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THROMBOSIS

Fatimah Eliana

Intrinsic Clotting Pathway

The Clotting Cascade

Blood or collagen contact

XII

Tissue trauma

XIIa (H)

XI

Extrinsic Clotting Pathway

Tissue factor

XIa (H)
(W) VII VIIa
(W) IX

IXa (H)
CA++

PF 3

VIII (W)

Common Pathway

(W) X

Xa (H)

(Next slide)

Common Pathway

Xa (H)
Ca++

PF 3
V (W)
(H) (F)

(W) Prothrombin

Thrombin

Ca++

Fibrinogen

CA++

Fibrin
(soluble)
(H)
XIIIa

Fibrin (insoluble)

XIII

Coagulation
Cascade

A series of conversions of
inactive proenzymes to
activated enzymes,
culminating in the
formation of thrombin
Thrombin then coverts the
soluble plasma protein
fibrinogen to insoluble
fibrous protein fibrin

Coagulation
Cascade
Intrinsic
Surface contact
Extrinsic
Tissue injury

Factors that favor or


inhibit thrombosis

Control of cascade to
prevent clotting elsewhere
Antithrombins
activated by
heparin like
molecules on
endothelial cells
Clinical
administration of
heparin minimizes
thrombosis

Proteins C and S
Vitamin K
dependent

Plasminogenplasmin system
Breaks down
fibrin and inhibits
its polymerization
Products of split
fibrin are
anticoagulants

Thrombus Formation

Clot is a thrombus formed in an arterial


or venous vessel
Thrombophlebitis - both inflammation
and clots are present
Some thrombus can be superficial but
its the DVT thats a concern
embolism to lungs

Arterial Thrombus

Begins with platelet adhesion to arterial


vessel wall
Adenosine diphosphate
(ADP) released from platelets
more
platelet aggregation blood flow inhibited
fibrin, platelets and erythrocite surround
clot
build up of size structure
occludes blood vessels tissue ischemia
The result of arterial thrombus is localized
tissue injury from lack of perfusion
Antiplatelet drugs primarily act by
preventing arterial thrombosis

Venous Thrombus

Usually from slow blood flow


Stagnation of the blood flow initiate the
coagulation cascadeproduction of fibrin
enmeshes erythrocyte andplatelets to form
the thrombus.
Venous thrombus has a long tail that can
break off to produce an embolus.
These travel to faraway sites then lodge in
lung (capillary level) inadequate O2 and
CO2 exchange occur (pulmonary and cerebral
embolism)

Types of foot ulcers

Arterial

Venous

Neuropathic

Foot ulcers

Arterial Venous

Neuropathic

Location

Distal Medial
malleolus point

Arterial disease
and risk factors for
atherosclerosis

Yes

No

No

Contra-lateral
pulses

No

Yes

Yes (maybe)

Skin changes of
venous HTN

No

Yes

No

Maybe No

Yes

Neuropathy

Pressure

DEEP VENOUS
THROMBOSIS

Definition

Deep vein thrombosis is the formation


of a blood clot in one of the deep veins
of the body, usually in the leg

Etiology

DVT usually originates in the lower


extremity venous level
Starting at the calf vein level and
progressing
proximally
to
involve
popliteal, femoral or iliac system.
80 -90 % pulmonary emboli originates
here

Virchow triad

More than 100 years ago, Virchow


described a triad of factors:
Venous stasis
Hypercoagulable state
Endothelial damage

Venous stasis

Prolonged bed rest (4 days or more)


A cast on the leg
Limb paralysis from stroke or spinal
cord injury
Extended travel in a vehicle

Hypercoagulability

Surgery and trauma responsible for


up to 40% of all thromboembolic
disease
Malignancy
Increased estrogen (fall in protein S):

all stages of pregnancy


the first three months postpartum,
after elective abortion
during treatment with oral contraceptive
pills

Inherited disorders of
coagulation

deficiency of protein S
deficiency protein C
deficiency antithrombin III.

