Imbalance of blood Coagulation and Anticoagulation

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Imbalance of blood Coagulation and
Anticoagulation
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• ?2005?6?24??7?23?,???????????????58??????????????3
  0??70????,????????????,????????????????????,??7?2
  3?,?17?????????????????????,???????,??????????????
  ??????????????
• ?????,????????????????????,?????????????????,
  

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• 63?????12????
•     ????????????15?63????????????????????23???5??,
  ????????????,?????????????????????????????????????
  ??,??12????,???63??????????
•     7?20???5?,????????,63????????,????????????????
  ??????10??,???????,?????????????????,??????,??????
  ???11??,?????????,????,???????????????????????????
  ???????,?????????,????????????????????????????????
  ??6?50?????????????????,??????????????,?????????

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• ?6?24??7?21?,?????????????????????20??????????????
  ????????,???????????????????,??7?21?,?9??????????
  ?????????????30??70?????

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Introduction

• 1 Blood coagulation
• 2 Anticoagulation
• 3 Fibrinolysis
• 4 Vascular endothelial cells

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1 Blood coagulation

• Blood coagulatlon system
• Blood platelet

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????
????
????
??????
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Intrisic pathway
Extrisic pathway
?(TF)
? ?a
?? ???a? Ca2
TF-?a?Ca2
Formation of prothrombin activator
?? ?a
?aCa2?PL
Prothrombin Thrombin
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?????????

• ?????????????????
• ??,??????????????
• ????????????????,????????
• ?????????????????????????????????????????????????V
  III?V?VII?IX?XI?

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?????????GP?b?GP?b/?a???
GP? b??vWF?? ???????,??
GP?b/?a?????????,??
??????????? ???????,???????????,???????
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Platelet accelerate clotting
???
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• ??????????????
• 1 ?????????????????
• 2 ????????????????
• 3 ??????????????,??????????,?????
• 4 ??????????????????,?????????,??????????

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2 The anticoagulation system

• 1. Cell
• reticuloendothelial system
• 2. Body fluid
• (1) antithrombin ? (AT-?,liver)
• (2) Protein C
• (3) tissue factor pathway inhibitor (TFPI)

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heparin
Inhibite the activity of thrombin
AT III
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prothrombin
coagulation activity
Inactivates ?a??a Inhibits ?a binding to PL
Leads to release t-PA decrease plasmin inhibitor
Activated PC (APC)
thrombin
Protein C, PC
Protein S
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TFPI???
???a-TF
F?a-TFPI-F?a-TF
TF-F?a

F?a-TFPI
F?a

TFPI ??? ???TFPI
??
(????) HS-TFPI

VEC
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3 The fibrinolytic system

• ????????????????????????????
• ????????????????????????????????,????????,??????
  ????????????

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Fibrinolytic Pathway
PAI-1
Plasminogen
Tissue Plasminogen Activator (t-PA) Urokinase
(uPA)
Thrombin, F?a, F?a
Plasmin Inhibitor
Fibrin, fibrinogen
Plasmin
Fibrin/ fibrinogen degradation products (FDP)
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4 ??????

• VEC??????TF
• VEC???PGI2?NO?ADP????,?????????????????
• VEC??????tPA?uPA????????,??????
• VEC?????
• ??TFPI???TM???????

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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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??????????

• ???????
• ???????
• ???????
• ??????
• ?????

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???????

• ??????????????
• ??????????? (??????????? )
• ???????????
• ????????? ( Vit k?????????? )
• ????????? (DIC )
• ????????????????

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??????????? (????) ? ?
? ? ???A
F???,X?????? ???B
F???,X?????? ???C
F???,??????
(??????)?? ???????
vWF?????,???????
???? .F???????
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?????????????????
??????????
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???????????????????????
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??? ????????(????)
???????? ????????
Vit K?? ???????
DIC ?????? ????? ?????? Vit K??? F??F??F??
???????? F?????
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???????????(??????) ? ? ? ?
? ? ?????
????????????
???? F?
????????????

