Hypercoagulable States - Thrombophilia

Primary Author: Smock, Kristi J., MD.

The widespread use of numerous anticoagulants for a variety of diseases, including the newest direct oral anticoagulant agents, has created clinical dilemmas for both anticoagulant monitoring and the interpretation of coagulation testing. Evaluations for thrombophilia may demonstrate interference once heparin and/or warfarin or one of the new direct agents is administered, making interpretation of results difficult. The table below details possible interferences with coagulation parameters based on the specific drug administered.

Anticoagulants and Possible Coagulation Test Interferences
Anticoagulant	Unfractionated Heparin	Low-Molecular-Weight Heparin (LMWH)	Warfarin	Direct Thrombin Inhibitors Argatroban, bivalirudin (Angiomax), dabigatran (Pradaxa)	Direct Factor Xa Inhibitors Rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa)
Common coagulation assays
PT/INR Prothrombin Time/International Normalized Ratio 0030224	No effect^~	No effect^~	Prolonged	No effect/prolonged^#	Prolonged^#/no effect
aPTT Partial Thromboplastin Time 0030235	Prolonged	No effect/prolonged	No effect/prolonged	Prolonged^#/no effect	No effect/prolonged^#
D-dimer D-Dimer 0030057	No effect	No effect	No effect	No effect	No effect
Fibrinogen Fibrinogen 0030130	No effect^~	No effect^~	No effect	No effect/underestimate^#	No effect
Fibrinogen antigen Fibrinogen Antigen 0030135	No effect	No effect	No effect	No effect	No effect
Reptilase time Reptilase Time with Reflex to Reptilase Time 1:1 Mix 0030295	No effect	No effect	No effect	No effect	No effect
Thrombin time Thrombin Time with Reflex to Thrombin Time 1:1 Mix 0030260	Prolonged	No effect/prolonged	No effect	Prolonged	No effect
Thrombotic risk assays
Activated protein C (APC) resistance APC Resistance Profile 0030127 OR APC Resistance Profile with Reflex to Factor V Leiden 0030192	No effect^~	No effect^~	No effect^{^}	Possible false negative	Possible false negative
Antithrombin activity, IIa method Antithrombin, Enzymatic (Activity) 0030010	No effect^*	No effect^*	No effect^*	Overestimate^#	No effect
Antithrombin antigen Antithrombin, Antigen 0030015	No effect*	No effect*	No effect*	No effect	No effect
Protein C activity, clot-based Protein C, Functional 0030113	No effect^~/overestimate	No effect^~/overestimate	Decreased	Overestimate^#	Overestimate^#
Protein C antigen Protein C, Total Antigen 0030111	No effect	No effect	Decreased	No effect	No effect
Protein S activity Protein S, Functional 0030114	No effect^~/overestimate	No effect^~/overestimate	Decreased	Overestimate^#	Overestimate^#
Protein S free antigen Protein S Free, Antigen 0098894	No effect	No effect	Decreased	No effect	No effect
Protein S total antigen Protein S, Total Antigen 0030112	No effect	No effect	Decreased	No effect	No effect
Lupus anticoagulants
DRVVT Preferred test – Lupus Anticoagulant Reflexive Panel 0030181 OR Dilute Russell Viper Venom Time (dRVVT) with Reflex to dRVVT 1:1 Mix and Confirmation 0030461	No effect^~/prolonged	No effect^~/prolonged	No effect/prolonged	No effect/prolonged^#	Prolonged/no effect
DRVVT confirmatory ratio Dilute Russell Viper Venom Time (dRVVT) with Reflex to dRVVT 1:1 Mix and Confirmation 0030461	No effect^~/false positive	No effect^~/false positive	No effect/possible false positive^{^}	Possible false positive	Possible false positive
Hexagonal phospholipid neutralization Preferred test – Lupus Anticoagulant Reflexive Panel 0030181 OR Hexagonal Phospholipid Neutralization 0030064	No effect^~/false positive	No effect^~/false positive	No effect/possible false positive^{^}	Possible false positive	Possible false positive
Platelet neutralization procedure Preferred test – Lupus Anticoagulant Reflexive Panel 0030181	No effect^~/false positive	No effect^~/false positive	No effect/possible false positive^{^}	Possible false positive	Possible false positive
Fibrinolytic assays
Alpha-2-antiplasmin Alpha-2-Antiplasmin, Activity 0098727	No effect	No effect	No effect	No effect	No effect
Fibrin/fibrinogen degradation products Fibrin/Fibrinogen Degradation Split Products, Plasma 2006491	No effect	No effect	No effect	No effect	No effect
Plasminogen activator inhibitor-1 Plasminogen Activator Inhibitor 1, Activity 0098781	No effect	No effect	No effect	No effect	No effect
Plasminogen activity Plasminogen Activity 0030190	No effect	No effect	No effect	No effect	No effect
tPA antigen Tissue Plasminogen Activator, Antigen 0099187	No effect	No effect	No effect	No effect	No effect
Soluble fibrin monomer Soluble Fibrin Monomer 0030126	No effect	No effect	No effect	No effect	No effect
Other assays
ADAMTS-13 ADAMTS13 Activity 0030056	No effect	No effect	No effect	No effect	No effect
Factor assays, clot-based^$ Factor II, Activity (Prothrombin) 0030007 Factor V, Activity 0030075 Factor VII, Activity 0030080 Factor VIII, Activity 0030095 Factor VIII Activity with Reflex to Bethesda Quantitative, Factor VIII 0030026 Factor IX, Activity 0030100 Factor IX Activity with Reflex to Bethesda Quantitative, Factor IX 0030032 Factor X, Activity 0030105 Factor XI, Activity 0030110 Factor XII, Activity 0030115 Factor XIII Activity 2006182 Factor XIII, Qualitative, with Reflex to Factor XIII 1:1 Mix 2002819	No effect/underestimate⁺	No effect/underestimate⁺	No effect/decreased vitamin K-dependent factors	Underestimate^#	Underestimate^#
von Willebrand factor antigen and activity von Willebrand Factor Antigen 0030285 von Willebrand Factor Activity (Ristocetin Cofactor) 0030250	No effect	No effect	No effect	No effect	No effect
^*Drug does not interfere with assay, but presence may affect analyte ^{^}Interference in high concentrations of anticoagulant medication ^~Reagent contains heparin neutralizer; effect may be seen with supratherapeutic drug levels ^#Drug, concentration, and reagent-dependent ⁺aPTT-based factor assays (factors 8, 9, 11, 12) are more likely to demonstrate assay interference and underestimation than PT-based factors assays (factors 2, 5, 7, 10). The effect is more pronounced with unfractionated heparin than with LMWH. ^$Presence of unfractionated heparin, LMWH, direct thrombin inhibitors, and direct Xa inhibitors may produce inhibitory patterns and may prevent accurate quantitation (underestimation) of factor activity. May also interfere with and cause false-positive Bethesda assays (false-positive coagulation factor inhibitor). Chromogenic Factor XIII activity may also be falsely decreased in the presence of direct thrombin inhibitors. Sources: Linkins, L, 2002; Molinaro, R, 2008; Genzen, J, 2005; Hillarp, A, 2010; Adcock, DM, 2015; Dale, BJ, 2014; Tsutsumi, Y, 2014