Acquired disorders of
coagulation

Nephrotic syndrome urinary loss of


antithrombin III (should be considered in
children presenting with thromboembolic
disease)
Autoimmune disorder accelerate coagulation:
Antiphospholipid syndrome (APS): antiphospholipid
antibody, anticardiolipin antibody
systemic lupus erythematosus (SLE): lupus
anticoagulant

Acquired disorders of
coagulation

Inflammatory processes, such as:


sickle cell disease
inflammatory bowel disease (IBD),

also
predispose
to
thrombosis,
presumably due to hypercoagulability

Endothelial Injury

Trauma, surgery and invasive procedure may


disrupt venous integrity.
Iatrogenic causes of venous thrombosis are
increasing due to the widespread use of
central
venous
catheters,
particularly
subclavian and internal jugular lines.
These lines are an important cause of upper
extremity DVT, particularly in children.

Clinical Pathophysiology

The nidus for a clot is often an intimal


defect
When a clot forms on an intimal defect,
the coagulation cascade promotes clot
growth proximally.
Thrombus
can
extend
from
the
superficial veins into the deep system
from which it can embolize to the lungs.

Clinical Pathophysiology

Opposing the coagulation cascade is


the endogenous fibrinolytic system.
After the clot organizes or dissolves,
most veins will recanalize in several
weeks.
Residual clots retract as fibroblasts and
capillary development lead to intimal
thickening.

Presentation and Physical


Examination

Calf pain or tenderness, or both


Swelling with pitting oedema
Swelling below knee in distal deep vein
thrombosis and up to groin in proximal
deep vein thrombosis
Increased skin temperature
Superficial venous dilatation
Cyanosis can occur with severe
obstruction

Presentation and Physical


Examination

Palpate distal pulses and evaluate


capillary refill to assess limb perfusion.
Move and palpate all joints to detect acute
arthritis or other joint pathology.
Neurologic evaluation may detect nerve
root irritation; sensory, motor, and reflex
deficits should be noted
Homans' sign: pain in the posterior calf or
knee with forced dorsiflexion of the foot

Presentation and Physical


Examination

Search for stigmata of PE such as


tachycardia (common), tachypnea or
chest findings (rare)
Exam for signs suggestive of underlying
predisposing factors.

Wells Clinical Prediction Guide

SCORE
Active cancer (treatment ongoing, or within 6 months or
palliative)

Paralysis or recent plaster immobilization

Recently bedridden for >3 days or major surgery <4


weeks

Localized tenderness along the distribution of the deep


venous system

Entire leg swelling

Calf swelling >3 cm compared to the asymptomatic leg

Pitting edema (greater in the symptomatic leg)

Collateral superficial veins (nonvaricose)

Alternative diagnosis (as likely or > that of DVT)

Wells Clinical Prediction


Guide

Total of Above Score


High probability
: Score > 3
Moderate probability : Score = 1 or 2
Low probability : Score 0

Diagnostic Studies

Clinical examination alone is able to


confirm only 20-30% of cases of DVT
Blood Tests
D-dimer: predictive value for DVT

INR:
useful
for
guiding
the
management of patients with known
DVT who are on warfarin (Coumadin)

D-dimer

D-dimer is a specific degradation product


of cross-linked fibrin.
Because
concurrent
production
and
breakdown of clot characterize thrombosis,
patients with thromboembolic disease
have elevated levels of D-dimer
Three major approaches for measuring Ddimer
ELISA
Latex agglutination
Blood agglutination test (SimpliRED)

D-dimer
False-positive
patients:

D-dimers

occur

in

recent (within 10 days) surgery or trauma,


recent myocardial infarction or stroke,
acute infection,
disseminated intravascular coagulation,
pregnancy or recent delivery,
active collagen vascular disease,
metastatic cancer

Imaging Studies

Invasive
Venography
Radiolabeled fibrinogen.

Noninvasive
Ultrasound with Doppler
Plethysmography
MRI techniques

Venography

Gold standard modality for the diagnosis


Advantages:
useful if the patient has a high clinical
probability of thrombosis and a negative
ultrasound
valuable in symptomatic patients with a
history of prior thrombosis in whom the
ultrasound is non-diagnostic.

Side Effects:
phlebitis
anaphylaxis

Venography

Nuclear Medicine
Studies

Because the
radioactive isotope
incorporates into a
growing thrombus,
this test can
distinguish new
clot from an old
clot

Plethysmography

Plethysmography
measures change
in lower extremity
volume in
response to
certain stimuli.

Ultrasonography

Color-flow Duplex scanning is the


imaging test of choice for suspected
DVT
Advantages:

inexpensive,
noninvasive,
widely available
can also distinguish other causes of leg
swelling, such as tumor, popliteal cyst,
abscess, aneurysm, or hematoma.

