Hypercoagulable do

1
Hypercoagulable d/o

• Factor V Leiden
• Prothrombin gene mutation
• Hyperhomocysteinemia
• Antiphospholipid antibody syndrome
• Protein C, Protein S, ATIII deficiency
• Whom to evaluate? Thrombosis before the age of
  45, positive family history, unusual sites,
  clotting on adequate anticoagulation

2
Ddx of Bilateral LE edema

• Renal disease acute GN, ARF, CRF, nephrotic
  syndrome
• Heart Failure biventricular (ischemic), cor
  pulmonale
• Liver Disease
• Chronic malabsorption with hypoalbuminemia
• Vascular IVC compression or thrombosis, chronic
  venous insufficiency, bil. DVTs
• Lymphatic obstruction tumor, fibrosis,
  infectious
• Endocrine/metabolic hypothyroidism,
  mineralocorticoid excess
• Drugs OCPs, NSAIDs, nifedipine, rosiglitazone

3
Evaluation

• In the setting of acute thrombosis, levels of
  protein C, S, and antithrombin III will be
  decreased
• Protein C and S are vitamin K dependent ATIII
  levels are decreased by heparin
• The genetic tests (factor V leiden, prothrombin
  gene mutation), as well as antiphospholipid aby
  assays and homocysteine levels, can be performed
  in the acute setting.

4
APC resistance/Factor V Leiden

• The mutation Arg506Gln of Factor V, or Factor V
  Leiden, results in a product that is not
  susceptible to cleavage by activated protein c.
• This results in more Factor V being available to
  generate thrombin through the prothombinase
  complex.
• The anticoagulant activity of activated protein C
  is diminished. (the cleaved factor V is a
  cofactor with protein S in fibrinolysis.)

5
APC resistance without Factor V Leiden

• Phenotypic resistance to APC can occur in the
  absence of the mutation demonstrated in a large
  Italian study 1999 of pts with venous
  thromboembolism.
• --15,109 people screened
• --2134 had resistance of activated proC
• --447 heterozygotes, 7 homozygotes
• Clinical significance of this is unclear

6
APC resistance/Factor V Leiden

• Heterozygosity accounts for 90-95 of cases
• Prevalence ranges from 1 to 8.5 (5)
• Highest in Greece and Sweden (approaches 15)
• Virtually absent in African Americans, Chinese,
  Japanese populations
• Homozygosity (5 of cases) greater thrombotic
  risk

7
APC resistance/Factor V Leiden

• Lifetime probability of developing thrombosis
• --protein S def 8.5X
• --ATIII def 8.1X
• --protein C def 7.3X
• --heterozygous Factor V Leiden 2.2X
• Increased incidence of second thrombotic defects
  in pts with Factor V Leiden
• Interaction with other risk factors occurs in
  OCP, pregnancy, obstetrical complications,
  immobilization.
• Does not occur in cancer, hip or knee
  replacement, PE, medical illness, recent surgery

8
APC resistance/Factor V Leiden

• Types of thrombosis deep veins of the legs,
  mesenteric veins, portal and hepatic veins,
  cerebral vein thrombosis
• Arterial thrombosis not well established.
  Unable to find increased incidence in those with
  strokes/MIs

9
Treatment

• Extended anticoagulation not helpful unless
• Two or more spontaneous thromboses
• One spontaneous life threatening thrombosis
• One spontaneous thrombosis at an unusual site
  (mesenteric, cerebral)
• One spontaneous thrombosis in the presence of
  more than one thrombophilic condition
• Pregnancy SQ heparin or LMWH during the second
  or third trimester and continued for 6 weeks into
  the postpartum period