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 should be considered when evaluating patients with thrombosis
- Antiphospholipid antibodies/lupus anticoagulant
- Malignancy
- Long-distance travel
- Trauma
- Surgery
- Immobilization
- Presence of a central venous catheter
- Pregnancy/postpartum
- Therapy-related thrombophilia
  - Hormone replacement therapy
  - Oral contraceptives
  - Tamoxifen/raloxifene
  - Chemotherapy
  - Heparin-induced thrombocytopenia

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

Inherited thrombophilic disorders

Inherited Thrombophilic Disorders
Disorder	Prevalence in Normals (%)	Frequency in Patients with VTE+ (%)	Relative Risk of First Episode of DVT++
Factor V Leiden (heterozygous)	0.05-4.8*	18.8	7
Factor V Leiden (homozygous)	0.02	1.5	80
Factor V with R2 mutation	0.06-0.12	10.0	7 (heterozygote) 10 (compound heterozygote)
Prothrombin G20210A allele	0.06-2.7*	7.1	2.8
Protein C deficiency	0.2-0.4	3.7	6.5
Protein S deficiency	0.2-0.4	2.3	5.0
Antithrombin deficiency	0.02-0.2	1.9	20
Dysfibrinogenemia	<0.01	0.8	Unknown
Hyperhomocysteinemia**	5-7	10	2.95
Elevated factor VIII level	11	25	4.8
Elevated factor IX level	10	20	2.8
Elevated factor XI level	10	19	2.2
Elevated lipoprotein (a) level	7	20	3.2
Elevated thrombin-activatable fibrinolysis inhibitor (TAFI)	9	14	1.7
Percent lowest in Asian or African descent; highest in Caucasian descent *>18.5 µmol/L +VTE = venous thromboembolism ++DVT = deep vein thrombosis Whitlatch, 2013

