and Hemostasis (ISTH) and by the J apanese
Association for Acute Medicine (J AAM).
Both systems have been prospectively validated and
have a high diagnostic rate; however, the J AAM criteria
appear to have an advantage for diagnosing the patient with
early DIC.
63

Risk assessment
Does the patient have an underlying disorder known to be
associated with overt DIC?
NO YES
Do not use this algorithm Order baseline
coagulation tests (platelet count, prothrombin time,
fibrinogen), soluble fibrin monomers, or fibrin degradation
products)
Score global coagulation test results Test Score
Platelet count (cells/mL) 100,000 =0
<100,000 =1
<50,000 =2
Elevated fibrin related marker No increase =
0Moderate increase =2
Strong increase =3 Prolonged Prothrombin time
<3 sec =0
>3 but <6 sec =1
>6 sec =2
Fibrinogen level (g/L) 1 =0
<1 =1
Calculate score
5 is compatible with overt DIC; repeat scoring daily
< 5 is suggestive (not affirmative) of non overt DIC;
repeat scoring next 1 to 2 days

Overt DIC refers to a decompensated hemostatic system,
Non overt DIC refers to a stressed but compensated
hemostatic system.

Japanese Association for Acute Medicine Scoring
System for DIC Criteria Score
Systemic inflammatory response syndrome criteria
3 1
02 0
Platelet count (cells/l)
<80,000 or >50% decrease within 24 hr 3
80,000 and < 120,000 or > 30% decrease within 24 hr 1
120,000 0
Prothrombin time (patients value/normal value)
1.2 1
<1.2 0
Fibrin/fibrinogen degradation products (mg/L)
25 3
10 and < 25 1
<10 0
A score of 4 indicates a diagnosis of disseminated
intravascular coagulation.
Management of DIC
The heterogeneity of DIC has made it difficult to diagnose
and treat these patients. The wide range of manifestations
ranging from thrombosis to hemorrhage, difficulty in
quantifying response to therapy, presence of coexisting
multiple organ failure and varying prognosis of the
underlying disease have made evaluation and treatment of
these patients difficult. As there is always a triggering
disease in the background of DIC and the outcome of DIC
depends mainly on the triggering disease, the first and
foremost step is to deal the triggering factor. The next
logical step is the use of anticoagulants so as to hold the
process of thrombosis. However controversy exists here as
the use of anticoagulant in the phase of hemorrhage might
aggravate bleeding. In general when bleeding is prominent
due to consumption of factors, one would be inclined to use
replacement therapy to control bleeding should be
considered.
Various therapeutic options which should be taken into
consideration in managing the patients of DIC include:
General measures
Treatment of the triggering disease: The most important
guiding principle for therapy of DIC is to identify the
triggering disease and manage it aggressively. In addition, it
is equally important to provide supportive care for
optimizing hemodynamic stability, maintaining adequate
oxygenation and acid base balance. A derangement of any
of these would by themselves serve to trigger and aggravate
DIC.
Blood component therapy: Decision regarding component
therapy is based on whether the patient is bleeding and if an
invasive procedure is planned. Replacement of depleted
blood components helps to control blood loss and this may
be maximally evident only after the consumptive process
has been interrupted. However, some think that component
therapy in patients with continuing consumption may 'add
fuel to the fire' by increasing microcirculation thrombosis,
worsening of the coagulopathy. They do not agree with the
use of the component therapy unless the antithrombin level
is normalized. Fresh frozen plasma and cryoprecipitate are
the preferred blood components.
64
Fresh plasma provides
all clotting factors and antithrombotic proteins. However,
fibrinogen may not increase with replacement of plasma
alone and cryoprecipitate provides greater quantities of
fibrinogen and is often required when serum fibrinogen
level is very low to start with. A general recommendation is
to start with 4 to 6 units of fresh frozen plasma and 2 to 3
units of cryoprecipitate and reassess the clotting profile. A
platelet count less than 50,000 per/l or persistent bleeding.

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Coagulation system Inhibitors of coagulation
Intrinsic system Extrinsic system Thrombin +Thrombomodulin

Protein C Protein S
X Xa fV & FVIII activation
PF (1+2) APC + fPS bound PS
Prothrombin Thrombin Antithrombin (PS+C4b)

Inhibition of f V +f VIII
fpA+fpB TAT complex
Fibrinogen Fibrin monomer Fibrin polymer D dimers
a FXIII


X and Y D and E sFM
fragments fragments

Antiplasmin
Plasmin PAP complex

Platelet aggregation

Plasminogen
Fibrinolytic system

Abbreviations
PF=Prothrombin fragment APC=Activated protein S f PS=Free protein S
b PS=Bound Protein S s FM=Soluble fibrin monomers PAP=Plasmin antiplasmin complex


