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Introduction to coagulation and laboratory tests Marc Jacquemin Special Haemostasis Laboratory Center for Molecular and Vascular Biology University of Leuven

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Page 1: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Introduction to coagulation and laboratory tests

Marc Jacquemin

Special Haemostasis Laboratory

Center for Molecular and Vascular Biology University of Leuven

Page 2: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Coagulation in a blood vessel: fibrin stabilises the hemostatic clot

Platelet immunostaining Fibrin staining

Page 3: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Polymerisation of fibrin stabilises the hemostatic clot = secondary hemostasis

Page 4: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Norledge BV, et al. Proteins. 2003;53:640-8

Expression of Tissue Factor (TF) and Factor VIIa on phospholipid surfaces in damaged tissues

Page 5: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

VIIa/TF

Initiation of coagulation

Page 6: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

IXa IX

X Xa

VIIa/TF

Initiation of coagulation

Page 7: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

IXa IX

X Xa

VIIa/TF

Initiation of coagulation

Prothrombin Thrombin

Page 8: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Va V

IXa IX

XIa XI

X Xa

VIIIa VIII

VIIa/TF

Initiation of coagulation

Prothrombin Thrombin

Amplification

Page 9: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Va V

IXa IX

XIa XI

X Xa

VIIIa VIII

VIIa/TF

Initiation of coagulation

Prothrombin Thrombin

Amplification

Page 10: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Va V

IXa IX

XIa XI

X Xa

VIIIa VIII

VIIa/TF

Initiation of coagulation

Prothrombin Thrombin

Amplification

Page 11: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Va V

IXa IX

XIa XI

X Xa

VIIIa VIII

VIIa/TF

Initiation of coagulation

Prothrombin Thrombin

Amplification

Page 12: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Va V

IXa IX

XIa XI

X Xa

VIIIa VIII

VIIa/TF

Initiation of coagulation

Prothrombin Thrombin

Amplification Fibrinogen Fibrin

Sustained hemostasis

Page 13: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Va V

IXa IX

XIa XI

X Xa

VIIIa VIII

VIIa/TF

Initiation of coagulation

Prothrombin Thrombin

Amplification Fibrinogen Fibrin

Sustained hemostasis

FXIII

Page 14: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

FVIII is bound to vWF in plasma

A1

FVIII

vWF

Page 15: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Factor VIIIa Factor IXa

Phospholipids

A3

A2

A1

C2

X 100.000 by Factor VIII

Factor X

Factor Xa

Haemostasis

Activated Factor VIII as cofactor of Factor IXa

Page 16: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Hydrophobic residues

Basic residues Phospholipid

binding site

Pratt et al., Nature 2000

FV and FVIII binding to phospholipids

Page 17: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Hydrophobic residues

Basic residues Phospholipid

binding site

Pratt et al., Nature 2000

FV and FVIII binding to phospholipids

Page 18: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Hydrophobic residues

Basic residues Phospholipid

binding site

Pratt et al., Nature 2000

FV and FVIII binding to phospholipids

Page 19: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

hydrophobic

basic

Phospholipids

FVII, FIX, FX, FII binding to phospholipids:

Gla domain

Page 20: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

d Ca ++

Gla Gla Val

Leu Phe

hydrophobic

basic

Phospholipids

Gla:�J�carboxy glutamic acid

FVII, FIX, FX, FII binding to phospholipids:

Gla domain

Page 21: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Glutamic acid

H CJ

CH�

COO-

J-carboxylase

protein CH�

Page 22: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Glutamic acid

-OOC J-carboxy glutamic acid

CJ

CH�

COO-

H CJ

CH�

COO-

J-carboxylase

protein CH�

CH�

Page 23: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Glutamic acid oxidized

vitamin K

reduced vitamin K

vitamin K

-OOC J-carboxy glutamic acid

CJ

CH�

COO-

H CJ

CH�

COO-

J-carboxylase

protein

VKOR

VKR

vitamin K

cycle

CH�

CH�

Page 24: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Glutamic acid oxidized

vitamin K

reduced vitamin K

vitamin K

-OOC J-carboxy glutamic acid

CJ

CH�

COO-

H CJ

CH�

COO-

J-carboxylase

protein

VKOR

VKR

vitamin K

cycle

anti-vit K

CH�

CH�

Page 25: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Coagulation and phospholipids

Page 26: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Coagulation and phospholipids

Modern times, 1936

Page 27: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Anti-phospholipid antibodies

Page 28: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Anti-phospholipid antibodies

Page 29: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Anti-phospholipid antibodies

Thrombosis

but no bleedings

Page 30: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Coagulation assays

Page 31: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Va V

IXa IX

XIa XI

X Xa

VIIIa VIII

VIIa/TF

Initiation of coagulation

Prothrombin Thrombin

Amplification Fibrinogen Fibrin

Sustained hemostasis

FXIII

Page 32: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Prothrombin time (PT) + TF + phospholipids + Ca++

Page 33: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

X Xa

VIIa

Prothrombin Thrombin

Fibrinogen Fibrin

Prothrombin time (PT) + TF + phospholipids + Ca++

Page 34: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

X Xa

VIIa

Prothrombin Thrombin

Fibrinogen Fibrin

Prothrombin time (PT) + TF + phospholipids + Ca++

time between the addition of reagents to citrate plasma and detection of a clot.

