Transcript Lecture 8-Hypercoagulation.ppt

Hypercoagulation
Thrombosis ~~ Virchow’s Triad
Congenital & Acquired
hypercoagulable states
Congenital
1. Protein C deficiency
2. Protein S deficiency
3. Antithrombin Ⅲ
deficiency
4. Factor V Leiden
5. Prothrombin gene
G20210A mutation
6. Hyper-homocysteinemia
7. Dysfibrinolysis
Acquired
1. Antiphospholipid
antibody syndrome
2. Malignancy
3. Surgery / Trauma
4. Pregnancy / Oral
contraceptives
5. Prolonged immobilization
6. Older age
Racial difference
• Asians &Africans: protein C deficiency,
protein S deficiency predominant
• Whites: Factor V Leiden, prothrombin gene
G20210A mutation predominant
Congenital & Acquired
hypercoagulable states
Congenital
1. Protein C deficiency
2. Protein S deficiency
3. Antithrombin Ⅲ
deficiency
4. Factor V Leiden
5. Prothrombin gene
G20210A mutation
6. Hyper-homocysteinemia
7. Dysfibrinolysis
Acquired
1. Antiphospholipid
antibody syndrome
2. Malignancy
3. Surgery / Trauma
4. Pregnancy / Oral
contraceptive
5. Prolonged immobilization
6. Older age
1. Protein C deficiency
• Synthesis in the liver; Vit-K dependent; Autosomal
dominant
• Inactivate factorⅤ and factorⅧ. It needs a cofactor:
protein S
• Deep vein thrombosis(DVT) 、pulmonary embolism(PE) 、
superficial thrombophlebitis: most common
manifestations
• Arterial thrombosis are rare
• Easy to occur warfarin-induced skin necrosis
(1/3 warfarin-induced skin necrosis underlying protein C
deficiency)
2. Protein S deficiency
• Synthesis in hepatocytes & megakaryocytes;
Vit-K dependent; Autosomal dominant
• Cofactor of activated protein C(APC)
• 74%: DVT ; 72%: superficial
thrombophelbitis
• Warfarin-induced skin necrosis may occur
3. Antithrombin Ⅲ
deficiency
• Synthesis in liver & endothelial cells
• Activated by binding to heparin-like
molecule
• Inhibits thrombin, factor Ⅸa,Ⅹa, XIa, XIIa
• DVT、PE、mesenteric vessels thrombosis
• Resistant to unfractionated heparin
• Must treat with low-molecular-weight
heparin(LMWH)
4. Factor V Leiden(=activated
protein C resistance)
• Point mutation of facotr V gene
• Results in impaired inactivation of factor V by activated
protein C
• Present in 5% of whites; virtually absent in Asians &
Africans
• Venous thrombosis & fetal wastage
• Heterozygosity: 2x ~ 3x risk
Homozygosity: 80x risk
• Heterozygosity factor V Leiden is a relative mild risk
factor of thrombosis, and appears not to affect life
expectancy
5. Prothrombin gene
G20210A mutation
• Prothrombin gene mutation: nucleotide
position 20210: G  A
• Elevated prothrombin levels and activity
• Increased risk of venous thrombosis
• Rare in Asians & Africans
6. Hyperhomocysteinemia(1)
•
•
•
•
1: methionine synthase
2: methylenetetrahydrolate reductase(MTFHR)
3: betaine-homocysteine methyltransferase
4: cystathionine β –synthase(CBS)
6. Hyperhomocysteinemia(2)
• Elevated homocysteine 
(1) vascular endothelial injury (via free oxygen radicals)
(2) decreased protein C activation
(3) increased factor V activity
(4) induction of endothelial cell tissue factor activity
• Causes: (1) cystathionine β–synthase def. (most common)
(2) Vit-B6, Vit-B12, folic acid deficiency
• Cause premature arterial atherosclerosis and venous
thromboembolism
• Tx: standard fashion + vitamin supplementation
7. Dysfibrinolysis
• 5 major forms:
(1) congenital plasminogen deficiency
(2) tissue plasminogen activator deficiency
(3) increased plasminogen activator inhibitor
(4) congenital dysfibrinogenemia
(5) factor XII deficiency (factor XII involved in
plasmin generation ~ kinin cascade)
1. Antiphospholipid
antibody syndrome (1)
• Most common of hypercoagulable disorder
• Heterogenous autoantibody binds to
phospholipid-protein complex
• Include lupus anticoagulant syndrome &
