Hypercoagulable States - Thrombophilia

  • Diagnosis
  • Screening
  • Background
  • Lab Tests
  • References
  • Related Content

Indications for Testing

  • Patient with new or recurrent venous thromboembolism (VTE) without obvious risk factors (see Differential Diagnosis, below)
    • Abnormalities may be identified in a significant number of patients; however, identification of an abnormality may not predict risk of recurrence or alter therapeutic plan
    • Use when the results will impact management of the patient or patient family members
    • Do not order testing for first DVT in the setting of known etiology (ASCP's Pathology-Related Choosing Wisely Recommendations, 2015 [Society for Vascular Medicine])
    • Do not test during acute episode – results do not alter therapy and some results may be inaccurate
  • Situations where testing should be considered (College of American Pathologists [CAP], American College of Medical Genetics [ACMG])
    • Idiopathic thrombosis in patient ≤50 years of age
    • Recurrent thrombosis
    • Unusual sites of thrombosis in the absence of risk factors
    • First-degree relatives with thromboses
    • Thrombotic event during pregnancy, or while taking oral contraceptives or hormone replacement therapy

Laboratory Testing

  • Based on family and patient history – nongenetic tests may be altered by anticoagulant therapy or acute phase reaction due to clot
  • Children are at very low risk for thrombophilia and should only have testing performed in consultation with hematologist (ACMG)
  • Consider acquired disorders such as antiphospholipid syndrome
  • If testing pursued, consider the following combination (ACMG)
    • Activated protein C resistance (with or without reflex to factor V Leiden [FVL] mutation); factor V R2 A4070G mutation
    • Prothrombin mutation
    • Antithrombin (AT) activity
    • Protein C activity
    • Free protein S
    • Testing for less-common disorders may be considered if results are uninformative and additional testing is considered necessary
  • The following tests are not recommended
    • Factor VIII activity (testing other factor activities such as FVIII and FIX is controversial and not currently recommended)
    • Factor XIII (F13A1) V34L variant – presence of variant associated with decreased/reduced risk for deep vein thrombosis, myocardial infarction and coronary artery disease in Caucasians
  • Before making a definitive diagnosis of an inherited thrombophilia, consider repeating abnormal functional or antigenic testing
    • False positives and false negatives may encourage inappropriate therapies or follow-up planning
    • Low results can be obtained due to patient condition/biologic variability, medications, and assay variability or interference
    • Normal ranges vary by age and gender and must be considered when interpreting results

Differential Diagnosis

  • Acquired thrombophilia is more common than inherited thrombophilia and its causes and should be considered when evaluating patients with thrombosis
  • Population testing is not recommended for unselected patients

Hypercoagulable states may be acquired or inherited. Hereditary thrombophilia is a genetically determined increased risk for thrombosis and thromboembolism.

Epidemiology

  • Adults
    • Incidence – 30-500/10,000 for all disorders
    •  Ethnicity – slightly higher among African Americans; lower in Asian and Native Americans

Pediatrics

  • Incidence – 0.05-14/100,000
  • Age – peak in neonates and infants <1 year
    • Second peak in puberty
  • Sex – M<F

Etiologies

  • Most common thrombophilias
    • Factor V Leiden
    • Prothrombin G20210A
  • Less common thrombophilias
    • Increased clotting factors
      • Elevated factor VIII (FVIII) levels are often found in patients with venous thrombosis, but routine testing is controversial
    • Protein C deficiency
    • Protein S deficiency
    • Hyperhomocysteinemia (acquired or inherited)
    • Antithrombin deficiency
    • Impaired clot lysis (dysfibrinogenemia, abnormal fibrinolysis)
  • Antiphospholipid syndrome is an acquired thrombophilic state

Factor V Leiden

Genetics and Pathophysiology

  • Factor V Leiden (FVL) mutation of the F5 gene is the most common inherited thrombophilia
    • Accounts for more than 90% of patients with activated protein C resistance (APC-R)
      • During normal hemostasis, APC limits clot formation by proteolytic inactivation of factors Va and VIIIa
      • FVL prevents inactivation of factor Va by APC at the normal rate, increasing the risk for thrombosis
    • Functional tests for APC-R are generally used to screen for FVL
      • DNA tests are used to confirm positive screening tests and to differentiate between heterozygotes and homozygotes
  • Autosomal dominant inheritance
    • Heterozygotes have a five- to tenfold increased risk
    • Homozygotes have a 50- to 100-fold increased risk

