DVT From Pathophysiologi to Prophylaxis 2006

NYOTO WIDYO ASTORO

HEMATOLOGI-ONKOLOGI MEDIK PENYAKIT DALAM RS GATOT SOEBROTO

HEMOSTASIS

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

HemostasisBV Injury

PlateletPlateletAggregation

Blood VesselBlood Vessel Constriction

CoagulationCoagulation Cascade

Stable Hemostatic Plug

Fibrin formation

Reduced

Blood flow

Tissue Factor

Primary hemostatic plug

Neural

Lab Tests•CBC-Plt•BT,(CT)•PT•PTT

Plt StudyMorphologyFunctionAntibody

Platelet Adhesion

and Activation

The primary haemostatic system:haemostasis and platelet plug formation

Vascularinjury

Formation ofplatelet plug

exposed sub endothelial tissue

trombosit

endothelial cells

sub endothelial tissue

Platelet aggregation

Adhesion

Activation

Aggregation

White clot

Primary haemostasis

The haemostatic system:secondary haemostasis and clot formation

ThrombinProthrombin

FibrinExtrinsic pathway

Intrinsic pathway

Factor Xa

Fibrin threads

Coagulation cascadeleads to clot formation

Clot growth

Fibrinogen

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

VIIa

Coagulation balance: endogenous activators : the core role of factor Xa

Boneu B, et al. Sang Thrombose Vaisseaux 1998; 10:291–313.

Cellular thromboplastin

Ca2+

Xa

XIa

Intrinsic system Extrinsic system

X

II

IX

XIIIa

XI

XII XIIa

Soluble fibrinFibrinogen Fibrin (clot)

XaVa

PLCa2+

VII

ThrombinIIa

IXaVIIIaCa2+

PL

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 activationEvidence of fibrinolytic activationEvidence of inhibitor consumptionEvidence 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 PlateletsRBCs

White Thrombus

SLOW FLOW : VENOUS CIRCULATION

Fibrin PlateletsRBCs

Red Thrombus

RED THROMBUS IN LUMEN OF VEIN

Fibrin PlateletsRBCs

White Thrombus

Fibrin PlateletsRBCs

Red Thrombus

High Flow Slow Flow

Platelets: Role in Thrombosis

RBCs, red blood cells.

Pathogenesis of DVT

Venous thromboembolismVenous thromboembolismVirchow's TriadVirchow's Triad

• StasisStasis• Activation of coagulationActivation of coagulation• Vessel damageVessel damage

Interpretation of Virchow’s triad using modern understanding of the physiologic mechanisms of thrombosis

Virchow’s Triad Modern interpretation

Stasis Immobility: of minor importance except that it may indicate underlying disease activityParalysis induces “ microtears” in venous endothelium

Blood coagulability Impaired inhibition of coagulation Deficiencies of AT III, PC, PS Factor V Leiden, prothrombin 20210Effects of inflammatory cytokines Increased monocytes tissue factor Increased plasminogen activator inhibitor

Venous injury Direct trauma Torsion during surgery Hydrodynamic trauma from tourniquet useEffects of inflammatory cytokines Endothelial cell apoptosis Increased endothelial cell tissue factor Decreased thrombomodulin expression

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 syndromeThis is partial list of common risk factors. Clinicians are advised to consider other factor orconditions that may predispose to VTE

Incidence Range of VTE Disease in Western Studies (Medical Illness)

DVT Proximal DVT PE Fatal PE

(%) (%) (%) (%)

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

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; 71:713-18Rahr HB et al. Thromb Res. 1999; 93: 121-7.

Activation of Coagulation (1)

0

0.5

1

1.5

2

2.5

3

3.5

pre-opDay 1North

F1+2

(nM

)

F1+2 , prothrombin fragment 1+2

00.20.40.60.8

11.21.41.61.8

pre-op

24hpost-op

Laparotomy (n=21) Laparoscopy (n=50)

Activation of Coagulation (2)

00.20.40.60.8

11.21.41.61.8

2

pre-opDay 1Day 7

Sol

uble

fibr

in (m

g/l)

0

1

2

3

4

5

6

7

pre-op

24hpost-op

Laparotomy (n=21) Laparoscopy (n=50)

Activation of Coagulation (3)

