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ΘΡΟΜΒΟΔΜΒΟΛΙΚΑ ΔΠΔΙΟΓΙΑ ΣΗ

ΜΔΘ

ΓΙΑΝΝΗ ΚΑΨΟΚΑΛΤΒΑ

ΔΙΓΙΚΔΤΟΜΔΝΟ ΑΝΑΙΘΗΙΟΛΟΓΙΑ Α.Ν.Θ.

„ΘΔΑΓΔΝΔΙΟ‟

Virchow's triad.

Kyrle P A , Eichinger S Blood 2009;114:1138-1139

©2009 by American Society of Hematology

Biomaterials Research - Manfred Maitz

The Blood Clotting Cascade

•Manfred Maitz

FZ-Rossendorf

•www.manfred.maitz-online.de

http://www.fz-rossendorf.de/

http://www.manfred.maitz-online.de/





The Clotting Cascade

FibrinogenFibrin

monomers

Fibrin

polymers

Thrombin




Factor F X

F IXaF IX

F XIaF XI

Surface Contact

Collagen

FXII activator

F XIIaF XII

Intrinsic Pathway

Ca2+

Ca2+

Ca2+

The Clotting Cascade

Factor F X

F VIIF VIIa

F III (Tissue

Thromboplastin)

Tissue/Cell Defect

Extrinsic Pathway

Ca2+

Ca2+

FibrinogenFibrin

monomers

Fibrin

polymers

ThrombinProthrombin I

Factor F Xa

Ca2+

Platelet Factor 3

Crosslinked

Fibrin Meshwork

F XIIIa F XIII

F VF Va

F VIIIaF VIII




Ser:O

H

RN

CO

HN

RC

Serine Proteases

H2O

O

RN

CO-

HN

RC

Ser

HTetraedric

Transition State

RN

C

O OH :O

HSer

Release of the

N-terminal peptide

HN H

RC

O

RN

CO Ser

Break of the

Peptide Bonding

Enzyme-acetyl-

transition-state




The Fibrinolytic System

Fibrin

degradation productsFibrinogen Fibrin-clot

PlasminPlasminogen

T-PA

F XIIa

HMWK

Kallikrein

Urokinase

Streptokinase

Clotting

Cascade



LIFEBLOOD

THE

ThrombosisCHARITY

Venous thromboembolism –

Definition, epidemiology,

aetiology and pathogenesis

These slides were kindly provided by AstraZeneca

Ulcus crurisChronic PE

PE

Venous thromboembolism

DVT

Post-thromboticsyndrome

Death

Deep vein insufficiency

Pulmonaryhypertension

Deep vein thrombosis

Veins of the leg

Common femoral vein

Thrombus

KneeProximal

Distal

Symptoms of post-thrombotic syndrome – long

“lag-phase” (years)

Pain

Oedema

Discoloration

Varices

Ulceration

Post-thrombotic syndrome

Post-thrombotic syndrome

Ulcus cruris venosum

Severe stasis and ulceration

Embolus

Pulmonaryartery

Pulmonaryvein

Leftatrium

Rightatrium

Rightventricle

Leftventricle

Thrombus formation in a deep vein

A fragment of a thrombus travelling

towards the lungs

Pulmonary embolism

Dyspnea, syncope, hypotension,

cyanosis

Embolus

Pulmonary embolism kills

Pulmonary embolism

Pleuritic pain, cough, haemoptysis

Symptoms may be vague or absent

Embolus

Pulmonary embolismDeep vein thrombosis

Venous thromboembolism (VTE)

Normal PA chest radiograph

Pulmonary hypertension PA chest

radiograph

Prominent pulmonary

artery segmentEnlarged, but “pruned” proximal

pulmonary artery

Venous thromboembolism is a

major problem

DVT

2 million

Pulmonary hypertension

30,000

Silent PE1 million

PE

600,000

Death

100,000

Post-thrombotic syndrome800,000

Hirsh J & Hoak J. Circulation 1996; 93:2212–45

Estimated annual incidence rates in the USA

Classification of level of VTE risk

Surgery in

patients with

multiple risk factors

(age >40, cancer,

prior VTE)

Hip or knee

arthroplasty, hip

fracture surgery

Major trauma,

spinal cord injury

Surgery in

patients 40-60

years with no

additional risk

factors

Minor surgery

in patients with

additional risk

factors

Minor surgery in

patients <40

years with no

additional risk

factors

Surgery in

patients >60

years, or age

40-60 with

additional

risk factors

(prior VTE,

cancer,

molecular

hyper-

coagulability)