Clinical Presentation

  • Venous thromboembolism (VTE) is the most common type of thrombotic event
    • Recurrent VTE (pulmonary embolism, DVT) is uncommon in heterozygotes unless additional risk factors are present
    • Increased risk of recurrent VTE in homozygotes
  • Pregnancy complications – recurrent miscarriage in the second trimester

Additional Risk Factors

  • Presence of F5 R2 (A4070G) mutation with FVL increases risk of thrombotic event tenfold
  • Patients with FVL mutation and recurrent episodes of thrombosis often have more than one genetic risk factor (eg, concomitant prothrombin G20210A mutation of F2, protein C deficiency, homocystinemia)
  • Acquired factors such as pregnancy, oral contraceptives, hormone replacement therapy, and immobilization increase the risk

Prothrombin G20210A

Genetics and Pathophysiology

  • Prothrombin G20210A mutation of the F2 gene is the second most common inherited thrombophilia
    • Results in elevated levels of plasma prothrombin leading to hypercoagulability (gain of function)
    • Detected using DNA tests
      • Factor II (prothrombin) activity testing may not identify the disease and should not be used for diagnosis
  • Autosomal dominant inheritance
    • Variable penetrance
      • Many patients who are either heterozygous or homozygous for G20210A do not experience VTE
    • Heterozygosity causes a two- to fourfold increase in thrombotic risk
    • Homozygosity is rare and increases thrombotic risk above that observed in G20210A heterozygotes

Clinical Presentation

  • VTE
  • Pregnancy complications – preeclampsia, placental abruption

Additional Risk Factors

  • Combined heterozygosity for both prothrombin G20210A and FVL mutations leads to thrombophilia with earlier onset, higher rate of recurrence, and more severe thrombotic events than either mutation alone
  • Increased risk of thrombosis associated with oral contraceptive use and pregnancy

Protein C Deficiency

Genetics and Pathophysiology

  • Protein C is a vitamin K-dependent plasma anticoagulant activated to APC by thrombin-thrombomodulin, which then inactivates factors Va and VIIIa
  • Inherited protein C deficiency is uncommon
    • Two forms
      • Type I – quantitative
      • Type II – qualitative
  • Autosomal dominant inheritance
    • Highly variable phenotypic expression
  • Functional assays preferred for diagnosis (rather than antigenic assays)
    • Protein C levels vary with age
  • Decreased levels in acute thrombotic states, disseminated intravascular coagulation (DIC), liver diseasemalnutrition (vitamin K deficiency), and with warfarin therapy
  • Increased levels in diabetes, nephrotic syndrome, pregnancy, and with oral contraceptive use
      • Elevated FVIII levels may result in falsely decreased values for some functional assays
      • Heparin and direct thrombin inhibitors may result in falsely elevated values for some functional assays

Clinical Presentation

  • Additional risk factors likely necessary to provoke thrombosis (eg, infection – VZV, meningococcal)
  • VTE in heterozygotes
  • Neonatal purpura fulminans (DIC) in homozygous infants – widespread thromboses with hemorrhagic skin necroses
  • Warfarin-induced skin necrosis is rarely seen

Protein S Deficiency

Genetics and Pathophysiology

  • Protein S is a vitamin K-dependent plasma anticoagulant that acts as a cofactor for activated protein C and exists in two forms
    • Free protein S – 40% of the total; physiologically active
    • Bound protein S (attached to C4b-binding protein) – 60% of the total; no anticoagulant activity
  • Inherited protein S deficiency is uncommon
    • Three forms
      • Type I – quantitative
      • Type II – qualitative
      • Type III (also called type IIa) – quantitative with normal levels of total protein S
    • Autosomal dominant inheritance
    • Antigenic tests for free protein S preferred for diagnosis
      • Free protein S values are higher in males than in females
  • Decreased levels in acute thrombotic states, nephrotic syndrome, inflammatory syndromes (due to increased C4b-binding protein), DIC, liver disease, malnutrition (vitamin K deficiency), pregnancy, and with estrogen and warfarin therapy
    • Elevated FVIII levels and/or APC resistance may result in falsely decreased values in some functional assays
    • Increased levels in heparin and direct thrombin inhibitors for some functional assays

