Disseminated Intravascular Coagulation

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Disseminated Intravascular Coagulation
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Introduction of DIC

• An acquired syndrome characterized by systemic
  intravascular coagulation and secondary bleeding
• Coagulation is always the initial event.
• Morbidity 0.2-0.5 Mortality 50-60
• Multiple causes

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Hemostasis Review

• Coagulation cascade
• Vascular Endothelium
• Anticlotting Mechanisms
• Fibrinolytic System
• Blood Flow Dynamics

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1.Coagulation

• Intrinsic Pathway
• Extrinsic Pathway
• Common Pathway
• Contact Pathway
• Tissue Factor Pathway
• Primary factor in DIC

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• Tissue Factor (TF)

• TF is a transmembrane glycoprotein which contains
  abundant phosphatide.
• When TF enters blood, the calcium ions combine F?
  to the phosphatide of TF to form a complex which
  can activate F? to F?a.
• F?a , calcium , F?a and phosphatide of PL act
  together to produce an activator of prothrombin.
  Finally thrombin can be produced.
  
• VEC is not express TF in normal state. But
  endotoxin stimulation of VEC also produces TF.
• Normal tissues and malignant tumors contain a
  large amount of TF. Different tissue contain
  different amount of TF

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• Activity of TF
• tissue Activity of TF (?/mg)
• Liver 10
• Muscle 20
• brain 50
• Lung 50
• Placenta 2000

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2.Vascular Endothelium

• Vascular endothelium expresses
• Tissue Plasminogen Activator (t-pA), t-PAI
• Tissue factor pathway inhibitor (TFPI)
• Tissue factor (TF)
• NO,PGI2 / ET
• Thrombomodulin (TM, ???????)

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prothrombin
coagulation activity
Activated PC (APC)
thrombin
Protein C, PC
Protein S
thrombomodulin (TM ) A cell surface
glycoprotein of endothelial cells that binds
thrombin and serves as a cofactor in the
activation of protein C and its regulation of
blood coagulation.
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3.Anticlotting Mechanisms

• 1) Antithrombin III (A-TIII)
• The major inhibitor of the coagulation cascade.
• Inhibits Thrombin (70-80)
• Inhibits activated Factors IX, X, XI, and XII.
• Activity is enhanced by heparin.
• Produced mainly by liver
• 2) Tissue factor pathway inhibitor
• (TFPI) ?a, Xa
• Produced by EC
• 3) Protein C sytem VEC (?a,?a, ?a )

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4. The fibrinolytic system
PAI-1
Plasminogen
Tissue Plasminogen Activator (t-PA) Urokinase
(uPA)
Thrombin, F?a, F?a
Plasmin Inhibitor
Fibrin, fibrinogen
Plasmin
Fibrin/ fibrinogen degradation products (FgDP /
FDP?)
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FgDP/ FDP

• ??
• ????(?)????,?????(?)??????????????

• ??
• 1 ??????????
• 2 ????
• 3 ??Plt????????

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• 5. Phagocytosis of mononuclear phagocyte system
  (MPS)
• Most of the products of intravascular
  coagulation (fibrin monomer, prothrombin etc.),
  as well as various initiators of the process
  (endotoxin, tissue fragments, antigen-antibody
  complexes etc.) are removed from the circulation
  by MPS through unselective phagocytosis.

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summary
anticoagulation
coagulation
1. Intact VEC
1.Intrinsic coagulation pathway (?? ?
a) 2.Extrinsic coagulation pathway (TF enters
into blood)
2.quite rapid blood flow velocity
3. Phagocytosis of MPS
4.physiological anticoagulation substances
AT-??PC?TFPI
5. Fibrinolytic system
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• The Concept of DIC
• The Causes and Accelerating factors of DIC
• The Pathophysiology of DIC
• Clinical Manifestations of DIC
• The Stages and Types of DIC
• The Diagnosis and Treatment of DC

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?.Concept of DIC
SYSTEMIC ACTIVATION OF COAGULATION

• DIC ?????????????????????????????????????????

Intravascular deposition of fibrin
Depletion of platelets and coagulation factors
Thrombosis of small and midsize vessels
Bleeding
DEATH
Organ failure
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??Causes and accelerating factors factors of DIC

• The causes and triggering factors of DIC
• Causes??DIC??????????(?????)

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Common Causes of DIC
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Triggering factors of DIC

• Tissue injury TF enters into blood
• VEC injury
• Endotoxin
• Ag-Ab complex
• Protease
• Othersparticles, virus, hypoxia

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2. Precipitating factor (accelerating factors )
of DIC

• (1) Impairment of the MPS
• (2) Liver Disease
• (3) Hypercoagulable state of blood
• (4) Microcirculation dysfunction
• (5) Others

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(1)Impairment of the mononuclear phagocyte system

• The mononuclear phagocyte system (MPS) is
  composed of mononuclear cell and phagocyte.
• Most of the products of intravascular
  coagulation (free fibrin, prothrombin activator),
  as well as various initiators of the process
  (endotoxin, tissue fragments, antigen-antibody
  complex, thromboplastins) are removed from the
  circulation by the unspecific phagocytosis of MPS

