5. • Anti-platelet properties
▪ Covers highly thrombogenic basement membrane
▪ Uninjured endothelium does not bind platelets
▪ PGI2 (prostacyclin) and NO from uninjured endothelium
inhibit platelet binding
▪ ADPase counters the platelet aggregating effects of ADP
6. ➢ HEPARIN-LIKE MOLECULES: activate anti-
thrombin III (inactivates active proteases)
THROMBOMODULIN: changes specificity of
thrombin (activates protein C , which inactivates factors
Va and VIIIa
Endothelial cells produce t- PA which activates
fibrinolysis via plasminogen to plasmin
7. Prothrombotic Properties of the
Endothelium
•Synthesis of von Willebrand factor
•Release of tissue factor
•Production of plasminogen activator inhibitors (PAI)
•Membrane phospholipids bind and facilitate
activation of clotting factors via Ca++ bridges
8.
9.
10. Injury of vessels wall
leads to contact
between blood and
subendothelial cells
FXa binds to FVa on the
cell surface
The complex between
TF and FVIIa activates
FIX and FX
Tissue factor (TF) is
exposed and binds to
FVIIa or FVII which
is subsequently
converted to FVIIa
1. Initiation phase
11. (PTT)
(PT)
✓ All Clotting Factors are
within a blood vessels
✓ Clotting Slower
✓ Initiating Factor
is
Outside the blood
Vessels ( Tissue
Factor)
✓ Clotting Faster
(Blood Vessel Injury)
(Tissue Injury)
12.
13. The FXa/FVa complex
converts small amounts
of prothrombin into
thrombin
The small amount of
thrombin generated
activates FVIII, FV, FXI
and platelets locally.
FXIa converts FIX
to FIXa
2. Amplification phase
Activated platelets
bind FVa, FVIIIa
and FIXa
19. • Activated protein C resistance (factor V Leiden)
• Protein S deficiency
• Protein C deficiency
• Antithrombin deficiency
• Hyperhomocysteinemia
• Prothrombin 20210A allele
• Dysplasminogenemia
• High plasminogen activator inhibitor
• Dysfibrinogenemia
• Elevated factor VIII
20. Physiologic Inhibitors of
coagulation
• Antithrombin III (serpin)
• Activated Protein C + protein S
– Inactivates Va and VIIIa (via proteolysis)
– NB: Factor V Leiden
• Thrombomodulin (EC glycoprotein)
– Binds to thrombin
– Decreases ability to produce fibrin
– Increases ability to activate Protein C
21. Non-physiologic inhibitors of coagulation
Vitamin K antagonists (in vivo only)
Ca chelators (in vitro only)
EDTA
Citrate
Oxalate
* Heparin (in vivo and in vitro)
22.
23. Abnormality Arterial Venous
Factor V Leiden - +
Prothrombin G20210A - +
Anti Thrombin Deficiency - +
Protein C Deficiency - +
Protein S Deficiency - +
Hyperhomocystinemia + +
Antiphospholipid Syndrome + +
27. Protein C pathway
• Factor V Leiden
• Protein C deficiency
• Protein S deficiency
Prothrombin G20210A mutation
Antithrombin deficiency
Hyperhomocystinemia
• C677T MTHFR mutation
28. Protein C deficiency
• Type I – number and activity
• Type II – activity
Protein S deficiency
• Type I – total and free forms
• Type II – cofactor activity
• Type III - free only
Autosomal dominant
• 0.2-0.5, 0.8 prevalence
37. MTHFR and Thrombosis
Hyperhomocystinemia implicated in both arterial and
venous thrombosis
Why is homocysteine thrombogenic? Theories:
Direct toxicity to endothelial cells
Inhibits Protein C activation
Promotes endothelial tissue factor expression
Surpresses endothelial cell surface heparin sulfate
38. Atherosclerosis, NTD, thromboembolism
Severe – homozygous
• 1 in 200,000-355,000
• Cystathionine -synthase
Mild to moderate
• Heterozygotes for CS mutation
• Homozygous for 667C-T MTHFR (11%)
39.
40. Autoimmune Acquired Prothrombotic Disorder
Very High Risk for recurrent thromboembolic
disease
both venous and arterial
Indefinite duration anticoagulation recommended
+/- immunosuppression
Strict Diagnostic Criteria
