08 dic
TRANSCRIPT
Dept. of PathologyDept. of PathologyMedical CollegeMedical College
Hunan Normal UniversityHunan Normal University(( 湖南师范大学医学院病理学教研室湖南师范大学医学院病理学教研室 )) 1
Chapter 8Chapter 8
Disturbance of Disturbance of HemostasisHemostasis(凝血与抗凝血平衡紊乱)(凝血与抗凝血平衡紊乱)
22
Disturbance of HemostasisDisturbance of Hemostasis
①① Coagulation and Coagulation and anticoagulation homeostasisanticoagulation homeostasis
②② Disseminated intravascular Disseminated intravascular coagulation (DIC)coagulation (DIC)
Apoptosis Oxygen Society Education Program Tome & Briehl 3
①① Coagulation SystemCoagulation System
②② Anticoagulation SystemAnticoagulation System
③③ Fibrinolytic SystemFibrinolytic System
The Three Hemostasis Systems
The ”Classic” Coagulation System
XII XIIa
XI XIa
IX IXa
II IIa
I Ia (Fibrin)
Phospholipid, Ca++, VIII
Phospholipid, Ca++, V
4
Prothrombin activator formation
Thrombin formation
Fibrin formation
X Xa
Intrinsic
Fibrin net
XIIIa
VIIa VII
Tissue factor (III)
Ca++TF
Extrinsic
X
II: ProthrombinI: Fibrinogen
①① Coagulation SystemCoagulation System
②② Anticoagulation SystemAnticoagulation System
③③ Fibrinolytic SystemFibrinolytic System
The Three Hemostasis Systems
1. 1. From From body fluid (plasma)body fluid (plasma)(1) (1) Antithrombin (AT- )Ⅲ ⅢAntithrombin (AT- )Ⅲ Ⅲ(2) (2) Thrombomodulin (TM) - protein C systemThrombomodulin (TM) - protein C system
(3) (3) Tissue factor pathway inhibitor (TFPI)Tissue factor pathway inhibitor (TFPI)
(4) Heparin (4) Heparin
2. From Cells2. From Cells(1) Vascular endothelial cells (VEC)(1) Vascular endothelial cells (VEC)
(2) Monocyte-macrophage system(2) Monocyte-macrophage system
(3) Liver cells(3) Liver cells
Anticoagulation System
6
The Effect of Antithrombin III
7
Tissue factor
XII XIIa
XI XIa
IX IXa
X Xa X
II IIa
I Ia (fibrin)
Phospholipid, Ca++, VIII
Phospholipid, Ca++, V
VIIa VII
Ca++TF
Extrinsic Intrinsic
AT-III
×
×
×
The Effect of Protein C
8
Tissue factor
XII XIIa
XI XIa
IX IXa
X Xa X
II IIa
I Ia (fibrin)
Phospholipid, Ca++, VIII
Phospholipid, Ca++, V
VIIa VII
Ca++TF
Extrinsic Intrinsic
aPC
×
×
Protein S
FVIIIa
FVa
Endothelial cell
The Effect of Protein C
ThrombomodulinProtein C
Activatedprotein C
ThrombinEPCR
9EPCR: Endothelial protein C receptor
↑ Release of tPA, uPA
A glycoprotein synthesized by vascular endothelial cells
(VECs).
Also called extrinsic pathway inhibitor (EPI).
Inactivate VIIa & Xa.
Tissue factor pathway inhibitor ( TFPI )
The Effect of TFPI
11
Tissue factor
XII XIIa
XI XIa
IX IXa
X Xa X
II IIa
I Ia (fibrin)
Phospholipid, Ca++, VIII
Phospholipid, Ca++, V
VIIa VII
Ca++TF
Extrinsic Intrinsic
TFPI
×
×
Produced in mast cells & basophils.Acts as cofactor for AT-III.
- promoting anticoagulant effect of AT-III.
Heparin
①① Coagulation SystemCoagulation System
②② Anticoagulation SystemAnticoagulation System
③③ Fibrinolytic SystemFibrinolytic System
The Three Hemostasis Systems
Involved in dissolving the clot that has already formed Involved in dissolving the clot that has already formed
in vessels.in vessels.
As soon as the clot is formed, its breakdown As soon as the clot is formed, its breakdown
(fibrinolysis) begins immediately. (fibrinolysis) begins immediately.