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• Kupffer cell in liver are very important in the
  clearance of activated clotting factors (?a, ?a
  and ?a)
• Any factors that decrease or impair MPS will
  accelerate the occurrence of DIC in a manner
  comparable to that produced experimentally in the
  general Shwarzman reaction (GSR) in animals

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Generalized Shwartzman reaction(GSR)

• 1924, Sanarelli
• ?????????i.v. Rat ?24h? i.v.
  ???????????? Rat died of shock
• DIC and shock
• haemorrhagic infarct
• Mechanism
• ???????????,?????????? ??the function of
  MPS ??DIC

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(2) Severe Liver Disease

• Some causes (Ag-Ab complex, drugs) of the disease
  may directly activate coagulation
• Acute severe hepatitis release TF and lysosome
  enzyme there is gutdrived endotoxemia at the
  late stage of hepatocirrhosis
• Impaired synthesis of some clotting factors such
  as FII, FVII, FV, FIX and FX also Antithrombin
  ,Proteins C (PC) and S (PS)
• Impaired synthesis anti-clotting factors such as
  of PC, PS and antithrombin can lead to
  susceptibility to DIC
• The damaged liver reduces the clearance of
  activated clotting factors such as F?a and F?a.
• Often associated with bleeding

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(3) Hypercoagulable state of blood

• Primary inherited lack of AT-?, PC and PS or
  PC-resisting syndrome
• Secondary

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1) Pregnancy

• the blood in pregnancy after 3 months begins
  to increase coagulability, which is most marked
  in the terminal stage of pregnancy
• a) PL and clotting factors (F?, F?,F ?, F ?,
  F ?, F?, F?) are increased
• b) the substances with the action of
  anticoagulation (AT-?) and with the activity of
  fibrinolysis (t-PA, u-PA)are decreased
• c) fibrinolysis inhibitors are increased
• ? form the hypercoagulable state of blood in
  pregnancy
• Therefore, obstetrical suddenness (such as
  amniotic fluid embolism, early separation of
  placenta, died fetus) is very easy to induce DIC

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2) Acidosis acidosis causes the reducing of pH
of the blood ?

• a) VEC can be damaged by increased H
• d) The activity of heparin is decreased.
• c) activity of clotting factors and
  platelets is increased
• d) disturbance the vessel movement activity
  and hemorheology?vessel permeability, blood
  oozing , ? high blood viscosity,
• vasodilation, slow blood flow velocity.
• ? hypercoagulable state of blood

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(4)Microcirculation dysfunction
Local vessel movement, blood, acidosis, VEC, WBC
Systemic shock?
Vessels movement and reaction? disorders of
hemorheology VEC was damaged Tissue was
damaged Inflammation and inflammatory
media Multiple Organs dysfunction ? formation
of DIC
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(5) Others
stress ? impaired movement of vessel

• Old age, smoking, late stage of pregnancy,
  diabetes , unapt using of inhibitor ?decreased
  activity of fibrinolysis system

Experiment alive animalEndotoxin or thrombin
i.v. ?microthrombosis is temporal, about 1hPlus
fibrinolytic inhibitor or NE ? the reservation
of microthrombosis
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??Pathophysiology of DIC
The course of DIC occurrence To trigger
coagulation ?the deposit and reserve of Fbn

• Activation of Blood Coagulation
• The changes of vessels movement and
  hemodynamics (?????)
• Impaired Fibrinolysis

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(?)Activation of Blood Coagulation

• 1?Tissue injury
• 2?VEC injury
• 3?Other pathways

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• 1.Severe tissue injury ?to activate extrinsic
  coagulation system

• causessever trauma, burn, major operation,
  malignant necrosis
• mechanismtissue factor enters into blood
• lysosome enzyme (may
  activate clotting factors)

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2. Extensive damage of VEC?loss of balance
between coagulation and anticoagulation

• causes infection, hypoxia, acidosis,
  antigen-antibody complex Fbn

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• Mechanism
• Damaged VEC (micro-V. and Capi) express TF ? to
  trigger extrinsic coagulation system
• VEC was damaged?blood contacts with exposed
  collagen to activate F? to form F?a ? intrinsic
  clotting cascade is triggered.
• WBC TNF, IL-1, PAF, superoxide, C3a C5a ??the
  injury of VEC
• Anticoagulation and fibrinolysis activity are
  decreased
• anticoagulants(TFPI , TM, AT-?) ?, PAI?
• ET ?, / NO ?, PGI2 ?
• Platelet activation.

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3. Other pathways to induce coagulation

• Activated mononuclear phagocyteTF, lysosome
  enzyme
• Malignant tumorsTF, cancer procoagulant(?F?)
• Trypsin (????) hemorrhagic acute pancreatitis,
  pancreas malignant tumor? Trypsin ? ?F?
• Exogenous toxin snake venom , bee venom
• ? ?F?, F?, F?
• Severe haemolysis ADP (?PL), ?????TF???

