Coagulation Disorders and Disseminated Intravascular Coagulation (DIC)

Coagulation Disorders and Disseminated Intravascular Coagulation (DIC)

Jianzhong Sheng MD, PhD

Department of PathophysiologySchool of MedicineZhejiang University

Normal Hemostasis

• First step in hemostasis is formation of a platelet aggregate

• At the molecular level interaction of coagulation factors takes place on the surface of activated platelets

• The Tissue Factor–FVIIa complex is the physiological activator of normal hemostasis

HemostasisSubendothelial matrixSubendothelial matrix

Nitric oxideNitric oxide

Endothelial cellEndothelial cell

Initiation of coagulation

Contact Tissue Factor + VIITissue Factor + VII

XIIIXIIIaa

XIIIXIII

ThrombinThrombin

FibrinFibrin(strong)(strong)

FibrinogenFibrinogen FibrinFibrin(weak)(weak)

IXIX

XIXI

XIXIaa

IXIXaa

XaXaVVaa

XIIXIIaa

ProthrombinProthrombin

TF-VIIaTF-VIIa

(Prothrombinase)(Prothrombinase)

PLPL

PLPL(Tenase)(Tenase)

VIIIVIIIaa

PLPL

XX

Intrinsic Pathway

HKHKaa

Extrinsic Pathway

Common Pathway

TF Pathway

Coagulation Pathways

Protein C, Protein S, Antithrombin III

TF-Bearing CellTF-Bearing Cell

VaVaTFTFVIIaVIIa XaXaXX IIII

IIa (Thrombin)IIa (Thrombin)

Normal Hemostasis


VaVaTFTF VIIaVIIa XaXa

XX IIIIIIaIIa

VIII/vWFVIII/vWF

VIIIaVIIIa

Normal Hemostasis



XX IIIIIIaIIa VIII/vWFVIII/vWF

VIIIaVIIIa

VV VaVa

PlateletPlatelet

Normal Hemostasis



XX IIIIIIaIIa

VIII/vWFVIII/vWF

VIIIaVIIIa

VV VaVa

PlateletPlatelet

Activated PlateletActivated Platelet

Normal Hemostasis



XX IIIIIIaIIa

VIII/vWFVIII/vWF

VIIIaVIIIa

VV VaVa

PlateletPlatelet

TFTF VIIaVIIaIXIX

IXaIXa


Normal Hemostasis



XX IIIIIIaIIa

VIII/vWFVIII/vWF

VIIIaVIIIa

VV VaVa

PlateletPlatelet

TFTF VIIaVIIaIXIX

IXaIXa


VIIIaVIIIa VaVaIXaIXaXaXa

IIaIIa

IIII

Normal Hemostasis

XX

Hoffman et al. Hoffman et al. Blood Coagul FibrinolysisBlood Coagul Fibrinolysis 1998;9(suppl 1):S61. 1998;9(suppl 1):S61.


PlateletPlatelet

TFTF

VIIIaVIIIa VaVa

VIIaVIIa

XX IIII


VaVaTFTF VIIaVIIa XaXa IIaIIa

IXIXVV VaVa

IIII

VIII/vWFVIII/vWF

VIIIaVIIIa

IXaIXa XX

IXaIXa IIaIIaXaXa

Normal Hemostasis

Hoffman et al. Hoffman et al. Blood Coagul FibrinolysisBlood Coagul Fibrinolysis 1998;9(suppl 1):S61. 1998;9(suppl 1):S61.



PlateletPlatelet

TFTF

VIIIaVIIIa VaVa

VIIIaVIIIa VaVa

VaVa

VIIaVIIa

TFTF VIIaVIIa XaXa

XX IIIIIIaIIa

IXIXVV VaVa

IIII

VIII/vWFVIII/vWF

VIIIaVIIIa

IIII

IXaIXa

XXIXIX

XX

IXaIXa

IXaIXaVIIaVIIaXaXa

IIaIIa

IIaIIa

XaXa

Normal Hemostasis: Pivotal role of TF/VIIa

Adhesion

GpIIb/IIIa

Platelet Activation Pathways

GpIIb/IIIaGpIIb/IIIa Aggregation

ADP

Adrenaline Platelet GpIb

Exposed Collagen

Endothelium

vWF

COLLAGEN

GpIIb/IIIaGpIIb/IIIa AggregationGpIIb/IIIaGpIIb/IIIa Aggregation

AdhesionAdhesion

ADP

Adrenaline

THROMBINTHROMBINHemophilia

Gp Glycoprotein

TissueTissueFactorFactor Factor Factor

VIIaVIIa

• The first step in all coagulation: The Tissue Factor- The first step in all coagulation: The Tissue Factor- Factor VIIa Factor VIIa complex formationcomplex formation