???? F??F??F??F? ?????
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???????????(????) ? ? ? ?
? ? ? ? F?(????)
G20210A F?
R506Q?R306T?(APC??) F??
V34L F?
?
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???????

• AT-??????
• ?????
• AT-? ????( Vit k?????????? )
• AT-???????? (DIC )
• ?????
• ??C???S??

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???AT-??????????
?? (???????? ) AT-???
??? ?????

???????AT-?
(???????? ) AT-??????
???????AT-?
DIC????AT-?
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???AT-?????
?? ?? ??
??
?? ??
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???PC?PS??
1.VitK?????????PC?PS?? VitK???????
2.???????????PC?PS??
3.?????????PS??
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???PC?????
(????????) ?? ?? ??
?? ? ? ?? ??
??????? ?? ?? ??
???????
?
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??S????(????????) ?? ???
??? ?? ( ?C4b????)
(?APC?????) ?? ?
????? ?? ?? ??
?? ?? ?? ??
?? ??
?? ? ????PS?????,???C4b???
???????

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???????

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

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???????????

• ? ?
  ? ?
• ? ?????????? ??t PA??
• (??????????????)
• ????(????) ??t PA??
• ? ???????? t PA?????
• (???????????) PAI????
• D I C
  ???????
• ? ????(??) ????
• ??????? ???a2-AP?
  
• 
  ???PAI??

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?????????

• ? ? ? ?
  ? ?
• PAI-1 4G/4G???PAI-1
  ??????
• PLg?? PLg????
  ??????

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??????

• ??????
• ???????
• ??
• ??
• ???????
• ?????
• ?????

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???????(lt100109/L)

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

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???????gt400109/L

• ? ? ?
  ? ? ?
• ?????? ??????????????
• 
  ????????????????
• ?????????
• ????? ????????????
• ????????,?????????????,??????

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??????????

• ? ? ? ? ? ?
• ?????
  ???????
• GP?b-?-? ??? ??
• Glanzmann
  ???????
• GP?b/? a ??? ???(???
• ???
  ?)
• GP?a/?a
  ???????
• 
  
• 
  
  
  

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??????????

• ? ? ? ?
  ? ?
• ?????? ????????????
• ???? ??????????
• ?????? ????????????
• ???? ?????????????
• ????????????

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?????????????

• 1.????????,?????
• 2.???????????,????????
• 3.??????TNF?IL-1,???????TF, ????
• 4.??????????????,?????

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?????

• ?????????
• ???????????????
• ????????
• ?????????

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Disseminated Intravascular Coagulation

• 1. Concept
• 2. Causes and Pathogenesis of DIC
• 3. Precipitating factor
• 4. Stages and types
• 5. Clinic manifestations
• 6. Treatment

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??,?,26?, ????????
??9???,??,????,????????????,??????????,?????,???
? 80/50mmHg,??95?/?????? ?????(???????)Hb
70g/L(110150),RBC 2.7?1012/L(3.55.0
?12/L),??????????? 85 ?109/L(100300
?109/L),?????1.78 g/L(24g/L)??????20.9
?(1214),3P????(??)????,RBC 4h??????75
?109 /L,?????1.6g /L
????????????????
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concept

• ???????????,???????????,????????,?????,???????
  ???????????????????????????,?????????????,????????
  ?????????????????????????

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Introduction of DIC
Micro- -thrombi
Etiological factors
Activation of Coagulation system Hyper- -coagul
able state
Hypocoagulable state
activation of fibrinoly--tic system
bleeding
shock organ dysfunction
Disturbance of microcirculation
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• Character of DIC?

Dysfunction of coagulation !

