Physiology of Haemostasis

dr. Rahmat Dani Satria., M.Sc., Sp.PK (K).,

Ph.D
Department of Clinical Pathology and Laboratory Medicine
Faculty of Medicine, Nursing and Public Health
Universitas Gadjah Mada
Yogyakarta
 HAEMOSTASIS
- Hemostasis can be defined simply as the process by which blood clots form
at sites of vascular injury.
- Hemostasis is a complex physiologic process that keeps circulating blood in
a fluid state and then, when an injury occurs, produces a clot to stop the
bleeding.

Hemodynamic Disorders, Thromboembolic Disease, and Shock

Kumar, Vinay, MBBS, MD, FRCPath, Robbins & Cotran Pathologic Basis of Disease, Chapter 4, 115-139
Major Components of Hemostasis
 HEMOSTASIS STEP
1. Primary Haemostasis
- Vasoconstriction (immediately)
- Platelet adhesion (seconds)
- Platelet aggregation (minute)
2. Secondary Haemostasis
- Activation coagulation factors (minutes)
- Formation fibrin (minutes)
3. Tertiary Haemostasis
- Activation of fibrinolysis (minutes)
- Lysis of the clot (hours)
Hemodynamic Disorders, Thromboembolic Disease, and Shock
Kumar, Vinay, MBBS, MD, FRCPath, Robbins & Cotran Pathologic Basis of Disease, Chapter 4, 115-139
Hemodynamic Disorders, Thromboembolic Disease, and Shock
Kumar, Vinay, MBBS, MD, FRCPath, Robbins & Cotran Pathologic Basis of Disease, Chapter 4, 115-139
Hemodynamic Disorders, Thromboembolic Disease, and Shock
Kumar, Vinay, MBBS, MD, FRCPath, Robbins & Cotran Pathologic Basis of Disease, Chapter 4, 115-139
Hemodynamic Disorders, Thromboembolic Disease, and Shock
Kumar, Vinay, MBBS, MD, FRCPath, Robbins & Cotran Pathologic Basis of Disease, Chapter 4, 115-139
Vessel walls

Procoagulant properties

1. Any harmful local stimulus

induces vasocontriction
(endothelin)
2. Expose collagen binds and
activates platelets
3. Exposed von Willebrand factor
(vWF), adhere to platelet
4. P-selectin promotes platelet
and leucocyte binding
5. Exposed TF activates the
plasma coagulation system
through factor VII

Fibrinolytic properties
1. tPA
2. TAFI

It should be emphasized that endothelial cells are central regulators of hemostasis;

the balance between the antithrombic and prothrombotic activities of endothelium
determines whether thrombus formation, propagation, or dissolution occur.
Hemodynamic Disorders, Thromboembolic Disease, and Shock
Kumar, Vinay, MBBS, MD, FRCPath, Robbins & Cotran Pathologic Basis of Disease, Chapter 4, 115-139
 PLATELET MORPHOLOGY

1 mm

Microscopy and Microanalysis 20(06):1-13 (2014)

Journal of Thrombosis and Thrombolysis volume 48, pages 430–438 (2019)
Membranes 2022, 12(2), 182
PLATELET GRANULE CONTENTS

Carsten Deppermann ,THE ROLE OF PLATELET GRANULES IN THROMBOSIS, HEMOSTASIS, STROKE AND INFLAMMATION, 2015
Hemodynamic Disorders, Thromboembolic Disease, and Shock
Kumar, Vinay, MBBS, MD, FRCPath, Robbins & Cotran Pathologic Basis of Disease, Chapter 4, 115-139

Platelet adhesion and aggregation. Von Willebrand factor functions as an adhesion bridge between subendothelial collagen and the glycoprotein Ib (GpIb) platelet receptor.
Aggregation is accomplished by fibrinogen bridging GpIIb-IIIa receptors on d...

Copyright © 2021 Copyright © 2021 by Elsevier, Inc. All rights reserved.

 SECONDARY HEMOSTASIS
The coagulation cascade is a series of amplifying enzymatic reactions that lead to
the deposition of an insoluble fibrin clot.

Hemodynamic Disorders, Thromboembolic Disease, and Shock

Kumar, Vinay, MBBS, MD, FRCPath, Robbins & Cotran Pathologic Basis of Disease, Chapter 4,
The coagulation cascade in the laboratory and in vivo. (A) Clotting is initiated in the laboratory by adding phospholipids, calcium, and either a negatively charged substance
such as glass beads (intrinsic pathway) or a source of tissue factor (ex...

Copyright © 2021 Copyright © 2021 by Elsevier, Inc. All rights reserved.

 Principle: Principle:
In this assay, clotting PT Tissue factor,
of plasma is initiated phospholipids, and
by the addition of calcium are added to
negatively charged plasma, and the time
particles (e.g., for a fibrin clot to form
ground glass) that is recorded.
activate factor XII
aPTT
(Hageman factor)
together with
phospholipids and
calcium, and the time
to fibrin clot
formation is recorded
Principle:
TT Thrombin are
added to plasma,
and the time for a
fibrin clot to form
is recorded.

Hemodynamic Disorders, Thromboembolic Disease, and Shock

Kumar, Vinay, MBBS, MD, FRCPath, Robbins & Cotran Pathologic Basis of Disease, Chapter 4,
The coagulation cascade in the laboratory and in vivo. (A) Clotting is initiated in the laboratory by adding phospholipids, calcium, and either a negatively charged substance
such as glass beads (intrinsic pathway) or a source of tissue factor (ex...

