Hypercoagulable States - Thrombophilia

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

Tabs Content

Clinical Overview

Key Points

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	LMWH	Warfarin	Direct Thrombin Inhibitors^a	Direct Factor Xa Inhibitors^b
Common coagulation assays
PT/INR Prothrombin Time/International Normalized Ratio 0030224	No effect^c	No effect^c	Prolonged	No effect/prolonged^d	Prolonged^d/no effect
aPTT Partial Thromboplastin Time 0030235	Prolonged	No effect/prolonged	No effect/prolonged	Prolonged^d/no effect	No effect/prolonged^d
D-dimer D-Dimer 0030057	No effect	No effect	No effect	No effect	No effect
Fibrinogen Fibrinogen 0030130	No effect^c	No effect^c	No effect	No effect/underestimate^d	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
APC resistance APC Resistance Profile 0030127 OR APC Resistance Profile with Reflex to Factor V Leiden 0030192	No effect^c	No effect^c	No effect^e	Possible false negative	Possible false negative
Antithrombin activity, IIa method Antithrombin, Enzymatic (Activity) 0030010	No effect^f	No effect^f	No effect^f	Overestimate^d	No effect
Antithrombin antigen Antithrombin, Antigen 0030015	No effect^f	No effect^f	No effect^f	No effect	No effect
Protein C activity, clot-based Protein C, Functional Protein C, Functional 0030113	No effect^c/overestimate	No effect^c/overestimate	Decreased	Overestimate^d	Overestimate^d
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^c/overestimate	No effect^c/overestimate	Decreased	Overestimate^d	Overestimate^d
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^c/prolonged	No effect^c/prolonged	No effect/prolonged	No effect/prolonged^d	Prolonged/no effect
DRVVT confirmatory ratio Dilute Russell Viper Venom Time (dRVVT) with Reflex to dRVVT 1:1 Mix and Confirmation 0030461	No effect^c/false positive	No effect^c/false positive	No effect/possible false positive^e	Possible false positive	Possible false positive
Hexagonal phospholipid neutralization Preferred test – Lupus Anticoagulant Reflexive Panel 0030181 OR Hexagonal Phospholipid Neutralization 0030064	No effect^c/false positive	No effect^c/false positive	No effect/possible false positive^e	Possible false positive	Possible false positive
Platelet neutralization procedure Preferred test – Lupus Anticoagulant Reflexive Panel 0030181	No effect^c/false positive	No effect^c/false positive	No effect/possible false positive^d	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^h 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^g	No effect/underestimate^g	No effect/decreased vitamin K-dependent factors	Underestimate^d	Underestimate^d
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
APC = activated protein C; aPTT = activated partial thromboplastin time; DRVVT = dilute Russell viper venom time; INR = international normalized ration; LMWH = low molecular weight heparin; PT = prothrombin time; tPA = tissue plasminogen activator ^aArgatroban, bivalirudin (Angiomax), dabigatran (Pradaxa) ^bRivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa) ^cReagent contains heparin neutralizer; effect may be seen with supratherapeutic drug levels ^fInterference in high concentrations of anticoagulant medication ^eDrug does not interfere with assay, but presence may affect analyte ^dDrug, concentration, and reagent dependent ^gaPTT-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. ^hPresence 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, 2002; Molinaro, 2008; Genzen, 2005; Hillarp, 2010; Adcock, 2015; Dale, 2014; Tsutsumi, 2014

Diagnosis

Indications for Testing

New or recurrent venous thromboembolism (VTE) without obvious risk factors (see Differential Diagnosis)
- 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 deep vein thrombosis (DVT) in the setting of known etiology (Five Things Physicians and Patients Should Question, 2015; Society for Vascular Medicine)
- Do not test during acute episode – results do not alter therapy and some results may be inaccurate
Any of the following situations (College of American Pathologists [CAP], 2002; Grody, American College of Medical Genetics and Genomics [ACMG], 2001)
- Idiopathic thrombosis in patient ≤50 years
- 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
Consider acquired disorders such as antiphospholipid syndrome
Children – very low risk for thrombophilia and should only have testing performed in consultation with hematologist (ACMG)
If testing pursued
- Do not test for protein C, protein S, or antithrombin (AT) levels during an active clotting event to diagnose a hereditary deficiency because these tests are not analytically accurate during an active clotting event (Choosing Wisely: 20 Things Physicians and Patients Should Question, 2017; American Society for Clinical Pathology)
- 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
  - AT activity
  - Protein C activity
  - Free protein S
- Less common disorders – testing 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 factor VIII and factor IX is controversial and not currently recommended
- Factor XIII (F13A1) V34L variant – presence of variant associated with decreased/reduced risk for DVT, 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

Screening

Population testing is not recommended for unselected patients.

