Download Coagulation (the basics) and recombinant Factor VIIa Mechanism of

Coagulation Disorders and
Disseminated Intravascular
Coagulation (DIC)
Jianzhong Sheng MD, PhD
Department of Pathophysiology
School of Medicine
Zhejiang 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
Hemostasis
Subendothelial matrix
Nitric oxide
Endothelial cell
Initiation of coagulation
Coagulation Pathways
Intrinsic Pathway
Contact
IX
Extrinsic Pathway
Tissue Factor + VII
TF Pathway
TF-VIIa
XI
X
Common Pathway
PL
XIIa HKa
Prothrombin
XIa
IXa
PL
VIIIa
(Tenase)
Xa
(Prothrombinase)
Protein C, Protein S,
Antithrombin III
PL
XIII
Va
Thrombin
Fibrinogen
Fibrin
(weak)
XIIIa
Fibrin
(strong)
Normal Hemostasis
X
TFVIIa
II
Xa Va
TF-Bearing Cell
IIa (Thrombin)
Normal Hemostasis
II
X
TF VIIa
Xa
Va
TF-Bearing Cell
IIa
VIII/vWF
VIIIa
Normal Hemostasis
II
X
TF VIIa
Xa
IIa
Va
VIII/vWF
VIIIa
TF-Bearing Cell
V
Va
Platelet
Normal Hemostasis
II
X
TF VIIa
VIII/vWF
Xa
Va
IIa
VIIIa
TF-Bearing Cell
V
Va
Platelet
Activated Platelet
Normal Hemostasis
II
X
TF VIIa
VIII/vWF
Xa
Va
IIa
VIIIa
TF-Bearing Cell
TF VIIa
IX
V
IXa
Activated Platelet
Va
Platelet
Normal Hemostasis
II
X
TF VIIa
VIII/vWF
Xa
Va
IIa
VIIIa
TF-Bearing Cell
TF VIIa
IXa
V
IX
X
Va
Platelet
II
Xa
IXa VIIIa
Va
Activated Platelet
IIa
Normal Hemostasis
II
X
TF VIIa
VIII/vWF
Xa
Va
IIa
VIIIa
TF-Bearing Cell
TF VIIa
IXa
V
IX
X
Va
Platelet
II
Xa
VIIIa
IXa
Va
Activated Platelet
IIa
Hoffman et al. Blood Coagul Fibrinolysis 1998;9(suppl 1):S61.
Normal Hemostasis:
Pivotal role of TF/VIIa
X
II
TF
VIIa
VIII/vWF
Xa
Va
IIa
VIIIa
TF-Bearing Cell
TF VIIa
IXa
V
IX
X
Va
Platelet
II
Xa
IXa VIIIa
Va
Activated Platelet
VIIa
Va
IXa VIIIa
Xa
IX
X
II
Hoffman et al. Blood Coagul Fibrinolysis 1998;9(suppl 1):S61.
IIa
IIa
Platelet Activation Pathways
COLLAGEN
THROMBIN
ADP
Hemophilia
Aggregation
GpIIb/IIIa
GpIIb/IIIa
GpIIb/IIIa
Adrenaline
Platelet
Adhesion
vWF
Endothelium
Exposed Collagen
Gp Glycoprotein
Bleeding through a Cut in a Vessel Wall
Tissue
Factor
Factor
VIIa
• The first step in all coagulation: The Tissue FactorFactor VIIa complex formation
Bleeding through a Cut in a Vessel Wall
TissueFactor- Factor
VIIa
Complex
• The first step in all coagulation: The Tissue FactorFactor VIIa complex formation
• This catalysis the coagulation cascade in normal
persons and in patients with bleeding disorders
Recombinant Factor VIIa Platelet Binding
TissueFactor- Factor
VIIa
rFactorVIIa
Complex
Platelets
Recombinant Factor VIIa (rFVIIa) in high concentration
binds to platelets; this complex catalysis further coagulation.
The local coagulation activation is greatly enhanced
Further Formation of a Hemostatic Plug
TissueFactor- rFVIIa
Complex
rFVIIa
Platelets
High peak levels of recombinant Factor VIIa
(rFVIIa) induces formation of a strong fibrin network.
This network cross-binds and forms a solid
hemostatic plug
Disseminated Intravascular
Coagulation (DIC)
DIC
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
-Xigris
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.
DIC
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
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Basic pathophysiology
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Entry into the circulation of procoagulant
substances
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Procoagulant stimulus is tissue factor (most
cases)
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Trigger systemic activation of the coagulation
system and platelets
Lead to the disseminated deposition of fibrinplatelet thrombi.
Lipoprotein
Not normally exposed to blood.
Tissue factor gains access to blood by
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Tissue injury,
Malignant cells,
Expression on the surfaces of monocytes and
endothelial cells by inflammatory mediators.
