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DIC can occur acutely but also on a slower, chronic basis, depending on the underlying problem.
[3]
It is common in the critically ill, and may participate in the development of multiple organ
failure, which may lead to death.[4]
Contents
[hide]
• 1 Epidemiology
• 2 Pathophysiology
• 3 Causes
• 4 Signs and symptoms
• 5 Diagnosis
• 6 Treatment
• 7 Prognosis
• 8 See also
• 9 References
[edit] Epidemiology
About half of DIC cases result from complications of pregnancy, and about a third result from
carcinomatosis. All other causes make up the remaining sixth of cases.[3]
[edit] Pathophysiology
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 thrombin 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 lose control, 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[5]. 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 activation, TF binds with
coagulation factors that then trigger both the intrinsic and the extrinsic pathways of coagulation.
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.[6]
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 feedback system develops in which increased clotting leads to more
clotting. At the same time, thrombocytopenia occurs because of the entrapment and consumption
of platelets. Clotting factors are consumed in the development of multiple clots, which
contributes to the bleeding seen with DIC.
[edit] Causes
DIC can occur in the following conditions:[3][4][7]
[edit] Diagnosis
Diagnosis is usually suggested by following conditions:[7]
• Severe cases with haemorrhage: The PT and APTT are usually very prolonged and the
fibrinogen level markedly reduced. 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. There is severe thrombocytopenia. The blood film may show
fragmented red blood cells (schistocytes).
• Mild cases without bleeding: There is increased synthesis of coagulation factors and
platelets. PT, APTT, and platelet counts are normal. fibrin degradation products are
raised.
• Thrombocytopenia
• Prolongation of prothrombin time and activated partial thromboplastin time
• A low fibrinogen concentration
• Increased levels of fibrin degradation products
[edit] Treatment
The only effective treatment is the reversal of the underlying cause. Anticoagulants are given
exceedingly rarely when thrombus formation is likely to lead to imminent death (such as in
coronary artery thrombosis or cerebrovascular thrombosis). Platelets may be transfused if counts
are less than 5,000-10,000/mm3 and massive hemorrhage is occurring, and fresh frozen plasma
may be administered in an attempt to replenish coagulation factors and anti-thrombotic factors,
although these are only temporizing measures and may result in the increased development of
thrombosis.
DIC results in lower fibrinogen levels (as it has all been converted to fibrin), and this can be
tested for in the hospital lab. A more specific test is for "fibrin split products" (FSPs) or "fibrin
degradation products" (FDPs) which are produced when fibrin undergoes degradation when
blood clots are dissolved by fibrinolysis.
[edit] Prognosis
Prognosis varies depending on the underlying disorder. The prognosis for those with DIC,
regardless of cause, is often grim. The colloquial reference "death is coming," refers to the lack
of existing and alternative forms of available treatment options, and to an expected worsening
prognosis.[11]
Images
Blood clot formation
Blood clots
Read More
Blood clots
Sepsis
Liver disease
Disseminated intravascular coagulation (DIC) is a serious disorder in which the proteins that
control blood clotting become abnormally active.
Causes
Normally, when you are injured, certain proteins in the blood become activated and travel to the
injury site to help stop bleeding. However, in persons with DIC, these proteins become
abnormally active.
Small blood clots form within the blood vessels. Some of these clots can clog up the vessels and
cut off blood supply to various organs such as the liver or kidney. These organs will then stop
functioning. Over time, the clotting proteins become "used up." When this happens, the person is
then at risk for serious bleeding from even a minor injury.
This disorder can result in clots or, more often, in bleeding. The bleeding can be severe.
Symptoms
Treatment
Blood clotting factors will be replaced with plasma transfusions. Heparin, a medication used to
prevent clotting, is sometimes used also.
Outlook (Prognosis)
Go to the emergency room or call 911 if you have bleeding that won't stop.
Prevention
Alternative Names
Consumption coagulopathy
ntroduction
Background
The subcommittee on DIC of the International Society on Thrombosis and Haemostasis has
suggested the following definition for DIC: "An acquired syndrome characterized by the
intravascular activation of coagulation with loss of localization arising from different causes. It
can originate from and cause damage to the microvasculature, which if sufficiently severe, can
produce organ dysfunction."1
DIC is not an illness on its own but rather a complication or an effect of progression of other
illnesses and is estimated to be present in up to 1% of hospitalized patients.2
DIC is always secondary to an underlying disorder and is associated with a number of clinical
conditions (see List below), generally involving activation of systemic inflammation. DIC has
several consistent components including activation of intravascular coagulation, depletion of
clotting factors, and end-organ damage (see Components of DIC). DIC is most commonly
observed in severe sepsis and septic shock. Indeed the development and severity of DIC
correlates with mortality in severe sepsis.3,4 Although bacteremia, including both gram-positive
and gram-negative organisms, is most commonly associated with DIC, other organisms
including viruses, fungi, and parasites may cause DIC.
