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8/1/11
Morgan L. McLemore, M.D.!
Hematology and Leukemia Section!
Winship Cancer Institute!
• 28 yo AAM, Acute SOB, Pleuritic CP.
– Bilateral PE, with right heart strain.
– No DVT, no family history, no obvious risk factors
• 38 yo Female, ?unprovoked DVT on coumadin
for 2 years. Protein C & S deficient.
– no family history, no obvious risk factors per chart
• 22 yo female claudication left LE for 8 months.
Left femoral artery thrombosis.
– Was on OCP, no family history
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Strongly Supportive Data
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Activated protein C resistance
Factor V Leiden
Prothrombin G20210A
Homocystinuria
Supportive Data
Increased plasma factors I (fibrinogen), II
(prothrombin),
VIII, IX, XI
Factor XIII polymorphisms
Hyperhomocysteinemia
Dysfibrinogenemia
Reduced tissue factor pathway inhibitor
Weakly Supportive Data
Reduced protein Z and Z-dependent protease inhibitor
Tissue plasminogen activator deficiency
Increased plasminogen activator inhibitor (PAI)-1
Increased thrombin-activatable fibrinolysis inhibitor
Hypoplasminogenemia and dysplasminogenemia
Hypofibrinolysis
• Deficiencies of ATIII, Proteins C&S
• Factor V Leiden (APCr)
• Prothrombin Gene Mutation
• LAC, ACL, APL
• Elevated Factor VIII levels
• Homocysteine
• Other Protein Z, Lipoprotein a etc.
• Deficiencies of ATIII, Proteins C&S
• Factor V Leiden (APCr)
• Prothrombin Gene Mutation
• LAC, ACL, APL
• Elevated Factor VIII levels
?
?
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JA Heit Hematology Educatioon Book 2007
Favaloro et al Semin Thromb Hemost 2009
• Antiphopholipid Antibodies • Pregnancy/postpartum
• Therapy-related:
• Malignancy
– Hormone replacement
• Myeloproliferative
therapy
disorders:
– Oral contraceptives
– Tamoxifen/raloxifene
– Chemotherapy/thalidomide
– Heparin-induced
thrombocytopenia
– Polycythemia vera
– Essential thrombocythemia
• Paroxysmal nocturnal
hemoglobinuria
• Nephrotic syndrome
• Inflammatory bowel
disease
• • • • Travel
Trauma
Surgery
Presence of a central
venous catheter
• Immobilization
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• The presence of hereditary thrombophilia
has not been used as a major factor to
guide duration of anticoagulation for VTE
in these guidelines because evidence from
prospective studies suggests that these
factors are not major determinants of the
risk of recurrence.
• First event with reversible or time limited risk
factor
– 3 months at INR 2-3
• Unprovoked VTE, first or second event
– 3-6 months at target INR, then consider
– indefinite anticoagulation at INR 2-3
• First (unprovoked) event in high risk
thrombophilas
– thrombophilias - indefinite anticoagulation
– Cancer until remission (consider chronic LMWH)
– Antiphospholipid antibody syndrome
– Antithrombin deficiency or multiple genetic defects
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• First event with reversible or time limited risk
factor
– 3 months at INR 2-3
• Unprovoked VTE, first or second event
– 3-6 months at target INR, then consider
– indefinite anticoagulation at INR 2-3
• First (unprovoked) event in high risk
thrombophilas
– thrombophilias - indefinite anticoagulation
– Cancer until remission (consider chronic LMWH)
– Antiphospholipid antibody syndrome
– Antithrombin deficiency or multiple genetic defects
• Arterial- Not routinely recommended
– Very young- unusual sites consider
• Portal/Mesenteric vein thrombosis,
– PNH
– JAKII -> up to 50% positive without complete
evidence of MPD
• Cerebral Vein Thrombosis
• • Normal
• Oral Contraceptives
• Factor V Leiden Heterozygote
• Both
• Homozygote FVL
%/year
0.008
0.03
0.06
0.30
0.50 or >
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• Venous Thromboembolism < 50 with a family history
– Unprovoked
– Provoked ? Strong Family History/Young
– Unprovoked- consider workup without family history
– Evidence of thrombophilia may raise threshold to withdrawal AC
in future
• Unusual Site- Cerebral venous and Portal/Mesenteric
vein thrombosis
– JAKII and PNH
• Second and third trimester pregnancy loss
• Consider
– Unprovoked in patients >50 APL/ACL/LAC
– Women on OCP
– Arterial LAC/APL only for unusual cases
• Acquired or inherited thrombophilia with 1st
provoked venous VTE
– Ensure prophylaxis in high risk settings.
