HEMOSTASIS

NYOTO WIDYO ASTORO

HEMATOLOGI-ONKOLOGI MEDIK
PENYAKIT DALAM RS GATOT SOEBROTO

Function of HEMOSTASIS
ARREST BLEEDING
MAINTAIN BLOOD IN FLUID STATE

HEMOSTASIS
Primary Hemostasis
Blood vessel contraction
Platelet Plug Formation

Secondary Hemostasis
Activation of Clotting Cascade
Deposition & Stabilization of Fibrin

Tertiary Hemostasis
Dissolution of Fibrin Clot
Dependent on Plasminogen Activation

Lab Tests

Hemostasis
Neural

Blood Vessel
Constriction

CBC-Plt
BT,(CT)
PT
PTT

BV Injury

Platelet
Adhesion
and
Activation

Platelet
Aggregation

Tissue
Factor

Coagulation
Cascade

Primary hemostatic plug

Reduced

Fibrin
formation

Blood flow

Plt Study
Stable Hemostatic Plug

Morphology
Function
Antibody

The primary haemostatic system:

haemostasis and platelet plug formation
Primary haemostasis
Platelet aggregation
trombosit

Adhesion

endothelial cells
sub endothelial tissue

Activation
Aggregation

Vascular
injury

White clot

Formation of
platelet plug

exposed sub
endothelial tissue

The haemostatic system:

secondary haemostasis and clot formation
Prothrombin

Intrinsic
pathway

Thrombin
Factor
Xa

Extrinsic
pathway

Fibrinogen

Fibrin

Activation of the
coagulation cascade
leads to generation of
thrombin and, in turn,
fibrin

Coagulation cascade
leads to clot formation

Fibrin threads

Clot
growth

Coagulation balance:
endogenous activators : the core role of factor Xa
Intrinsic system
XII

Extrinsic system

XIIa

IX

II

Cellular
thromboplastin
VIIa

XIa

XI

Xa
Va
Ca2+
PL
Fibrinogen

Xa

IXa
VIIIa
Ca2+
PL

VII

Ca2+

Thrombin
IIa
Soluble fibrin

XIIIa

Fibrin (clot)

Boneu B, et al. Sang Thrombose Vaisseaux 1998; 10:291313.

DIC

Disseminated Intravascular
Coagulation
.an acquired syndrome characterized by the
intravascular activation of coagulation with loss of
localization arising from different causes. It can
originate from and cause damage to the
microvasculature, which if sufficiently severe, can
produce organ dysfunction
Scientific and Standardization Committee of the International Society on
Thrombosis and Haemostasis, Paris July 2001

DISSEMINATED INTRAVASCULAR
COAGULATION
Activation of coagu-lation
by triggering events
Depends on host response
Influenced by comorbid
conditions
Thrombosis and bleeding

Underlying
disorder
Systemic activation of coagulation

Widespread
intravascular
fibrin
deposition

Consumption
of platelets
and clotting
factors

Thrombosis and
organ failure

(severe) Bleeding

DIC in the Surgical patient

Massive trauma / burns

Head injuries
Disseminated malignant disease
Limb gangrene
Infection / sepsis
Hemodynamic problems including hypoxia

Minimal clinical findings

in the diagnosis of DIC
Clinical evidence of thrombosis,
hemorrhage, or both, and
Should be occuring in the
appropriate clinical setting

Laboratory criteria based on

DIC pathophysiology
Evidence of procoagulant activation
Evidence of fibrinolytic activation
Evidence of inhibitor consumption
Evidence of end-organ damage or failure

Evidence of procoagulation

Elevated prothrombin fragment 1+2

Elevated fibrinopeptide A
Elevated fibrinopeptide B
Elevated thrombin-antithrombin
complex
Elevated D-dimer

Evidence of fibrinolytic activation

Elevated D-dimer
Elevated FDP
Elevated plasmin
Elevated plasmin antiplasmin complex

Evidence for inhibitor

consumption

Decreased AT-III
Decreased alpha-2-antiplasmin
Decreased heparin cofactor II
Decreased protein C or S
Elevated TAT complex
Elevated PAP complex