Trauma, especially neurotrauma, is also frequently associated with DIC. DIC is more frequently
observed in those patients with trauma who develop the systemic inflammatory response
syndrome.5 Evidence indicates that inflammatory cytokines play a central role in DIC in both
trauma patients and septic patients. In fact, systemic cytokine profiles in both septic patients and
trauma patients are nearly identical.6
• Sepsis/severe infection
• Trauma (neurotrauma)
• Organ destruction
• Malignancy (solid and myeloproliferative malignancies)
• Severe transfusion reactions
• Rheumatologic illness
o Adult Stills disease
o Lupus
• Obstetric complications
o Amniotic fluid embolism
o Abruptio placentae
o Hemolysis, elevated liver enzymes, low platelets (HELLP)
syndrome/eclampsia
o Retained dead fetus syndrome
• Vascular abnormalities
o Kasabach-Merritt syndrome
o Large vascular aneurysms
• Severe hepatic failure
• Severe toxic reactions
o Envenomations
o Transfusion reactions
o Transplant rejection
DIC exists in both acute and chronic forms. DIC develops acutely when sudden exposure of
blood to procoagulants occurs, including tissue factor (tissue thromboplastin), generating
intravascular coagulation. Compensatory hemostatic mechanisms are quickly overwhelmed, and,
as a consequence, a severe consumptive coagulopathy leading to hemorrhage
develops. Abnormalities of blood coagulation parameters are readily identified, and organ failure
frequently occurs in acute DIC.
In contrast, chronic DIC reflects a compensated state that develops when blood is continuously
or intermittently exposed to small amounts of tissue factor. Compensatory mechanisms in the
liver and bone marrow are not overwhelmed, and there may be little obvious clinical or
laboratory indication of the presence of DIC. Chronic DIC is more frequently observed in solid
tumors and in large aortic aneurysms.8
Pathophysiology
DIC is caused by widespread and ongoing activation of coagulation, leading to vascular or
microvascular fibrin deposition, thereby compromising an adequate blood supply to various
organs. Four different mechanisms are primarily responsible for the hematologic derangements
seen in DIC: increased thrombin generation, a suppression of anticoagulant pathways, impaired
fibrinolysis, and inflammatory activation.9 Activation of intravascular coagulation is mediated
almost entirely by the intrinsic clotting pathway.
Exposure to tissue factor in the circulation occurs via endothelial disruption, tissue damage, or
inflammatory or tumor cell expression of procoagulant molecules, including tissue factor. Tissue
factor activates coagulation by the intrinsic pathway involving factor VIIa. Factor VIIa has been
implicated as the central mediator of intravascular coagulation in sepsis. Blocking the factor VIIa
pathway in sepsis has been shown to prevent the development of DIC, whereas interrupting
alternative pathways did not demonstrate any effect on clotting.10,11 The tissue factor-VIIa
complex then serves to activate thrombin, which, in turn, cleaves fibrinogen to fibrin while
simultaneously causing platelet aggregation. Evidence suggests that the intrinsic (or contact)
pathway is also activated in DIC, while contributing more to hemodynamic instability and
hypotension than to activation of clotting.12
Tissue factor pathway inhibitor (TFPI) is another anticoagulant mechanism that is disabled in
DIC. TFPI inhibits the tissue factor-VIIa complex. Although levels of TFPI are normal in
patients with sepsis, a relative insufficiency in DIC is evident. TFPI depletion in animal models
predisposes to DIC, and TFPI blocks the procoagulant effect of endotoxin in humans.15 The
intravascular fibrin produced by thrombin is normally eliminated via a process termed
fibrinolysis. The initial response to inflammation appears to be augmentation of fibrinolytic
action; however, this response soon reverses as inhibitors (plasminogen activator inhibitor-1
[PAI-1], TAFI) of fibrinolysis are released.16 Indeed, high levels of PAI-1 precede DIC and
predict poor outcomes.17 Fibrinolysis cannot keep pace with increased fibrin formation,
eventually resulting in under-opposed fibrin deposition in the vasculature.
