Disseminated intravascular coagulation (DIC)

Hu Xiaolan（胡晓兰）, MD, Associate Professor of Pathophysiology, Zhejiang University School of Medicine

Email: huxiaolan1998@yahoo.com.cn

• The function of coagulation system(Extrinsic, Intrinsic pathway)

• The function of anticoagulation(TFPI, PC system, ATIII and fibrinolytic system)

• The regulation of balance by VEC

The key factors for balance of coagulation-anticoagulation:

The function of TMThe function of TM--PC systemPC system

The chain reaction of blood coagulation

FXI FXIa FVII/FVIIa-TF-Ca2+ (on membrane)↓ ↓

FIX FIXa TFPI-FXaFVIIIa Ca2+-PL prothrombin (FII)

PCIFX Fxa PL-Ca2+

Fva APC (PS) XIII

thrombin TM-on-VECXIIIa ATIII PC

Fbn Fbn FM Fbg(cross-linked) (soluble)

TF = tissue factor; TFPI = TF pathway inhibitor; Fbg = fibrinogen; Fbn = fibrin; FM = fibrin monomer; PC = protein C; APC = activated PC; PS = protein S; PCI = PC inhibitor ATIII = antithrombin III; TM = thrombomodulin; VEC = vascular EC

The fibrinolysis system

Plasminogen (PLg)(Extra-activating pathway) (Intra-activating pathway)

tissue-type plasminogen activation of clotting systemactivator (t-PA) XIa

urokinase-type plasminogen thrombinactivator (u-PA)

XIIa XII(Exogenous activator)urokinase(UK) kallikrein (KK) streptokinase (SK )

prekallikrein(PK)Plasmin (Pln)

Fbg Fbn FDP(fibrinogen) (fibrin) (Fbg/Fbn degradation products)

Inhibit Xa,VIIa,TF

Inhibit platelet aggregation FibrinolysisPrevent fibrin

clot formation

TraumaAdrenalinThrombin

ADP

NO, PGI2

Xa, IIa

Plasmin

PlasminoginActivators

(t-PA, u-PA)

InactivateVa,VIIIa

PS

ThrombinPC APC

↑TM

Inhibit Xa, IIa

AT III+

Heparin

TFPI

Anticoagulant function of endothelial cells

What is DIC?In the 1990’s: “DIC is an acquired syndrome characterized by the activation of intravascular up to intravascular fibrin formation. The process may be accompanied by secondary fibrinolysis or inhibited fibrinolysis”Recently: “DIC is an acquired syndrome characterized by the intravascular activation of coagulation without a specific localization and arising from different causes. it can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction”

extensive microthrombin extensive hemorrhage

organ dysfunction Shock aneamia

Normal balance of coagulation-anticoagulation

Hypocoagulable stateHypercoagulable state

Unbalance of coagulation-anticoagulation and DIC

extensive activation of clotting factors and platelets

consumption of clotting

factors and platelets

secondary fibrinolysis

hemorrhage

organ dysfunction Shock anemia

Etiology of DICType Diseases

Infection disease 31%-43% Gram-negative or Gram-positive sepsis, viral hemorrhagic fever, viral hepatitis

Malignancy 24%-34% Solid tumors, acute leukemia

Obstetric conditions 4%-12% Preeclampsia, placental abruption, ammiotic fluid embolism, caesarean birth, septic abortion

Trauma 1-5% Physical force, burn, brain trauma, surgical operations

Severe allergic/toxic reactions Snake bite

Severe immunologic reactions Transfusion reaction

The tissue factor and systemic activation of coagulationEndothelial lesion and unbalance of procoagulation and anticoagulationEntrance of procoagulation substances to bloodBlood cells damage

Pathogenesis of DIC

Severe trauma, burns, surgical operation, obstetric accident, tumor tissue necrosis or metastasis,

blood cell injury (radiation or chemical therapy for leukemia)

Excessive destruction of tissue

Numerous TF entering the blood

Activating clotting reactions

Besides, lysozymes released by lysosome of damaged cells may also promote the activation of clotting system.

The tissue factor and systemic activation of coagulation

Infectious, endotoxinemia, Ag-Ab complex, persistent ischemia and hypoxia, acidosis

extensive damage of vascular endothelial cells

.

activatingclottingreactions

(activating Mo/Mf, T-lymphocyte → release TNF, IL-1, IFN, PAF, O2·－)

Endothelial lesion and unbalance of procoagulation and anticoagulation

releasing TF subendothelial exposure

platelets adhesionAggregationand release

Endothelial lesion and unbalance of procoagulation and anticoagulation

Inhibit platelet aggregation Prevent fibrin clot formation fibrinolysis

TraumaAdrenalinThrombinADP NO PGI2 ADPase

TEPI

Inhibit Xa, VIIa,TF Inactivate Va,VIIIa Inhibit Xa,IIa

APCPCthrombin

TM

PSPlasmin

Plasminogenactivators(t-PA,u-PA)

AT-III+

Heparin

Endothelial cell injury

① Activation of Mo/Mf, WBC → release TF, lysozymes

② Malignant tumors → release TF, cancer procoagulant

③ Hemorrhagic pancreatitis, cancer of pancreas → release trypsin (may activate prothrombin directly)

④ Exogenous toxin → activate FX, prothrombin or transfer Fbg to Fbn directly

⑤ Extensive hemolysis → release ADP → activate platelets release erythrin → TF-like effect

Entrance of procoagulation substances to blood

1.RBC damage

2.WBC damage

Blood cells damage

1. Disturbance of coagulation---Bleeding

The prime and common symptom of DIC is bleeding.