Geerts WH et al. Chest 2004;126:338S–400S

Low risk High risk Highest riskModerate risk

Thromboembolic risk categories

Geerts WH et al. Chest 2004;126:338S–400S

Frequency of

fatal PE (%)

Frequency of

calf DVT (%)Category

Frequency of

proximal DVT (%)

Highest risk 40-80 10-20 0.2-5

High risk 20-40 4-8 0.4-1.0

Moderate risk 10-20 2-4 0.1-0.4

Low risk 2 0.4 <0.01

Pregnancy

Oral contraceptives

Hormone replacement

therapy

Immobilisation

Surgery

Persistent Transient

Acquired

Age

History of VTE

Malignancy

Antiphospholipid antibody syndrome

Genetic

Thrombophilia

VTE – risk factors

Thrombophilia and risk of recurrence

Antithrombin deficiency

Homozygous factor VLeiden

Combined defects

Antiphospholipid antibodies (LA/ACA)

Protein C deficiency

Protein S deficiency

Heterozygous factor VLeiden

Heterozygous prothrombin gene mutation

Risk

Risk importance

Pathogenesis of VTE

Virchow´s triad

Stasis Injury to the vessel wall

Hypercoagulability

Rudolf Virchow

Pathogenesis of VTE

Virchow´s triad

Injury to the vessel wall

Damage to the vessel wall can be

produced by direct trauma such as

major hip or knee surgery, stab

wounds or insertion of venous

catheters, by direct invasion from

cancer cells, or as a consequence of

age. Support structures in vessel

walls deteriorate with age, leading to

weakness and a predisposition to

damage from distension.

Stasis

Hypercoagulability

Pathogenesis of VTE

Virchow´s triad

Injury to the

vessel wall

Hypercoagulability

Stasis

Stasis describes the slowing or even

cessation of blood flow. This

commonly occurs in veins as a result

of immobility or paralysis and can

lead to concentration and subsequent

activation of coagulation factors.

Stasis can also cause the vessel walls

to become distended, resulting in

endothelial damage.

Pathogenesis of VTE

Virchow´s triad

Stasis Injury to the vessel wall

Hypercoagulability

The term hypercoagulability means an increased propensity to

clot. Hypercoagulability can occur as a result of a genetic

defect, stasis, malignancy or hormone changes such as

during pregnancy, during administration of oral contraceptives

or hormone replacement therapy.

6. Vessel wall with activated endothelium

(colour-enhanced scanning electron micrograph)

This scanning electron micrograph shows how the

endothelium has reacted to compression and damage during

surgery. The endothelial cells are activated and the clotting

cascade has started. The formation of thrombin is the pivotal

step in fibrin formation and thrombus development.

Potentially Important Clinical Risk

Factors for VTE in Critically Ill

Patients

• Factors present before ICU admission

• Surgery

• Trauma

• Malignancy and its treatment

• Sepsis

• Immobilization

• Bedrest

• Stroke

• Spinal cord injury

• Increased age

• Pregnancy/puerperium

• Estrogens

•

Venous Thromboembolism and Its

Prevention in Critical Care

Journal of Critical Care, Vol 17, No 2

(June), 2002: pp 95-104

Potentially Important Clinical Risk

Factors for VTE in Critically ill

Patients

• Factors acquired in ICU

• Central venous lines

• Sepsis

• Pharmacologic sedation, paralysis

• Mechanical ventilation

Venous Thromboembolism

and Its Prevention in Critical

Care

Journal of Critical Care, Vol 17,

No 2 (June), 2002: pp 95-104

Incidence of DVT in Hospitalized

Patients

• Patient Group DVT Incidence

• Bedrest medical patients 10%–20%

• General abdominal surgery 15%–40%

• Neurosurgery 15%–40%

• Stroke 20%–50%

• Tibial fracture 20%–70%

• Hip or knee surgery 40%–60%

• Major trauma 40%–70%

• Spinal cord injury 60%–80%

• ICU 10%–80%

Venous

Thromboembolism and Its

Prevention in Critical

CareJournal of Critical

Care, Vol 17, No 2 (June),

2002: pp 95-104

Why ICU-specific studies addressing

VTE risks and prophylaxis are essential

• Symptoms or signs of possible VTE are much more common in critical

care patients; however,confirming (or excluding) this diagnosis is often

more difficult and is associated with greater risks for investigation among

these patients.