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

Etiologies

Most common thrombophilias

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

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
- 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 disease, malnutrition (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)
Hyperhomocysteinemia (acquired or inherited)
- 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
    - Clotting cascade with an emphasis on inherited thrombophilias

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
Impaired clot lysis (dysfibrinogenemia, abnormal fibrinolysis)

Acquired thrombophilic state

Antiphospholipid syndrome

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

Recommended Use

Preferred initial test to detect activated protein C resistance and confirm presence of factor V Leiden mutation

Initial screening for suspected factor V deficiency

Profile includes thrombosis common etiologies, factor VIII activity, PTT, prothrombin G20210A mutation

Reflex pattern – if APC resistance is normal, then no further testing will be added; if APC resistance is low, and then factor V Leiden by PCR will be added

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

Recommended Use

Acceptable panel to screen for uncommon inherited thrombophilias

Prior to ordering screen, screen for APC resistance

Panel includes PTT, free functional protein C, protein S antigen, antithrombin enzymatic activity

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

Recommended Use

Acceptable panel to detect and subtype protein C and S deficiencies

Panel includes functional protein C, total antigen protein C, protein S free antigen, total antigen protein S

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

Reflex pattern – if functional protein C is low, total antigen protein C will be added; if free protein S is low, total antigen protein S will be added

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

Recommended Use

Use to detect and subtype protein S deficiency

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

Reflex pattern – if low free antigen protein S is detected, then total antigen protein S will be added

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

Recommended Use

Acceptable screening panel for acquired thrombophilia; not considered initial testing for evaluation of thrombophilia

Panel includes antiphospholipid antibodies, d-dimer and clotting time assays, and homocysteine

Reflex pattern – If PTT and dRVVT are normal, then no further testing is performed; if PTT is abnormal, thrombin time is added; if thrombin time is normal, PTT 1:1 mix is added; if thrombin time is abnormal, reptilase time and PTT heparin neutralization is added; if PTT heparin neutralization is abnormal, PTT 1:1 mix is added; if PTT 1:1 mix is abnormal, platelet neutralization procedure is added; if dRVVT is abnormal, dRVVT 1:1 mix is added; if dRVVT 1:1 mix is abnormal, dRVVT confirmation is added; if platelet neutralization procedure and dRVVT confirmation are normal or if one is normal and the other not done, hexagonal phospholipid neutralization is added

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

Recommended Use

Acceptable panel to screen for common inherited thrombophilias

Panel includes APC resistance profile, prothrombin G20210A mutation, aPTT, FVIII activity, and homocysteine

Reflex pattern – if APC resistance is normal, then no further testing will be added; if APC resistance is abnormally low, then factor V Leiden by PCR will be added

Limitations

See individual components

Follow-up

See individual components

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 BJ, Keeling D, Machin S, Mackie I, Makris M, Nokes T, Perry D, Tait RC, 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 SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013; 15(2): 153-6. PubMed

Varga EA, Kujovich JL. 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

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

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

Kling SJ, Griffee M, Flanders MM, Rodgers GM. 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 RC, Rodgers GM, Wiener CM. A necessary detour. Am J Med. 2006; 119(8): 651-3. PubMed

Rondina MT, Pendleton RC, Wheeler M, Rodgers GM. The treatment of venous thromboembolism in special populations. Thromb Res. 2007; 119(4): 391-402. PubMed

Seipp MT, Durtschi JD, Voelkerding KV, Wittwer CT. Multiplex amplicon genotyping by high-resolution melting. J Biomol Tech. 2009; 20(3): 160-4. PubMed

Shirts BH, Rodgers GM, Smock KJ. Prothrombin time, activated partial thromboplastin time and dilute Russell's Viper Venom times are not shorter in patients with the prothrombin G20210A mutation, and dilute Russell's Viper Venom time may be longer. Thromb Res. 2012; 130(3): e134-8. PubMed

Stinnett JM, Pendleton R, Skordos L, Wheeler M, Rodgers GM. Venous thromboembolism prophylaxis in medically ill patients and the development of strategies to improve prophylaxis rates. Am J Hematol. 2005; 78(3): 167-72. PubMed

Yang DT, Flanders MM, Kim H, Rodgers GM. Elevated factor XI activity levels are associated with an increased odds ratio for cerebrovascular events. Am J Clin Pathol. 2006; 126(3): 411-5. PubMed

Zhou L, Wang L, Palais R, Pryor R, Wittwer CT. High-resolution DNA melting analysis for simultaneous mutation scanning and genotyping in solution. Clin Chem. 2005; 51(10): 1770-7. PubMed