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Disseminated

intravascular
coagulation

Disseminated intravascular coagulation


(DIC) is a condition in which blood clots
form throughout the body, blocking small
blood vessels.[1] Symptoms may include
chest pain, shortness of breath, leg pain,
problems speaking, or problems moving
parts of the body.[1] As clotting factors and
platelets are used up, bleeding may
occur.[1] This may include blood in the
urine, blood in the stool, or bleeding into
the skin.[1] Complications may include
organ failure.[2]
Disseminated intravascular
coagulation
Other names Disseminated
intravascular
coagulopathy,
consumptive
coagulopathy,
defibrination
syndrome[1]
Micrograph showing acute thrombotic
microangiopathy due to DIC in a kidney biopsy. A
clot is present in the hilum of the glomerulus
(center of image).

Specialty Haematology

Symptoms Chest pain, shortness


of breath, leg pain,
problems speaking,

problems moving part


of the body, bleeding[1]

Complications Organ failure[2]

Types Acute, chronic[1]

Causes Sepsis, surgery, major


trauma, cancer,
complications of
pregnancy, snake bites,
frostbite, burns[1]

Diagnostic method Blood tests[2]

Differential diagnosis Thrombotic


thrombocytopenic
purpura, hemolytic-
uremic syndrome[1]

Treatment Directed at the


underlying condition[3]

Medication Platelets,
cryoprecipitate, fresh

frozen plasma,
heparin[2]

Prognosis 20–50% risk of death[4]

Frequency 1% of people admitted


to hospital[4]
Relatively common causes include sepsis,
surgery, major trauma, cancer, and
complications of pregnancy.[1] Less
common causes include snake bites,
frostbite, and burns.[1] There are two main
types: acute (rapid onset) and chronic
(slow onset).[1] Diagnosis is typically
based on blood tests.[2] Findings may
include low platelets, low fibrinogen, high
INR, or high D-dimer.[2]
Treatment is mainly directed towards the
underlying condition.[2][3] Other measures
may include giving platelets,
cryoprecipitate, or fresh frozen plasma.[2]
Evidence to support these treatments,
however, is poor.[2] Heparin may be useful
in the slowly developing form.[2] About 1%
of people admitted to hospital are affected
by the condition.[4] In those with sepsis
rates are between 20% and 50%.[4] The risk
of death among those affected varies from
20 to 50%.[4]

Signs and symptoms


In DIC, the underlying cause usually leads
to symptoms and signs, and DIC is
discovered on laboratory testing. The
onset of DIC can be sudden, as in
endotoxic shock or amniotic fluid
embolism, or it may be insidious and
chronic, as in cancer. DIC can lead to
multiorgan failure and widespread
bleeding.[5]

Causes
DIC can occur in the following
conditions:[5][6][7][8]

Solid tumors and blood cancers


(particularly acute promyelocytic
leukemia)
Obstetric complications: abruptio
placentae, pre-eclampsia or eclampsia,
amniotic fluid embolism, retained
intrauterine fetal demise, septic
abortion, post partum haemorrhage
Massive tissue injury: severe trauma,
burns, hyperthermia, rhabdomyolysis,
extensive surgery
Sepsis or severe infection of any kind
(infections by nearly all microorganisms
can cause DIC, though bacterial
infections are the most common):
bacterial (Gram-negative and Gram-
positive sepsis), viral, fungal, or
protozoan infections
Transfusion reactions (i.e., ABO
incompatibility haemolytic reactions)
Severe allergic or toxic reactions (i.e.
snake venom)
Giant haemangiomas (Kasabach–
Merritt syndrome)
Large aortic aneurysms

Liver disease, HELLP syndrome,


thrombotic thrombocytopenic
purpura/Haemolytic uremic syndrome, and
malignant hypertension may mimic DIC
but do not occur via the same pathways.
Pathophysiology

The coagulation cascade of secondary haemostasis.