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(?) The changes of vessels movement and
hemodynamics

• sympatho-adrenomedullary system (SAS)
• Damaged VEC NO?, PGI2?/ ET ?
• activated plateletTXA2?
• PAF, histamine, Bradykinin? ? capillary
  permeability ?blood viscosity ?

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(?) Impaired Fibrinolysis

• 1?Decreased fibriolysis
• Damaged VEC negative charge ?,
• the expression and absorbing of TFPI?,
  AT-??,
• TM?, t-PA?, PAI-1?
• 2?Secondary increased fibriolysis
• coagulation? F?a
• Fbn ?VEC
  release t-PA
• the activation of fibriolysis ? FgDP/
  FDP ?anticlotting
• ?bleeding

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?? Clinical Manifestations of DIC

• Bleeding
• Shock
• MODS
• Microangiopathic hemolytic anemia

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1?bleeding is the most obvious clinical
finding, is seen in 7080 of DIC case, is life
threatening.
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• Mechanism of bleeding in DIC
• (1) Consumption of coagulative factors (
• ?????????) and platelet
• (2) Secondary activation of fibrinolysis
  system
• plasminogen ? plasmin
• fibrin ? fibrinogen
  FDP
• ?a??????a consumption

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• (3) Formation of FDP? anticoagulation
• fibrinogen
• plasmin
• X?A?B
• Y?D
  FgDP/FDP
• D?E
• 
  fibrin
• plasmin
• 
  X'?Y'?D?E'
• 
  
• X?Y?Dinhibit fibrin monomer aggregation
• Y?E have anti-thrombin action
• Most of them inhibit platelet aggregation and
  release

Water-soluble Small peptide
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• (4) Vessel was damaged
• primary factors
• secondary factors hypoxia, acidosis,
• free radical

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• 2. Microcirculation disturbance -shock
• (1) microthrombi ? the blood return ?
• (2) excess bleeding ? blood volume ?
• (3) Cardiac output ?heart or lung thrombi,
  acidosis
• (4) Vasodilation and permeability of capillary?
• (a) activation of complement and kinin
  system?histamine, kinin release
• peripheral resistance ?
• permeability of capillary
  ?
• A,B,C ? ? histamine, kinin
• (b)FDP vasodilation
• permeability of
  capillary ?

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3. Multiple organ dysfunction syndrome (MODS)

• (1) primary disease ?cause organ dysfunction
• (2) extensive microthrombi in organs ?
• serious ischemic tissue damage
• (3) interaction between organs
• e.g. pulmonary infection ?DIC, pulm.
  dysfunction
• ? PaO2?, PaCO2?
• pulmonary artery pressure ? ? heart
  dysfunction
• ?aggravate microcirculation disturbance

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4. microangiopathic hemolytic anemia (??????????)

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Microscopic findings in DIC

• Fragments
• Schistocytes (????)
• Paucity of platelets

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RBC hanging on fibrin strands (scan electron
microscope ,left?2000,right?5200)
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?? The Stages and Types of DIC

• 1? Stages of DIC
• 1.Hypercoagulable stage clotting system is
  activated, thrombin in blood, microthrombi
• 2.Hypocoagulable stage clotting factors and PL?,
• bleeding
• 3.Secondary fibrinolytic stage
• FgDP/FDP?inhibit PL aggregation and fibrin
  formation ? bleeding?, shock ,MODS

2?types of DIC
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?? Diagnosis and Treatment of DIC
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1. Diagnosis of DIC

• Presence of disease associated with DIC
• Appropriate clinical setting
• Clinical evidence of thrombosis, hemorrhage or
  both.
• Laboratory studies
• no single test is accurate
• serial test are more helpful than single test

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Conditions Associated With DIC

• Malignancy
• Leukemia
• Cardiovascular
• cardiac arrest
• Acute MI
• Hypothermia/Hyperthermia

• Pulmonary
• ARDS
• Pulmonary embolism
• Severe acidosis
• Severe anoxia
• Anaphylaxis

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Conditions Associated With DIC

• Infectious/Septicemia
• Bacterial
• Gm - / Gm
• Viral
• Hepatitis
• Fungal
• Intravascular hemolysis
• Acute Liver Disease

• Tissue Injury
• trauma
• extensive surgery
• tissue necrosis
• head trauma
• Obstetric
• Amniotic fluid emboli
• Placental abruption
• died fetus

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Clinical Manifestations of DIC
Ischemic Findings are earliest!
Bleeding is the most obvious clinical finding
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2. Treatment of DIC 1) ?????????
2) ??????? 3) ????, ??????, ?????
4) ??????????
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Summary

• DIC is an acquired syndrome characterized
  systemic intravascular coagulation.
• Coagulation is the initial event. TF entering
  into blood is primary triggering factor of
  coagulation.
• Bleeding is the most common clinical
  manifestation due to the consumption (of
  coagulation factors and platelet) and secondary
  activation of fibrinolytic system
• Morbidity and mortality remain high.

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• The Concept of DIC
• The Causes and Influencing factors of DIC
• The Pathophysiology of DIC
• Clinical Manifestations of DIC
• The Stages and Types of DIC
• The Diagnosis and Treatment of DC

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