The features of bleeding in DIC : (1) High occurrence rate (70~80%)(2) Difficult to explain by primary disease(3) Manifold bleeding types (4) Difficult to be cured by regular hemostatics

Clinical Presentations of DIC

Bleeding

Nose bleeding hemorrhage in the gum

hemorrhage in the skin

The causes of bleeding in DIC including:(1) Excessive consumption of coagulation substances

(clotting factors and platelets);(2) Secondary enhance of fibrinolysis(3) Anticoagulation effects of fibrin degradation products;

Fbg / Fbn FDP(fragment X,Y,E,D)X,Y + FM → soluble fibrin monomer complex (SFMC)

(4) Injury of capillary wall caused by primary cause of DIC and secondary hypoxia, acidosis, cytokines and free radical.

PLn fibrinolysin

DIC, especially acute DIC, is often associated with shock

Shock in sever degree or in late stage can also promote the production of DIC

2. Disturbance of microcirculation - shock

(1) Extensive microthrombusformation

(2) Extensive bleeding

permeability↑ plasma exudation(3) Activating kinin, histamin↑ shock

microvessel dilation(4) FDP (A,B,C)

(5) Microthrombuscoronary perfusion ↓

pulmonary hypertensioncardiac load↑

Ischemia, hypoxia& acidosis

returned bloodto heart↓

effective circulation blood volume ↓

peripheral resistance↓

heart function andcardiac output↓

3. Multiple organs dysfunction (MOD)

MOD is usually the most important cause of death in DIC.Extensive microthrombus formation in the organs→ ischemia, hypoxia, impairment of metabolism and function, or even necrosisand organ failure.

Lung →ARDS; kidney →ARF; Digestive system →nausea, vomiting, diarrhea, hemorrhage; Liver→ jaundice and hepatic failure; Heart →CO↓, PAWP↑; Pituitary necrosis →Sheehan's syndrome; Adrenal cortex hemorrhagic necrosis

→Waterhouse-friderichsen's syndrome; CNS →bleeding, edema (somnolence, coma, convulsion)

4. Microangiopathic hemolytic anemia微血管病性溶血性贫血

schistocyte裂体细胞. (crenated cells, triangular cells, helmet-shaped cells)

RBC moving through fibrin-net

Mononuclear phagocyte system dysfunction

Severe liver dysfunction

Hypercoagulable state

Microcirculation dysfunction

Fibrinolytic system dysfunction

Factors influencing the development of DIC

1. Stages of DIC

PathophysiologyClinicalLaboratory findings

(1)Hypercoagulable stage(2)Consuming hypocoagulable stage(3)Secondary fibrinolytic Stage

Exessive activation of clotting factorsand formation of microthrombin

Increased consumption of clotting factors and platelet

Considerable formation of plasmin and FDP

Stages and types of DIC

1. Stages of DIC

PathophysiologyClinicalLaboratory findings

(1)Hypercoagulable stage(2)Consuming hypocoagulable stage(3)Secondary fibrinolytic Stage

Hypercoagulable

Bleeding

Bleeding markedly

1. Stages of DIC

PathophysiologyClinicalLaboratory findings

(1)Hypercoagulable stage(2)Consuming hypocoagulable stage(3)Secondary fibrinolytic Stage

Shortened clotting and recalcificationtime; Increased adherence of platelet

Prolonged clotting and recalcification time Reduction of platelet count and Fbg markedly

Shortened CLT, Prolonged TT 3P test (+), Increased FDP

CLT = clot-lysis timeTT = thrombin time

Develop time Common causes

Clinic feature

2. Types of DIC

According to the rate of development, divide into 3 types

Acute

Subacute

Chronic

a few hours to days

within days to weeks

months

Develop timeCommon causes

Clinic feature

2. Types of DIC

According to the rate of development, divide into 3 types

Acute

Subacute

Chronic

metastasis of malignanttumors; retained dead fetus

severe infection or trauma ammiotic fluid embolism

malignant tumors collagenosis

Develop time Common causes

Clinic feature

2. Types of DIC

According to the rate of development, divide into 3 types

Acute

Subacute

Chronic

microthrombin formation bleeding

shock, blooding

mild or concealed

Pathophysiology bases of prevention and treatment of DIC

(1) Earlier diagnosis and treatment

(2) Treatment of the causative disease

(3) Anticoagulation treatment (to block the vicious cycleof clotting response)

(4) Protection of organ function

(5) Supplement of fresh blood or plasma, concentrated platelet or clotting factors (to recover coagulation-anticoagulation balance)

(6) Antifibrinolysis treatment

A syndrome resulting from the disturbance balance ofcoagulation and fibrinolytic processes, characterized byextensive intravascular microthrombosis and impairment of hemostasia, is called disseminated intravascular coagulation.

Diseases or pathologic process which may lead to DIC are called etiologic disease of DIC. Any of them is usually trigger or promote DIC through one or several factors, which are called triggering factor.

Summary

extensive hemorrhage at skin, mucosa and internal organs

The pathogenesis of DIC are:1) Activation of clotting system (tissue and VEC injury)2) Change of vasomotorial activity and blood fluidity; 3) Disturbance of fibrinolysis

The clinical presentations of DIC include: 1) ;

2) ; 3) ; 4) .

Summary

Disturbance of microcirculation (shock)Multiple organs dysfunction (MOD)Microangiopathic hemolytic anemia

Following factors may influence the development of DIC:1) Impairment of function of mononuclear-macrophage; 2) Severe dysfunction of the liver; 3) Hypercoagulable state; 4) Disorder of microcirculation; 5) Dysfunction of fibrinolytic system

Pathophysiology basis of diagnosis of DIC:1) Causative diseases;2) Characteristic symptoms and signs of DIC; 3) Positive laboratory findings

Summary