Evidence for end-organ damage

Elevated LDH
Elevated creatinine
Decreased pH
Decreased paO2
Needs 2 out of 4 above items for diagnosis

Treatment of DIC
Cornerstone: management of
underlying problem
Plasma and/or platelet
replacement
Anticoagulant strategies
Administration of coagulation
inhibitors

TROMBOSIS

What is thrombosis ?
Thrombosis is the formation or
presence of a blood clot inside a
blood vessel or cavity of the heart

Thrombosis
Arterial thrombosis (white
thrombus)
Venous thrombosis (red
thrombus)

Pathophysiology

Pathophysiology
thrombosis

HIGH FLOW : ARTERIAL CIRCULATION

Fibrin

White Thrombus

RBCs

Platelets

SLOW FLOW : VENOUS CIRCULATION

Fibrin

RBCs

Red Thrombus

Platelets

RED THROMBUS IN LUMEN OF

VEIN

Platelets: Role in Thrombosis

High Flow

Fibrin

RBCs

Slow Flow

Platelets

White Thrombus
RBCs, red blood cells.

Fibrin

RBCs

Platelets

Red Thrombus

Pathogenesis of DVT

Venous thromboembolism
Virchow's Triad
Stasis
Activation of coagulation
Vessel damage

Interpretation of Virchows triad using

modern understanding of the physiologic
mechanisms of thrombosis
Virchows Triad

Modern interpretation

Stasis

Immobility: of minor importance

except that it may indicate
underlying disease activity
Paralysis induces microtears in
venous endothelium
Impaired inhibition of coagulation
Deficiencies of AT III, PC, PS
Factor V Leiden, prothrombin 20210
Effects of inflammatory cytokines
Increased monocytes tissue factor
Increased plasminogen activator inhibitor
Direct trauma
Torsion during surgery
Hydrodynamic trauma from tourniquet use
Effects of inflammatory cytokines
Endothelial cell apoptosis
Increased endothelial cell tissue factor
Decreased thrombomodulin expression

Blood coagulability

Venous injury

Medical Illness as the risk

factors for DVT

1. Stasis predisposes
to venous thrombosis
By preventing activated coagulation factors
from being diluted by non activated blood
By preventing clearence of activated
coagulation factor
By preventing mixing of activated coagulation
factors with their inhibition

Venous stasis is produced

By immobility
By venous obstruction
By venous dilatation
By increased blood viscosity

KONTRAKSI OTOT

KONTRAKSI OTOT

Medical Illness as the risk

factors for DVT

Medical Illness as RISK FACTORS for VTE

Age > 40 years (VTE risk increases with advancing age)

Intensive care unit (ICU) admission
Prior history of VTE (DVT or PE)
Obesity
Ischemic (nonhemoragic) stroke
Heart Failure
Chronic lung disease
Respiratory failure
Pneumonia
Infection
Malignancy
Thrombophilia (hematological disorder that promote thrombosis)
Active collagen-vascular disorder
Inflammatory disorder (e.g inflammatory bowel disease, etc)
Central venous line/catheter
Varicose veins
Birth control pills
Estrogen replacement therapy
Nephrotic syndrome

This is partial list of common risk factors. Clinicians are advised to consider other factor or
conditions that may predispose to VTE

Incidence Range of VTE Disease

in Western Studies (Medical Illness)
DVT

Proximal DVT

PE

Fatal

(%)

(%)

(%)

(%)

AMI

24.0

2.6-6.1

Stroke

55.0

1.6

0.6

Acute medical conditions

16.0

4.9

1.0

0.3

PE

Pathogenesis II
2.Hypercoagulable state(1)
Activation of blood coagulation
Activation of the intrinsic pathway by
contact of F XII with collagen on the
exposed subendothelium of damaged
vessel (intrinsic pathway)
Activation of the extrinsic pathway by the
release of tissue thromboplastin into blood
stream as a result of cell damage

2.Hypercoagulable state(2)
Activation of blood coagulation
Endothelial cell activation
Activated leukocyte that migrate to area of
vascular damage

Surgical Procedures as the

risk factors for DVT

Pathogenesis II :
2.Hypercoagulable State (1)
Activation of coagulation :
Laparotomy vs laparoscopy

Rahr HB et al. Thromb Hemost 1994; 71:713-18

Rahr HB et al. Thromb Res. 1999; 93: 121-7.