• Main morphologic change of DIC
• extensive formation of
  microthrombi
• Manifestations of DIC bleeding, shock,
• dysfunction of multiple organs ,anemia  

• Pathogenesis of DIC activation of
• clotting
  factors

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Causes of DIC

• Infection
• Malignancy
• Trauma
• Obstetrical emergency
• Emergency

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Pathogenesis

• Severe tissue injury ?to activate extrinsic
  coagulation system
• Extensive damage of VEC?loss of balance between
  coagulation and anticoagulation
• Excessive destruction of the circulating blood
  cells
• Other procoagulant material entering the blood

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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 to
  activate extrinsic coagulation system

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Figure 1. Initiation of the coagulation protease
cascade by the TFFVIIa complex. TF is a
transmembrane glycoprotein that localizes
FVII/FVIIa to the cell surface. The substrates
FIX and FX are proteolytically cleaved by FVIIa
to form proteolytically active FIXa and FXa.
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tissue factor,TF

• ??263 aa,?????
• ?????????????,?????????????????
• ????????????????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. Extensive damage of VEC?loss of balance
between coagulation and anticoagulation

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

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VEC????? ???DIC?
????????VEC,???TNF?IL-1?PAF?C5a??VEC???
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(1)??TF,??????
(2) ????????? TM/PC?HS/AT III ???? TFPI
(3)????????tPA??,?PAI-1????,????
(4)?????????NO?PGI2?ADP???,???????????????,???????
????????????
(5)?????????????????????????
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• 3. Excessive destruction of the circulating blood
  cells
• Red cell, white cell or PL membranes become
  damaged and release procoagulants within the
  blood ?may trigger both the intrinsic and
  extrinsic clotting sequences.

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• Severe haemolysis
• antigen-antibody reaction ( transfusion of
  a large amount of incompatible blood) ?
• intravascular haemolysis ? the release of
  the following substances
• a) adenosine diphosphate (ADP)
• to promote PL aggregation, and PL
  release ?blood clotting
• b) phospholipoprotein adsorb clotting
  factor (F?,F?,F?,F?)?formation of a great amount
  of thrombin ? blood clotting

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• 2) leucocyte is damaged or activated
• leukemia patients receive chemotherapy or
  radiotherapy ? a great deal of leucocytes are
  damaged ? release of TF-like substance ? blood
  clotting
• mononuclear cell ,neutrophilic granulocyte can be
  activated under infection (by endotoxin or
  cytokine IL-1, TNF-a) ? to express TF? blood
  clotting
• 3)platelet is activated secondary activation is
  more frequent (VEC was damaged).

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• 4. Other procoagulant material entering the blood
• 1)a great deal of parenzyme released into
  blood ? ?a
• acute pancreatitis, tumor of pancreas
• ?
• parenzyme (proteolytic enzyme) released into
  blood
• ? ? ?a ? ? ?a ?
  ? ?a
• ?
  ?
• Formation of a large amount of thrombin ?DIC

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• 2) Extrinsic toxin enters into blood ? ?a
• bee venom, snake venom
• 3) Some malignant tumor cells ? to express TF
  and cancer procoagulant

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??????
?????TF?????????
????
??
RBC,WBC,Plt?????????
????????,???????
DIC????XII,TF??? DIC??(??)??II?IIa
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• ???????DIC??
• ??????????????????????????TF????
• ???????TM?HS???????
• ?????????????,????,???????????????,?????????
• ???????????????????,?????????????,????????,???????
  ???
• ??????????????????tPA??,?PAI-1???????????????,????
  ???????

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• Precipitating factor
• Impairment of clearance mechanism
• Liver Disease
• Hypercoagulable state of blood
• Microcirculation dysfunction

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• 1. Impairment of the mononuclear phagocyte
  system- block out
• MPS??????(LPS,
• ????,?????)
• ??????,?????
• ???????????
• ??,??????,FDP
• ?????,??,????
• ? MPS Impairment

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Generalized Shwartzman reaction(GSR)

• i.v. endotoxin?24h? i.v. endotoxin ?DIC
• i.v.????? 24h ? i.v. endotoxin ?DIC

?
?
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2.Hepatic dysfunction

• 1.??????????????????
• 2.????PC?AT-?????
• 3.???????????

??????????????????
???????????????????
?????????TF
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3? Hypercoagulable state of blood
??????????
pregnancy
?????????
?????????
???????
????
acidosis
??????
?????PL?????
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4. Microcirculation dysfunction
????,??????,?????
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??????
??
??
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??
??
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??????
??
??
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??????
??
??
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??????
??
??
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??????
??
??
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??????
??
??
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Stages of DIC

• 1.???
• ??????,?a?,????,?????
• 2.??????
• ??????,??????,??????,??
• 3.????????
• ???? ? ?,FDP ??????? ? ? ,????