Inflammatory and coagulation pathways interact in substantial ways. Many of the activated
coagulation factors produced in DIC contribute to the propagation of inflammation by
stimulating endothelial cell release of proinflammatory cytokines. Factor Xa, thrombin, and the
tissue factor-VIIa complex have each been demonstrated to elicit proinflammatory
action. Furthermore, given the anti-inflammatory action of activated protein C and AT, their
impairment in DIC contributes to further dysregulation of inflammation.7,18,19
Frequency
United States
Approximately 18,000 cases of DIC occurred in 1994. DIC may occur in 30-50% of patients
with sepsis.
Mortality/Morbidity
Morbidity and mortality depend on both the underlying disease and the severity of coagulopathy.
Assigning a numerical figure for DIC-specific morbidity and mortality is difficult. Below are
examples of mortality rates in diseases complicated by DIC:
• Idiopathic purpura fulminans associated with DIC has a mortality rate of 18%.
• Septic abortion with clostridial infection and shock associated with severe DIC
has a mortality rate of 50%.
• In the setting of major trauma, the presence of DIC approximately doubles
the mortality rate.3,4
Sex
Age
In addition to the symptoms related to the underlying disease process, typically, a history of
blood loss and hypovolemia, such as gastrointestinal bleeding, is present. Look for symptoms
and signs of thrombosis in large vessels, such as deep venous thrombosis (DVT), and of
microvascular thrombosis, such as renal failure. Bleeding from at least 3 unrelated sites is
particularly suggestive of DIC.
• Epistaxis
• Gingival bleeding
• Mucosal bleeding
• Cough
• Dyspnea
• Confusion, disorientation
• Fever
[ CLOSE WINDOW ]
Table
Features Affected
Patients, %
Bleeding 64%
Shock 14%
Features Affected
Patients, %
Bleeding 64%
Shock 14%
Physical
• Circulation
o Signs of spontaneous and life-threatening hemorrhage
o Signs of subacute bleeding
o Signs of diffuse or localized thrombosis
• Central nervous system
o Nonspecific altered consciousness/stupor
o Focal deficits not usually present
• Cardiovascular system
o Hypotension
o Tachycardia
o Circulatory collapse
• Respiratory system
o Pleural friction rub
o Signs of adult respiratory distress syndrome (ARDS)
• Gastrointestinal system
o Hematemesis
o Hematochezia
• Genitourinary system
o Signs of azotemia and renal failure
o Acidosis
o Hematuria
o Oliguria
o Metrorrhagia
o Uterine hemorrhage
• Dermatologic system
o Petechiae
o Purpura
o Hemorrhagic bullae
o Acral cyanosis
o Skin necrosis of lower limbs (purpura fulminans)
o Localized infarction and gangrene
o Wound bleeding and deep subcutaneous hematomas
o Thrombosis
Causes
Causes of DIC can be classified as acute or chronic, systemic or localized. DIC may be the result
of a single or multiple conditions.
• Acute DIC
o Infectious
Bacterial (eg, gram-negative sepsis, gram-positive infections,
rickettsial)
Viral (eg, HIV, cytomegalovirus [CMV], varicella, hepatitis)
Fungal (eg, Histoplasma)
Parasitic (eg, malaria)
o Malignancy
Hematologic (eg, acute myelocytic leukemias)
Metastatic (eg, mucin-secreting adenocarcinomas)
o Obstetric
Placental abruption
Amniotic fluid embolism
Acute fatty liver of pregnancy
Eclampsia
o Trauma
o Burns
o Motor vehicle accidents (MVAs)
o Snake envenomation
o Transfusion
o Hemolytic reactions
o Massive transfusion
o Liver disease - Acute hepatic failure
o Prosthetic devices
o Shunts (Denver, LeVeen)
o Ventricular assist devices
• Chronic DIC
o Malignancies
Solid tumors
Leukemia
o Obstetric
Retained dead fetus syndrome
Retained products of conception
o Hematologic
Myeloproliferative syndromes
Paroxysmal nocturnal hemoglobinuria
o Vascular
Rheumatoid arthritis
Raynaud disease
o Cardiovascular - Myocardial infarction
o Inflammatory
Ulcerative colitis
Crohn disease
Sarcoidosis
• Localized DIC
o Aortic aneurysms
o Giant hemangiomas (Kasabach-Merritt syndrome)
o Acute renal allograft rejection
o Hemolytic uremic syndrome
Medication
Therapy should be based on etiology and aimed at eliminating the underlying disease. Therapy
should be appropriately aggressive for the patient's age, disease, and severity and location of
hemorrhage/thrombosis. Treatment for acute DIC includes anticoagulants, blood components,
and antifibrinolytics.