Background

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^a	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^a	7.1	2.8
Protein C deficiency	0.2-0.4	3.7	6.5
Protein S deficiency	0.16-0.21	2.3	5.0
Antithrombin deficiency	0.02	1.9	20
Dysfibrinogenemia	<0.01	0.8	Unknown
Hyperhomocysteinemia^b	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 TAFI	9	14	1.7
^aPercent lowest in Asian or African descent; highest in Caucasian descent ^b>18.5 µmol/L DVT, deep vein thrombosis; TAFI, thrombin-activatable fibrinolysis inhibitor; VTE, venous thromboembolism Source: Whitlatch, 2008

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 (FVL)
- Genetics and pathophysiology
  - 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
  - Incomplete autosomal dominant inheritance
    - Heterozygotes have a 5- to 10-fold 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, deep vein thrombosis [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 10-fold
  - ≥1 genetic risk factor – concomitant prothrombin G20210A mutation of F2, protein C deficiency, homocysteinemia
  - Acquired thrombophilic disorders (eg, malignancy, hyperhomocysteinemia, high factor VIII levels)
  - Nongenetic factors such as pregnancy, oral contraceptives, hormone replacement therapy, selective estrogen-receptor modulators, travel, immobilization, central venous catheters, surgery, transplantation, and advanced age
Prothrombin G20210A
- Genetics and pathophysiology
  - Prothrombin G20210A mutation of the F2 gene – 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 2- to 4-fold 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 – 2 forms
    - Type I – quantitative
    - Type II – qualitative
  - Autosomal dominant inheritance – highly variable phenotypic expression
  - Functional assays preferred over antigenic assays for diagnosis – 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 – varicella-zoster virus [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 2 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
    - 3 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 variants or polymorphisms
  - 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 MTHFR gene variants
    - Most common variants – c.665C>T (p.Ala222Val) (previously designated C677T) and c.1286A>C (p.Glu429la) (previously designated A1298C)
    - Homozygosity for the c.665C>T variant is a risk factor for hyperhomocysteinemia
  - Autosomal recessive inheritance
  - Elevated plasma homocysteine level may be associated with a mild increase in risk for VTE independent of MTHFR status, but meta-analyses have cast doubt on the association between moderate homocysteine elevation and increased risk for coronary heart disease and VTE (Hickey, 2013)
  - The American College of Medical Genetics recommends MTHFR genotyping not be ordered as part of routine workup for thrombophilia due to questionable clinical significance (Hickey, 2013)
  - 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
  - 2 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 occur 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

ARUP Lab Tests

Panel to evaluate for inherited and acquired thrombophilias

Thrombotic Risk Reflexive Panel 2006385

Method: Chromogenic Assay/Electromagnetic Mechanical Clot Detection/Quantitative Enzymatic/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Polymerase Chain Reaction/Fluorescence Monitoring/Microlatex Particle Mediated Immunoassay

Recommended test to detect activated protein C (APC) resistance and confirm presence of a factor V Leiden variant

APC resistance profile may be affected by supratherapeutic concentrations of heparin, direct thrombin inhibitors, extreme factor V deficiency, or lupus anticoagulants with markedly prolonged baseline clotting times

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

APC Resistance Profile with Reflex to Factor V Leiden 0030192

Method: Electromagnetic Mechanical Clot Detection/Polymerase Chain Reaction/Fluorescence Monitoring

Reflex pattern: if APC resistance is normal, then no further testing will be added; if APC resistance is low, then factor V Leiden by polymerase chain reaction (PCR) will be added

Acceptable panel to screen for uncommon inherited thrombophilias

Thrombotic Risk, Inherited Etiologies (Uncommon) 0030177

Method: Electromagnetic Clot Detection/Microlatex Particle-Mediated Immunoassay/Chromogenic Assay

Panel includes partial thromboplastin time (PTT), free functional protein C, protein S antigen, antithrombin enzymatic activity