Under homeostatic conditions, the body is


maintained in a finely tuned balance of
coagulation and fibrinolysis. The activation
of the coagulation cascade yields
thrombin that converts fibrinogen to fibrin;
the stable fibrin clot being the final product
of hemostasis. The fibrinolytic system
then functions to break down fibrinogen
and fibrin. Activation of the fibrinolytic
system generates plasmin (in the
presence of thrombin), which is
responsible for the lysis of fibrin clots. The
breakdown of fibrinogen and fibrin results
in polypeptides called fibrin degradation
products (FDPs) or fibrin split products
(FSPs). In a state of homeostasis, the
presence of plasmin is critical, as it is the
central proteolytic enzyme of coagulation
and is also necessary for the breakdown
of clots, or fibrinolysis.
In DIC, the processes of coagulation and
fibrinolysis are dysregulated, and the result
is widespread clotting with resultant
bleeding. Regardless of the triggering
event of DIC, once initiated, the
pathophysiology of DIC is similar in all
conditions. One critical mediator of DIC is
the release of a transmembrane
glycoprotein called tissue factor (TF). TF is
present on the surface of many cell types
(including endothelial cells, macrophages,
and monocytes) and is not normally in
contact with the general circulation, but is
exposed to the circulation after vascular
damage. For example, TF is released in
response to exposure to cytokines
(particularly interleukin 1), tumor necrosis
factor, and endotoxin.[9] This plays a major
role in the development of DIC in septic
conditions. TF is also abundant in tissues
of the lungs, brain, and placenta. This
helps to explain why DIC readily develops
in patients with extensive trauma. Upon
exposure to blood and platelets, TF binds
with activated factor VIIa (normally
present in trace amounts in the blood),
forming the extrinsic tenase complex. This
complex further activates factor IX and X
to IXa and Xa, respectively, leading to the
common coagulation pathway and the
subsequent formation of thrombin and
fibrin.[7]
The release of endotoxin is the
mechanism by which Gram-negative
sepsis provokes DIC. In acute
promyelocytic leukemia, treatment causes
the destruction of leukemic granulocyte
precursors, resulting in the release of large
amounts of proteolytic enzymes from their
storage granules, causing microvascular
damage. Other malignancies may enhance
the expression of various oncogenes that
result in the release of TF and
plasminogen activator inhibitor-1 (PAI-1),
which prevents fibrinolysis.[10]

Excess circulating thrombin results from


the excess activation of the coagulation
cascade. The excess thrombin cleaves
fibrinogen, which ultimately leaves behind
multiple fibrin clots in the circulation.
These excess clots trap platelets to
become larger clots, which leads to
microvascular and macrovascular
thrombosis. This lodging of clots in the
microcirculation, in the large vessels, and
in the organs is what leads to the
ischemia, impaired organ perfusion, and
end-organ damage that occurs with DIC.

Coagulation inhibitors are also consumed


in this process. Decreased inhibitor levels
will permit more clotting so that a positive
feedback loop develops in which
increased clotting leads to more clotting.
At the same time, thrombocytopenia
occurs and this has been attributed to the
entrapment and consumption of platelets.
Clotting factors are consumed in the
development of multiple clots, which
contributes to the bleeding seen with DIC.

Simultaneously, excess circulating


thrombin assists in the conversion of
plasminogen to plasmin, resulting in
fibrinolysis. The breakdown of clots
results in an excess of FDPs, which have
powerful anticoagulant properties,
contributing to hemorrhage. The excess
plasmin also activates the complement
and kinin systems. Activation of these
systems leads to many of the clinical
symptoms that patients experiencing DIC
exhibit, such as shock, hypotension, and
increased vascular permeability. The acute
form of DIC is considered an extreme
expression of the intravascular
coagulation process with a complete
breakdown of the normal homeostatic
boundaries. DIC is associated with a poor
prognosis and a high mortality rate.

There has been a recent challenge


however to the basic assumptions and
interpretations of the pathophysiology of
DIC. A study of sepsis and DIC in animal
models has shown that a highly expressed
receptor on the surface of hepatocytes,
termed the Ashwell-Morell receptor, is
responsible for thrombocytopenia in
bacteremia and sepsis due to
Streptococcus pneumoniae (SPN) and
possibly other pathogens. The
thrombocytopenia observed in SPN sepsis
was not due to increased consumption of
coagulation factors such as platelets, but
instead was the result of this receptor's
activity enabling hepatocytes to ingest and
rapidly clear platelets from circulation.[11]
By removing pro-thrombotic components
before they participate in the coagulopathy
of DIC, the Ashwell-Morell receptor
lessens the severity of DIC, reducing
thrombosis and tissue necrosis, and
promoting survival. The hemorrhage
observed in DIC and among some tissues
lacking this receptor may thereby be
secondary to increased thrombosis with
loss of the mechanical vascular barrier.
This discovery has possible significant
clinical implications in devising new
approaches to reducing the morbidity and
mortality of DIC.