Anticoagulant agents
These agents are used in the treatment of clinically evident intravascular thrombosis when the
patient continues to bleed or clot 4-6 h after initiation of primary and supportive therapy.
Thrombosis can present as purpura fulminans or acral ischemia. Take special precaution in
obstetric emergencies or massive liver failure. The anti-inflammatory properties of antithrombin
III may be particularly useful in DIC secondary to sepsis.
Heparin
Use and dose of heparin is based on severity of DIC, underlying cause, and extent of thrombosis.
Monitoring results of therapy is mandatory. Heparin augments antithrombin III activity and
prevents conversion of fibrinogen to fibrin. Does not actively lyse but inhibits further
thrombogenesis. Prevents reaccumulation of a clot after spontaneous fibrinolysis.
• Dosing
• Interactions
• Contraindications
• Precautions
Adult
Not established
• Dosing
• Interactions
• Contraindications
• Precautions
Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin,
dextran, dipyridamole, and hydroxychloroquine may increase toxicity
• Dosing
• Interactions
• Contraindications
• Precautions
• Dosing
• Interactions
• Contraindications
• Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may
use if benefits outweigh risk to fetus
Precautions
Used for moderately severe–to– severe DIC or when levels are depressed markedly. Alpha 2-
globulin that inactivates thrombin, plasmin, and other serine proteases of coagulation, including
factors IXa, Xa, XIa, XIIa, and VIIa. These effects inhibit coagulation.
• Dosing
• Interactions
• Contraindications
• Precautions
Adult
Total Units = (Desired Level - Initial Level) (0.6 X Total Body Weight kg) IV q8h with a desired
level >125% or loading dose of 100 U/kg IV over 3 h; followed by continuous infusion of 100
U/kg/d
Pediatric
Not established
• Dosing
• Interactions
• Contraindications
• Precautions
• Dosing
• Interactions
• Contraindications
• Precautions
Documented hypersensitivity
• Dosing
• Interactions
• Contraindications
• Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may
use if benefits outweigh risk to fetus
Precautions
Caution in hypotension; despite measures taken to delete infectious agents from human product,
potentially still can transmit disease or contain unknown infectious agents
These agents inhibit factors Va and VIIIa of the coagulation cascade. They may also inhibit
plasminogen activator inhibitor-1 (PAI-1).
Drotrecogin alfa-activated (Xigris)
Indicated for reduction of mortality in patients with severe sepsis associated with acute organ
dysfunction and at high risk of death. Recombinant form of human activated protein C that exerts
antithrombotic effect by inhibiting factors Va and VIIIa. Has indirect profibrinolytic activity by
inhibiting PAI-1 and limiting formation of activated thrombin-activatable-fibrinolysis-inhibitor.
May exert anti-inflammatory effect by inhibiting human tumor necrosis factor (TNF) production
by monocytes, blocking leukocyte adhesion to selectins, and limiting thrombin-induced
inflammatory responses within microvascular endothelium.
• Dosing
• Interactions
• Contraindications
• Precautions
Adult
Pediatric
Not established
• Dosing
• Interactions
• Contraindications
• Precautions
None reported; coadministration with drugs that affect hemostasis may increase risk of bleeding
(eg, warfarin, heparin, thrombolytics, glycoprotein IIb/IIIa inhibitors)
• Dosing
• Interactions
• Contraindications
• Precautions
Documented hypersensitivity; increased risk of bleeding (eg, active internal bleeding, recent
hemorrhagic stroke, recent intraspinal or intracranial surgery, recent or current trauma, presence
of epidural catheter, intracranial neoplasm, cerebral herniation, severe head trauma)
• Dosing
• Interactions
• Contraindications
• Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may
use if benefits outweigh risk to fetus
Precautions
Bleeding is most common serious adverse effect; caution with conditions that increase risk of
bleeding including INR >3, concurrent therapeutic heparin (>15 U/kg/h), within 6 wk of GI
bleeding episode, within 3 d of thrombolytic therapy, within 7 d of platelet inhibitors
administration, within 3 mo of ischemic stroke, intracranial arteriovenous malformation or
aneurysm, known bleeding diathesis, chronic severe hepatic disease; stop infusion if clinically
significant bleeding occurs; caution with thrombocytopenia (<50 X 109/L); chronic severe
hepatic disease and known bleeding diathesis not associated with the acute coagulopathy related
to sepsis
Blood components
Blood components are used to correct abnormal hemostatic parameters. These products should
be considered only after initial supportive and anticoagulant therapy. Washed PRBCs and
platelet concentrates are considered safe in uncontrolled DIC. Specialized blood components
(cryoprecipitate, FFP) may interfere with or improve DIC.
