Medical Analysis

Introduction to Lupus Anticoagulant (LA): Clinical Overview and History

Lupus anticoagulant (LA) is a medical term coined by Feinstein and Rapaport in 1972 [1] to designate an inhibitor of coagulation that impairs prothrombinase activation of prothrombin (PT), which was first recognized in the plasma of patients with systemic lupus erythematosus (SLE). It acts at the junction of the intrinsic and extrinsic coagulation pathways by interfering with the activation of prothrombin by the prothrombin activator complex (factor Xa, V, calcium, and phospholipid). Basically; one must know it that Lupus anticoagulant testing is a series of tests used to detect lupus anticoagulant (LA) in the blood [12]. LA is an autoantibody associated with excess blood clot formation [10]. Commonly associated with Antiphospholipid syndrome and thrombosis and pregnancy loss [4].

Pathophysiology of Lupus Anticoagulant: Mechanisms and Immune Response

The LAC attacks healthy cells and cell proteins and generally target essential components of cell membranes called phospholipids that play a role in blood clotting [11]. These antibodies often relate to an immune system disorder called antiphospholipid syndrome [4]. Even though it is suspected that something triggers for occurrence of LAC due to inherited predisposition; it is till date accepted that the real cause is still remained undefined [8].

Clinical Indications for Lupus Anticoagulant Testing and Evaluation

In the evaluation of unexplained prolonged partial thromboplastin time (PTT) [12]. Autoimmune disorders [2]. Prolonged clotting time [12]. Unexplained thrombosis [13]. Recurrent miscarriages [13]. Along with tests for cardiolipin antibody and anti-beta-2-glycoprotein to diagnose antiphospholipid syndrome (APS) [4]. Along with tests such Antithrombin or proteins C and S to diagnose thrombophilia [13]. To determine whether the lupus anticoagulant is temporary (transient) or persistent [2]. Unexplained thrombosis or thromboembolism [13].

Essential Diagnostic Principles: Multi-Step LA Testing Protocols

Nobody can measure LA directly [12]; rather it comprises series of tests or procedures to reach to identify existence of LA in the blood [12]. A series of tests are used to confirm or rule out the autoantibody [2]. It comprises three studies [2]. 1. Screening study, 2. Mixing Study & 3. confirmation study [2].

Comprehensive Screening Studies for Coagulation Evaluation

Activated partial thromboplastin time (aPTT). Dilute Russell viper venom time (dRVVT) [9]. Kaolin clotting time (KCT). Silica clotting time (SCT). Dilute Russell viper venom test (DRVVT) : The assay uses Russell viper venom (RVV) in a system containing limiting quantities of diluted rabbit brain phospholipid [9]. RVV directly activates coagulation factor X, leading to formation of fibrin clot [9]. A LA-sensitive PTT (PTT-LA) test [7]. (It uses reagents containing low levels of phospholipid [7].)

Mixing Studies: Differentiating Factor Deficiency from Inhibitors

Mix patient plasma with normal plasma [12]. Repeat the test and see the evaluation [12]. It differentiates factor deficiency from inhibitor [12]. If same results persist : It is inhibitor [12]. If correction appears : It is deficiency [12].

Confirmatory Tests and Advanced Detection Methods

1 Phospholipid neutralization test [15]. 2 Hexagonal phase phospholipid neutralization assay [11]. 3 Platelet neutralization procedure (PNP) [15]. Methods of detection: Electromagnetic Mechanical Clot Detection/Chromogenic Assay [12].

Detailed DRVVT Interpretation Guidelines and Reference Values

Generally correction test or neutralization test is kept reserved if DRVVT is not prolonged [15]. However; as DRVVT fails to detect LA usually; it is recommended to get done silica clotting time (SCT) [9].

Importance of Calculations in Coagulation Ratios

Calculate dRVVT clotting time on following samples separately [15]. Patient’s Plasma : Label value as A [15]. Control Plasma : Label value as B [15]. Patient’s Plasma + PL : Label value as C [15]. Control plasma + PL : Label value as D [15]. Calculate ratios : A/B = X & C/D = Y [15]. Now if (X – Y/X) * 100 > EF %. So this is correction [15]. (The value may vary [15].) So in a patient in whom the dRVVT is prolonged (A value) the correction percentage more than even 10 % is consistent with the presence of a Lupus Anticoagulant [15].