There is activation of intrinsic as well as


extrinsic coagulation pathway, this results
in excess thrombus formation in the blood
vessels. Due to extensive coagulation
there is consumption of coagulation
factors which causes bleeding.

Diagnosis
The diagnosis of DIC is not made on a
single laboratory value, but rather the
constellation of laboratory markers and a
consistent history of an illness known to
cause DIC. Laboratory markers consistent
with DIC include:[3][7][12]

Characteristic history (this is important


because severe liver disease can
essentially have the same laboratory
findings as DIC)
Prolongation of the prothrombin time
(PT) and the activated partial
thromboplastin time (aPTT) reflect the
underlying consumption and impaired
synthesis of the coagulation cascade.
Fibrinogen level has initially thought to
be useful in the diagnosis of DIC but
because it is an acute phase reactant, it
will be elevated due to the underlying
inflammatory condition. Therefore, a
normal (or even elevated) level can
occur in over 57% of cases. A low level,
however, is more consistent with the
consumptive process of DIC.
A rapidly declining platelet count
High levels of fibrin degradation
products, including D-dimer, are found
owing to the intense fibrinolytic activity
stimulated by the presence of fibrin in
the circulation.
The peripheral blood smear may show
fragmented red blood cells (known as
schistocytes) due to shear stress from
thrombi. However, this finding is neither
sensitive nor specific for DIC

A diagnostic algorithm has been proposed


by the International Society of Thrombosis
and Haemostasis. This algorithm appears
to be 91% sensitive and 97% specific for
the diagnosis of overt DIC. A score of 5 or
higher is compatible with DIC and it is
recommended that the score is repeated
daily, while a score below 5 is suggestive
but not affirmative for DIC and it is
recommended that it is repeated only
occasionally:[12][13] It has been
recommended that a scoring system be
used in the diagnosis and management of
DIC in terms of improving outcome.[14]

Presence of an underlying disorder


known to be associated with DIC (no=0,
yes=2)
Global coagulation results
Platelet count (> 100k = 0, < 100 = 1,
< 50 = 2)
Fibrin degradation products such as
D-Dimer (no increase = 0, moderate
increase = 2, strong increase = 3)
Prolonged prothrombin time (< 3
sec = 0, > 3 sec = 1, > 6 sec = 2)
Fibrinogen level (> 1.0g/L = 0;
< 1.0g/L = 1[15])

Treatment
Treatment of DIC is centered around
treating the underlying condition.
Transfusions of platelets or fresh frozen
plasma can be considered in cases of
significant bleeding, or those with a
planned invasive procedure. The target
goal of such transfusion depends on the
clinical situation. Cryoprecipitate can be
considered in those with a low fibrinogen
level.

Treatment of thrombosis with


anticoagulants such as heparin is rarely
used due to the risk of bleeding.

Recombinant human activated protein C


was previously recommended in those
with severe sepsis and DIC, but
drotrecogin alfa has been shown to confer
no benefit and was withdrawn from the
market in 2011.

Recombinant factor VII has been proposed


as a "last resort" in those with severe
hemorrhage due to obstetric or other
causes, but conclusions about its use are
still insufficient.[16]

Prognosis
Prognosis varies depending on the
underlying disorder, and the extent of the
intravascular thrombosis (clotting). The
prognosis for those with DIC, regardless of
cause, is often grim: Between 20% and
50% of patients will die.[17] DIC with sepsis
(infection) has a significantly higher rate of
death than DIC associated with trauma.[17]

Epidemiology
DIC is observed in approximately 1% of
academic hospital admissions.[18] DIC
occurs at higher rates in people with
bacterial sepsis (83%),[19] severe trauma
(31%),[20] and cancer (6.8%).[21]