• • Many ICU patients have reduced cardiorespiratory reserve. Therefore,

small pulmonary emboli, well tolerated by non-ICU patients, may be

poorly tolerated by critically ill patients.

• • Critically ill patients have the highest morbidity and mortality of

hospitalized patients, and it is unclear whether the relative benefit of

different prophylaxis strategies are similar between these and other

patients.

• • Bleeding associated with anticoagulant prophylaxis may be more

frequent and associated with greater morbidity in ICU patients

Venous Thromboembolism and Its Prevention in Critical CareJournal of Critical Care, Vol 17, No 2 (June), 2002: pp 95

384/99 medslides.com38


State of the Art

•American Journal of

•Respiratory and Critical Care

Medicine

•Vol 159, 1999



• Two major clinical manifestations

– deep venous thrombosis (DVT)

– pulmonary embolism (PE)

– 30% DVT pts develop symptomatic PE

50%-60% DVT pts develop asymptomatic

PE

• VTE affects 1/1000 persons yearly

• PE causes 50,000 death in the U.S.

yearly


DVT - Risk factors and

Prevalence

• DVT most often originates in the

deep veins of the major calf muscles

• venous stasis

• trauma

• surgery

• childbirth

• increasing age

• all cancers


Thrombophilia

• Definition

• recurrent venous or arterial

thrombosis from inherited or acquired

causes


Inherited Thrombophilic States

•

Prevalence (%)

• Patients

with

VTE

1st

• Event

• Activated protein C resistance 3-4 20

50 3-7

• Hyperhomocysteinemia - 15 -

-

• Protein C deficiency 0.2-0.4 3 1-

9 5-12

• Protein S deficiency 0.1 2 1-

13 4-11

General

Population Recurrence RR*

* Relative Risk for recurrent VTE. Relative to an index case no inherited

thrombophillia.

Am J Respir Crit Care Med. Vol 159: 1-14; 1999


Activated Protein C Resistance

• Inheritated abnormality known as factor V Leiden

• involves a point mutation (adenine for guanine)

that results in the substitution of glutamine for

arginine at position 506 on factor V

• activated protein-C becomes resistant to

degradation

• the heterozygous state (5% of Caucasians) carries

a 3 to 5 fold increased risk for VTE

• Factor V Leiden can be identified in 20% of

patients with one episode and 50% of those with

recurrent VTE


Prevention of Venous

Thromboembolism• Without Prophylaxis

(%) Recommended With Prophylaxis (%)

• Risk Group Prox DVT Fatal PE Prophylaxis Prox DVT

Fatal PE

• Hip replacement 20-30 2-4 WAR, LMWH 5

0.1-0.2

• Knee replacement 20-30 2-4 WAR, LMWH, IPC 5

0.1-0.2

• Hip fracture 25-35 2-4 WAR, LMWH 10

0.2-0.4

• Major trauma 20 0.5-1.0 LMWH, IPC 10

<0.1

• Abdominal or pelvic

• cancer surgery 20 0.5-1.0

LMWH, IPC, WAR 10 <0.1

• Abdominal surgery,

• coronary artery 5-7 0.5

UF, LMWH, IPC <1 <0.1

• bypass graft WAR, ES


ES = elastic stockings; IPC = intermittent pneumatic compression; UF = unfractionated heparin


Prevention

• Anticoagulation and other antithrombotics form

the basis for prophylaxis

• Drugs are continued for 5-7 d for high-risk; 7-10

d for orthopedic procedure on the lower

extremity

• No prophylactic technique is completely

effective


Vena Caval Filters

prophylactic device for pulmonary

embolism• patient with proximal DVT

– who cannot receive anticoagulants

– who has failed anticoagulants

• patient undergoing pulmonary embolectomy

• patient undergoing pulmonary endarterectomy

for chronic thromboembolic pulmonary

hypertension

• filters appear to prevent PE within the following

2 wks but did not affect short or long-term

mortality


Diagnosis

• Of patients with suspected DVT, only one in four

will prove to have DVT

• Differential diagnosis:

– cellulitis, heart failure with edema, ruptured Baker‟s

cyst, chronic venous insufficiency

• Diagnostic tests:

