Pathophysiology of DIC

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Disseminated Intravascular Coagulation

Sidney F. Rhoades, M.D.
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NO disclosures No off label usage of
medications or products of any kind
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Objectives

• To attempt to not confuse you in regards to DIC
• Define DIC and understand classification
• Understand the epidemiology, etiology and risk
  factors of DIC
• Describe signs and symptoms of DIC
• Understand the laboratory findings in DIC

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Defining DIC

• Also known as consumption coagulopathy and
  defibrination syndrome
• Acquired Condition
• Systemically producing thrombosis and
  hemorrhage
• Initiated by several disorders or illnesses
• Consist of exposure of blood to procoagulants
• - tissue factor
• - cancer procoagulant

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Defining DIC

• Formation of Fibrin within the circulation
• Fibrinolysis
• Depletion of clotting factors
• End Organ Damage

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Defining DIC

• A systemic disorder of clotting and bleeding
  after exposure to blood procoagulants thereby
  causing fibrin formation and degradation (FDP).
• Abnormal acceleration of the coagulation cascade,
  resulting in thrombosis
• Depletion of the clotting factors causing
  hemorrhage

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DIC is a disorder of diffuse activation of the
clotting cascade that results in depletion of
clotting factors in the blood.
http//health-pictures.com/disseminated-intravascu
lar-coagulation.htm
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Epidemiology of DIC
Incidence DIC is complication of underlying
illness occurring in 1 of hospitalized
patients
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Classification Acute or Chronic

• Acute DIC
• -develops rapidly over a period of hours
• -presents with sudden bleeding from multiple
  sites
• -treated as a medical emergency
• Chronic DIC
• -develops over a period of months
• -maybe subclinical
• -eventually evolves into an acute DIC pattern
• (Otto, 2001)

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Classification Acute or Chronic

• Acute
• -blood is exposed to a large amount of tissue
  factor
• over a brief period of time
• -massive generation of thrombin
• -acutely triggers the coagulation cascade
• -overwhelming the inhibitory mechanisms

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Classification Acute or Chronic
Tissue factor -integral membrane glycoprotein
not normally expressed on the vascular cell
surface -caused by
vessel wall damage -circulates in the blood as
a derivative of monocytes and
macrophages -platelets also
generate tissue factor in order to generate
thrombin
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Classification Acute or Chronic
Secondary Fibrinolysis -process of degrading
fibrin creating FSP normally cleared from
circulation -interrupts normal fibrin
polymerization -binds to platelet surface
glycoprotein Iib/IIIa -caused by tissue
plasminogen activator plasminogen ?
plasmin -cleaves other proteins other than
fibrin like fibrinogen -eats up other
clotting factors
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Classification Acute or Chronic
Chronic -also known as compensated
DIC -blood is continuously or intermittently
exposed to small amounts of tissue
factor -liver and bone marrow are able to
replenish the depleted coagulation proteins
and platelets
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Etiology and Pathology of DIC
Extrinsic (endothelial) -Shock or trauma
-Infection gram positive and gram
negative bacterial and nonbacterial
infection -Obstetric complications eclamp
sia, placenta abruption, fetal death
-Malignancies Acute promyleocytic
leukemia, AML, cancers of lung, colon,
breast, prostate
Intrinsic (blood vessel) -Infectious
vasculitis certain viral
infections rocky mountain spotted fever
-Vascular disorders -Intravascular
hemolysis hemolytic transfusion reactions
-Miscellaneous snakebite, pancreatitis, liver
disease
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Extrinsic (endothelial) continued

• Shock
• -reduced blood flow and tissue damage
• encourages thrombin formation
• Trauma
• -extensive surgery
• -release of tissue enzymes and phospholipids
• -head injury
• one study of 159 patients found
• coagulopathy in 41 of pts with CT
• evidence of brain injury and 25 of those
  without

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Gunshot wound to the carotid artery
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Extrinsic (endothelial) continued