DIC
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
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Tissue factor triggers
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Thrombin
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Protease
Induces fibrin formation and platelet
activation
Other procoagulants
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Cysteine protease
Mucin（粘液素）
Trypsin
DIC
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
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Acute DIC
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Coagulation factors are consumed
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
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
Laboratory manifestations
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Prolonged prothrombin time (PT)
Prolonged Activated partial thromboplastin time
(aPTT)
Thrombocytopenia.
Increased fibrin formation
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Stimulates compensatory process of secondary
fibrinolysis,
Plasminogen activators generate plasmin to digest
fibrin (and fibrinogen) into fibrin(ogen) degradation
products (FDPs).
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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 compromise
the blood supply to some organs and lead to
multiorgan failure
DIC
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
DIC
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
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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
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-Background
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-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
Causes
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Infection
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Most common cause of DIC.
The syndrome particularly is associated
with gram-negative or gram-positive
sepsis
Can be triggered by a variety of other
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Bacterial
Fungal
Viral
Rickettsial, and protozoal
microorganisms.
DIC
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-Background
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-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
Obstetrics
 The placenta and uterine
contents are rich sources
of
 Tissue factor
 Other procoagulants
that normally are
excluded from the
maternal circulation
DIC
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
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Clinical manifestations of DIC
may accompany obstetric
complications, especially in the
third trimester.
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These syndromes range from
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Acute, fulminant, and often fatal
DIC in amniotic fluid embolism
 Blood is exposed to large
amounts of tissue factor in a
short period of time creating
large amounts of thrombin
 Multiorgan failure
Chronic or subacute DIC with a
retained dead fetus.
 Exposure to small amounts of
tissue factor
DIC
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
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Other obstetric problems
associated with DIC include
Abruptio placentae（胎盘剥离）
Toxemia
Septic abortion.
DIC
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
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Clinical manifestations
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Determined by
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Nature
Intensity
Duration of the underlying stimulus.
Chronicity
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Low-grade DIC is often asymptomatic
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Chronic disease
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Diagnosed only by laboratory abnormalities.
Bleeding is most common clinical finding
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Generalized or widespread ecchymoses
Thrombotic complications
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Trousseau's syndrome in cancer
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Gangrene of the digits or extremities
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Hemorrhagic necrosis of the skin
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Purpura fulminans
Enhanced by
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Coexistence of liver disease
DIC
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
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Diagnosis of severe, acute (easy)
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Prolongation of PT, aPTT and Thrombin
time
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Due to consumption and inhibition of
clotting factors
Thrombocytopenia
Fibrin degradatin products
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Increased due to secondary fibrinolysis
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Measured by latex agglutination or Ddimer assays.
Schistocytes may be seen in the
peripheral blood smear
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Neither sensitive nor specific for DIC.
DIC
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
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Chronic or compensated forms of DIC
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Highly variable patterns of abnormalities
in "DIC screen" coagulation tests.
Increased FDPs and prolonged PT are
generally more sensitive measures than
are abnormalities of the aPTT and
platelet count.
Overcompensated synthesis of consumed
clotting factors and platelets in some
chronic forms
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Cause shortening of the PT and aPTT
and/or thrombocytosis
Though, elevated levels of FDPs indicate
secondary fibrinolysis in such cases.
DIC
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
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Treatment
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Identify underlying cause and
treat
All other therapies are temporizing
DIC
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
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Asymptomatic patients with
self-limited DIC
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Have only laboratory
manifestations of the
coagulopathy
No treatment may be necessary.
DIC
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
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Actively bleeding or who are at high
risk of bleeding,
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Blood component treatments of choice
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Transfusions of platelets
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Fresh-frozen plasma (FFP)
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Improve the thrombocytopenia
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
DIC
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
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Special cases
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Profound hypofibrinogenemia
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Additional transfusion of
cryoprecipitate,
Plasma concentrate enriched in
fibrinogen
Sepsis
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Infusion of antithrombin III
concentrate may be considered as an
adjunctive measure
DIC
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
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Pharmacologic inhibitors of
coagulation and fibrinolysis
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Heparin
Theoretical benefit
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It blocks thrombin and the secondary
fibrinolysis.
Might exacerbate the bleeding tendency
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Usually reserved for
Forms manifested by
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Thrombosis
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Acrocyanosis （发绀）
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Cancer
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Vascular malformations
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Retained dead fetus
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Acute promyelocytic leukemia.
早幼粒细胞
DIC
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-Background
-Pathophysiology
-Etiology
-Clinical Manifestations
-Diagnosis
-Treatment
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Antifibrinolytic agents,
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ε-aminocaproic acid and
tranexamic acid
Generally are contraindicated
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May precipitate thrombosis
May be effective in decreasing
life-threatening bleeding
Thank you