anticardiolipin antibody syndrome
• Exact mechanism is unknown
• Venous and arterial thrombosis, recurrent
spontaneous abortion, stroke, TIA(transient
ischemic attack)
1. Antiphospholipid
antibody syndrome (2)
• Idiopathic(primary) or associated with SLE,
infection, drug reactions(secondary)
• Livedo reticularis, thrombocytopenia
• PT,PTT prolonged
• Diagnosis: specific assay to detect
antiphospholipid antibody(lupus anticoagulants,
anticardiolipin antibodies) in the serum; falsepositive VDRL
2. Malignancy
• 15% patients with cancer have clinical thrombosis
• Esp. mucin-secreting adenocarcinoma(GI or lung),
pancreatic cancer, acute promyelocytic leukemia
• Mechanisms: hypercoagulability, endothelial
injury, venous stasis
• DVT, PE, Trousseau’s syndrome(migratory
superficial thrombophlebitis), non-bacterial
thrombotic endocarditis(NBTE) : fibrin-platelet
vegetations on heart valvessystemic
embolization
• Occurrence of Trousseau’s syndrome or without
known cancer  vigorous search for occult
malignancy
3. Surgery / Trauma
• Mechanisms:
(1) release of tissue factor from injured tissue
(2) decreased plasma level of anticoagulants
• Particularly common in orthopedic surgery
• Hip and knee surgery without anticoagulant
prophylaxis  45~70% DVT
4. Pregnancy / Oral
contraceptives
1. Placenta: placental plasminogen activator
inhibitor type 2
2. Enlarged uterus venous stasis in the leg
3. Pelvic vein injury
4. Trauma of cesarian section
• Oral contraceptives promote liver synthesis of
coagulation factors
When to suspect
hypercoagulability?
• Thrombosis < 50 years
• Family history
• Thrombosis in an unusual site(e.g.
mesenteric v. or cerebral v.)
• Idiopathic or recurrent thrombosis
• Unexplained spontaneous abortions
• Massive thrombosis
Clinical features
• DVT: unilateral leg pain & swelling, tenderness
on compression calf muscle, Homan’s sign(pain
during dorsiflexion of the foot), increased
circumference at least 1 cm
• PE: dyspnea, tachypnea, tachycardia, chest pain,
decreased breathing sounds, hemoptysis
Diagnosis ~ DVT
Standard,
accurate, but
invasive
Positive
predictive value
> 90%
Diagnosis ~ PE
>50% patients
Normal result can
not rule out PE
Pulmonary
angiography
is standard
test
Diagnosis for congenital
hypercoagulable state
• Functional, antigenic, DNA-based assays
• Avoid test when:
(1) active thrombosis
(2) anticoagulants treatment
(3) pregnancy, estrogen use
(4) liver disease
(5) DIC
Treatment ~ initial management
Keep PTT
1.5~2.5
Long term treatment ~ oral
anticoagulant(Warfarin)
• Vit-K antagonist
• Should be adjusted according to PT(INR)
• Inhibition of protein C first(6~8 hr), then inhibits
other clotting factors(24~48 hr)
 transient hypercoagulable state  Warfarininduced skin necrosis
• Warfarin started within 24 hr after initiation of
heparin. Heparin should be given for at least 4
days and not discontinued until the INR in the
therapeutic range(2.0 to 3.0) for 2 consecutive
days
Complications of treatment
1.
2.
3.
4.
5.
Bleeding
Heparin-induced thrombocytopenia
Heparin-induced osteoporosis
Warfarin-induced skin necrosis
Post-thrombotic syndrome (venous
hypertension caused by valvular
incompetence) : pain, swelling, ulceration
New oral anticoagulant
Drugs
•
•
•
•
Oral
Less bleeding
No monitoring.
Good choice if we use it in the right
way .
References
• Hypercoagulability syndromes: Arch intern med/Vol 161,
Nov 12, 2001
• Genetic susceptibility to venous thrombosis: N Engl J
Med, Vol 344, No. 16, April 19, 2001
• Management of venous thromboembolism: N Engl J Med,
December 12, 1996
• Goldman: Cecil textbook of medicine, 21st ed. Chapter
187
• Robbins pathologic basis of disease, sixth ed. Chapter 5
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