International Society of Thrombosis and Hemostasis (ISTH) Recommendations

Prolonged result on at least one of two coagulation tests that are dependent on phospholipids, such as PTT-LA or DRVVT [3]. Prolonged result on a mixing study (evidence of clotting inhibition) [3]. Shortened clotting time occurs after adding excess phospholipids (demonstrates dependence of the inhibitor on phospholipids) [3]. Ruling out coexisting specific coagulation factor inhibitor, such as factor VIII, which could result in catastrophic bleeding if not identified [3].

Comprehensive Reference Ranges for Coagulation Parameters

Clinical Relevance, Situations, and Outcomes Guidance

Interferences Affecting Lupus Anticoagulant Testing

Heparin therapy [16]. Direct oral anticoagulants [16]. False positives [16]. False negatives [16].

For Non-Medicos

Understanding Lupus Anticoagulant: What Patients Need to Know

Lupus anticoagulant (LA) is a type of protein antibody produced by your immune system that mistakenly targets cell elements called phospholipids, which are important for normal blood clotting [11]. Despite its name, most people who have it do not have lupus, but it is frequently linked to an increased tendency to form unwanted blood clots inside blood vessels or cause complications during pregnancy [4]. Doctors check for this condition using specialized blood tests when patients experience unexplained blood clots, repeated miscarriages, or unexpected results on routine clotting screens [13].

Why Doctors Order Lupus Anticoagulant Tests and What Results Mean

Healthcare providers order these evaluations to figure out why a patient’s blood is taking too long to clot in initial lab work or to investigate conditions like Antiphospholipid Syndrome (APS) [4]. Because no single test can measure LA directly, laboratories perform a multi-step process involving screening tests (like aPTT or dRVVT), mixing studies to see if a clotting factor is missing or blocked by an inhibitor, and confirmation tests using extra phospholipids [12]. If the tests show that clotting times correct themselves when excess phospholipids are added, it confirms the presence of a lupus anticoagulant, helping physicians design safer long-term treatment and prevention plans [3].

References:

1. Feinstein, D. I., & Rapaport, S. I. (1972). Acquired inhibitors of blood coagulation. Progress in Hemostasis and Thrombosis, 1, 75–95.

2. Pengo, V., Tripodi, A., Reber, G., Rand, J. H., Biron-Andréani, C., Bretelle, F., Castilla, J., Danese, S., de Groot, P. G., Devreese, K., Furie, B., Lakos, G., Lambert, T., Petrovic, M., Saria, E., Tomassini, L., vazquez-Madrid, R., & Wu, O. (2009). Update of the guidelines for lupus anticoagulant detection. Journal of Thrombosis and Haemostasis, 7(10), 1737–1740. https://doi.org/10.1111/j.1538-7836.2009.03555.x

3. Devreese, K. M. J., de Groot, P. G., de Laat, B., Erkan, D., Favaloro, E. J., Mackie, I., Martinuzzo, M., Pessin-Chesnet, D., Rand, J. H., Tripodi, A., & Atsumi, T. (2020). Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis: Update of the guidelines for lupus anticoagulant detection and interpretation. Journal of Thrombosis and Haemostasis, 18(11), 2828–2839. https://doi.org/10.1111/jth.15047

4. Miyakis, S., Lockshin, M. D., Atsumi, T., Branch, D. W., Brey, R. L., Cervera, R., Derksen, R. H. W. M., de Groot, P. G., Koike, T., Meroni, P. L., Reber, G., Shoenfeld, E., Tincani, A., Vlachoyiannopoulos, P. G., & Khamashta, M. A. (2006). International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). Journal of Thrombosis and Haemostasis, 4(2), 295–306. https://doi.org/10.1111/j.1538-7836.2006.01753.x

5. Triplett, D. A. (2000). Antiphospholipid-protein antibodies: laboratory detection and diagnostic use. Thrombosis Research, 99(5), 415–435. https://doi.org/10.1016/S0049-3848(00)00249-1