References
1. "Disseminated Intravascular
Coagulation | NHLBI, NIH" .
www.nhlbi.nih.gov. Retrieved
20 December 2017.
2. "Disseminated Intravascular
Coagulation (DIC) - Hematology and
Oncology" . Merck Manuals
Professional Edition. September 2016.
Retrieved 20 December 2017.
3. Levi, M (2007). "Disseminated
Intravascular Coagulation". Critical
Care Medicine. 35 (9): 2191–2195.
doi:10.1097/01.CCM.0000281468.941
08.4B . PMID 17855836 .
4. Gando, Satoshi; Levi, Marcel; Toh,
Cheng-Hock (2 June 2016).
"Disseminated intravascular
coagulation". Nature Reviews Disease
Primers. 2: 16037.
doi:10.1038/nrdp.2016.37 .
PMID 27250996 .
5. Robbins, Stanley L.; Cotran, Ramzi S.;
Kumar, Vinay; Collins, Tucker (1999).
Robbins' Pathologic Basis of Disease
(6 ed.). Philadelphia: Saunders.
ISBN 0-7216-7335-X.
6. Davidson's Principles and Practice of
Medicine (19 ed.). Churchill
Livingstone. 2002. ISBN 0-443-07036-
9.
7. Haematology: Basic Principles and
Practice (6 ed.). Elsevier Saunders.
2012. ISBN 1437729282.
8. Clark, Michael; Kumar, Parveen J.
(1998). Clinical Medicine: A Textbook
for Medical Students and Doctors (4
ed.). Philadelphia: W.B. Saunders.
ISBN 0-7020-2458-9.
9. Kumar, Vinay; Abbas, Abul K.; Fausto,
Nelson; & Mitchell, Richard N. (2007).
Robbins Basic Pathology (8th ed.).
Saunders Elsevier. pp. 469-471
ISBN 978-1-4160-2973-1
10. Rak J, Yu JL, Luyendyk J, Mackman N
(2006). "Oncogenes, trousseau
syndrome, and cancer-related changes
in the coagulome of mice and
humans" . Cancer Res. 66 (22):
10643–6. doi:10.1158/0008-
5472.CAN-06-2350 . PMID 17108099 .
11. Grewal, PK; Uchiyama, S; Ditto, D;
Varki, N; Le, DT; Nizet, V; Marth, JD
(June 2008). "The Ashwell receptor
mitigates the lethal coagulopathy of
sepsis" . Nature Medicine. 14 (6):
648–55. doi:10.1038/nm1760 .
PMC 2853759 . PMID 18488037 .
12. Levi, M; Toh, C-H; et al. (2009).
"Guidelines for the diagnosis and
management of disseminated
intravascular coagulation". British
Journal of Haematology. 145 (5): 24–
33. doi:10.1111/j.1365-
2141.2009.07600.x .
PMID 19222477 .
13. Taylor, F; Toh, C-h; et al. (2001).
"Towards Definition, Clinical and
Laboratory Criteria, and a Scoring
System for Disseminated Intravascular
Coagulation". Thrombosis and
Haemostasis. 86 (5): 1327–30.
PMID 11816725 .
14. Gando, S (2012). "The Utility of a
Diagnostic Scoring System for
Disseminated Intravascular
Coagulation". Critical Care Clinics. 28
(3): 378–88.
doi:10.1016/j.ccc.2012.04.004 .
PMID 22713612 .
15. "Guidelines for the diagnosis and
management of disseminated
intravascular coagulation". British
Journal of Haematology. 145 (1): 24–
33. doi:10.1111/j.1365-
2141.2009.07600.x .
16. Franchini, M; Manzato, F; Salvagno GL;
et al. (2007). "Potential role of
recombinant activated factor VII for
the treatment of severe bleeding
associated with disseminated
intravascular coagulation: a
systematic review". Blood Coagul
Fibrinolysis. 18 (7): 589–93.
doi:10.1097/MBC.0b013e32822d2a3
c . PMID 17890943 .
17. Becker, Joseph U and Charles R Wira.
Disseminated intravascular
coagulation at eMedicine, 10
September 2009
18. Matsuda, T (Jan–Feb 1996). "Clinical
aspects of DIC--disseminated
intravascular coagulation". Pol J
Pharmacol. 48 (1): 73–5.
PMID 9112631 .
19. Smith, OP (1997). "Use of protein-C
concentrate, heparin, and
haemodiafiltration in meningococcus-
induced purpura fulminans". Lancet.
350 (9091): 1590–1593.
doi:10.1016/s0140-6736(97)06356-3 .
20. Gando, S (1999). "Disseminated
intravascular coagulation and
sustained systemic inflammatory
response syndrome predict organ
dysfunctions after trauma: application
of clinical decision analysis". Ann
Surg. 229 (1): 121–127.
doi:10.1097/00000658-199901000-
00016 . PMID 9923809 .
21. Sallah, S (2001). "Disseminated
intravascular coagulation in solid
tumors: clinical and pathologic study".
Thromb. Haemost. 86 (3): 828.

External links
Classification ICD-10: D65 • D

ICD-9-CM: 286.6 •
MeSH: D004211 •
DiseasesDB: 3765

External resources MedlinePlus: 000573 •


eMedicine: med/577
emerg/150

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