Heparin therapy: Heparin is an effective anticoagulant and its anticoagulant effect is produced by inhibiting thrombin
Pathogenesis of DIC
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135
formation and function. Although consumption of
coagulation factors may be interrupted with heparin therapy,
the bleeding complications may increase. Anticoagulant
response with heparin alone may not be effective due to low
levels of antithrombin in DIC. Thus, the role of heparin in
DIC has always been controversial it should thus be very
cautiously used and carefully monitored. Low molecular
weight heparin appears to offer the benefit of decreased
bleeding complications compared to unfractionated heparin
in the treatment of DIC. When heparin is used, it is
administered at a dose of 15 U/kg/hr as a continuous
infusion. Some prefer subcutaneous administration of
Heparin at a dose of 80-100 U/kg every 4-6.
66
In general
heparin should be used in DIC when it shows the features of
thrombotic manifestations such as end organ failures.
Heparin should not be used in DIC with head trauma,
massive liver failure and obstetrical accidents. There are no
adequate studies of heparin use in DIC with sepsis.
Inhibitor therapy: Various inhibitors of coagulation such
as antithrombin, protein C and tissue factor pathway
inhibitor (TFPI) also play very important role in managing
these patients
Antithrombin III: Of these inhibitors, the role of
antithrombin seems most promising. About 90% of patients
with DIC have very low serum antithrombin III levels. This
may be an important factor, which sustains the
coagulopathy. Many studies in obstetric and non-obstetric
DIC have shown that simultaneous infusion of antithrombin
III and heparin produce clinical improvement and
correction of coagulation defects within 2 hours.
67
The
initial dose of 2500 units of antithrombin III (40 mg/kg) is
followed by a continuous infusion of 50 units/ hour. Clinical
studies have shown a trend towards improved survival of
DIC with sepsis when antithrombin was administered alone
or with heparin.
79
Antithrombin is effective in inhibiting
thrombin generation and does not have the risk of inducing
bleeding, and so seems to be a better alternative than
heparin in halting the unwanted clotting process particularly
in sepsis. One study regarding use of antithrombin III in
patients with DIC, was conducted in J apan and published in
October 2009 and suggested that a significant reduction in
the DIC score and an improvement in the prothrombin time
ratio was observed with small dose of antithrombin III in
sepsis-associated DIC.
68

Activated Protein C (APC): Inactivates fVa and f VIIIa,
thus decreasing thrombin formation and promotes
fibrinolysis by complex formation with PAI. APC has been
used particularly in meningococcemia and recent trials have
suggested that in a relatively small dosage APC can
improve DIC more efficiently than can heparin, without
increasing bleeding.
69

TFPI is also a specific inhibitor of the tissue factor-VIIIa
complex, thereby inhibiting intravascular coagulation and
its use has improved the outcome in these patients
particularly when underlying cause is sepsis.
70

Antifibrinolytic agents: Antifibrinolytic agents such as
epsilon-aminocaproic acid and tranexamic acid are rarely
needed in DIC; one exception to this is acute promyelocytic
leukemia patients in whom there may be primary activation
of the fibrinolytic system
83.
However the use of these
agents can potentially aggravate intravascular thrombosis.
Thus, antithrombolytic drugs are contraindicated in DIC,
although they remain drugs of choice in primary fibrinolysis
where fibrinogen is lysed in the absence of thrombosis.
They are indicated in DIC only when bleeding continues
inspite of using the other treatment modalities.
Therapy of chronic DIC: Therapy of underlying disease is
most important part of management for both acute and
chronic DIC. Patients with chronic DIC are initially treated
with anti-coagulant doses of heparin to maintain a PTT 1.5-
2 times normal. In other cases of chronic DIC, low dose (5-
10U/kg/hour) of heparin may be sufficient to reverse the
coagulopathy.
71
Heparin therapy is contra-indicated in
patients with intracranial meta-static disease and chronic
DIC.
Differential Diagnosis
Microangiopathic Hemolytic Anemia (MAHA)
MAHA comprise thrombocytopenic thrombotic purpura, the
hemolytic uremic syndrome, chemotherapy-induced.
Although some characteristics of MAHA and the resulting
thrombotic occlusion of small and midsize vessels may
mimic the clinical picture of DIC, these disorders are a
distinct group of diseases. The common feature of MAHA
appears to be endothelial damage, which causes the
adhesion and aggregation of platelets, the formation of
thrombin, and the impairment of fibrinolysis. Mucosal
bleeding along with renal and cerebral dysfunction,
presence of thrombocytopenia and schistocytes in peripheral
blood and normal coagulation profile are the indicators of
MAHA.
Although hemolytic anemia and schistocytes are also
sometimes present in patients with severe DIC(because of
the presence of intravascular fibrin), these are invariable
findings in patients with MAHA.
Liver Disease: Coagulopathy in liver disease is usually due
to inadequate hepatic synthesis of clotting factors.
Thrombocytopenia and FDP levels may help in
differentiating between these conditions but splenic
sequestration of platelets may make this distinction blurred.
Estimation of factor VIII levels is useful - it is low in DIC
but normal in liver disease due to its synthesis at non-
hepatic sites.
Primary Fibrinolysis: Primary fibrinogenolysis may occur
in many conditions which also cause DIC like snake bite,
prostatic carcinoma or prostatic surgery, mucinous
adenocarcinomas and large hemangiomas. Fibrinogen is
lysed without accompanying microcirculatory thrombosis.
The diagnosis of Primary Fibrinolytic Syndrome has to be
kept in mind upon any further difficulty in establishing the
differential diagnosis for DIC.
72
Antifibrinolytic agents
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136
which are contraindicated in DIC are extremely useful in
this condition
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