Copyright © 2021 Copyright © 2021 by Elsevier, Inc. All rights reserved.

 Apabila kompleks faktor jaringan-faktor VIIa
bisa mengaktifkan faktor X secara
independen, sulit dimengerti mengapa
kelainan perdarahan berat yang sering
ditemukan adalah defisiensi faktor VIII
(hemofilia A) atau faktor IX (hemofilia B)
• Defisiensi komponen di jalur intrinsik
misalnya defisiensi faktor XI (hemofilia C)
dapat menyebabkan manifestasi
perdarahan yang bervariasi di antara
individu
• Sedangkan defisiensi Faktor XII, high
molecular weight kininogen (HMWK) atau
prekalikrein (PK) tidak menimbulkan
perdarahan yang serius walaupun sama-
sama menyebabkan pemanjangan APTT.
• Demikian pula apabila terjadi defisiensi
faktor ekstrinsik yaitu faktor VII, maka terjadi
manifestasi perdarahan walau jalur intrinsik
normal
15
 Tissue Factor Complex is The Most Important
Coagulation INITIATOR In-Vivo
Normal physiologic coagulation
requires the presence of two
cell types
1. Cells that express tissue
factor (usually extravascular)
2. Platelets (intravascular)

Explains why FXa is

insufficient to
Cell-based model of compensate for a
coagulation deficiency in FVIII or FIX,
resulting hemophilia

Rodak’s Hematology: clinical principles and applications (2016)

Kumar, Vinay, MBBS, MD, FRCPath, Robbins & Cotran Pathologic Basis of Disease, Chapter 4, 16
In Vivo, Physiologic Coagulation
CELL BASED MODEL OF COAGULATION

1. INITIATION
2. AMPLIFICATION
3. PROPAGATION
 INISIASI
FVIIa TFPI

Xa
Va IIa Small amount of
TF TF
Thrombi
(3% to 5%)
Tissue factor-bearing cell

AMPLIFIKASI
- It occur within minute
XI VIII APC
- TFPI shuts down initiation phase VIIIa
- The small quantity of thrombin generated is the key factor for
further thrombin and subsequent fibrin production.
Platelet
Activated platelet

V Va
1. Amplification of the coagulant response occurs as the “action” moves from the TF-bearing cell to the platelet surface
2. The procoagulant stimulus is amplified and accumulate activated cofactors on their surfaces
dr.dani, 2023
 PROPAGASI ZPI

protein Z–dependent protease inhibitor

X
IX Tenase complex Prothrombinase complex

VIIIa Xa Va
XIa
Activated platelet

- The active proteases combine with their cofactors on the platelet surface - the site
best adapted to generate hemostatic amounts of thrombin
- The tenase & prothrombinase complex are formed on the platelet surface
- The activity of the procoagulant complexes produces the burst of thrombin generation
that results in fibrin polymerization
dr.dani, 2023
CLOT STABILIZATION
Polymerized fibrin and platelet aggregates undergo contraction to form a solid,
permanent plug that prevents further hemorrhage. At this stage,
counterregulatory mechanisms (e.g., tissue plasminogen activator [t-PA] made
by endothelial cells) are set into motion that limit clotting to the site of injury

Prothrombinase complex

Xa Va

Protrombin Trombin

XIII XIIIa

FIBRINOGEN FIBRIN Crosslinked Fibrin

dr.dani, 2023
 FIBRINOLYSIS (TERTIARY HEMOSTASIS)

Hemodynamic Disorders, Thromboembolic Disease, and Shock

Kumar, Vinay, MBBS, MD, FRCPath, Robbins & Cotran Pathologic Basis of Disease, Chapter 4, 115-139

The fibrinolytic system, illustrating various plasminogen activators and inhibitors (see text).

Copyright © 2021 Copyright © 2021 by Elsevier, Inc. All rights reserved.

 COAGULATION REGULATORY MECHANISM

Rodak’s Hematology: clinical principles and applications (2016)

 The Principal Regulators are TFPI, AT, & APC

The coagulation pathway is

regulated by TFPI, APC, and
the serpins (AT and ZPI).
Acquired or inherited
deficiencies of these proteins
may be associated with
increased incidence of venous
thromboembolic disease, as
the hemostatic balance is
shifted more toward
coagulation than termination
of the activated pathway

Rodak’s Hematology: clinical principles and applications (2016)

 MARKER KOAGULASI DAN FIBRINOLISIS

Ned Tijdschr Klin Chem Labgeneesk 2016; 41: 17-27

 KESIMPULAN
• Pembuluh darah, trombosit, factor koagulasi, system
fibrinolysis dan inhibitor adalah komponen utama dalam
hemostasis.
• Trombosit berperan dalam hemostasis primer dan sekunder
melaui adesi, agregasi dan sekresi
• Secara in vivo, koagulasi diinisiasi oleh ekspresi tissue factor.
• Sebagian besar aktivasi factor koagulasi terjadi di permukaan
trombosit (permukaan fosfolipid).
• Fibrinolisis akan mendegradasi thrombus sebagai bentuk
keseimbangan
• Proses koagulasi diregulasikan oleh TFPI, APC, and the
serpins (AT dan ZPI). Kontrol koagulasi melalui protein
tersebut mencegah terjadinya thrombosis secara berlebihan

Rodak’s Hematology: clinical principles and applications (2016)