• Unprovoked VTE consider indefinite anticoagulation.
– Need to constantly reassess need and desire for
continued AC
– Bleeding risk, Severity of event, family history,
underlying thrombophilia, lifestyle
• 28 yo AAM, Acute SOB, Pleuritic CP.
– Bilateral PE, with right heart strain.
– No DVT, no family history, no obvious risk factors
• Extensive thrombophilia workup negative
• FVL, PTGm, LAC, APL negative. Protein C, S
and ATIII normal
• Recommended Indefinite anticoagulation
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• Acquired or inherited thrombophilia with 1st
provoked venous VTE
– Ensure prophylaxis in high risk settings.
• Unprovoked VTE consider indefinite anticoagulation.
– Need to constantly reassess need and desire for
continued AC
– Bleeding risk, Severity of event, family history,
underlying thrombophilia, lifestyle
• 28 yo AAM, Acute SOB,
Pleuritic CP. Hypoxic
– Bilateral PE, with right
heart strain.
– No DVT, no family history,
no obvious risk factors
• 42 yo AAM, Pleuritic CP.
Not hypoxic
– Unilatareal PE
– No DVT, no family history,no
obvious risk factors
– No DVT, no family history, no
obvious risk factors
• Extensive thrombophilia
workup negative
• Extensive thrombophilia
workup negative
• Recommended Indefinite
anticoagulation
• Indefinite anticoagulation
recommended
• 7 years later…….
• 22 yo female claudication left LE for 8
months. Left femoral artery thrombosis.
– Was on OCP*, no family history
• FVL, PTGm, LAC, Protein C, s and ATIII
normal
• Multiple positive APL/LAC. ANA +, DAT+
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• 28 yo WM TIAs
• High titer APLs
• 55 yo WF TIAs
• Low titer + LAC
• Smoker, HTN, Chol
• 44 year old
• Marked increased LFTs
• Moderate Anemia,
thrombocytopenia
• Portal Vein thrombosis
• 80% GPI negative
granulocytes
• 13 of the 46 family members
determined to be protein-C deficient
• Blood. 1989;73(3):712
• Protein S 30-50% affected family
members
• Ann Intern Med. 1987;106(5):677
• • Normal
• Oral Contraceptives
• Factor V Leiden Heterozygote
• Both
• Homozygote FVL
%/year
0.008
0.03
0.06
0.30
0.50 or >
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ATIII
Pregnancy
Liver Disease
DIC
Nephrotic Syndrome
Major Surgery
Acute Thrombosis
Protein C
Heparin
Estrogens
Warfarin
Warfarin
Estrogens
ATIII
Pregnancy
Liver Disease
DIC
Nephrotic Syndrome
Major Surgery
Acute Thrombosis
Protein C
Protein S
Pregnancy
Liver Disease
DIC
Heparin
Estrogens
Warfarin
Liver Disease
DIC
Protein S
Pregnancy
Liver Disease
DIC
Inflammation
Acute Thrombosis Acute Thrombosis
Liver Disease
DIC
Inflammation
Acute Thrombosis Acute Thrombosis
Warfarin
Estrogens
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8/1/11
38 yo Female, ?unprovoked DVT on coumadin
for 2 years. Protein C & S deficient*.
– no family history, no obvious risk factors per
chart
• Taken off Coumadin for three weeks,
Protein C and S levels normal
• Further Discussion/History
• Deficiencies of ATIII, Proteins C&S
• Factor V Leiden (APCr)
• Prothrombin Gene Mutation
• LAC, ACL, APL
• Elevated Factor VIII levels
• JAKII, PNH for mesenteric/portal
thrombosis
?
• Venous Thromboembolism < 50 with a family history
– Unprovoked
– Provoked ? Strong Family History/Young
– Unprovoked- consider workup without family history
– Evidence of thrombophilia may raise threshold to withdrawal AC
in future
• Unusual Site- Cerebral venous and Portal/Mesenteric
vein thrombosis
– JAKII and PNH
• Second and third trimester pregnancy loss
• Consider
– Unprovoked in patients >50 APL/ACL/LAC
– Women on OCP
– Arterial LAC/APL only for unusual cases
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8/1/11
• Venous Thromboembolism < 50 with a family history
– Unprovoked
– Provoked ?
– Unprovoked- consider workup without family history
– Evidence of thrombophilia may raise threshold to withdrawal AC
in future
• Unusual Site- Cerebral venous and Portal/Mesenteric
vein thrombosis
– JAKII and PNH
• Second and third trimester pregnancy loss
• Consider
– Unprovoked in patients >50
– Women on OCP
– Arterial LAC/APL only for unusual cases
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