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Types of DIC

• 1. according to speed
• Acute
• ???????????????????????????
• Chronic
• ???????????????
• Subacute
• ??????

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• 2. According to compensation
• ??? ???? ?????
• ???? ???? ??gt?? ??lt??
• DIC?? ? ??
  ??,???
• ? ? ??? ??
  ???
• ?????           ????? ????? 

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Manifestations of DIC

• 1. Bleeding
• 2. Microcirculation disturbance shock
• 3. Multiple system organ dysfunction
• 4. microangiopathic hemolytic anemia,MHA

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DIC??(???????)
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• 1. Bleeding
• (1) consumption of coagulative factor
• ????????? and platelet
• (2) activation of fibrinolysis system
  coagulation?

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XII
????
????
???? ???
XIIa
XIIf
??? ??
???
????
???????
???????????????????
?????? ??FDP
??
????????
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• (3) formation of FDP? anticoagulation
• fibrinogen
• plasmin
• X?A?B
• Y?D
  FDP
• D?E
• 
  fibrin
• plasmin
• 
  X'?Y'?D?E'
• 
  
• X?Y?Dinhibition of fibrin aggregation
• Y?Eaction of antithrombin
• FDP inhibition of platelet aggregation, release

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FDP??

• 3P ??(plasma protamin paracoagunation test)
• D-?????Fbn??????D
• D?????? ????
• ?????????

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2. Multiple system organ dysfunction
?????
????,??
????
????
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DIC?,?????????????????!
??????? ?????? ??????? ?????
?-???? ???????
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????
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• 3. 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 alexin 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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4. microangiopathic hemolytic anemia (MHA)
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• concept
• ??DIC??????DIC??????????????,???????????
  ??(MHA)
• character
• ????????(schistocyte)
• mechanism
• 1.?????????
• 2.????????

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RBC?????????(????,??2000,??5200)
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Principle of treatment

• 1.To diagnose DIC
• and to treat it as soon as possible
• 2.To prevent primary diseases
• 3.Anticoagulation treatment
• AT-III?heparin
• 4. To maintain and protect important organs
• 5. Supplemental therapy
• 6. Anti- fibrinolysis therapy

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??,?,26?, ????????
??9???,??,????,????????????,??????????,?????,???
? 80/50mmHg,??95?/?????? ?????(???????)Hb
70g/L(110150),RBC 2.7?1012/L(3.55.0
?12/L),??????????? 85 ?109/L(100300
?109/L),?????1.78 g/L(24g/L)??????20.9
?(1214),3P????(??)????,RBC 4h??????75
?109 /L,?????1.6g /L
????????????????
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Clinical Case
A 56-year-old man was admitted to the emergency
department after a car accident. He had several
bone fractures, a cerebral contusion, and
hemodynamic instability caused by a ruptured
spleen. Emergency splenectomy and aggressive
administration of fluids restored hemodynamic
stability, and the patient was transferred to the
intensive care unit (ICU). A few hours later,
profuse extravasation was noted from the
abdominal drains, endotracheal tube, and puncture
sites of all intravascular lines.
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Clinical Case
Laboratory tests showed a rapidly falling
hemoglobin level and a platelet count of
25,000/µL (normalgt150,000/µL). The prothrombin
time (PT) was 29 sec (normal, lt12.5). The level
of fibrinogen degradation products was 360-520
g/L (normal, lt40) and the plasma antithrombin III
level was 28 (normal, 80-120).
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Clinical Case
Based on these findings, the diagnosis was DIC
secondary to severe trauma. Surgical exploration
revealed diffuse oozing of blood at the site of
the operation, but only partial surgical
hemostasis could be achieved. The patient was
given supportive treatment with large infusions
of fresh plasma and platelet concentrates. The
bleeding stopped 48 hours later. Coagulation
parameters eventually returned to normal and the
subsequent clinical course was uneventful.
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