08 dic

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）

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

Prothrombin activator formation

Thrombin formation

Fibrin formation

Intrinsic

Fibrin net

VIIa VII

Tissue factor (III)

Ca++TF

Extrinsic

II: ProthrombinI: Fibrinogen

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

The Effect of Antithrombin III

Tissue factor

XII XIIa

XI XIa

IX IXa

X Xa X

II IIa

I Ia (fibrin)

VIIa VII

Ca++TF

Extrinsic Intrinsic

AT-III

The Effect of Protein C

Tissue factor

XII XIIa

XI XIa

IX IXa

X Xa X

II IIa

I Ia (fibrin)

VIIa VII

Ca++TF

Extrinsic Intrinsic

Protein S

FVIIIa

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

Tissue factor

XII XIIa

XI XIa

IX IXa

X Xa X

II IIa

I Ia (fibrin)

VIIa VII

Ca++TF

Extrinsic Intrinsic

Produced in mast cells & basophils.Acts as cofactor for AT-III.

- promoting anticoagulant effect of AT-III.

Heparin

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)

Plasminogen Activator Inhibitor (PAI)

Antiplasmin

Plasminogen Activator Tissue-type (tPA)

Urokinase-type (uPA)

Thrombin, F a, ⅫF aⅪ

Kallikrein

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

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

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

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

Causes of DIC• Infectious diseasesInfectious diseases• MalignancyMalignancy• TraumaTrauma• Obstetrical emergencyObstetrical emergency• Others Others

Activity of TF in Human Tissues

Tissue Activity of TF （ /mg ）• Liver 10 • Muscle 20• Brain 50• Lung 50• Placenta 2000

Stage of Stage of hypercoagulabilityhypercoagulability

Stage of Stage of hypocoagulabilityhypocoagulability

Stage of Stage of secondary fibrinolysissecondary fibrinolysis

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 ）

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

Clinical Manifestations

• BleedingBleeding

• Circulatory disturbance - shockCirculatory disturbance - shock

• Multiple organ dysfunction syndrome Multiple organ dysfunction syndrome

• Microangiopathic hemolytic anemiaMicroangiopathic hemolytic anemia

Clinical Manifestations

Pulmonary Microthrombus Pulmonary Microthrombus

Bleeding During

Bleeding During DIC

Anemia During DIC

Microangiopathic hemolytic anemia

(MAHA)

Formation of Schistocytes

Schistocyte Formation

Fibrin strandsRBC

RBC RBC fragments

RBCs trapped on fibrin nets in DIC (scanning electron microscope ）

Direction ofblood flow

Fibrin

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)

• The coagulation defect

• Partial thromboplastin time (PTT)

• Prothrombin time

• Thrombin time

• Fibrinogen concentration54

THE ”CLASSIC” COAGULATION SYSTEM

Surface contact Tissue factor

XII XIIa

XI XIa

IX IXa

X Xa X

II IIa

I Ia (fibrin)

VIIa VII

PTT Prothrombin time

• Tests for fibrinolysis

• Fibrinogen degradation products (FDP)

• D-dimer

• Plasma protamine paracoagulation test

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

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

Treatment: anticoagulation1.heparin

• Dosage

– The optimal dosage of heparin is the

source of some disagreement;

– 50u/kg, intravenous infusion, Q6h

– 5000-10000u, subcutaneously,Q12-

• 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

Treatment: anticoagulation1.heparinlow-molecular-weight heparin(LMWH)

• 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;

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;

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

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.

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

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；

– 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；

– 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

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

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

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