Clinical Presentation

  • Additional risk factors likely necessary to provoke thrombosis
  • VTE most common; arterial thrombosis may occur
  • Neonatal purpura fulminans (DIC) in homozygous infants
  • Warfarin-induced skin necrosis (rare)

Antithrombin Deficiency

Genetics and Pathophysiology

  • Antithrombin (AT) – plasma anticoagulant; inactivates thrombin, factor Xa, and other activated clotting factors
    • AT activity enhanced by heparin-like glycosaminoglycans on the endothelial surface and by pharmaceutical heparin
    • Synthesized in the liver
  • Two forms of inherited antithrombin deficiency
    • Type I – quantitative
    • Type II – qualitative
  • Autosomal dominant inheritance
    • Functional assays preferred for diagnosis
    • Homozygous state is embryonic lethal
  • Decreased levels occurs in acute thrombotic states, liver disease, DIC, nephrotic syndrome, and heparin therapy; mild decreases may be seen in pregnancy or with oral contraceptive use
  • Increased levels may occur with long-term warfarin therapy

Clinical Presentation

  • VTE
  • Recurrent thrombosis may occur even in the absence of additional risk factors
  • Some deficient patients are resistant to heparin therapy

Hyperhomocysteinemia

Acquired

  • Independent risk factor for thromboembolic events
  • Most patients with hyperhomocysteinemia have no genetic mutations or polymorphisms
  • Acquired hyperhomocysteinemia is the result of defective homocysteine metabolism and may be the result of  vitamin B6, B12, or folic acid deficiency
  • Thrombotic risk most closely associated with increased fasting plasma homocysteine levels regardless of underlying etiology
    • Plasma homocysteine testing is recommended over DNA-based tests

Inherited

  • Homocysteine metabolism defects caused by variants in of the MTHFR gene
    • Most common variants – c.665C>T (p.Ala222Val) (previously designated C677T) and c.1286A>C (p.Glu429la) (previously designated A1298C)
      • Only homozygotes for the c.665C>T variant have been significantly associated with elevated plasma homocysteine levels
  • Autosomal recessive inheritance
  • Elevated plasma homocysteine level may be a risk factor for atherosclerotic vascular disease and venous thrombosis independent of MTHFR status
  • Inherited hyperhomocysteinemia rare

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations.
Click on number for test-specific information in the ARUP Laboratory Test Directory

APC Resistance Profile with Reflex to Factor V Leiden 0030192
Method: Electromagnetic Mechanical Clot Detection/Polymerase Chain Reaction/Fluorescence Monitoring

Limitations

APC resistance profile may be affected by heparin levels above 2 IU/mL, direct thrombin inhibitors, and low factor V activity levels (<50%)

Perform PCR testing as first-line test if these are present

APC resistance due to a cause other than a factor V mutation will not be detected

Thrombotic Risk, Inherited Etiologies (Uncommon) 0030177
Method: Electromagnetic Clot Detection/Microlatex Particle-Mediated Immunoassay/Chromogenic Assay

Limitations

See individual components

Follow Up

See individual components

Protein C, Functional with Reflex to Protein C, Total and Protein S, Free with Reflex to Protein S, Total 2003386
Method: Electromagnetic Mechanical Clot Detection/Enzyme-Linked Immunosorbent Assay/Microlatex Particle-Mediated Immunoassay

Protein S, Free Antigen with Reflex to Protein S, Total Antigen 2002269
Method: Microlatex Particle-Mediated Immunoassay

Thrombotic Risk (Acquired) Reflexive Panel 0030268
Method: Electromagnetic Clot Detection/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Immunoturbidimetry/Quantitative Enzymatic

