Factor VIII Activity

CPT: 85240
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Test Details

Synonyms

  • Antihemophilic Factor (AHF)

Use

Used in the evaluation of an isolated prolonged aPTT. Diagnosis of hemophilia A and as an aid in the diagnosis of von Willebrand factor (vWF) deficiency6-9

Limitations

Factor VIII is an acute phase reactant and can be elevated in a number of clinical conditions. This can affect the accuracy of the test in diagnosing hemophilia. Factor VIII levels should not be used to determine the carrier status of females. Genetic testing should be used for this purpose. Factor VIII inhibitors (both autoantibodies that develop after replacement therapy and autoantibodies that develop spontaneously) can result in low factor VIII levels. A lupus anticoagulant may cause factor VIII activity to appear spuriously low and a chromogenic factor VIII activity is recommended in this circumstance. Direct Xa or thrombin inhibitor therapy may cause factitiously low results.

Methodology

Factor VIII activity is determined utilizing an aPTT-based one-stage clotting time assay. Factor VIII-depleted plasma is used as the substrate and the clotting time with the patient plasma is compared to the clotting time of normal pooled plasma.

Reference Interval

50% to 150%

Additional Information

Factor VIII is a large glycoprotein cofactor (320 kilodaltons) that is produced mainly in hepatocytes, but also to some extent by liver macrophages, megakaryocytes, and endothelial cells.6,10 Factor VIII circulates in the plasma bound to von Willebrand factor (vWF) at a concentration of approximately 0.1 mg/mL.10 The plasma half-life of factor VIII is short at about 8 to 10 hours.10 Factor VIII deficiency should be suspected when a patient with excessive bleeding has a normal protime (PT) and an extended activated partial thromboplastin time (aPTT).

Hemophilia A, or classic hemophilia, occurs as the result of congenital deficiency of factor VIII.6,11 Clinical features of hemophilia A are the same as for hemophilia B which is caused by factor IX deficiency (see Factor IX Activity [086298]). Hemophilia A is the second most common inherited bleeding abnormality (second only to von Willebrand disease), occurring in approximately 1 of every 5000 live male births.6,11 Hemophilia A accounts for approximately 85% of all hemophilia cases.11 This condition is transmitted as an X chromosome-linked hereditary disorder.11 The majority of cases occur in men whose mothers are carriers of the genetic defect. About 30% of factor VIII deficiencies arise in men as spontaneous mutations.6,11 The prevalence of hemophilia A is equal in all ethnic groups.6,11 Female carriers of hemophilia A may rarely present with excessive bleeding.6 Hemophilia symptoms can also occur in female carriers who have a high degree of lyonization of the factor VIII alleles.11 Females with Turner syndrome karyotype XO, can also be symptomatic.11

The severity of hemophilia A can be defined by the level of factor VIII activity.7,11 Severe hemophilia, which represents approximately half the cases, is associated with a factor VIII level <1%. About 10% of cases are moderate with factor VIII levels of 1% to 5% and the remaining 30% to 40% of hemophiliacs have the mild condition with factor VIII levels above >5%.

Approximately 45% of cases of severe hemophilia A occur as the result of a genetic inversion of intron 22 of the factor VIII gene locus.7,11,12 This genetic mutation results in the production of a protein that has no functional or immunologic factor VIII activity.11 Numerous deletions, point mutations, and missense mutations have also been implicated in hemophilia A.7,11 Family studies combined with genetic testing can determine if at-risk women are carriers for a hemophilia A mutation.11 Factor VIII activity levels should not be used as the method of determining carrier status because a number of clinical conditions including pregnancy, infection, or inflammation can affect activity levels.11