– ultrasound with manual compression

– impedance plethysmography

– contrast venography

– fibrin degradation product D-dimer


Diagnostic Approach to DVT



Natural History of DVT

• Untreated proximal DVT

– clinical PE occurs in 1/3 to 1/2 of patients

– sub-clinical PE occurs in another 1/3

– untreated PE tends to recur in days to weeks

• Post-phlebitic syndrome (10-30% of

DVT)

– pain, edema, skin discoloration, and

ulceration associated with chronic venous

insufficiency


Pulmonary Embolism

• Three major clinical presentations:

• 1. dyspnea with or without pleuritic chest

pain and hemoptysis

• 2. hemodynamic instability and syncope

(usually associated with massive pulmonary

embolism)

• 3. mimicking indolent pneumonia or heart

failure, especially in the elderly


Common symptoms of Acute

PE

• PIOPED study found

– Dyspnea

– Pleuritic chest pain

– Tachypnea (resp rate 20 / min)

• in 97% of patients with angiographic

proven PE

• The absence of this triad reduces the

clinical probability of PE


Estimating Clinical Probability of

Pulmonary Embolism

• High Risk factor present

(80-100% probable) Otherwise unexplained dyspnea, tachypnea, or

pleuritic

chest pain

Otherwise unexplained radiographic or gas

exchange

abnormality

• Intermediate Neither high nor low clinical probability

(20-79% probable)

• Low Risk factor not present

(1-19% probable) Dyspnea, tachypnea, or pleuritic pain possibly

present

but unexplained by another condition

Radiographic or gas exchange abnormality

possibly

present but explainable by another condition



Diagnostic Test

• Ventilation-perfusion lung scan

– 2 moderate-to-large perfusion defects (>25% of a lung

segment) with intact ventilation in a clear chest x-ray in the

involved area

• Widened (A-a) O2 gradient

– low PO2, low PCO2

• Chest x-ray

– central pulmonary artery engorgement, paucity of peripheral

vessels (Westermark sign)

• Electrocardiogram

– nonspecific ST-T changes, right-axis, S1-Q3-T3, P-pulmonale


Suspect Pulmonary Embolism ?

Give heparin IV and order V/Q scan

Low V/Q probability,

low clinical probability

High V/Q probability +

high clinical probability

Intermediate V/Q probability,

Low or high V/Q prob with

discordant clinical probability

Probability

V/Q Clinical

1. Low Mid

2. Mid Low

No treatment

Probability

V/Q Clinical

3. Low High

4. Mid Mid / High

5. High Low / Mid

Leg Ultrasound Treat

_

Pulmonary

Angiography

+

+



CTPHChronic Thromboembolic Pulmonary

Hypertension

• Result of recurrent or unresolved PE

• Occurs in 1% of patients with PE

• Sx: increasing dyspnea, exertion constant

• Diagnosis:

– diagnosis should be considered in any one with

unexplained dyspnea on exercise

– V/Q scan shows multiple large defects


Treatment

• iv heparin until the diagnosis is ruled out

• heparin - UFH or LMWH

• warfarin / coumarin derivatives

• adjunctive recommendations:

– bed rest until heparin is therapeutic

– elastic stockings until patient becomes

ambulatory ( post-thrombotic syndrome)


Body Weight-Based Dosing

of Intravenous Heparin• Initial dosing: Loading 80 U/kg 18 U/kg/hg (APTT in 6 hrs)

• APTT(s) Dose Change Additional Next APTT (h)

• (x normal) (U/kg/h) Action

• <35 (1.2 x) +4 Rebolus 80 U/kg 6

• 35-45 (1.2-1.5x) +2 Rebolus 40 U/kg 6

• 46-70 (1.5-2.3x) 0 0 6*

• 71-90 (2.3-3.0x) -2 0 6

• >90 (<3x) -3 Stop infusion 1 h 6* During first 24 h, thereafter, once / day



Low-Molecular-Weight Heparin

• Drug Prophylactic Indication Treatment Dose

• Ardeparin Knee arthroplasty 130 anti-Xa U/kg bid

(Normaiflo)

• Dalteparin Abdominal surgery 120 anti-Xa U/kg bid

(Fragmin)

• Enoxaparin Hip or knee arthroplasty, 1-1.5 mg/kg bid

(Lovenox) Abdominal surgery (1 mg 100 anti-Xa

units)

• Danaparoid Hip arthroplasty

(Orgaran)