Limitations

See individual components

Follow Up

Interpretation provided in test report

Thrombotic Risk, Inherited Etiologies (Most Common) with Reflex to Factor V Leiden 0030133
Method: Electromagnetic Clot Detection/Quantitative Enzymatic/Polymerase Chain Reaction/Fluorescence Monitoring

Limitations

See individual components

Follow Up

See individual components

Additional Tests Available

APC Resistance Profile 0030127
Method: Electromagnetic Mechanical Clot Detection

Comments

Acceptable initial test to detect activated protein C resistance due to a factor V Leiden mutation

Preferred test is APC resistance profile with reflex to factor V Leiden;  however, factor V Leiden (F5) R506Q mutation is the preferred initial test for individuals with supratherapeutic concentrations of heparin, direct thrombin inhibitors, extreme factor V deficiency, or lupus anticoagulants with markedly prolonged baseline clotting times

Prothrombin (F2) G20210A Mutation 0056060
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Comments

Order to detect prothrombin G20210A mutation

Antithrombin, Enzymatic (Activity) 0030010
Method: Chromogenic Assay

Comments

Recommended test to detect antithrombin (AT) deficiency

Antithrombin Panel 0030370
Method: Chromogenic Assay/Microlatex Particle-Mediated Immunoassay

Comments

Order to detect and subtype AT deficiency

Panel includes Antithrombin, Enzymatic (Activity); Antithrombin, Antigen

Antithrombin, Antigen 0030015
Method: Microlatex Particle-Mediated Immunoassay

Comments

Not recommended as an initial test to detect AT deficiency

Use to determine subtype in AT-deficient individuals

Protein C and S Panel, Functional 0030182
Method: Electromagnetic Mechanical Clot Detection

Comments

Acceptable panel to detect protein C and S deficiencies

Preferred test for detecting protein S deficiency is protein S free antigen

Panel includes Protein C, Functional; Protein S, Functional

Do not order if the individual has been on warfarin therapy in the previous 2-4 wks

Protein C, Functional with Reflex to Protein C, Total Antigen 0030041
Method: Electromagnetic Mechanical Clot Detection/Enzyme-Linked Immunosorbent Assay

Comments

Acceptable test to detect and subtype protein C deficiency

Do not order if individual has been on warfarin therapy in the previous 2-4 wks

Reflex pattern – if Protein C functional is decreased, then Protein C, total antigen, will be added

Protein C and S Panel, Total, Antigen 0030116
Method: Microlatex Particle-Mediated Immunoassay

Comments

Not recommended

Preferred tests for detection of protein C and S deficiencies are Protein C functional and protein S free antigen

Panel includes Protein C, Total Antigen; Protein S, Total Antigen

Do not order if individual has been on warfarin therapy in the previous 2-4 wks

Protein S Free, Antigen 0098894
Method: Microlatex Particle-Mediated Immunoassay

Comments

Recommended test to detect protein S deficiency

Do not order if individual has been on warfarin therapy in the previous 2-4 wks

Protein S, Functional 0030114
Method: Electromagnetic Mechanical Clot Detection

Comments

Acceptable test for detecting protein S deficiency

Preferred test is protein S free, antigen

Do not order if the individual has been on warfarin therapy in the previous 2-4 wks

Protein S, Total Antigen 0030112
Method: Microlatex Particle-Mediated Immunoassay

Comments

Not recommended for detecting protein S deficiency; preferred test is protein S free antigen

Use to subtype deficiency in known protein S-deficient individuals in combination with protein S free antigen or protein S functional

Do not order if individual has been on warfarin therapy in the previous 2-4 wks

Protein C, Functional 0030113
Method: Electromagnetic Mechanical Clot Detection

Comments

Recommended test to detect protein C deficiency

Do not order if individual has been on warfarin in the previous 2-4 wks

Protein C, Total Antigen 0030111
Method: Enzyme Immunoassay

Comments

Not recommended for detecting protein C deficiency; preferred test is protein C functional

Use to subtype deficiency in known protein C-deficient individuals

Do not order if individual has been on warfarin therapy in the previous 2-4 wks

Homocysteine, Total 0099869
Method: Quantitative Enzymatic

Comments

Not recommended for risk assessment of CVD or VTE

Acceptable screening test for disorders of methionine metabolism

Methylenetetrahydrofolate Reductase (MTHFR) 2 Variants 0055655
Method: Polymerase Chain Reaction/High Resolution Melt Analysis