Patients with hemophilia A can present with any number of bleeding manifestations.6,11 Often, infants with severe hemophilia are first diagnosed during the neonatal period because of excessive bleeding after circumcision or due to cord necrosis.11 Hemophilic infants also frequently suffer from intracranial hemorrhage or scalp hematomas. Spontaneous hemarthroses, a common symptom of hemophilias, typically do not occur until the child starts walking.7,11 Hematomas can often be observed at the sites of intramuscular injections for vaccination or medication. The most common sites of spontaneous bleeding in patients with severe hemophilia involve the joints and muscles. Recurrent bleeding leads to chronic muscle injury and degeneration of the joint tissue.6,11 Gastrointestinal bleeding can occur in approximately 10% of hemophiliacs.11 Males with mild-to-moderate hemophilia and female carries may have an increased bleeding tendency, especially following surgery or trauma.7

Most individuals with von Willebrand disease will have decreased factor VIII levels because the von Willebrand factor (vWF) is the carrier protein for factor VIII in plasma.6,11 Individuals with von Willebrand disease type 2 Normandy will have normal to slightly low vWF ristocetin cofactor activity and von Willebrand factor antigen and low factor VIII levels due to defective binding of factor VIII to the variant vWF molecule.11

Factor VIII levels are elevated at birth and increase during pregnancy.6 Factor VIII is an acute phase reactant with levels that rise during periods of acute stress, following surgery, and in inflammatory conditions.6 Levels can also increase as the result of strenuous exercise or the administration of several drugs including epinephrine, DDAVP, or estrogen (for birth control or hormone replacement therapy). Factor VIII levels can be elevated in a number of clinical conditions including carcinoma, leukemia, liver disease, renal disease, hemolytic anemia, diabetes mellitus, deep vein thrombosis, and myocardial infarction.6

Persistent elevation of factor VIII above 150% is associated with an increased risk for venous thrombosis of more than fivefold.10,13 Elevated factor VIII is also associated with an increased risk for recurrence of venous thromboembolism. Risk is graded such that the higher the factor VIII activity, the higher the risk.14 The basis for this increased risk is not well understood as genetic studies of the factor VIII and von Willebrand factor genes failed to identify a genetic basis for this increased risk.10 Values >150% are observed in 20% to 25% of individuals with venous thrombosis or thromboembolism in the absence of other known causes of factor VIII elevation.13

A syndrome of combined factor VIII and V deficiencies has been described in over 60 families in and around the Mediterranean basin.15

Hemophilia A patients receiving replacement products can develop inhibitors to factor VIII due to the production of alloantibodies.6,8 Acquired hemophilia caused by the development of autoantibodies to factor VIII can also occur.9 This rare condition (1 in 1,000,000 individuals) can following pregnancy and in elderly individual with autoimmune disorders. In this life-threatening condition, patients have bleeding symptoms similar to those seen in severe congenital hemophilia A.

Specimen Requirements

Specimen

Plasma, frozen

Volume

2 mL

Minimum Volume

1 mL

Container

Blue-top (sodium citrate) tube

Patient Preparation

Ideally the patient should not be on anticoagulant therapy. Avoid warfarin (Coumadin®) therapy for two weeks prior to the test and heparin, direct Xa, and thrombin inhibitor therapies for about three days prior to testing. Do not draw from an arm with a heparin lock or heparinized catheter.

Collection

Blood should be collected in a blue-top tube containing 3.2% buffered sodium citrate.1 Evacuated collection tubes must be filled to completion to ensure a proper blood-to-anticoagulant ratio.2,3 The sample should be mixed immediately by gentle inversion at least six times to ensure adequate mixing of the anticoagulant with the blood. A discard tube is not required prior to collection of coagulation samples unless the sample is collected using a winged (butterfly) collection system. With a winged blood collection set a discard tube should be drawn first to account for the dead space of the tubing and prevent under-filling of the evacuated tube.4,5 When noncitrate tubes are collected for other tests, collect sterile and nonadditive (red-top) tubes prior to citrate (blue-top) tubes. Any tube containing an alternative anticoagulant should be collected after the blue-top tube. Gel-barrier tubes and serum tubes with clot initiators should also be collected after the citrate tubes. To avoid delays in turnaround time when requesting multiple tests on frozen samples, please submit separate frozen specimens for each test requested.

Please print and use the Volume Guide for Coagulation Testing to ensure proper draw volume.

Storage Instructions

Freeze.