• Trauma (cont.)
• -syndrome developed one to four hours after
  injry
• -studies show direct evidence of procoagulant
  release
• and thrombin formation in cerebrovenous
• blood within six hours of isolated head trauma
• -studies showed increased D-dimer and soluble
  fibrin
• concentrations indicating coagulation and
  fibrinolysis
• Infection
• both gram positive and gram negative
• bacterial and nonbacterial infection
• Overt DIC reportedly occurs in 30-50 of Pts
  with
• gram negative sepsis
• Activation of the endothelial pathway via
  endotoxin
• Endotoxin also activates factor XII of the
  intrinsic pathway

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Question Are we missing out in regards to
coding and increased severity/mortality?
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Extrinsic (endothelial) continued

• Malignancies
• -3rd most frequent cause of DIC
• -accounts for 7 of clinically evident cases
• -can cause acute DIC in Acute Promyelocytic
  Leukemia
• -pulmonary or cerebrovascular hemmorrhage in
  up to 40 patients
• -treat with rapid induction tumor cell
  differentiation with all-trans retinoic acid
• down-regulates the receptor annexin II,
• a RC for plasminogen on the
  promyelocyte

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DIC with microangiopathic hemocytic anemia in a
34 y/o female, Hb 8.6 g/dL, MCV 104.5 fL, MCHC
32.8 g/dL, platelets 11,000/uL, WBC 59,000/uL.
Patient had a history of disseminated non-small
cell carcinoma of the lung. She presented to the
ER in extremis and expired within a few hours of
admission. (http//commons.wikimedia.org/wiki/Fil
eDIC_With_Microangiopathic_Hemolytic_Anemia_(3019
20983).jpg)
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Extrinsic (endothelial) continued

• Obstetric complications
• -seen in more than 50 of amniotic fluid
  embolism and abrupteoplacentae
• - the greater the abruption the higher the
  severity
• - thromboplastins integrated into mothers blood
  system
• - peripartum hemorrhage may be spontaneous
• - 20 in women with HELLP
• - septic abortions
• - dead fetus syndrome

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Clinical Manifestations

• Bleeding (64)
• Renal dysfunction (25)
• Hepatic dysfunction (19)
• Respiratory dysfunction (16)
• Shock (14)
• Thromboembolism (7)

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Clinical Manifestations

• Bleeding
• -petechiae
• -ecchymoses
• -blood oozing from wound sites
• -intravenous lines
• -mucosal surfaces
• Acute Renal Failure
• -microthrombosis of afferent arterioles
• -cortical ischemia
• -necrosis
• -hypotension ? ATN

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Clinical Manifestations

• Hepatic Dysfunction
• -jaundice (from liver disease and hemolysis)
• -hepatocellular injury (from sepsis/shock)
• Pulmonary Disease
• -hemorrhage with hemoptysis
• -ARDS
• -pulmonary microthrombosis

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Clinical Manifestations

• Central Nervous System
• -coma
• -delirium
• -transient focal neurologic symptoms
• -microthrombi, hemorrhage, and hypoperfusion
  are causes

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CASE
STUDY
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Case Study
Cc chest pain, N/V HPI 67 y.o. female
significant PMHx of rheumatoid arthritis
on Enbrel, pericarditis presently on
prednisone taper and known previous pleural
effusion with a negative previous workup for
tuberculosis. Pt. presented complaining of N/V
and 7/10 sharp chest pain at her anterior
chest wall radiating across the upper part of the
chest, worsening with inspiration. She had
productive green sputum and white count 42,000.
Pts temp was 100.3
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Case Study
PMhx GERD, depression, hypercholesterolemia,
pericarditis, pleural Effusion,
rheumatiod arthritis PSHhx noncontributory Med
s Enbrel, Votaren, Ultram, Nexium, Zocor,
Pristiq, tylenol4, hydrocodone-apap, Melatonin,
Erythromycin, prednisone, Gel eye
drops AllergiesNKDA ROS ten point review
otherwise negative Social history Patient lives
with her family, no hx of tobacco or Etoh
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Case Study
Physical exam Vitals T 100.3 RR 20 P 128 BP
103/60 95 RA WD WN Elderly female appearing
ill no acute distress and oriented to person,
place and time HEENT AT, NC Anictericno
conjuctival pallor mmm Neck Supple with no JVD
and negative HJR Chest Moderately good air
entry bilaterally with few bibasilar
crackles CVS tachycardic, Regular S1S2
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Case Study
Labs at 2145 on 7/17/10 Na 137 CL101 BUN
23 glucose 158 K 4.2 CO2 23 Cr0.57
Bilirubin total 0.7 PT 13.7 INR 1.0 SGOT
60 PTT 17.3 SGPT 37
trp 0.04 Alk Phos 73 BNP
79 WBCs 42.1 Hgb 14.7 plt 385 EKG
sinus tachycardia, 114 no ST-T changes CXR
enlarged cardiac silhouette no infiltrates or
pulmonary congestion
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Case Study