Acceptable panel to detect and subtype protein C and S deficiencies

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

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

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

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

Detect and subtype protein S deficiency

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

Protein S, Free Antigen with Reflex to Protein S, Total Antigen 2002269

Method: Microlatex Particle-Mediated Immunoassay

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

Acceptable screening panel for common inherited thrombophilias

Thrombotic Risk, Inherited Etiologies (Most Common) with Reflex to Factor V Leiden 0030133

Method: Electromagnetic Clot Detection/Quantitative Enzymatic/Polymerase Chain Reaction/Fluorescence Monitoring

Panel includes APC resistance profile, prothrombin G20210A mutation, activated partial thromboplastin time (aPTT), factor VIII (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

Related Tests

Screen for alpha-2-antiplasmin deficiency

Not a first-line test for diagnosing inherited thrombotic or bleeding disorders

Alpha-2-Antiplasmin, Activity 0098727

Method: Chromogenic Assay

Reflexive panel to assist in diagnosis of thrombotic thrombocytopenic purpura (TTP) and in distinguishing between inherited and acquired forms of TTP

ADAMTS13 Reflex Panel 3000239

Method: Quantitative Enzyme-Linked Immunosorbent Assay

Assist in diagnosing congenital or inherited thrombotic thrombocytopenic purpura (TTP)

ADAMTS13 Activity 0030056

Method: Chromogenic Assay

Assist in distinguishing between inherited and acquired forms of thrombotic thrombocytopenic purpura (TTP)

Recommended initial test for the identification of autoantibodies to ADAMTS13; more specific for acquired TTP than ADAMTS13 antibody test

If TTP is suspected but antibodies are not identified by inhibitor test, ADAMTS13 antibody testing is recommended

ADAMTS13 Inhibitor 3000228

Method: Quantitative Enzyme-Linked Immunosorbent Assay

Assist in distinguishing between inherited and acquired forms of thrombotic thrombocytopenic purpura (TTP)

Not recommended as the initial test for identification of autoantibodies to ADAMTS13; ADAMTS13 antibody test is less specific for acquired TTP than the inhibitor test

Order when acquired TTP is suspected but antibodies are not identified by the ADAMTS13 inhibitor test

ADAMTS13 Antibody 3000182

Method: Quantitative Enzyme-Linked Immunosorbent Assay

Not recommended as an initial test to detect antithrombin (AT) deficiency

Use to determine subtype in AT-deficient individuals

Antithrombin, Antigen 0030015

Method: Microlatex Particle-Mediated Immunoassay

Recommended test to detect AT deficiency

Antithrombin, Enzymatic (Activity) 0030010

Method: Chromogenic Assay

Detect and subtype AT deficiency

Antithrombin Panel 0030370

Method: Chromogenic Assay/Microlatex Particle-Mediated Immunoassay

Acceptable initial test to detect activated protein C (APC) resistance due to a factor V Leiden (FVL) variant

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

APC Resistance Profile 0030127

Method: Electromagnetic Mechanical Clot Detection

Aid in diagnosing and following disseminated intravascular coagulation (DIC)

D-Dimer 0030057

Method: Immunoturbidimetry

Preferred test is a lupus anticoagulant reflexive panel

Dilute Russell Viper Venom Time (dRVVT) with Reflex to dRVVT 1:1 Mix and Confirmation 0030461

Method: Electromagnetic Mechanical Clot Detection

Reflex pattern: if dilute Russell viper venom time (dRVVT) is elevated, then dRVVT 1:1 mix will be added; if the dRVVT 1:1 mix is elevated, then the dRVVT confirmation test will be added

Evaluate for possible factor II deficiency

For prothrombin variant testing (inherited thrombotic risk factor), order prothrombin (F2) c.*97G>A (G20210A) pathogenic variant

Factor II, Activity (Prothrombin) 0030007

Method: Electromagnetic Mechanical Clot Detection

Evaluate possible factor V deficiency

For FVL testing, order APC resistance profile with reflex to FVL or FVL R506Q mutation

Factor V, Activity 0030075

Method: Electromagnetic Mechanical Clot Detection

Detect FVL variant

Genetic test for the most common genetic cause of thrombophilia

F5 gene variants, other than p.Arg534Gln (R506Q), are not evaluated by this assay