Preferred to whole blood since they limit volume, immune, and storage complications. Obtain
PRBCs after centrifugation of whole blood. Use washed or frozen PRBCs in individuals with
hypersensitivity transfusion reactions.
• Dosing
• Interactions
• Contraindications
• Precautions
Adult
Pediatric
Not established
• Dosing
• Interactions
• Contraindications
• Precautions
None reported
• Dosing
• Interactions
• Contraindications
• Precautions
Competent adult or legal guardian may refuse blood product; immediate consultation with
hospital ethical and legal staff is mandated
• Dosing
• Interactions
• Contraindications
• Precautions
Pregnancy
Precautions
Use CMV-negative units or filtered ones; transfusion reactions and transmission of blood-borne
pathogens are a concern; benefits should outweigh risks associated with such products
• Dosing
• Interactions
• Contraindications
• Precautions
Adult
Pediatric
Not established
• Dosing
• Interactions
• Contraindications
• Precautions
None reported
• Dosing
• Interactions
• Contraindications
• Precautions
Competent adult or legal guardian may refuse blood product; immediate consultation with
hospital ethical and legal staff mandated
• Dosing
• Interactions
• Contraindications
• Precautions
Pregnancy
Precautions
Platelets should be CMV-negative or the pheresis units from single donors filtered; benefits
should outweigh risks associated with such products
This treatment entails removing blood from body, spinning it to separate cells from plasma, and
replacing cells suspended in fresh frozen plasma, albumin, or saline. Contains coagulation
factors as well as protein C and protein S. Can be performed by using either 2 large-bore
peripheral IV sites or multiple lumen central line. Recommended with active bleeding and
fibrinogen <100 mg/dL.
• Dosing
• Interactions
• Contraindications
• Precautions
Adult
Administer as in adults
• Dosing
• Interactions
• Contraindications
• Precautions
None reported
• Dosing
• Interactions
• Contraindications
• Precautions
Documented hypersensitivity
• Dosing
• Interactions
• Contraindications
• Precautions
Pregnancy
Precautions
• Dosing
• Interactions
• Contraindications
• Precautions
Adult
Each bag contains 80-100 U of factor VIII; base administration on fibrinogen levels,
antithrombin III levels, and coagulation parameters
Pediatric
Not established
• Dosing
• Interactions
• Contraindications
• Precautions
None reported
• Dosing
• Interactions
• Contraindications
• Precautions
• Dosing
• Interactions
• Contraindications
• Precautions
Pregnancy
Precautions
Benefits should outweigh risks associated with transfusion therapy; viral contamination and
infection are remotely possible, although unlikely because of prescreening
Antifibrinolytic agents
These agents are used only after all other therapeutic modalities have been tried and deemed
unsuccessful. Increase in circulating plasmin and laboratory evidence of decreased plasminogen
should be documented. Antifibrinolytics may be useful in cases of DIC secondary to
hyperfibrinolysis associated with acute promyelocytic leukemia and other forms of cancer.
Inhibits fibrinolysis via inhibition of plasminogen activator substances and, to a lesser degree,
through antiplasmin activity. Main problem is that thrombi that form during treatment are not
lysed, and clinical significance of reducing bleeding is uncertain.
• Dosing
• Interactions
• Contraindications
• Precautions
Adult
Load 5-10 g IV slowly; followed by 2-4 g/h IV; not to exceed 30 g/d
Pediatric
Not established
• Dosing
• Interactions
• Contraindications
• Precautions
• Dosing
• Interactions
• Contraindications
• Precautions
• Dosing
• Interactions
• Contraindications
• Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may
use if benefits outweigh risk to fetus
Precautions
Do not administer unless definite diagnosis of hyperfibrinolysis has been made; caution in
cardiac, hepatic, or renal disease
Tranexamic acid (Cyklokapron)
• Dosing
• Interactions
• Contraindications
• Precautions
Adult
Pediatric
Not established