Fibrinolytic System
Fibrinolytic Pathway
Plasminogen
Plasmin
Fibrin/Fibrinogen
Fibrin/Fibrinogendegradation products (FDP)
15
Plasminogen Activator Inhibitor (PAI)
Antiplasmin
Plasminogen Activator Tissue-type (tPA)
Urokinase-type (uPA)
Thrombin, F a, ⅫF aⅪ
Kallikrein
Apoptosis Oxygen Society Education Program Tome & Briehl 17
Regulation of Hemostasis
Regulation of HemostasisVascular Endothelial Cells (VECs)Vascular Endothelial Cells (VECs)
11 、、 Anti-coagulationAnti-coagulation :: - Physical barrier, inhibiting aggregation of platelets- Physical barrier, inhibiting aggregation of platelets
- Produce or absorb anticoagulants- Produce or absorb anticoagulants :: TFPI, AT-TFPI, AT- , TMⅢ, TMⅢ
22 、、 Pro-coagulationPro-coagulation :: -- Produce or absorb coagulantsProduce or absorb coagulants :: TF, a, a, aⅨ Ⅹ ⅪTF, a, a, aⅨ Ⅹ Ⅺ - Secrete adhesion molecules- Secrete adhesion molecules: : FN, ICAM-1FN, ICAM-1
33 、、 FibrinolysisFibrinolysis: :
- Promotion of tPA- Promotion of tPA
- Inhibition of PAI- Inhibition of PAI
44 、、 Vascular toneVascular tone :: Dilation or constrictionDilation or constriction
Damaged VECsDamaged VECsNormal VECsNormal VECs
19
2121
Disturbance of HemostasisDisturbance of Hemostasis
①① Coagulation and Coagulation and anticoagulation homeostasisanticoagulation homeostasis
②② Disseminated intravascular Disseminated intravascular coagulation (DIC)coagulation (DIC)
Meningococcus in blood
Adrenal gland hemorrhage
Waterhouse-Friderichsen Syndrome
Apoptosis Oxygen Society Education Program Tome & Briehl 23
Disseminated intravascular
coagulation (DIC)①① ConceptConcept
②② Causes Causes
③③ PathogenesisPathogenesis
④④ Precipitating factorsPrecipitating factors
⑤⑤ Clinic manifestations Clinic manifestations
⑥⑥ Pathophysiological basis of prevention and Pathophysiological basis of prevention and
treatment of DIC (3P, DD)treatment of DIC (3P, DD)
A pathological process characterized by A pathological process characterized by widespread intravascular coagulationwidespread intravascular coagulation that results that results in the formation of microthrombi throughout the in the formation of microthrombi throughout the body, followed by depletion of coagulation factors body, followed by depletion of coagulation factors and platelets, and and platelets, and subsequent fibrinolysis and subsequent fibrinolysis and hemorrhagehemorrhage..
Concept of DIC
Hypercoagulable state
Hypocoagulable state
25
SYSTEMIC ACTIVATION OF COAGULATION
Intravascular deposition of
fibrin
Depletion of platelets and coagulation
factors
Thrombosis of blood vessels Bleeding
Organ failure DEATHDEATH
Hypercoagulable state Hypocoagulable state
Apoptosis Oxygen Society Education Program Tome & Briehl 26
Disseminated intravascular
coagulation (DIC)①① ConceptConcept
②② Causes Causes
③③ PathogenesisPathogenesis
④④ Precipitating factorsPrecipitating factors
⑤⑤ Clinic manifestations Clinic manifestations
⑥⑥ Pathophysiological basis of prevention and Pathophysiological basis of prevention and
treatment of DIC (3P, DD)treatment of DIC (3P, DD)
Causes of DIC• Infectious diseasesInfectious diseases• MalignancyMalignancy• TraumaTrauma• Obstetrical emergencyObstetrical emergency• Others Others
27
28
Activity of TF in Human Tissues
Tissue Activity of TF ( /mg )• Liver 10 • Muscle 20• Brain 50• Lung 50• Placenta 2000
29
Apoptosis Oxygen Society Education Program Tome & Briehl 32
Disseminated intravascular
coagulation (DIC)①① ConceptConcept
②② Causes Causes
③③ PathogenesisPathogenesis
④④ Precipitating factorsPrecipitating factors
⑤⑤ Clinic manifestations Clinic manifestations
⑥⑥ Pathophysiological basis of prevention and Pathophysiological basis of prevention and
treatment of DIC (3P, DD)treatment of DIC (3P, DD)
Stage of Stage of hypercoagulabilityhypercoagulability
Stage of Stage of hypocoagulabilityhypocoagulability
Stage of Stage of secondary fibrinolysissecondary fibrinolysis
33
Apoptosis Oxygen Society Education Program Tome & Briehl 34
Disseminated intravascular
coagulation (DIC)①① ConceptConcept
②② Causes Causes
③③ PathogenesisPathogenesis
④④ Precipitating factorsPrecipitating factors
⑤⑤ Clinic manifestations Clinic manifestations
⑥⑥ Pathophysiological basis of prevention and Pathophysiological basis of prevention and
treatment of DIC (3P, DD)treatment of DIC (3P, DD)
Precipitating FactorsPrecipitating Factors• Impairment of clearance mechanism Impairment of clearance mechanism
- Mononuclear phagocyte system dysfunction- Mononuclear phagocyte system dysfunction• Liver DiseaseLiver Disease
- Synthesis of coagulation factors - Synthesis of coagulation factors ↓↓• Hypercoagulable state of bloodHypercoagulable state of blood
- Pregnancy- Pregnancy• Microcirculation dysfunctionMicrocirculation dysfunction
- Acidosis, plasma viscosity - Acidosis, plasma viscosity ↑↑, platelet aggregation, platelet aggregation
Generalized Shwartzman Reaction ( GSR )
36
Thorium dioxide destroys the mononuclear phagocyte function.