Results of F5 genotyping can be accurately determined for individuals on oral anticoagulant and standard heparin therapy

Rare diagnostic errors may occur due to rare sequence variations

Not recommended for population screening and testing of asymptomatic minors for FVL; exceptions may include young female smokers who have experienced myocardial infarction or individuals <50 years with acute arterial thrombosis in the absence of other risk factors (see Test Fact Sheet for full list of contraindications for FVL testing)

Factor V Leiden (F5) R506Q Mutation 0097720

Method: Polymerase Chain Reaction/Fluorescence Monitoring

Determine thrombotic risk in individuals known to be FVL heterozygotes

F5 variants other than R2 (A4070G) are not evaluated

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

Factor V, R2 Mutation Detection by PCR 2014248

Method: Polymerase Chain Reaction

Evaluate possible factor VII deficiency

Factor VII, Activity 0030080

Method: Electromagnetic Mechanical Clot Detection

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 VIII, Activity 0030095

Method: Electromagnetic Mechanical Clot Detection

Diagnose factor VIII deficiency, detect factor VIII inhibitors, and monitor factor VIII replacement therapy

Factor VIII Activity with Reflex to Bethesda Quantitative, Factor VIII 0030026

Method: Electromagnetic Mechanical Clot Detection

Reflex pattern: if factor VIII activity is 20 percent or less, then Bethesda quantitative, factor VIII will be added

Assess genetic risk for thrombosis

Assessment of genetic susceptibility for pulmonary embolism and deep vein thrombosis (venous thromboembolism [VTE]), myocardial infarction (MI), or coronary artery disease (CAD) in Caucasians with a personal or family history of thrombotic event

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

Variants in the F13A1 or F13B genes, other than the V34L sequence variant, are not evaluated

Diagnostic errors can occur due to rare sequence variations

The protective effect of the V34L sequence variant has not been established for ethnicities other than Caucasians and may be altered by other genetic and nongenetic factors not assessed by this test

Factor XIII (F13A1) V34L Variant 2003220

Method: Polymerase Chain Reaction/Fluorescence Monitoring

Diagnose factor IX deficiency (hemophilia B) and monitor factor IX replacement therapy

Factor IX, Activity 0030100

Method: Electromagnetic Mechanical Clot Detection

Diagnose factor IX deficiency, detect factor IX inhibitors, and monitor factor IX replacement therapy

Factor IX Activity with Reflex to Bethesda Quantitative, Factor IX 0030032

Method: Electromagnetic Mechanical Clot Detection

Reflex pattern: if factor IX activity is <20%, then Bethesda quantitative, factor IX will be added

Evaluate possible factor X deficiency

Factor X, Activity 0030105

Method: Electromagnetic Mechanical Clot Detection

Diagnose factor XI deficiency (hemophilia C)

Factor XI, Activity 0030110

Method: Electromagnetic Mechanical Clot Detection

Evaluate the cause of an isolated prolonged partial thromboplastin time (PTT) in a patient who is not currently bleeding

Factor XII, Activity 0030115

Method: Electromagnetic Mechanical Clot Detection

Preferred first-line test to diagnose inherited or acquired factor XIII (FXIII) deficiency

More specific than qualitative assays for FXIII

Appropriate for evaluation of individuals with a bleeding disorder who present with normal prothrombin time (PT), PTT, and platelet count test results

Monitor therapy in individuals being treated for FXIII deficiency

Confirm abnormalities identified in the qualitative FXIII assay (clot solubility test)

A low FXIII level does not distinguish deficiency from a low value due to FXIII autoantibodies

Factor XIII Activity 2006182

Method: Chromogenic Assay

Most useful for acquired or severe FXIII deficiency testing

Abnormal results should be confirmed with quantitative testing

Distinguish between FXIII deficiency and a FXIII inhibitor

Factor XIII, Qualitative, with Reflex to Factor XIII 1:1 Mix 2002819

Method: Qualitative Solubility

Reflex pattern: if clot lysis occurs in the initial testing, then FXIII 1:1 mix will be added where the test is repeated using a 1:1 mix of patient plasma and pooled normal plasma to distinguish between FXIII deficiency and a FXIII inhibitor

D-dimer is the preferred test for evaluating coagulopathies (eg, disseminated intravascular coagulation [DIC])

