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Mechanisms of Thrombosis
Maureane Hoffman, MD, PhD
Professor of Pathology
Duke University Medical Center
Durham, NC, USA

Thrombosis

Formation of a blood clot in an

artery or vein of a living creature

What Causes Thrombosis?

Virchows Triad:
Altered blood flow (Turbulence/Stasis)
Vascular Injury/Inflammation
Hypercoagulability

Vascular Injury
endothelial cell

TF
VIIa

TF

Hypercoagulability
The coagulant/anticoagulant
proteins, blood cells and
endothelial cells each play roles

Hypercoagulability is multifactorial
Lifestyle and environmental
factors play critical roles

Hypercoagulability is multifactorial
This is different from
hemorrhagic disorders which
are often single gene defects

Relative Risk of Thrombosis

Normal

Oral contraceptive

Factor V Leiden, heterozygous

5-7

FV Leiden, hetero + OC

30-35

FV Leiden, homozygous

80

FV Leiden, homo + OC

?>100

Prothrombin 20210AT, heterozygous

Prothrombin 20210AT, hetero + OC

16

Inflammation can also Promote a

Hypercoagulable State
Activates endothelial cells
Enhances TF expression
Reduces TM and heparan sulfate expression
Enhances expression of endothelial adhesion
molecules

Arterial Thrombosis
Often results from deposition of
atherosclerotic plaque in the wall of an artery
(vascular injury), which narrows the channel
(altered blood flow)
Platelet deposition often linked to arterial
thrombosis
Rupture of the plaque can precipitate acute
thrombosis

Atherosclerosis starts young

Coronary Artery Thrombosis - Plaque Rupture

Thrombosis in the Aorta

Venous Thrombosis
Blocks return of deoxygenated blood
Common in the lower extremities, but can
also occur in the upper extremities
Symptoms include swelling, bluish
discoloration and pain
The most feared complication of venous
thrombosis is pulmonary embolism

Venous Thrombosis
Associated with stasis (immobility)
Associated with hypercoagulability
Inherited disorders (FV Leiden, AT
deficiency, Protein C/S deficiency)
Acquired disorders (obesity, smoking,
inflammation, oral contraceptives, cancer,
antiphospholipid syndrome)

Pulmonary Emboli

Lines of Zahn in a pulmonary embolus

Bottom Line
Thromboembolism is multifactorial, and risk
factors accumulate (or even multiply)
Arterial and venous thrombosis have different
mechanisms and, thus, different risk factors

How do we study thrombosis?

Clinical observation
Histology of thrombotic disorders
Effect of pharmaceutical agents
Animal models

We have learned the most from our

human patients
Human thrombosis is spontaneous and likely
develops over an extended period of time
hours/days/weeks or even longer
There are no realistic animal models of
thrombosis
Ferric chloride injury
Laser injury
Wessler model

How might immunoglobulin products

cause thrombosis?
Increased blood viscosity due to protein or
sucrose
Increased viscosity has been associated with
venous thrombosis in myeloma and MGUS
FXI(a) contamination
Reinhart WH, Berchtold PE. Effect of high-dose intravenous immunoglobulin therapy on blood rheology.
Lancet. 339(8794):662-664, 1992
Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation factor XI is a contaminant in intravenous
immunoglobulin preparations. Am J Hematol. 65(1):30-34, 2000

Arterial and venous thrombosis

associated with immunoglobulin infusion:
Two different mechanisms?
60

Arterial
Venous

50
40
30
20
10
0
during infusion

4-24 hr

1-7 d

>7d

time til thrombosis

Marie et al, Intravenous immunoglobulin-associated arterial and venous

thrombosis: report of a series and review of the literature. British J Dermatol
155(4):714-21, 2006
Dr. Dorothy Scott, personal communication, Adverse events reported to the FDA

Characteristics of patients who developed

arterial thrombosis in association with
immunoglobulin infusion
Older
Heavier
More risk factors for vascular disease
Hypertension
Diabetes
Hyperlipidemia
Coronary artery disease

Characteristics of patients who developed

venous thrombosis in association with
immunoglobulin infusion
Younger
Few risk factors except thrombophilia
Higher IVIg dose (or conditions treated with
higher doses)

Can we draw any conclusions?

No - but the existing data suggest some
hypotheses
Patients who have existing risk factors are
at higher risk for thrombosis associated with
immunoglobulin infusion
Viscosity seems more associated with
venous thrombosis
FXIa seems more likely to be associated
with rapid onset arterial thrombosis