↓Endotoxin
↓DIC
Thorium dioxide ( 二氧化钍 )
Why More DIC in Pregnant Women?
Hypercoagulable State
Platelets ↑
Coagulation factors ↑
I, II, III, V, VII, IX, X, XII
PAI-1 (produced from placenta) ↑
Anticoagulation factors ↓
AT-III, tPA, uPA孙慧兰
Apoptosis Oxygen Society Education Program Tome & Briehl 39
Disseminated intravascular
coagulation (DIC)①① ConceptConcept
②② Causes Causes
③③ PathogenesisPathogenesis
④④ Precipitating factorsPrecipitating factors
⑤⑤ Clinic manifestations Clinic manifestations
⑥⑥ Pathophysiological basis of prevention and Pathophysiological basis of prevention and
treatment of DIC (3P, DD)treatment of DIC (3P, DD)
Clinical Manifestations
• BleedingBleeding
• Circulatory disturbance - shockCirculatory disturbance - shock
• Multiple organ dysfunction syndrome Multiple organ dysfunction syndrome
• Microangiopathic hemolytic anemiaMicroangiopathic hemolytic anemia
40
Clinical Manifestations
42
Pulmonary Microthrombus Pulmonary Microthrombus
43
Pulmonary Microthrombus Pulmonary Microthrombus
45
Bleeding During
DIC
46
Bleeding During DIC
Anemia During DIC
47
Microangiopathic hemolytic anemia
(MAHA)
Formation of Schistocytes
Schistocyte Formation
force
Fibrin strandsRBC
RBC RBC fragments
RBCs trapped on fibrin nets in DIC (scanning electron microscope )
Direction ofblood flow
Fibrin
Apoptosis Oxygen Society Education Program Tome & Briehl 51
Disseminated intravascular
coagulation (DIC)①① ConceptConcept
②② Causes Causes
③③ PathogenesisPathogenesis
④④ Precipitating factorsPrecipitating factors
⑤⑤ Clinic manifestations Clinic manifestations
⑥⑥ Pathophysiological basis of prevention and Pathophysiological basis of prevention and
treatment of DIC (3P, DD)treatment of DIC (3P, DD)
Laboratory Tests for DIC
• Basic blood examinationsBasic blood examinations
• Platelet count: Blood Platelet Count (BPC) ↓Platelet count: Blood Platelet Count (BPC) ↓
• Peripheral blood smear: Peripheral blood smear:
- Schistocytes (in approximately 50% of cases)- Schistocytes (in approximately 50% of cases)
53
• The coagulation defect
• Partial thromboplastin time (PTT)
• Prothrombin time
• Thrombin time
• Fibrinogen concentration54
Laboratory Tests for DIC
THE ”CLASSIC” COAGULATION SYSTEM
Surface contact Tissue factor
XII XIIa
XI XIa
IX IXa
X Xa X
II IIa
I Ia (fibrin)
Phospholipid, Ca++, VIII
Phospholipid, Ca++, V
VIIa VII
Ca++
PTT Prothrombin time
55
• Tests for fibrinolysis
• Fibrinogen degradation products (FDP)
• D-dimer
• Plasma protamine paracoagulation test
(3P)
56
Laboratory Tests for DIC
Fbg: FibrinogenFM: Fibrin monomerFbn: FibrinPln: Plasmin
3P Test: Plasma Protamine Paracoagulation TestPurpose: Purpose: Examining the existence of FDP Examining the existence of FDP
protamine
Dissociating FM
Fibrin multimer(Clot)
Fbg FM FbnⅡ a
XⅢa
FDPPln Pln
FM—X(Soluble complex)
(A, B, C X,Y)
Fbg FM FbnⅡ a XⅢa
Pln Primary fibrinolysis
A,B,C,X,Y+
D-Monomer
A,B,C,X,Y+
D-Dimer
Secondary Pln fibrinolysis
D-Dimer TestPurpose: Purpose: Examining the existence of secondary fibrinolysis Examining the existence of secondary fibrinolysis
Treat primary diseases and Treat primary diseases and eliminate predisposing factors.eliminate predisposing factors.