If fibrin degradation products (FDP) testing is being considered, this plasma test, rather than the serum test, is the recommended test

Fibrin/Fibrinogen Degradation Split Products, Plasma 2006491

Method: Latex Agglutination

Determine if fibrinogen deficiency is a potential cause of bleeding

Fibrinogen 0030130

Method: Electromagnetic Mechanical Clot Detection

Follow-up test for decreased fibrinogen activity to determine if the decrease is due to insufficient fibrinogen or dysfunctional fibrinogen

Fibrinogen Antigen 0030135

Method: Radial Immunodiffusion

Preferred test is a lupus anticoagulant reflexive panel

Hexagonal Phospholipid Neutralization 0030064

Method: Qualitative Clotting

Acceptable screening test for disorders of methionine metabolism (congenital hyperhomocysteinemia)

Not recommended for risk assessment of cardiovascular disease (CVD) or VTE

Homocysteine, Total 0099869

Method: Quantitative Enzymatic

Use for unexplained prolonged PTT or for patients with a significant probability of having antiphospholipid syndrome (APS)

For APS, order with anticardiolipin (aCL) and anti-beta-2-glycoprotein 1 (anti-b2GP1) antibody IgG and IgM assays

Lupus Anticoagulant Reflexive Panel 0030181

Method: Electromagnetic Mechanical Clot Detection

Panel includes dilute Russell viper venom time (dRVVT); dRVVT 1:1 mix (performed if dRVVT >44 seconds); dRVVT confirmation test (performed if dRVVT 1:1 mix >44 seconds); PTT; thrombin time; reptilase time; PTT heparin neutralized; PTT 1:1 mix (performed if PTT >48 seconds); platelet neutralization procedure (performed if PTT 1:1 mix >48 seconds); hexagonal phospholipid neutralization

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

Determine genetic contribution to hyperhomocysteinemia for individuals with elevated plasma homocysteine

Not recommended for recurrent pregnancy loss, thrombophilia screening, neural tube defect risk assessment, or testing of family members of individuals with identified MTHFR variants

Only the 2 MTHFR gene variants (c.665C>T and c.1286A>C) will be targeted

Diagnostic errors can occur due to rare sequence variations

Methylenetetrahydrofolate Reductase (MTHFR) 2 Variants 0055655

Method: Polymerase Chain Reaction and Fluorescence Monitoring

Initial test for suspected bleeding disorder

Partial Thromboplastin Time 0030235

Method: Electromagnetic Mechanical Clot Detection

Detect elevated concentrations of plasminogen activator inhibitor 1 (PAI-1)

Low concentrations of PAI-1 may not be accurately quantified

Not a first-line test for diagnosing inherited thrombotic or bleeding disorders

Plasminogen Activator Inhibitor 1, Activity 0098781

Method: Bioimmunoassay

Screen for plasminogen deficiency

Not a first-line test for diagnosing inherited thrombotic or bleeding disorders

Plasminogen Activity 0030190

Method: Chromogenic Assay

Acceptable panel to detect protein C and S deficiencies

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

Panel includes functional protein C and functional protein S

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

Protein C and S Panel, Functional 0030182

Method: Electromagnetic Mechanical Clot Detection

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

Panel includes total antigen protein C and total antigen protein S

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

Protein C and S Panel, Total, Antigen 0030116

Method: Microlatex Particle-Mediated Immunoassay , Enzyme Immunoassay

Recommended test to detect protein C deficiency

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

Protein C, Functional 0030113

Method: Electromagnetic Mechanical Clot Detection

Acceptable test to detect and subtype protein C deficiency

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

Protein C, Functional with Reflex to Protein C, Total Antigen 0030041

Method: Electromagnetic Mechanical Clot Detection/Enzyme-Linked Immunosorbent Assay

Reflex pattern: if functional protein C is decreased, then protein C total antigen will be added

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

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 weeks

Protein C, Total Antigen 0030111

Method: Enzyme Immunoassay

Recommended test to detect protein S deficiency

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

Protein S Free, Antigen 0098894

Method: Microlatex Particle-Mediated Immunoassay

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 weeks

Protein S, Functional 0030114

Method: Electromagnetic Mechanical Clot Detection

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

Subtype deficiency in known protein S-deficient individuals in combination with protein S free antigen or functional protein S

