Fatimah Eliana

The Clotting Cascade

Intrinsic Clotting Pathway Extrinsic Clotting Pathway

Blood or collagen contact Tissue trauma

XII XIIa (H) Tissue factor

XI 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++

CA++
Fibrinogen Fibrin (soluble)

(H)
XIIIa XIII

Fibrin (insoluble)
 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

Plasminogen-plasmin
activated by heparin system
like molecules on
Breaks down fibrin
endothelial cells
 Clinical administration
and inhibits its
of heparin minimizes polymerization
thrombosis Products of split
Proteins C and S fibrin are
Vitamin K dependent anticoagulants
Inactivate cofactors Va
and VIIIa
 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 it’s the
DVT that’s 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
cascadeproduction 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)
 Anticoagulants (heparin/warfarin) primarily act by
preventing venous thrombosis
 Types of foot ulcers

Arterial Venous Neuropathic

Foot ulcers Arterial Venous Neuropathic

Location Distal Medial Pressure

malleolus point

Arterial disease Yes No No

and risk factors for
atherosclerosis

Contra-lateral No Yes Yes (maybe)

pulses

Skin changes of No Yes No

venous HTN

Neuropathy Maybe No Yes

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 1
palliative)
Paralysis or recent plaster immobilization 1
Recently bedridden for >3 days or major surgery <4 weeks 1
Localized tenderness along the distribution of the deep venous 1
system
Entire leg swelling 1
Calf swelling >3 cm compared to the asymptomatic leg 1
Pitting edema (greater in the symptomatic leg) 1
Collateral superficial veins (nonvaricose) 1
Alternative diagnosis (as likely or > that of DVT) 1
 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 D-dimer
 ELISA
 Latex agglutination
 Blood agglutination test (SimpliRED)
 D-dimer

False-positive D-dimers occur in patients:
 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
o Arthritis
o Asymmetric peripheral edema secondary to
CHF, liver disease, renal failure, or nephrotic
syndrome
o Lymphangitis, Lymphedema
o 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
• Duration can be 12 hour.
 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
 ARTERY THROMBOSIS
THROMBOSIAS
Similar name Red thrombi White thrombi
Contain Rich in fibrin and Higher concentration of
trapped RBC platetelts, lower
concentration of RBC
Prevention Medication that Medication that block
interrupt cloting platelet activation
cascade (anticoagulant) (antiagregation)
Anticoagulant also used
because thrombin is
potent activator of
platelets and arterial clots
contain fibrin