Comments

Order to determine genetic cause for hyperhomocysteinemia and predict sensitivity to antifolate medications

MTHFR variants other than c.665C>T and c.1286A>C are not evaluated by this test

Do not use for the risk assessment of hereditary thrombophilia

Clinical sensitivity – undefined; dependent upon multiple contributing factors

 Analytical sensitivity/specificity – 99%

Factor VIII, Activity 0030095
Method: Electromagnetic Mechanical Clot Detection

Comments

Order to diagnose hemophilia A, acquired factor VIII deficiency, or as part of a diagnostic workup for von Willebrand disease

Not recommended when screening for thrombophilia

Factor V, R2 Mutation 2001549
Method: Polymerase Chain Reaction

Comments

Order to determine thrombotic risk in individuals known to be factor V Leiden heterozygotes

FVL mutations other than R2 (A4070G) are not evaluated

Test is not for individuals who are known to be negative or homozygous for FVL

Analytical sensitivity/specificity – 99.9%

Factor XIII (F13A1) V34L Variant 2003220
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Comments

Risk-benefit assessment for preventive or therapeutic interventions for VTE, MI, or CAD in Caucasians

Clinical sensitivity – varies by ethnicity

Analytical sensitivity and specificity – 99%

Thrombotic Risk, DNA Panel 0056200
Method: Polymerase Chain Reaction

Comments

Acceptable panel to detect two most common inherited thrombophilias

Includes factor V Leiden (F5) R506Q, MTHFR2 mutations (c.665C>T and c.1286A>C), and prothrombin (F2) G20210A mutations

Factor V Leiden (F5) R506Q Mutation 0097720
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Comments

Genetic test for the most common genetic cause of thrombophilia

Analytical sensitivity/specificity – 99.9%

Guidelines

American College of Medical Genetics and Genomics. Choosing Wisely - Five Things Patients and Providers Should Question. An initiative of the ABIM Foundation. [Initial posting Jul 2015; Accessed: Nov 2015]

American College of Obstetricians and Gynecologists Women's Health Care Physicians. ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy. Obstet Gynecol. 2013; 122(3): 706-17. PubMed

American Society for Clinical Pathology. Choosing Wisely - Pathology-Related Choosing Wisely Recommendations. An initiative of the ABIM Foundation. [Initial posting Feb 2015; Accessed: Nov 2015]

Baglin T, Gray E, Greaves M, Hunt B, Keeling D, Machin S, Mackie I, Makris M, Nokes T, Perry D, Tait R, Walker I, Watson H, British Committee for Standards in Haematology. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol. 2010; 149(2): 209-20. PubMed

De Stefano V, Rossi E. Testing for inherited thrombophilia and consequences for antithrombotic prophylaxis in patients with venous thromboembolism and their relatives. A review of the Guidelines from Scientific Societies and Working Groups. Thromb Haemost. 2013; 110(4): 697-705. PubMed

Harris E. Guidelines for Thrombophilia Testing. National Health Service Foundation Trust. England [Review date Apr 2013; Accessed: Aug 2015]

Hickey S, Curry C, Toriello H. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013; 15(2): 153-6. PubMed

Varga E, Kujovich J. Management of inherited thrombophilia: guide for genetics professionals. Clin Genet. 2012; 81(1): 7-17. PubMed

VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines . American College of Chest Physicians - Medical Specialty Society. 2001 January (Revised 2012 February). NGC: 008939

General References

Anderson J, Weitz J. Hypercoagulable states. Clin Chest Med. 2010; 31(4): 659-73. PubMed

Favaloro E, McDonald D, Lippi G. Laboratory investigation of thrombophilia: the good, the bad, and the ugly. Semin Thromb Hemost. 2009; 35(7): 695-710. PubMed

Favaloro E. The futility of thrombophilia testing. Clin Chem Lab Med. 2014; 52(4): 499-503. PubMed

Franchini M. The utility of thrombophilia testing. Clin Chem Lab Med. 2014; 52(4): 495-7. PubMed