Bleeding through a Cut in a Vessel WallBleeding through a Cut in a Vessel Wall

TissueFactor- TissueFactor- Factor Factor VIIa VIIa

ComplexComplex

• The first step in all coagulation: The Tissue The first step in all coagulation: The Tissue Factor- Factor- Factor VIIaFactor VIIa complex formation complex formation

• This catalysis the coagulation cascade in This catalysis the coagulation cascade in normalnormal persons persons and in patients with bleeding and in patients with bleeding disordersdisorders

Bleeding through a Cut in a Vessel WallBleeding through a Cut in a Vessel Wall

Platelets

rFactorVIIarFactorVIIa

Recombinant Factor VIIa (rFVIIa)Recombinant Factor VIIa (rFVIIa) in high concentration in high concentration binds to platelets; thisbinds to platelets; this complex catalysis further complex catalysis further coagulation. coagulation. The local coagulation activation is greatly enhancedThe local coagulation activation is greatly enhanced

TissueFactor- TissueFactor- Factor Factor VIIa VIIa

ComplexComplex

Recombinant Factor VIIa Platelet BindingRecombinant Factor VIIa Platelet Binding

rFVIIarFVIIa

Platelets

High peak levels of recombinant Factor VIIaHigh peak levels of recombinant Factor VIIa(rFVIIa) induces formation of a strong fibrin (rFVIIa) induces formation of a strong fibrin

network.network.This network cross-binds and forms a solid This network cross-binds and forms a solid

hemostatic plughemostatic plug

TissueFactor-TissueFactor- rFVIIarFVIIa ComplexComplex

Further Formation of a Hemostatic Further Formation of a Hemostatic PlugPlug

Disseminated Intravascular Coagulation (DIC)

Primarily a thrombotic process Systemic process producing

both thrombosis and hemorrhage

Also called consumption coagulopathy and defibrination syndrome1

Its clinical manifestation may be widespread hemorrhage in acute, fulminant cases2.

-Background -Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment -Xigris

DIC

Basic pathophysiology Entry into the circulation of procoagulant sub

stances Trigger systemic activation of the coagulation

system and platelets Lead to the disseminated deposition of fibrin-

platelet thrombi. Procoagulant stimulus is tissue factor (most c

ases) Lipoprotein Not normally exposed to blood.

Tissue factor gains access to blood by Tissue injury, Malignant cells, Expression on the surfaces of monocytes and e

ndothelial cells by inflammatory mediators.

-Background -Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment

DIC

Tissue factor triggers Thrombin

Protease Induces fibrin formation and platele

t activation Other procoagulants

Cysteine protease Mucin （粘液素） Trypsin


DIC

Acute DIC Coagulation factors are consum

ed at a rate in excess of the capacity of the liver to synthesize them,

Platelets are consumed in excess of the capacity of bone marrow megakaryocytes to release them.


DIC

DIC Laboratory manifestations

Prolonged prothrombin time (PT) Prolonged Activated partial thromboplastin ti

me (aPTT) Thrombocytopenia. Increased fibrin formation

Stimulates compensatory process of secondary fibrinolysis,

Plasminogen activators generate plasmin to digest fibrin (and fibrinogen) into fibrin(ogen) degradation products (FDPs).

FDPs are potent circulating anticoagulants that contribute further to the bleeding manifestations of DIC.

Intravascular fibrin deposition can cause fragmentation of red blood cells and lead to the appearance of schistocytes in blood smears

Hemolytic anemia is unusual in DIC. Microvascular thrombosis in DIC can compromis

e the blood supply to some organs and lead to multiorgan failure



DIC

DIC always has an underlying etiology Must be identified and eliminated

to treat the coagulopathy （凝血病） successfully.

