Other names for Factors I, II, III, and IV
Factor Other name
I Fibrinogen
II Prothrombin
III Tissue Factor
IV Calcium








Most common bleeding disorders
Bleeding disorder Incidence
Von Willebrand Disease 0.5 - 2% of general population
Hemophilia A and B 1 in 5000 males
1 in 10,000 overall
Hemophilia A is 4 times more common


Reference 1, 2
Types of VWD and their characteristics
Type I VWD
  • Defect: Mild-moderate deficiency (5-30% reduction) of VWF and Factor VIII
  • Transmission: Autosomal dominant
  • Bleeding severity: Mild to moderate
  • % of affected individuals: 60 - 80%
Type II VWD
  • Defect: Qualitative defect of VWF
  • Transmission: Autosomal dominant
  • Bleeding severity: Typically moderate
  • % of affected individuals: 10 - 30%
Type III VWD
  • Defect: Severe or complete deficiency of VWF and moderately severe Factor VIII deficiency
  • Transmission: Autosomal recessive
  • Bleeding severity: Severe
  • % of affected individuals: 1 - 5%%




Reference [4,5,18,21]
Prevalence of hypercoagulable disorders
Disorder General population Patients with VTE
High concentration of Factor VIII 11% 25%
Antiphospholipid antibodies 0 - 5% 24%
Factor V Leiden 5% 20%
Hyper-homocysteinemia 5% 10%
Prothrombin 20210A 2% 6%
Protein C deficiency 0.2 - 0.4% 3%
Protein S deficiency <0.5% 2%
Antithrombin deficiency 0.02% 1%


  • Reference [18,22]
Clinical features associated with APA syndrome
Obstetrical
Miscarriages (see APA criteria for more)
Severe preeclampsia
Intrauterine growth restriction
Hematologic / Vascular
Recurrent VTE, especially at young age
Stroke and TIA, especially at young age
Acute and chronic renal thrombosis
Hemolytic anemia
Laboratory
Prolonged activated partial-thromboplastin time (aPTT)
False positive syphilis testing (RPR test)
Thrombocytopenia (< 100,000 per mm3)
Other
Systemic lupus erythematosus
Cardiac valve vegetations
Livedo reticularis and livedoid vasculopathy

  • GPL - IgG phospholipid; MPL - IgM phospholipid
  • Reference [22]
Diagnostic criteria for APA syndrome
Antiphospholipid antibody syndrome is present if at least one clinical criteria and one laboratory criteria are met
Clinical criteria (one of the following):
  • Vascular thrombosis - defined as ≥ 1 clinical episodes of arterial, venous (excluding superficial veins), or small vessel thrombosis, in any tissue or organ. Thrombosis must be confirmed by objective criteria. For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall.
  • Pregnancy morbidity (any of the following)
    • One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus
    • One or more premature births of a morphologically normal neonate before the 34th week of gestation because of: (i) eclampsia or severe preeclampsia defined according to standard definitions, or (ii) recognized features of placental insufficiency
    • Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded.
Laboratory criteria (one of the following):
  • Lupus anticoagulant (LA) - LA present in plasma, on two or more occasions at least 12 weeks apart
  • Anticardiolipin (aCL) antibody - aCL antibody of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (i.e. > 40 GPL or MPL, or > the 99th percentile), on two or more occasions, at least 12 weeks apart
  • Anti-Beta 2 glycoprotein I (aB2GI) antibody - aB2GI antibody of IgG and/or IgM isotype in serum or plasma (in titer > the 99th percentile), present on two or more occasions, at least 12 weeks apart




  • Reference [18]
Clinical features associated with inherited thrombophilias
VTE at young age (< 50 years)
VTE brought on by weak provoking factor (e.g. oral contraceptives, minor surgery, immobility)
Strong family history of VTE (first-degree family member affected at young age)
Recurrent VTE, especially at young age
VTE in unusual site (e.g. cerebral veins, splanchnic veins)

  • Reference [18,19]
Clinical features associated with acquired thrombophilias (APA syndrome)
Miscarriages (see APA criteria for more)
Severe preeclampsia
Intrauterine growth restriction
Recurrent VTE, especially at young age
Systemic lupus erythematosus
Elevated activated partial-thromboplastin time (aPTT)
False positive syphilis testing (RPR test)

  • FVL - Factor V Leiden mutation, PTG - prothrombin gene mutation, APA - antiphospholipid antibodies
  • Reference [18]
Testing for thrombophilia after first VTE
Clinical scenario Testing to consider
Provoked VTE
  • Do not test
Weakly-provoked VTE
  • No clear recommendation for extended anticoagulation in these patients (see VTE treatment recs)
  • Negative thrombophilia testing does not equate to a reduced risk for recurrence
  • Test results may be useful if patient has a female family member of childbearing age, because positive results may mean the female family member is also affected. This information may be useful when considering estrogen-containing hormone products and pregnancy.
  • Consider FVL, PTG, protein C and S, and antithrombin
  • Consider APA testing especially for arterial thrombosis, extensive VTE, or recurrent VTE
Unprovoked VTE
  • Extended anticoagulation is recommended for most patients (see VTE treatment recs)
  • Negative thrombophilia testing does not equate to a reduced risk for recurrence
  • Test results may be useful if patient has a female family member of childbearing age, because positive results may mean the female family member is also affected. This information may be useful when considering estrogen-containing hormone products and pregnancy.
  • Consider FVL, PTG, protein C and S, and antithrombin
  • Consider APA testing especially for arterial thrombosis, extensive VTE, or recurrent VTE
Cerebral vein VTE
  • Test for FVL, PTG, protein C and S, antithrombin, and APA
Splanchnic vein VTE
  • Test for FVL, PTG, protein C and S, antithrombin, and APA
  • Also test for myeloproliferative neoplasms and paroxysmal nocturnal hemoglobinuria


  • aPTT-LA - activated partial thromboplastin time-lupus anticoagulant, dRVVT - dilute Russell Viper Venom Time
  • Reference [18,21]
Test Anticoagulation effects
Activated protein C resistance
(screening test for Factor V Leiden mutation)
  • Do not perform if anticoagulated
  • Presence of lupus anticoagulant can also invalidate test
Factor V Leiden mutation
  • Not affected by anticoagulation
  • PCR test that looks directly for the mutation
Prothrombin gene mutation
  • Not affected by anticoagulation
  • PCR test that looks directly for the mutation
Protein C deficiency
  • Protein C activity assay is recommended first
  • Do not perform if anticoagulated
  • Presence of lupus anticoagulant can also invalidate test
Protein S deficiency
  • Free protein S antigen levels are recommended first
  • Warfarin will invalidate test
Lupus anticoagulant tests
(aPTT-LA and dRVVT)
  • Do not perform if anticoagulated
Anticardiolipin antibodies (IgG, IgM)
  • Not affected by anticoagulation
  • ELISA test that detects the presence of antibodies
Anti-Beta 2 glycoprotein I antibodies (IgG, IgM)
  • Not affected by anticoagulation
  • ELISA test that detects the presence of antibodies