Page 35: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

PT results

• time (seconds)

Page 36: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

PT results

• time (seconds) • percent (%) by comparison to PT with dilutions of plasma 13 sec = 100% 40 sec = 10%

Page 37: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

PT results

• time (seconds) • percent (%) by comparison to PT with dilutions of plasma 13 sec = 100% 40 sec = 10% Follow up of

Anti-vit K treatment

Page 38: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

PT results

• time (seconds) • percent (%) by comparison to PT with dilutions of plasma 13 sec = 100% 40 sec = 10% • International Normalized Ratio (INR) 13 sec = 1 40 sec = 3.5

Follow up of Anti-vit K treatment

Page 39: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

APTT (Activated Partial Thromboplastin Time)

+ phospholipids + Ca++

+ non physiological surface (glass, silica, kaolin)

Page 40: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

APTT (Activated Partial Thromboplastin Time)

XIIa XII

HK / PK Contact Activation

pathway

+ phospholipids + Ca++

+ non physiological surface (glass, silica, kaolin)

Page 41: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Va V

IXa IX

XIa XI

X Xa

VIIIa VIII

Prothrombin Thrombin

Fibrinogen Fibrin

APTT (Activated Partial Thromboplastin Time)

XIIa XII

HK / PK Contact Activation

pathway

+ phospholipids + Ca++

+ non physiological surface (glass, silica, kaolin)

Page 42: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Interpretation of coagulations assays

Page 43: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

X Xa

VIIa

Prothrombin Thrombin (IIa)

Fibrinogen Fibrin

PT

Prolonged isolated PT

Page 44: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Va V

IXa IX

XIa XI

X Xa

VIIIa VIII

Prothrombin Thrombin (IIa)

Fibrinogen Fibrin

APTT nl XIIa XII

HMWK / PK

X Xa

VIIa

Prothrombin Thrombin (IIa)

Fibrinogen Fibrin

PT >

Prolonged isolated PT

Page 45: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Isolated prolonged PT (lower % value, increased INR)

acquired decreased FVII

• early liver disease • early anti-vit K treatment

« anti-phospholipid » antibody *

constitutive FVII defect

not bleeding disorders *

Page 46: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Va V

IXa IX

XIa XI

X Xa

VIIIa VIII

Prothrombin Thrombin (IIa)

Fibrinogen Fibrin

APTT > XIIa XII

HMWK / PK

X Xa

VIIa

Prothrombin Thrombin (IIa)

Fibrinogen Fibrin

PT nl

Prolonged isolated APTT

Page 47: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Isolated prolonged APTT

acquired • inhibitor antibody (FVIII) • « anti-phospholipid » antibody

constitutive • Von Willebrand disease • hemophilia A and B (FVIII, FIX) • FXI • FXII (contact activation pathway)

not bleeding disorders *

*

*

FVIII vWF

Page 48: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Differential diagnosis of isolated prolonged APTT

mix of patient’s plasma with normal plasma

Page 49: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Differential diagnosis of isolated prolonged APTT

mix of patient’s plasma with normal plasma

Correction of the APTT:

DECREASED FACTOR low titer or slow acting antibody

Factors XII, FXI, FIX, FVIII?

Page 50: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Differential diagnosis of isolated prolonged APTT

mix of patient’s plasma with normal plasma

NO correction of the APTT:

ANTIBODY

inhibitor antibody? anti-phospholipid antibody?

Correction of the APTT:

DECREASED FACTOR low titer or slow acting antibody

Factors?

Page 51: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Prolonged PT and APTT

Page 52: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Va V

IXa IX

XIa XI

X Xa

VIIIa VIII

Prothrombin Thrombin (IIa)

Fibrinogen Fibrin

APTT

XIIa XII

HMWK / K

X Xa

VIIa

Prothrombin Thrombin (IIa)

Fibrinogen Fibrin

PT

Page 53: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Va V

IXa IX

XIa XI

X Xa

VIIIa VIII

Prothrombin Thrombin (IIa)

Fibrinogen Fibrin

APTT

XIIa XII

HMWK / K

X Xa

VIIa

Prothrombin Thrombin (IIa)

Fibrinogen Fibrin

PT

Page 54: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

Acquired prolonged aPTT and PT

Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII, IX, X, II

• acute DIC V • massive blood transfusion V

• lupus inhibitor none after dilution • antibody to FV V

• rare systemic diseases Gaucher’s disease V, X

Nieman Pick disease Amyloid

• heparin • oral anticoag treatment VII, IX, X, II

Page 55: Introduction to coagulation and laboratory tests · Acquired prolonged aPTT and PT Clinical state Deficiency • advanced liver disease VII, V, IX, X , II • vit K deficiency VII,

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