Disseminated Intravascular Coagulation
Robert R. Zaid D.O.
Genesys Regional Medical Center
PGY-I
Barcelona - Gaudi
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• Primarily a thrombotic process
– Systemic process producing both
thrombosis and hemorrhage
– Also called consumption
coagulopathy and defibrination
syndrome1
– Its clinical manifestation may be
widespread hemorrhage in acute,
fulminant cases2.
1. Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,
HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY
2. Uptodote, 2005, www.utdol.com, Clinical feadures, diagnosis and teratment of disseminated intravascular coagulation
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• Basic pathophysiology
– Entry into the circulation of procoagulant
substances
• Trigger systemic activation of the coagulation
system and platelets
• Lead to the disseminated deposition of fibrinplatelet thrombi.
– Procoagulant stimulus is tissue factor (most
cases)
• Lipoprotein
• Not normally exposed to blood.
– Tissue factor gains access to blood by
• Tissue injury,
• Malignant cells,
• Expression on the surfaces of monocytes and
endothelial cells by inflammatory mediators.
Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,
HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY
Stein B, Fuster V, Israel DH, et al. Platelet inhibitor agents in cardiovascular disease: an update. J Am Coll Cardiol. 1989;14:813–836.
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• Tissue factor triggers
– Thrombin
• Protease
• Induces fibrin formation and platelet
activation
• Other procoagulants
– Cysteine protease
– Mucin
– Trypsin
Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,
HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• Acute DIC
– Coagulation factors are consumed at
a rate in excess of the capacity of
the liver to synthesize them,
– Platelets are consumed in excess of
the capacity of bone marrow
megakaryocytes to release them.
Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,
HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• Laboratory manifestations
– Prolonged prothrombin time (PT)
– Prolonged Activated partial thromboplastin time
(aPTT)
– Thrombocytopenia.
– Increased fibrin formation
• Stimulates compensatory process of secondary
fibrinolysis,
• Plasminogen activators generate plasmin to digest
fibrin (and fibrinogen) into fibrin(ogen) degradation
products (FDPs).
– FDPs are potent circulating anticoagulants that
contribute further to the bleeding manifestations of
DIC.
• Intravascular fibrin deposition can cause
fragmentation of red blood cells and lead to the
appearance of schistocytes in blood smears
• Hemolytic anemia is unusual in DIC.
• Microvascular thrombosis in DIC can compromise
the blood supply to some organs and lead to
multiorgan failure
Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,
HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
Citadel Park
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• DIC always has an underlying
etiology
– Must be identified and eliminated to
treat the coagulopathy successfully.
– The development of DIC in many of
these disorders is associated with an
unfavorable outcome1.
• Occurs in 1% of hospitalized
patients2
• Mortality rate approaches 40-80%
1. Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,
HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY
2. Uptodote, 2005, www.utdol.com, Clinical feadures, diagnosis and teratment of disseminated intravascular coagulation
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• Causes
– Infection
• Most common cause of DIC.
• The syndrome particularly is associated
with gram-negative or gram-positive
sepsis
• Can be triggered by a variety of other
–
–
–
–
Bacterial
Fungal
Viral
Rickettsial, and protozoal
microorganisms.
Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,
HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• Obstetrics
– The placenta and uterine contents
are rich sources of
• Tissue factor
• Other procoagulants that normally are
excluded from the maternal circulation
Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,
HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY
La Familia
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
– Clinical manifestations of DIC may
accompany obstetric complications,
especially in the third trimester.
• These syndromes range from
– Acute, fulminant, and often fatal DIC in
amniotic fluid embolism
» Blood is exposed to large amounts
of tissue factor in a short period of
time creating large amounts of
thrombin
» Multiorgan failure
– Chronic or subacute DIC with a retained
dead fetus.
» Exposure to small amounts of tissue
factor
Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,
HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
– Other obstetric problems associated
with DIC include
• Abruptio placentae
• Toxemia
• Septic abortion.
Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,
HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• Clinical manifestations
– Determined by
• Nature
• Intensity
• Duration of the underlying stimulus.
– Chronicity
• Low-grade DIC is often asymptomatic
– Diagnosed only by laboratory abnormalities.
– Bleeding is most common clinical finding
» Generalized or widespread ecchymoses
• Chronic disease
– Thrombotic complications
» Trousseau's syndrome in cancer
» Gangrene of the digits or extremities
» Hemorrhagic necrosis of the skin
» Purpura fulminans
– Enhanced by
• Coexistence of liver disease
Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,
HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY
Candy Factory
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• Diagnosis of severe, acute (easy)
– Prolongation of PT, aPTT and Thrombin time
• Due to consumption and inhibitiion of clotting
factors
– Thrombocytopenia
– Fibrin degradatin products
• Increased due to secondary fibrinolysis
– Measured by latex agglutination or D-dimer
assays.
– Schistocytes may be seen in the peripheral
blood smear
• Neither sensitive nor specific for DIC.
Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,
HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• Chronic or compensated forms of DIC
– Highly variable patterns of abnormalities in
"DIC screen" coagulation tests.