Causes for Rejection

Severe hemolysis; improper labeling; clotted specimen; specimen diluted with IV fluids; samples thawed in transit; improper sample type; sample out of stability.

Clinical Information

Special Instructions

If the patient's hematocrit exceeds 55%, the volume of citrate in the collection tube must be adjusted. Refer to Coagulation Collection Procedures for directions.

Footnotes

1. Adcock DM, Kressin DC, Marlar RA. Effect of 3.2% vs 3.8% sodium citrate concentration on routine coagulation testing. Am J Clin Pathol. 1997 Jan; 107(1):105-110. 8980376
2. Reneke J, Etzell J, Leslie S, Ng VL, Gottfried EL. Prolonged prothrombin time and activated partial thromboplastin time due to underfilled specimen tubes with 109 mmol/L (3.2%) citrate anticoagulant. Am J Clin Pathol. 1998 Jun; 109(6):754-757. 9620035
3. National Committee for Clinical Laboratory Standardization. Collection, Transport, and Processing of Blood Specimens for Coagulation Testing and General Performance of Coagulation Assays; Approved Guideline. 5th ed. Villanova, Pa: NCCLS; 2008. Document H21-A5:28(5).
4. Gottfried EL, Adachi MM. Prothrombin time and activated partial thromboplastin time can be performed on the first tube. Am J Clin Pathol. 1997; 107(6):681-683. 9169665
5. McGlasson DL, More L, Best HA, Norris WL, Doe RH, Ray H. Drawing specimens for coagulation testing: Is a second tube necessary? Clin Lab Sci. 1999 May-Jun; 12(3):137-139. 10539100
6. Adcock DM, Bethel MA, Macy PA. Coagulation Handbook. Aurora, Colo: Esoterix−Colorado Coagulation; 2006.
7. Triplett DA. Coagulation abnormalities. In: McClatchey KD, ed. Clinical Laboratory Medicine. 2nd ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 2002:1033-1049.
8. Dimichele D. Inhibitors: Resolving diagnostic and therapeutic dilemmas. Haemophilia. 2002 May; 8(3):280-287. 12010424
9. Boggio LN, Green D. Acquired hemophilia. Rev Clin Exp Hematol. 2001 Dec; 5(4):389-404. 11844135
10. Chandler WL, Rodgers GM, Sprouse JT, et al. Elevated hemostatic factor levels as potential risk factors for thrombosis. Arch Pathol Lab Med. 2002 Nov; 126(11):1405-1414. 12421150
11. Cohen AJ, Kessler CM. Hemophilia A and B. In: Kitchens CS, Alving BM, Kessler CM, eds. Consultative Hemostasis and Thrombosis. Philadelphia, Pa: WB Saunders Co;2002:43-56.
12. Lakich D, Kazazian HH, Antonarakis SE, Gitschier J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nat Genet. 1993 Nov; 5(3):236-241. 8275087
13. Kamphuisen PW, Eikenboom JC, Rosendaal FR, et al. High factor VIII antigen levels increase the risk of venous thrombosis but are not associated with polymorphisms in the von Willebrand factor and factor VIII gene. Br J Haematol. 2001 Oct; 115(1):156-158. 11722428
14. Cristina L, Benilde C, Michela C, Mirella F, Giuliana G, Gualtiero P. High plasma levels of factor VIII and risk of recurrence of venous thromboembolism. Br J Haematol. 2004 Feb; 124(4):504-510. 14984502
15. Ginsburg D, Nichols WC, Zivelin A, Kaufman RJ, Seligsohn U. Combined factors V and VIII deficiency−The solution. Haemophilia. 1998 Jul; 4(4):677-682. 9873813

References

Adcock DM, Gosselin R. Direct oral anticoagulants (DOACs) in the laboratory: 2015 Review. Thromb Res. 2015 Jul; 136(1):7-12. 25981138

LOINC® Map

Order Code Order Code Name Order Loinc Result Code Result Code Name UofM Result LOINC
086264 Factor VIII Activity 3209-4 086264 Factor VIII Activity % 3209-4

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