Ultrasonography

Clinical limitations
Reader dependent
Duplex scans are less likely
to detect non-occluding
thrombi.
During the second half of
pregnancy, US becomes
less specific, because the
gravid uterus compresses
the inferior vena cava,
thereby changing Doppler
flow in the lower extremities

Magnetic Resonance
Imaging

It detects leg, pelvis,


and pulmonary
thrombi
97% sensitive and
95% specific for DVT
It distinguishes a
mature from an
immature clot.
MRI is safe in all
stages of pregnancy.

Differential Diagnosis

Cellulitis
Thrombophlebitis
Arthritis
Asymmetric peripheral edema secondary
to CHF, liver disease, renal failure, or
nephrotic syndrome
Lymphangitis, Lymphedema
Extrinsic compression of iliac vein
secondary to tumor, hematoma, or
abscess

Differential Diagnosis

Hematoma
Muscle or soft tissue injury
Neurogenic pain
Postphlebitic syndrome
Prolonged immobilization or limb paralysis
Ruptured Baker cyst
Stress fractures or other bony lesions
Varicose veins

Management

Using the pretest probability from the Wells


Clinical Prediction rule: high, moderate, or low
risk.
The results from duplex ultrasound are
incorporated as follows:
If the patient is high or moderate risk and
the duplex ultrasound study is positive,
treat for DVT.
If the patient is low risk and the duplex
study is negative, DVT has been ruled out.
If the patient is high risk but the ultrasound
study was negative, the patient still has a
significant probability of DVT

Management

When discordance exists between the


pretest probability and the duplex study
result, further evaluation is required.
If the patient is low risk but the ultrasound
study
is
positive,
some
authors
recommend a second confirmatory study
such as a venogram before treating for
DVT
Results of D-dimer assay to guide
management

Management

Anticoagulation
Thrombolytic therapy for DVT
Surgery for DVT
Filters for DVT
Compression stockings

Anticoagulation

Heparin prevents extension of the


thrombus
Heparin's anticoagulant effect is related
directly to its activation of antithrombin III.
Antithrombin III, the body's primary
anticoagulant, inactivates thrombin and
inhibits the activity of activated factor X in
the coagulation process.

Anticoagulation

The optimal regimen for the treatment


of DVT is anticoagulation with heparin or
an low molecular weight heparin (LMWH)
followed by full anticoagulation with oral
warfarin for 3-6 months
Warfarin therapy is overlapped with
heparin for 4-5 days until the INR is
therapeutically elevated to between 2-3.

Anticoagulation

After an initial bolus of 80 U/kg, a


constant maintenance infusion of 18 U/kg
is initiated. The aPTT is checked 6 hours
after the bolus and adjusted accordingly.
The aPTT is repeated every 6 hours until 2
successive
aPTTs
are
therapeutic.
Thereafter, the aPTT is monitored every
24 hours as well as the hematocrit and
platelet count.

Anticoagulation

The
hemorrhagic
complications
attributed to heparin are thought to
arise from the larger higher molecular
weight fragments.

Anticoagulation

Advantages of Low-Molecular-Weight
Heparin Over Standard Unfractionated
Heparin

Superior bioavailability
Superior or equivalent safety and efficacy
Subcutaneous once- or twice-daily dosing
No laboratory monitoring
Less thrombocytopenia

Low-Molecular-Weight
Heparin

At the present time, 3 LMWH preparations:


Enoxaparin,
Dalteparin, and
Ardeparin

Warfarin

Interferes with hepatic synthesis of


vitamin K-dependent coagulation factors
Dose must be individualized and adjusted
to maintain INR between 2-3
2-10 mg/d PO
Caution in active tuberculosis or diabetes;
patients with protein C or S deficiency are
at risk of developing skin necrosis

Thrombolytic therapy
for DVT
Advantages include:

prompt resolution of symptoms,


prevention of pulmonary embolism,
restoration of normal venous circulation,
preservation of venous valvular function,
prevention of postphlebitic syndrome.

Thrombolytic therapy

Thrombolytic therapy does not prevent


clot propagation,
rethrombosis, or
subsequent embolization.

Heparin therapy and oral anticoagulant


therapy always must follow a course of
thrombolysis.

Thrombolytic therapy

Thrombolytic therapy is also not


effective once the thrombus is adherent
and begins to organize
The hemorrhagic complications of
thrombolytic therapy are formidable
(about 3 times higher), including the
small but potentially fatal risk of
intracerebral hemorrhage.