– Increased FDPs and prolonged PT are
generally more sensitive measures than are
abnormalities of the aPTT and platelet
count.
– Overcompensated synthesis of consumed
clotting factors and platelets in some chronic
forms
• Cause shortening of the PT and aPTT and/or
thrombocytosis
• Though, elevated levels of FDPs indicate
secondary fibrinolysis in such cases.
Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,
HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY
Street entertainers
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• Treatment
– Identify underlying cause and treat
– All other therapies are temporizing
Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,
HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• Asymptomatic patients with selflimited DIC
– Have only laboratory manifestations
of the coagulopathy
– No treatment may be necessary.
Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,
HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• Actively bleeding or who are at high risk
of bleeding,
– Blood component treatments of choice
• Transfusions of platelets
– Improve the thrombocytopenia
• Fresh-frozen plasma (FFP)
– Replace all consumed coagulation factors and
correct the prolonged PT and aPTT.
• Large volumes of plasma in severe cases
– The theoretical concern that these blood
products may "fuel the fire" and exacerbate
the DIC has not been supported by clinical
experience
Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,
HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• Special cases
– Profound hypofibrinogenemia
• Additional transfusion of cryoprecipitate,
• Plasma concentrate enriched in
fibrinogen
– Sepsis
• Infusion of antithrombin III concentrate
may be considered as an adjunctive
measure
Schafer, A., I., Cecil Textbook of Medicine, Saunders, 2004, chapter 179,
HEMORRHAGIC DISORDERS: DISSEMINATED INTRAVASCULAR COAGULATION, LIVER FAILURE, AND VITAMIN K DEFICIENCY
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
•
Pharmacologic inhibitors of
coagulation and fibrinolysis
– Heparin
– Theoretical benefit
•
•
It blocks thrombin and the secondary
fibrinolysis.
Might exacerbate the bleeding tendency
– Usually reserved for
– Forms manifested by
» Thrombosis
» Acrocyanosis
» Cancer
» Vascular malformations
» Retained dead fetus
» Acute promyelocytic leukemia.
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• Antifibrinolytic agents,
– ε-aminocaproic acid and tranexamic
acid
– Generally are contraindicated
• May precipitate thrombosis
– May be effective in decreasing lifethreatening bleeding
Festivals
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• XIGRIS® (Lilly)
Drotrecogin alfa (activated)
– Recombinant form of human
Activated Protein C
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
•
•
General Pharmacology
Activated Protein C
– Antithrombotic effect
– Inhibits Factors Va and VIIIa.
•
•
•
Indirect profibrinolytic activity through its
ability to inhibit plasminogen activator
inhibitor-1 (PAI-1)
Limits generation of activated thrombinactivatable-fibrinolysis-inhibitor.
In vitro data indicate that Activated Protein C
may exert an anti-inflammatory effect by
inhibiting human tumor necrosis factor
production by monocytes
– Blocks leukocyte adhesion to selectins
– Limits the thrombin-induced inflammatory
responses within the microvascular
endothelium.
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
•
Clinical study (PROWESS)
– 1690 patients with severe sepsis
– Entry criteria included a systemic
inflammatory response presumed due to
infection and at least one associated acute
organ dysfunction
– The study was terminated after a planned
interim analysis due to significantly lower
mortality in patients on Xigris than in
patients on placebo
•
(210/850, 25% vs. 259/840, 31% p=0.005).
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• INDICATIONS AND USAGE
– Xigris is indicated for the reduction
of mortality in adult patients with
severe sepsis (sepsis associated
with acute organ dysfunction) who
have a high risk of death (APACHE
II)
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
•
Contraindications
– Active internal bleeding
– Recent (within 3 months) hemorrhagic
stroke
– Recent (within 2 months) intracranial or
intraspinal surgery, or severe head trauma
– Trauma with an increased risk of lifethreatening bleeding
– Presence of an epidural catheter
– Intracranial neoplasm or mass lesion or
evidence of cerebral herniation
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
•
Warnings
–
–
–
–
–
–
–
–
–
–
–
–
Concurrent therapeutic dosing of heparin to treat an active
thrombotic or embolic event
Platelet count <30,000 × 10 6 /L, even if the platelet count is
increased after transfusions
Prothrombin time-INR >3.0
Recent (within 6 weeks) gastrointestinal bleeding
Recent administration (within 3 days) of thrombolytic therapy
Recent administration (within 7 days) of oral anticoagulants or
glycoprotein IIb/IIIa inhibitors
Recent administration (within 7 days) of aspirin >650 mg per
day or other platelet inhibitors
Recent (within 3 months) ischemic stroke
Intracranial arteriovenous malformation or aneurysm
Known bleeding diathesis
Chronic severe hepatic disease
Any other condition in which bleeding constitutes a significant
hazard or would be particularly difficult to manage because of
its location .
Disseminated Intravascular Coagulation
-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
• DOSAGE AND
ADMINISTRATION
– Xigris should be administered
intravenously at an infusion rate of
24 µg/kg/hr for a total duration of
infusion of 96 hours.
Any questions?