* LMWH < 5.6 kD, lose anti-IIa activity, cannot be reliably monitored with APTT


Incidence of DVT in Hospitalized

Patients

• Patient Group DVT Incidence

• Bedrest medical patients 10%–20%

• General abdominal surgery 15%–40%

• Neurosurgery 15%–40%

• Stroke 20%–50%

• Tibial fracture 20%–70%

• Hip or knee surgery 40%–60%

• Major trauma 40%–70%

• Spinal cord injury 60%–80%

• ICU 10%–80%

Venous

Thromboembolism and Its

Prevention in Critical

CareJournal of Critical

Care, Vol 17, No 2 (June),

2002: pp 95-104

Why ICU-specific studies addressing

VTE risks and prophylaxis are essential

• Symptoms or signs of possible VTE are much more common in critical

care patients; however,confirming (or excluding) this diagnosis is often

more difficult and is associated with greater risks for investigation among

these patients.

• • Many ICU patients have reduced cardiorespiratory reserve. Therefore,

small pulmonary emboli, well tolerated by non-ICU patients, may be

poorly tolerated by critically ill patients.

• • Critically ill patients have the highest morbidity and mortality of

hospitalized patients, and it is unclear whether the relative benefit of

different prophylaxis strategies are similar between these and other

patients.

• • Bleeding associated with anticoagulant prophylaxis may be more

frequent and associated with greater morbidity in ICU patients

Venous Thromboembolism and Its Prevention in Critical CareJournal of Critical Care, Vol 17, No 2 (June), 2002: pp 95


Effect of Antithrombin III/Heparin

FibrinogenFibrin

monomers

Prothrombin I Thrombin

Factor F XaFactor F X Factor F X

F VIIF VIIa

F IXaF IX

F XIaF XI

Surface Contact

Collagen

FXII activator

F XIIaF XII

F III (Tissue

Thromboplastin)

Tissue/Cell Defect

Intrinsic Pathway Extrinsic Pathway

Platelet Factor 3

Ca2+

Ca2+

Ca2+

Ca2+Ca2+

Fibrin

polymersCrosslinked

Fibrin Meshwork

F XIIIa F XIII

F VF Va

F VIIIaF VIII

Ca2+




Thrombin Time (TT)

FibrinogenFibrin

monomers



F VIIF VIIa

F IXaF IX

F XIaF XI

Surface Contact

Collagen

FXII activator

F XIIaF XII

F III (Tissue

Thromboplastin)

Tissue/Cell Defect


Platelet Factor 3

Ca2+

Ca2+

Ca2+

Ca2+Ca2+

Fibrin

polymersCrosslinked

Fibrin Meshwork

F XIIIa F XIII

F VF Va

F VIIIaF VIII

Ca2+




The Quick (PT)-Test

FibrinogenFibrin

monomers



F VIIF VIIa

F IXaF IX

F XIaF XI

Surface Contact

Collagen

FXII activator

F XIIaF XII

F III (Tissue

Thromboplastin)

Tissue/Cell Defect


Platelet Factor 3

Ca2+

Ca2+

Ca2+

Ca2+Ca2+

Fibrin

polymersCrosslinked

Fibrin Meshwork

F XIIIa F XIII

F VF Va

F VIIIaF VIII

Ca2+




Partial Thromboplastin Time [(a)PTT]

FibrinogenFibrin

monomers



F VIIF VIIa

F IXaF IX

F XIaF XI

Surface Contact

Collagen

FXII activator

F XIIaF XII

F III (Tissue

Thromboplastin)

Tissue/Cell Defect


Platelet Factor 3

Ca2+

Ca2+

Ca2+

Ca2+Ca2+

Fibrin

polymersCrosslinked

Fibrin Meshwork

F XIIIa F XIII

F VF Va

F VIIIaF VIII

Ca2+




Surface Sensitive Steps

FibrinogenFibrin

monomers



F VIIF VIIa

F IXaF IX

F XIaF XI

Surface Contact

Collagen

FXII activator

F XIIaF XII

F III (Tissue

Thromboplastin)

Tissue/Cell Defect


Platelet Factor 3

Ca2+

Ca2+

Ca2+

Ca2+Ca2+

Fibrin

polymersCrosslinked

Fibrin Meshwork

F XIIIa F XIII

F VF Va

F VIIIaF VIII

Ca2+



•Management of venous thromboembolism in the

intensive

•care unit

•Stephen M. Pastores MD, FACP, FCCP, FCCM⁎

•Journal of Critical Care (2009) 24, 185–191

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