• Pt. became more hypotensive , clammy and
  diaphoretic
• She was transferred to the ICU and given fluid
  boluses as well as pressors
• Due to Pts immunocompromised state Pt. was
  placed on Imipenem and Vancomycin.
• Pt was ultimately intubated after ABGs returned
  and were noted to be significantly worse.

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Case Study
Labs at 0240 on 7/18/10 Na 137 CL106 BUN 24
glucose 168 K 3.5 CO2 22 Cr 0.73
Bilirubin total 1.3 SGOT 38
SGPT 29 trp 0.16 Alk Phos
46 WBCs 46.5 Hgb 11.8
plt 416
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Case Study
Labs at 0710 on 7/18/10 Na 133 CL109 BUN
22 glucose 224 K 4.2 CO2 15 Cr0.67
Bilirubin total 0.9 SGOT
30 SGPT 26 Alk Phos
45 WBCs 44.4 Hgb 12.6
plt 438 U/A Nitrite negative, leukocyte est
negative Bilirubin negative, Urobilinogen 0.2E.
U/dl
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Case Study
Labs at 1340 on 7/18/10 Na 134 CL105 BUN
22 glucose 279 K 5.2 CO2 12 Cr1.13
Bilirubin total 2.0 PT 39.7 INR 3.8 SGOT
527 PTT 80.2 SGPT 724
LDH 1261 Alk Phos 39 amylase
126 Fibrinogen 157 (221-480 mcg/dl) Fibrin Spit
products 10-40 (Less than 10) D.DIMER 14.48
(0.00-0.48 mcg/dl)
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Case Study
Risk Factors for Death 1. Increased age 2.
Severity of organ dysfunction 3. Severity of
hemostatic abnormalities
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Treatment of DIC
Patients bleed from thrombocytopenia and
coagulation factor deficiency -transfuse
platelets and coagulation factors in Pts
bleeding or with high risk of
bleeding -after surgery or those requiring
invasive procedures -Patients with marked
thrombocytopenia lt20,000 -moderate
thrombocytopenia lt50,000/microL and
bleeding -serious bleeding should have 1-2
units per 10kg per day
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Treatment of DIC
Actively bleeding patients -with elevated
prothrombin time/INR or Fibrinogen
concentration lt 50mg/dl -transfuse FFP
-cyroprecipitate for fibrinogen
replacement -preferable to keep fibrinogen
level gt100mg/dl
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Treatment of DIC

• Heparin
• no controlled trials indicating benefit
• little evident that it improves organ dysfunction
• use is limited to specific Patients with chronic
  DIC and
• mostly thrombotic manifestations
• -migratory thrombophlebitis
• used in retained dead fetus and
  hypofibrinogenemia
• prior to induction of labor
• excessive bleeding assoc with giant hemangioma
• aortic aneurysm prior to resection

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Treatment of DIC
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Treatment of DIC

• Xigris
• activated protein C
• anticoagulant and anti-inflammatory activities
• direct anti-inflammatory effect on endothelial
  cells
• studies show modulation of gene expression
• inhibits TNF expression of cell adhesion
  molecules
• ICAM-1, VCAM-1, E-selectin by down
• regulation of Transcrition facor
  NF-kB
• enhances anti-apoptotic genes

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Comparison of DIC to TTP/HUS

• TTP/HUS
• has normal coagulation components
• little or no prolongation of the PT or PTT
• will share microangiopathic blood smear
• TTP will have thrombocytopenia and schistocytes
• clinical settings are usually different than DIC
• associated sepsis, trauma, malignancy, OB

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The End