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

Protein S, Total Antigen 0030112

Method: Microlatex Particle-Mediated Immunoassay

Detect prothrombin c.*97G>A (G20210A) pathogenic variant

Evaluate for increased genetic risk of VTE in a variety of populations

Diagnostic errors can occur due to rare sequence variations

F2 gene variants, other than c.*97G>A (G20210A), will not be detected

Prothrombin (F2) c.*97G>A (G20210A) Pathogenic Variant 0056060

Method: Polymerase Chain Reaction/Fluorescence Monitoring

Initial test for evaluating bleeding disorders and monitoring oral anticoagulation therapy (warfarin/Coumadin)

Prothrombin Time/International Normalized Ratio 0030224

Method: Electromagnetic Mechanical Clot Detection

Assist in diagnosing dysfibrinogenemia or abnormalities with fibrin polymerization

Reptilase Time with Reflex to Reptilase Time 1:1 Mix 0030295

Method: Electromagnetic Mechanical Clot Detection

Not recommended; order D-dimer test instead

Soluble Fibrin Monomer 0030126

Method: Qualitative Hemagglutination

Acceptable panel to detect 2 most common inherited thrombophilias (prothrombin related and FVL related)

Thrombotic Risk, DNA Panel 0056200

Method: Polymerase Chain Reaction/Fluorescence Monitoring

Assist in diagnosing dysfibrinogenemia or abnormalities with fibrin polymerization

Screen samples for the presence of heparin or direct thrombin inhibitors

Thrombin Time with Reflex to Thrombin Time 1:1 Mix 0030260

Method: Electromagnetic Mechanical Clot Detection

Determine quantity of tissue plasminogen (tPA) in plasma

May be helpful in detecting disorders of the fibrinolytic system

Not a first-line test for diagnosing inherited thrombotic or bleeding disorders

Tissue Plasminogen Activator, Antigen 0099187

Method: Enzyme-Linked Immunosorbent Assay

Order in conjunction with von Willebrand factor activity (ristocetin cofactor) and factor VIII activity as part of initial workup of suspected von Willebrand disease

von Willebrand Factor Antigen 0030285

Method: Microlatex Particle-Mediated Immunoassay

Order in conjunction with von Willebrand factor antigen and factor VIII activity as part of initial workup of suspected von Willebrand disease

von Willebrand Factor Activity (Ristocetin Cofactor) 0030250

Method: Platelet Agglutination

Evaluate prolonged clotting times such as PT and/or PTT when cause is unknown

Most useful for the workup of patients with unexpected prolonged clotting times

Condition-specific testing is recommended if the cause for the prolonged clotting time is known

Prolonged Clot Time Reflex Panel 2014318

Method: Electromagnetic Mechanical Clot Detection/Qualitative Hemagglutination/Platelet Agglutination/Microlatex Particle-Mediated Immunoassay

Panel includes factor II activity; Bethesda quantitative, factor VIII and factor IX; D-dimer; factor V activity; lupus anticoagulant interpretation; factor VII activity; hexagonal phospholipid neutral reflex; PTT-D heparin neutralized; factor VIII activity; factor IX activity; factor X activity; factor XI activity; factor XII activity; soluble fibrin monomer; fibrinogen; platelet neutralization; dRVVT confirmation; PTT-LA screen; prothrombin time; von Willebrand factor activity; thrombin time; von Willebrand factor antigen; reptilase time; PTT-D 1:1 mix; dRVVT screen; dRVVT 1:1 mix; PT, inhibitor screen, 1:1: mix; prolonged clot time reflex panel interpretation

Test Fact Sheet(s)

Factor V Leiden (F5) R506Q Variant

Medical Experts

Krautscheid, Patti, MS, LCGC, Genetic Counselor, Molecular Genetics and Special Genetics Laboratories at ARUP Laboratories

Mao, Rong, MD, FACMG, Laboratory Section Chief, Molecular Genetics and Genomics, at ARUP Laboratories; Professor of Clinical Pathology, Adjunct Associate Professor, Pediatrics, and Co-Director, Clinical Molecular Genetics Fellowship Program, University of Utah

Rodgers III, George M., MD, PhD, Medical Director, Hemostasis/Thrombosis at ARUP Laboratories; Professor of Internal Medicine and Adjunct Professor of Clinical Pathology, University of Utah

Smock, Kristi J., MD, Medical Director, Hemostasis/Thrombosis at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