6. Favaloro, E. J., & Wong, R. C. W. (2006). Laboratory testing for lupus anticoagulant (LA): a review of current recommendations and the role of novel diagnostics. Pathology, 38(5), 405–415. https://doi.org/10.1080/00313020600930101

7. Brandt, J. T., Triplett, D. A., Alving, B., & Scharrer, I. (1995). Criteria for the diagnosis of lupus anticoagulant: an update. Thrombosis and Haemostasis, 74(4), 1185–1190. https://doi.org/10.1055/s-0038-1649910

8. Arnout, J. (2003). The pathogenesis of the antiphospholipid syndrome: a hypothesis based on parallel mechanisms. Thrombosis and Haemostasis, 90(1), 6–8. https://doi.org/10.1160/TH03-04-0238

9. Martinuzzo, M. E., Forastiero, R. R., & Carreras, L. O. (1993). Evaluation of various procedures for detection of lupus anticoagulants. Thrombosis and Haemostasis, 70(5), 790–794. https://doi.org/10.1055/s-0038-1649673

10. Galli, M., Luciani, D., Bertolini, G., & Barbui, T. (2003). Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood, 101(5), 1827–1832. https://doi.org/10.1182/blood-2002-02-0441

11. Thiel, J., & Chan, O. (2014). The coagulation system and the lupus anticoagulant: mechanisms of action and laboratory pitfalls. Seminars in Thrombosis and Hemostasis, 40(04), 433–440. https://doi.org/10.1055/s-0034-1376878

12. Moore, G. W., & Smith, M. P. (2015). The laboratory identification of lupus anticoagulant: a qualitative and quantitative evaluation. International Journal of Laboratory Hematology, 37(3), 320–329. https://doi.org/10.1111/ijlh.12285

13. Keeling, D., Mackie, I., Moore, G. W., Greer, I. A., & Van Den Besselaar, A. M. (2012). Guidelines on the investigation and management of antiphospholipid syndrome. British Journal of Haematology, 157(1), 47–58. https://doi.org/10.1111/j.1365-2141.2012.09037.x

14. Clinical and Laboratory Standards Institute (CLSI). (2014). Laboratory Testing for the Lupus Anticoagulant; Approved Guideline (CLSI document H58-A). CLSI.

15. Tripodi, A., & Mannucci, P. M. (2001). Laboratory diagnosis of lupus anticoagulants. Journal of Thrombosis and Haemostasis, 85(5), 785–790. https://doi.org/10.1055/s-0037-1616719

16. Favaloro, E. J., & Lippi, G. (2011). Laboratory testing for lupus anticoagulants: a review of issues affecting pre-analytical, analytical, and post-analytical phases. Seminars in Thrombosis and Hemostasis, 37(07), 789–799. https://doi.org/10.1055/s-0031-1297298

17. Exner, T., Triplett, D. A., & Taberner, D. (1991). A discussion of test procedures for the lupus anticoagulant: an international collaborative study. Thrombosis and Haemostasis, 66(2), 215–219. https://doi.org/10.1055/s-0038-1646394

FAQ’s:

• What is Lupus Anticoagulant?
  An autoantibody targeting cell phospholipids, associated with excess blood clot formation.

• Who discovered lupus anticoagulant?
  Feinstein and Rapaport discovered it in 1972 as a coagulation inhibitor.

• What triggers lupus anticoagulant?
  The exact cause remains undefined, though inherited predispositions are suspected.

• Why order LA testing?
  To evaluate unexplained PTT prolongation, thrombosis, or recurrent miscarriages.

• What are the three test stages?
  Screening study, mixing study, and confirmation study.

• What do mixing studies determine?
  They differentiate specific clotting factor deficiencies from active coagulation inhibitors.

• What does dRVVT measure?
  It evaluates clotting time using diluted rabbit brain phospholipid and viper venom.

• How do phospholipids confirm LA?
  Adding excess phospholipids shortens the prolonged clotting time, showing inhibitor dependence.

• What interferes with LA testing?
  Heparin therapy and direct oral anticoagulants can cause false results.

• Is LA linked to lupus?
  Most people with LA do not have systemic lupus erythematosus.

  Related Tests

• Prothrombin Time (PT ) Test
• Activated Partial Thromboplastin Time (aPTT) Test
• Cardiolipin Antibody (IgG, IgM, IgA)