Improving microcirculation.Improving microcirculation.
Restore balance between Restore balance between coagulation and anti-coagulation.coagulation and anti-coagulation.
Protect organ function.Protect organ function.
Principles of Treatment
Treatment: Anticoagulation1.Heparin
• IndicationsIndications– forms manifested by thrombosis or forms manifested by thrombosis or
acrocyanosis acrocyanosis – forms that accompany forms that accompany
• cancercancer• vascular malformationsvascular malformations• retained dead fetusretained dead fetus• acute promyelocytic leukemiaacute promyelocytic leukemia
63
Treatment: anticoagulation1.heparin
• Dosage
– The optimal dosage of heparin is the
source of some disagreement;
– 50u/kg, intravenous infusion, Q6h
– 5000-10000u, subcutaneously,Q12-
24h
64
Treatment: anticoagulation1.heparin
• Laboratory monitoring– aPTT: a prolongation of between 1.5
and 2 times normal;– CT;
• Reversal of heparin effect– 1mg protamine sulfate : 100u heparin– infused intravenously– rate of infusion < 5mg/min
65
Treatment: anticoagulation1.heparinlow-molecular-weight heparin(LMWH)
66
Treatment: anticoagulation1.heparin
• LMWH– Characteristics
•Posses higher anti-Ⅹa activity than anti-thrombin activity;
•Longer half-time and a higher, more reliable bioavailability
•A lower incidence of bleeding complications.
– Usage• 75-150IUA Ⅹa/Kg.d, subcutaneously,
×3-5days. 67
Treatment: anticoagulation2. others
• AT-Ⅲ– Decrease the dose of heparin;
– Improve the response.
– Dose: 1500-3000u Bid-Tid,
intravenous infusion×5-7days;
68
Treatment: Antiplatelet drugs
• Indications– in hypercoagulability state; – the diagnosis of DIC is still not certain; – in mild cases.
• Usage – compound danshen infusion
20-40ml Bid-Tid×3-5days– Low molecular weight dextran 500-
1000ml/d×3-5days
– Ticlopidine 250mg Bid p.o. ×5-7days – Dipyridamole 500mg/d ×3-5days;
69
Treatment: Haemostatic support
• platelet concentrates– platelet count <20×109/L or have severe life-
threatening bleeding; • fresh frozen plasma (FFP)
– 10-15ml/kg body weight when the INR of PT is greater than 1.5;
• cryoprecipitate– 1-4 unit/10kg body weight when the fibrinogen
concentration is 0.8g/l or less. • Fibrinogen
– 1st dose: 2-4g (1-1.5g→↑50mg/L)• PPSB
– 200u=200ml FFP
70
Treatment: Fibrinolytic inhibitors
• Indications– the underlying disorders have
already controlled or cured;– excessive fibrinolysis is observed;– Late stage of DIC;
• Contraindications– patients with early stage of DIC.
71
Treatment: Fibrinolytic inhibitors
• Usage– PAMBA( 氨甲苯酸 ) 600-800mg/d– tranexamic acid( 氨甲环酸 ) 500-
700mg/d– ε-aminocaproic acid( 氨基已酸 ) 4-10g/d
Attention– These agents should be preceded by
replacement of depleted blood components and continuous heparin infusion. 72
Summary
73
治疗:总结• DIC各期治疗原则
– 早期•首选肝素加血小板聚集抑制药;•禁用纤溶抑制药;•不需输血及补充凝血因子;
74
治疗:总结• DIC各期治疗原则
– 中期•肝素治疗为主;•适当输血及补充凝血因子;•在应用肝素基础上慎重使用小剂量抗纤溶药;
75
治疗:总结• DIC各期治疗原则
– 晚期•抗纤溶药以及输血补充凝血因子为主;•如不能确定血管内凝血是否终止可同时
使用小剂量肝素;76
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.
Clinical Case
77
Laboratory tests showed a rapidly falling hemoglobin level and a platelet count of 25,000/µL (normal>150 , 000/µL). The prothrombin time (PT) was 29 sec (normal, <12.5). The level of fibrinogen degradation products was 360-520 g/L (normal, <40) and the plasma antithrombin III level was 28% (normal, 80-120).
Clinical Case
78
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.
Clinical Case
79
Thanks