Hossain N, Paidas M. Inherited thrombophilia: diagnosis and anticoagulation treatment in pregnancy. Clin Lab Med. 2013; 33(2): 377-90. PubMed

Johnson N, Khor B, Van Cott E. Advances in laboratory testing for thrombophilia. Am J Hematol. 2012; 87 Suppl 1: S108-12. PubMed

Lindhoff-Last E, Luxembourg B. Evidence-based indications for thrombophilia screening. Vasa. 2008; 37(1): 19-30. PubMed

Lippi G. Thrombophilia testing. Useful or hype? Clin Chem Lab Med. 2014; 52(4): 467-9. PubMed

Middeldorp S. Evidence-based approach to thrombophilia testing. J Thromb Thrombolysis. 2011; 31(3): 275-81. PubMed

Trampus-Bakija A. Pediatric thrombosis. Clin Chem Lab Med. 2010; 48 Suppl 1: S97-S104. PubMed

van Ommen H, Middeldorp S. Thrombophilia in childhood: to test or not to test. Semin Thromb Hemost. 2011; 37(7): 794-801. PubMed

Walker P, Gregg A. Screening, testing, or personalized medicine: where do inherited thrombophilias fit best? Obstet Gynecol Clin North Am. 2010; 37(1): 87-107, Table of Contents. PubMed

Whitlatch N, Ortel T. Thrombophilias: when should we test and how does it help? Semin Respir Crit Care Med. 2008; 29(1): 25-39. PubMed

Yang J, Chan A. Pediatric thrombophilia. Pediatr Clin North Am. 2013; 60(6): 1443-62. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Barker S, Bale S, Booker J, Buller A, Das S, Friedman K, Godwin A, Grody W, Highsmith E, Kant J, Lyon E, Mao R, Monaghan K, Payne D, Pratt V, Schrijver I, Shrimpton A, Spector E, Telatar M, Toji L, Weck K, Zehnbauer B, Kalman L. Development and characterization of reference materials for MTHFR, SERPINA1, RET, BRCA1, and BRCA2 genetic testing. J Mol Diagn. 2009; 11(6): 553-61. PubMed

Chandler W, Rodgers G, Sprouse J, Thompson A. Elevated hemostatic factor levels as potential risk factors for thrombosis. Arch Pathol Lab Med. 2002; 126(11): 1405-14. PubMed

Erali M, Schmidt B, Lyon E, Wittwer C. Evaluation of electronic microarrays for genotyping factor V, factor II, and MTHFR. Clin Chem. 2003; 49(5): 732-9. PubMed

Flanders M, Phansalkar A, Crist R, Roberts W, Rodgers G. Pediatric reference intervals for uncommon bleeding and thrombotic disorders. J Pediatr. 2006; 149(2): 275-7. PubMed

Flanders M, Rodgers G. Evaluation of a Russell's viper venom-based protein C assay. Thromb Haemost. 2004; 92(2): 430-1. PubMed

Gundry C, Vandersteen J, Reed G, Pryor R, Chen J, Wittwer C. Amplicon melting analysis with labeled primers: a closed-tube method for differentiating homozygotes and heterozygotes. Clin Chem. 2003; 49(3): 396-406. PubMed

Jackson B, Holmes K, Phansalkar A, Rodgers G. Testing for hereditary thrombophilia: a retrospective analysis of testing referred to a national laboratory. BMC Clin Pathol. 2008; 8: 3. PubMed

Kling S, Griffee M, Flanders M, Rodgers G. Factor V deficiency caused by a novel missense mutation, Ile417Thr, in the A2 domain. J Thromb Haemost. 2006; 4(2): 481-3. PubMed

Liew M, Pryor R, Palais R, Meadows C, Erali M, Lyon E, Wittwer C. Genotyping of single-nucleotide polymorphisms by high-resolution melting of small amplicons. Clin Chem. 2004; 50(7): 1156-64. PubMed

Pendleton R, Rodgers G, Wiener C. A necessary detour. Am J Med. 2006; 119(8): 651-3. PubMed

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Medical Reviewers

Last Update: January 2016