The development of DIC in many of these disorders is associated with an unfavorable outcome1.

Occurs in 1% of hospitalized patients Mortality rate approaches 40-80%


DIC

Causes Infection

Most common cause of DIC. The syndrome particularly is associate

d with gram-negative or gram-positive sepsis

Can be triggered by a variety of other Bacterial Fungal Viral Rickettsial, and protozoal microorgani

sms.


DIC

Obstetrics The placenta and uterine c

ontents are rich sources of Tissue factor Other procoagulants th

at normally are excluded from the maternal circulation


DIC

Clinical manifestations of DIC may accompany obstetric complications, especially in the third trimester.

These syndromes range from Acute, fulminant, and often fatal DI

C in amniotic fluid embolism Blood is exposed to large amou

nts of tissue factor in a short period of time creating large amounts of thrombin

Multiorgan failure Chronic or subacute DIC with a retai

ned dead fetus. Exposure to small amounts of ti

ssue factor


DIC

Other obstetric problems associated with DIC include

Abruptio placentae （胎盘剥离）ToxemiaSeptic abortion.

DIC -Background -Pathophysiology -Etiology -Clinical Manifestations -Diagnosis -Treatment

Clinical manifestations Determined by

Nature Intensity Duration of the underlying stimulus.

Chronicity Low-grade DIC is often asymptomatic

Diagnosed only by laboratory abnormalities. Bleeding is most common clinical finding

Generalized or widespread ecchymoses Chronic disease

Thrombotic complications Trousseau's syndrome in cancer Gangrene of the digits or extremities Hemorrhagic necrosis of the skin Purpura fulminans

Enhanced by Coexistence of liver disease


DIC

Diagnosis of severe, acute (easy) Prolongation of PT, aPTT and Thrombin t

ime Due to consumption and inhibition of clot

ting factors Thrombocytopenia Fibrin degradatin products

Increased due to secondary fibrinolysis Measured by latex agglutination or D-dim

er assays. Schistocytes may be seen in the peripher

al blood smear Neither sensitive nor specific for DIC.


Chronic or compensated forms of DIC Highly variable patterns of abnormalities

in "DIC screen" coagulation tests. Increased FDPs and prolonged PT are ge

nerally more sensitive measures than are abnormalities of the aPTT and platelet count.

Overcompensated synthesis of consumed clotting factors and platelets in some chronic forms

Cause shortening of the PT and aPTT and/or thrombocytosis

Though, elevated levels of FDPs indicate secondary fibrinolysis in such cases.


DIC

Treatment Identify underlying cause and

treat All other therapies are

temporizing


Asymptomatic patients with self-limited DIC Have only laboratory manifestati

ons of the coagulopathy No treatment may be necessary.


DIC

Actively bleeding or who are at high risk of bleeding,

Blood component treatments of choice Transfusions of platelets

Improve the thrombocytopenia Fresh-frozen plasma (FFP)

Replace all consumed coagulation factors and correct the prolonged PT and aPTT.

Large volumes of plasma in severe cases The theoretical concern that these blood

products may "fuel the fire" and exacerbate the DIC has not been supported by clinical experience


Special cases Profound hypofibrinogenemia

Additional transfusion of cryoprecipitate,

Plasma concentrate enriched in fibrinogen

Sepsis Infusion of antithrombin III concent

rate may be considered as an adjunctive measure


DIC

Pharmacologic inhibitors of coagulation and fibrinolysis Heparin Theoretical benefit

It blocks thrombin and the secondary fibrinolysis.

Might exacerbate the bleeding tendency Usually reserved for Forms manifested by

Thrombosis Acrocyanosis （发绀） Cancer Vascular malformations Retained dead fetus Acute promyelocytic leukemia.

早幼粒细胞


Antifibrinolytic agents, ε-aminocaproic acid and tranex

amic acid Generally are contraindicated

May precipitate thrombosis May be effective in decreasing lif

e-threatening bleeding


DIC

Thank you

Documents

Coagulation Disorders and Disseminated Intravascular Coagulation (DIC)