Activation of Coagulation (1)

Laparotomy (n=21)

Laparoscopy (n=50)

3.5
3

F1+2 (nM)

2.5
2
1.5
1
0.5
0
F1+2 , prothrombin fragment 1+2

pre-op
Day 1
North

1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0

pre-op
24h
post-op

Activation of Coagulation (2)

Soluble fibrin (mg/l)

Laparotomy (n=21)

2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0

Laparoscopy (n=50)

7
6
5
pre-op
Day 1
Day 7

4
3
2
1
0

pre-op
24h
post-op

Activation of Coagulation (3)

Laparotomy (n=21)

Laparoscopy (n=50)

FbDP (ng FE/MI)

2500
2000
1500
1000

pre-op
Day 1
Day 7

500
0
FbDP, fibrin degradation products
FE, fibrinogen equivalents

450
400
350
300
250
200
150
100
50
0

pre-op
24h
post-op

Pathogenesis III
3.Vascular damage(1)
Caused shedding of endothelial
Nondenuding
Result in the exposure of blood to
subendothelium

3.Vascular damage (2)

Activation of the extrinsic pathway due to
tissue thromboplastin derived from the
vascular damage
Vascular damage that is accompanied by
endothelial cell detachment probably
contribute to venous thrombosis in patient
undergoing hip surgery, knee surgery

Surgical Procedures as the

risk factors for DVT

Classification of DVT risk

Low risk
Minor surgery
Age <40
No other risk factors
Moderate risk
Major surgery
Age >40
No other risk factors
High risk
Major surgery
Age >40
MI
Additional risk factors

Highest risk
Major surgery
Age >40
History of VTE
Hip fracture
THR or TKR
CVA
Spinal cord injury
Trauma
Malignancy
Congenital
hypercoagulability

VTE, venous thromboembolism; THR, total hip replacement; TKR, total knee
replacement; MI, myocardial infarction; CVA, cerebrovascular accident

Chest 1998;114:531S-60S

Incidence Range of VTE Disease

in Western Studies (Surgical)
DVT

Proximal DVT

PE

Fatal

(%)

(%)

(%)

(%)

THR

45.0-57.0

23.0-36.0

0.7-30

0.1-0.4

TKR

40.0-84.0

9.0-20.0

1.8-7

0.2-0.7

Hip fracture
12.9

36.0-60.0

17.0-36.0

4.3-24.0

3.6-

General surgery

6.0-35.5

6.0-8.0

1.3-2.0

0.6-2.0

Major trauma

28.0-68.0

4.0->50.0

0.5-2

PE

Why does a DVT happen?

Venous thrombosis:
pathogenesis and clinical consequences (1)

Slow, turbulent blood flow in valve cusps result

in areas of local stasis

Stasis leads to the development of a thrombus

composed of red cells and fibrin

Prandoni P, et al. Haematologica 1997; 82:423428.

Venous thrombosis:
clot formation in the venous lumen

1.

2.

Fibrin polymerisation
stabilises the clot

3.

Slow turbulent flow in the

veins induces stasis and
promotes coagulation

Clot growth

Venous thrombosis:
pathogenesis and clinical consequences (2)

Thrombus growth results in proximal

progression along the vein

Deep vein thrombosis

Damage to veins (PTS)

Pulmonary embolism

Prandoni P, et al. Haematologica 1997; 82:423428.

KAKI KIRI BENGKAK

Risk Factor for DVT according to

Virchows Triad
Venous stasis
Age > 60 yrs

Vessel Damage

Coagulation activation

obesity

pregnancy

Immobilization or paralysis

Orthopaedic surgery

Trauma of lower limbs

Cardiac insufficiency

Myocardial infarction (acute

phase)