0

500

1000

1500

2000

2500

pre-opDay 1Day 7

FbD

P (n

g FE

/MI)

050

100150200250300350400450

pre-op

24hpost-op

Laparotomy (n=21) Laparoscopy (n=50)

FbDP, fibrin degradation productsFE, fibrinogen equivalents

Pathogenesis III3.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

Chest 1998;114:531S-60S

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

Incidence Range of VTE Disease

in Western Studies (Surgical)DVT Proximal DVT PE Fatal

PE (%) (%) (%) (%)

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 36.0-60.0 17.0-36.0 4.3-24.0 3.6-12.9

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

•Why does a DVT happen?

Venous thrombosis: pathogenesis and clinical consequences (1)

Stasis leads to the development of a thrombus composed of red cells and fibrin

Slow, turbulent blood flow in valve cusps result in areas of local stasis

Prandoni P, et al. Haematologica 1997; 82:423–428.

Venous thrombosis: clot formation in the venous lumen

Slow turbulent flow in the veins induces stasis and promotes coagulation

1.

Fibrin polymerisation stabilises the clot2. Clot growth3.

Venous thrombosis: pathogenesis and clinical consequences (2)

Deep vein thrombosis

Thrombus growth results in proximal progression along the vein

Pulmonary embolismDamage to veins (PTS)

Prandoni P, et al. Haematologica 1997; 82:423–428.

KAKI KIRI BENGKAK

Risk Factor for DVT according to Virchow’s Triad

Venous stasis Vessel Damage Coagulation activation

Age > 60 yrs +

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 Total in US /year Definable /100.000 cases reason

• Deep Vein Thrombosis 159/100.000 398.000 80%

• Pulmonary Embolus 139/100.000 347.000 80 %• Fatal Pulmonary Emb. 94/100.000 235.000 80 %• Myocardial Infarction 600/100.000 1.500.000 67 %• Fatal MI 300/100.000 750.000 67 % • Cerebrovascular thromb. 600/100.000 1.500.000 30 %• Fatal Cereb. Trhromb. 396/100.000 990.000 30 % • Total serious thromb. In US 1498/100.000 3.742.000 50 %• Total deaths from above thrmb. 790/100.000 1.990.000 50 %

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

1. Gillum RF. Am Heart J. 1987;114(5):1262–12642. Anderson FA Jr, et al. Arch Intern Med.1991;151(5): 933–9383. Silverstein MD, et al. Arch Intern Med. 1998;158(6):585–593

4. NIH Consensus Development. JAMA. 1986 Aug 8;256(6):744–7495. Giuntini C, et al. Chest. 1995 Jan;107(1 Suppl):3–9S 

Deep vein thrombosis (DVT) only

Pulmonary embolism (PE) with

or without DVT

Annual incidence (US data)

<69/100,000<145/100,000

Incidence of VTE: The third most common

vascular disease

Complications ofDeep 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

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

1. Pesavento R, et al. Minerva Cardioangiologica. 1997;45:369–3752. Girard P, et al. Chest. 1999;116:903–908

Embolus

Migration

Thrombus

Annual incidence of leg ulcer after a DVT = 1–2%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$10,00021. Kurz X, et al. Int Angiol. 1999;18(2):83–1022. Blair SD, et al. BMJ. 1988;297:1159–1161

Complications of VTE: Leg ulcer, a severe consequence

Post Thrombophlebitic syndrome

Post Thrombophlebitic syndrome

Post Thrombophlebitic syndrome

Post Thrombophlebitic syndrome

Post Thrombophlebitic syndrome

Post Thrombophlebitic syndrome

Economic burden of VTE

1. Bick RL. Clin Appl Thromb Hemost. 1999;5(1):2–9 2. Medicare & DRG. 1996

3. Bergqvist D, et al. Ann Intern Med. 1997;126:454–457

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

Average cost per admission in the US ($)

PE1

DVT1

MI2

Stroke2

12,595

9,337

9,643

6,367

0 5000 100002500 7500 12500

Incidence Range of VTE Disease

in Western StudiesDVT Proximal DVT PE Fatal

PE (%) (%) (%) (%)

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 36.0-60.0 17.0-36.0 4.3-24.0 3.6-12.9

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