Surgery for DVT

Indication:
when
anticoagulant
therapy
is
ineffective, unsafe, contraindicated .

The major surgical procedures for DVT


are clot removal and partial interruption
of the inferior vena cava to prevent
pulmonary embolism

These pulmonary emboli removed at autopsy look


like casts of the deep veins of the leg where they
originated.

This patient underwent a thrombectomy.


The thrombus has been laid over the approximate
location in the leg veins where it developed.

Filters for DVT

Indications for insertion of an inferior


vena cava filter:
Pulmonary
embolism
with
contraindication to anticoagulation
Recurrent pulmonary embolism despite
adequate anticoagulation

Filters for DVT

Controversial indications:
DVT with contraindication to
anticoagulation
DVT in patients with pre-existing
pulmonary hypertension
Free floating thrombus in proximal vein
Failure of existing filter device
Post pulmonary embolectomy

Filters for DVT

Inferior vena cava filters reduce the


rate of pulmonary embolism but have
no effect on the other complications of
deep vein thrombosis.
Thrombolysis should be considered in
patients with major proximal vein
thrombosis and threatened venous
infarction

Compression stockings
(routinely recommended

Complications

Acute pulmonary embolism


Hemorrhagic complications
Chronic venous insufficiency

Progression of Chronic Venous Insufficiency

From UpToDate 2006

Prophylaxis

Identify any patient who is at risk.


Prevent dehydration.
During operation avoid prolonged calf
compression.
Passive leg exercises should be encourged
whilst patient on bed.
Foot of bed should be elevated to increase
venous return.
Early mobilization should be rule for all
surgical patients.

ARTERY THROMBOSIS

Arterial Thrombus

Begins with platelet adhesion to arterial


vessel wall
Adenosine diphosphate
(ADP) released from platelets
more
platelet aggregation blood flow inhibited
fibrin, platelets and erythrocite surround
clot
build up of size structure
occludes blood vessels tissue ischemia
The result of arterial thrombus is localized
tissue injury from lack of perfusion
Antiplatelet drugs primarily act by
preventing arterial thrombosis

Arterial thrombosis
angiographic picture

Severe arterial
thrombosis

Thrombus in left
atrium

Clot on bicuspid aortic


valve

Bacterial endocarditis

Severe internal carotid


stenosis

Multi-level peripheral vascular disease

External iliac

Superficial femoral

Tibial

Antiplatelet Drugs

Aspirin,
Dipyridamole
(Persantine),
Ticlopidine (Ticlid) abciximab (ReoPro),
tirofiban (Aggrastat)
Action: prevent thrombosis in the
arteries
by
suppressing
platelet
aggregation
Use:
Prevention of MI, stroke for patient with
family history, DM
Prevention of repeat MI, stroke in patient
having TIA

Antiplatelet Drugs

Persantine,Ticlid = similar to ASA but


more expensive
ReoPro, Aggrastat = mainly for acute
coronary syndromes. Route = IV

Thrombolytic

.Thrombolytics
promote
fibrinolytic
mechanism (convert plasminogen to
plasmin and destroys the fibrin in the
clot)
Administering a thrombolytic drug
clot disintegrates
Side effects:
hemorrhage, allergic
reactions
Onset and peak are immediate and
rapid

Thrombolytic

Use :
Acute MI - within 4 hrs to dissolve clot
and unblock artery, so decrease
necrosis to myocardium.

Other uses:
pulmonary embolism
DVT
noncoronary arterial occlusion

Thrombolytic

Streptokinase,
Urokinase,
Tissue
plasminogen
activator
(t-PA),
anisoylated plasminogen streptokinase
activator complex (APSAC)
Streptokinase and Urokinase: enzymes
that act to convert plasminogen to
plasmin
t-PA and APSAC: activate plasminogen
by acting specifically on clot.

Aorto-bifemoral
bypass

CONCLUSION

VEIN
THROMBOSIAS

ARTERY
THROMBOSIS

Similar
name

Red thrombi

White thrombi

Contain

Rich in fibrin and


trapped RBC

Higher concentration
of platetelts, lower
concentration of RBC

Prevention

Medication that
interrupt cloting
cascade
(anticoagulant)

Medication that block


platelet activation
(antiagregation)
Anticoagulant also
used because thrombin
is potent activator of
platelets and arterial