Stroke

Cancer

General surgery

Inherited or acquired
haemostasis deficiencies

+
+

Venous insufficiency or
varicosis

Previous history of deep vein

thrombosis

EPIDEMIOLOGY

Incidence of thrombosis in
United States of America
Disease

US incidence
/100.000

Total in US /year
cases

Deep Vein Thrombosis

Pulmonary Embolus
139/100.000
347.000
Fatal Pulmonary Emb.
94/100.000
235.000
Myocardial Infarction
600/100.000 1.500.000
Fatal MI
300/100.000
750.000
Cerebrovascular thromb.
600/100.000 1.500.000
Fatal Cereb. Trhromb.
396/100.000
990.000
Total serious thromb. In US
1498/100.000 3.742.000
Total deaths from above thrmb.
790/100.000 1.990.000

Bick RL, Clin Appl Throm Hemos 3, Suppl 1, 1997

159/100.000

398.000

Definable
reason
80%
80 %
80 %
67 %
67 %
30 %
30 %
50 %
50 %

Incidence of VTE:
The third most common
vascular disease
Annual incidence (US data)
Deep vein
thrombosis
(DVT) only
<145/100,000

Pulmonary
embolism (PE) with
or without DVT
<69/100,000

1. Gillum RF. Am Heart J. 1987;114(5):12621264

2. Anderson FA Jr, et al. Arch Intern Med.1991;151(5): 933938
3. Silverstein MD, et al. Arch Intern Med. 1998;158(6):585593
4. NIH Consensus Development. JAMA. 1986 Aug 8;256(6):744749
5. Giuntini C, et al. Chest. 1995 Jan;107(1 Suppl):39S

Complications of
Deep Vein Thrombosis
Permanent vascular damage to lower limb
Post thrombotic venous insufficiency
Postphlebitic syndrome
Pulmonary embolism (PE)
Pulmonary hypertension

TROMBUSEMBOLI

VTE: A strong relationship between

DVT and PE
Almost 50% of patients with
proximal DVT of the leg
have asymptomatic PE1

Migration

Embolus
DVT (mainly asymptomatic)
is found in around 80%
of patients with PE2

Thrombus

1. Pesavento R, et al. Minerva Cardioangiologica. 1997;45:369375

2. Girard P, et al. Chest. 1999;116:903908

Complications of VTE:
Leg ulcer, a severe consequence
Annual incidence of leg ulcer after a DVT = 12%1
Venous ulcer, a highly chronic condition: 1
Cases not healed at 4 months:
50%
2 years:
20%
5 years:
8%
Around 60% of patients have two or more recurrences of venous
ulcer

Venous ulcer, a very costly disease:

Direct medical costs if no healing at 12 weeks
US$10,0002

1. Kurz X, et al. Int Angiol. 1999;18(2):83102

2. Blair SD, et al. BMJ. 1988;297:11591161

Post Thrombophlebitic
syndrome

Post Thrombophlebitic
syndrome

Post Thrombophlebitic
syndrome

Post Thrombophlebitic
syndrome

Post Thrombophlebitic
syndrome

Post Thrombophlebitic
syndrome

Economic burden of VTE

Direct inpatient costs of a
VTE event are comparable
with myocardial infarction
(MI) or stroke1,2

Additional long-term
healthcare costs of
a DVT: 75% of the
initial cost3
12,595

PE1
9,337

DVT1

9,643

MI2
6,367

Stroke2
0

2500

5000

7500

10000

12500

Average
cost per
admission
in the US ($)

1. Bick RL. Clin Appl Thromb Hemost. 1999;5(1):29

2. Medicare & DRG. 1996
3. Bergqvist D, et al. Ann Intern Med. 1997;126:454457

Incidence Range of VTE Disease

in Western Studies
DVT

Proximal DVT

PE

Fatal

(%)

(%)

(%)

(%)

THR

45.0-57.0

23.0-36.0

0.7-30

0.1-0.4

TKR

40.0-84.0

9.0-20.0

1.8-7

0.2-0.7

Hip fracture
12.9

36.0-60.0

17.0-36.0

4.3-24.0

3.6-

General surgery

6.0-35.5

6.0-8.0

1.3-2.0

0.6-2.0

Major trauma

28.0-68.0

4.0->50.0

0.5-2

AMI

24.0

2.6-6.1

Stroke

55.0

1.6

0.6

Acute medical conditions

16.0

4.9

1.0

0.3

PE