05/01/2023 1

Pathophysiology of Thromboembolism

Continued...

05/01/2023 2

Pregnancy is associated with:• 2x fibrinogen• 20 -1,000% factors VII, VIII, IX, X & XII• vWF by 400 % at term

• Prothrombin and factor V remain unchanged • Modest factor XIII and XI• 40% protein S

In contrast

Why is pregnancy at risk?

05/01/2023 3

Pregnancy-specific risk factors • Parity• Postpartum endomyometritis• Operative vaginal delivery • Cesarean delivery 9x in

the risk of thromboembolism compared with vaginal delivery

Risk factors for TE

05/01/2023 4

Compression of the inferior vena cava, and

Pelvic veins by the enlarging uterus Hormone-mediated in DVC 2° to:

Estrogen Local production of prostacyclin and NO

Note: Left leg veins thrombosis > right leg

thrombosis2° lower flow velocities

05/01/2023 5

Non-Obstetrical Risk factors

• Age >35 years • Obesity• Trauma• Immobility• Infection • Smoking

• Nephrotic syndrome• Cancer• Surgery• Prior history of DVT or PE

05/01/2023 6

Introduction• Three primary abnormalities that lead to thrombus

formation (called Virchow's triad)

1. Endothelial injury 2. Vascular stasis

3.Hypercoagulability

05/01/2023 7

Endothelial injury

vascular

stasis

Hypercoagulability

THROMBOSIS

Virchow's

triad

1. Endothelial Injury• Dysfunction or mechanical trauma • Contribute thrombus formation • Heart • Arterial circulation

• Major consequence of endothelial cell injury:• Vasculitis• Endocardial injury

2. Abnormal Blood FlowTurbulence • Cause arterial and cardiac thrombosis by• Endothelial injury or dysfunction• Disrupt laminar flow   • Forming countercurrents and local pockets

of stasisStasis • Major contributor in the venous thrombi• Prevent dilution of activated clotting

factors

3. Hypercoagulability• Definition:• Alteration of the coagulation pathways

that predisposes to thrombosis• Also called thrombophilia

• Divided into:1. Primary (genetic)2. Secondary (acquired) disorders

TABLE: Hypercoagulable States1. PRIMARY (GENETIC) Common   • Factor V mutation (G1691A mutation; factor V

Leiden)   • Prothrombin mutation (G20210A variant)   • 5,10-Methylenetetrahydrofolate reductase

(homozygous C677T mutation)  •  Increased levels of factors VIII, IX, XI, or fibrinogen

Rare  • Antithrombin III deficiency    • Protein C deficiency   • Protein S deficiency

Very Rare  •  Fibrinolysis defects   • Homozygous homocystinuria (deficiency of

cystathione β-synthetase)

2. SECONDARY (ACQUIRED) High Risk for Thrombosis

• Antiphospholipid antibody syndrome• Heparin-induced thrombocytopenia    • Prolonged bedrest or immobilization   • Myocardial infarction   • Atrial fibrillation  •  Tissue injury (surgery, fracture, burn)    • Cancer  •  Prosthetic cardiac valves   • Disseminated intravascular coagulation  

Lower Risk for Thrombosis

•  Cardiomyopathy   • Nephrotic syndrome •  Hyperestrogenic states (pregnancy and

postpartum)  •  Oral contraceptive use    • Sickle cell anemia• Smoking

Antiphospholipid Antibody Syndrome (APAS)

Definition:• Xized by arterial or venous thrombosis or

specific pregnancy complications • in women with laboratory evidences of

(APAs) to proteins bound to anionic phospholipids

Previously called Lupus anticoagulant syndrome Antiphospholipid Antibodies (APAs) • Self-recognition Igs• Directed against proteins bound to

phospholipids

clinical manifestations Recurrent thromboses Repeated miscarriages

• Inhibit throphoblastic invasion• placental vessels thrombosis

Cardiac valve vegetations Thrombocytopenia Pulmonary embolism Pulmonary hypertension Stroke Bowel infarction Renal failure

• Renal Microangiopathy

Two forms of APAS : I. Primary APAS• Patients exhibit only a hypercoagulable

state • Lack evidence of autoimmune disorders• Occasionally with certain drugs or

infections II. Secondary APAS• Well-defined autoimmune disease like SLE

DiagnosisThe diagnosis of APAS requires 1. The presence of prior or current vascular

thrombosis, or characteristic obstetric complications

2. At least one laboratory criterion (e.g., anticardiolipin antibodies or lupus anticoagulant

These antibodies must be present on two ormore occasions at least 6 weeks apart fordiagnosis

Factor V Leiden Mutation

Activated Protein C Resistance Most prevalent thrombophilic syndromes Characterized by resistance of plasma To the anticoagulant effects of activated protein C• Heterozygous mutation 20 to 40 % of

nonpregnants with thromboembolic disease• Homozygous inheritance 100-fold

Netherlands

Protein C Deficiency

• With protein S inactivating factors Va and VIIIa • Protein C levels are unchanged during normal

pregnancy Predisposes to coagulation

• Prevalence is 2 to 5 per 1000• Inheritance is autosomal dominant • Risk of thromboembolism in pregnant women

is 3-20 %

Most episodes occur during the puerperium

Antithrombin Deficiency

• One of the most important inhibitors of thrombin in clot formation• The most thrombogenic of the heritable

coagulopathies Homozygous antithrombin deficiency is lethal

!!! Although antithrombin deficiency is rare, Affect 1 in 5000 individuals, Lifetime risk of thrombosis is 50-90 %

50- 60 % during pregnancy , and 33 % during the puerperium

R references

T hank Y ou!!!