Guidelines

Varga EA, Kujovich JL. Management of inherited thrombophilia: guide for genetics professionals. Clin Genet. 2012; 81(1): 7-17. PubMed
Practice Bulletin No. 197: Inherited Thrombophilias in Pregnancy Obstet Gynecol. 2018; 132(1): e18-e34. PubMed
Choosing Wisely. An initiative of the ABIM Foundation. [Accessed: Aug 2019]
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
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
Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013; 15(2): 153-6. PubMed
College of American Pathologists Consensus Conference XXXVI: Diagnostic Issues in Thrombophilia. Arch Pathol Lab Med. 2002; 126(11): 1277-433. PubMed
Grody WW, Griffin JH, Taylor AK, Korf BR, Heit JA, ACMG Factor V. Leiden Working Group. American College of Medical Genetics consensus statement on factor V Leiden mutation testing. Genet Med. 2001; 3(2): 139-48. PubMed

General References

Adcock DM, Gosselin R. Direct Oral Anticoagulants (DOACs) in the Laboratory: 2015 Review. Thromb Res. 2015; 136(1): 7-12. PubMed

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

Dale BJ, Ginsberg JS, Johnston M, Hirsh J, Weitz JI, Eikelboom JW. Comparison of the effects of apixaban and rivaroxaban on prothrombin and activated partial thromboplastin times using various reagents. J Thromb Haemost. 2014; 12(11): 1810-5. PubMed

Favaloro EJ, 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 EJ. 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

Hillarp A, Baghaei F, Blixter F, Gustafsson KM, Stigendal L, Sten-Linder M, Strandberg K, Lindahl TL. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost. 2011; 9(1): 133-9. PubMed

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

Johnson NV, Khor B, Van Cott EM. 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

Linkins LA, Julian JA, Rischke J, Hirsh J, Weitz JI. In vitro comparison of the effect of heparin, enoxaparin and fondaparinux on tests of coagulation. Thromb Res. 2002; 107(5): 241-4. 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

Molinaro RJ, Szlam F, Levy JH, Fantz CR, Tanaka KA. Low plasma fibrinogen levels with the Clauss method during anticoagulation with bivalirudin. Anesthesiology. 2008; 109(1): 160-1. PubMed

Samama MM, Martinoli J, LeFlem L, Guinet C, Plu-Bureau G, Depasse F, Perzborn E. Assessment of laboratory assays to measure rivaroxaban--an oral, direct factor Xa inhibitor. Thromb Haemost. 2010; 103(4): 815-25. PubMed

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

Tsutsumi Y, Shimono J, Ohhigashi H, Ito S, Shiratori S, Teshima T. Analysis of the influence of dabigatran on coagulation factors and inhibitors. Int J Lab Hematol. 2015; 37(2): 225-30. 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 AR. 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 NL, Ortel TL. Thrombophilias: when should we test and how does it help? Semin Respir Crit Care Med. 2008; 29(1): 25-39. PubMed

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

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Chandler WL, Rodgers GM, Sprouse JT, Thompson AR. 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 MM, Phansalkar AR, Crist RA, Roberts WL, Rodgers GM. Pediatric reference intervals for uncommon bleeding and thrombotic disorders. J Pediatr. 2006; 149(2): 275-7. PubMed

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

Genzen JR, Miller JL. Presence of direct thrombin inhibitors can affect the results and interpretation of lupus anticoagulant testing. Am J Clin Pathol. 2005; 124(4): 586-93. PubMed

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

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

Van Cott EM, Smock KJ, Chen D, Hsu P, Zantek ND, Meijer P. Testing for dabigatran and rivaroxaban by clinical laboratories. Am J Hematol. 2016; 91(11): E464-E467. 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

Educational Videos

Last Update: December 2019

Hypercoagulable States - Thrombophilia

Key Points

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Screening

Background

Epidemiology

Etiologies

Most Common Thrombophilias

Less Common Thrombophilias

Acquired Thrombophilic State

ARUP Lab Tests

Test Fact Sheet(s)

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult


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Hypercoagulable States - Thrombophilia

Key Points

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Screening

Background

Epidemiology

Etiologies

Most Common Thrombophilias

Less Common Thrombophilias

Acquired Thrombophilic State

ARUP Lab Tests

Test Fact Sheet(s)

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult