Antiphospholipid Syndrome - thrombosis and miscarriage

Written By Megan Gardner

Introduction

This article is a summary of a review paper on the topic of antiphospholipid syndrome that was published in 2020, by Michelle Petri, M.D. M.P.H., in the journal Translational Research.

Antiphospholipid syndrome (APS) is a common cause of hypercoagulability which presents as thrombosis (in the arteries, veins, or microvasculature) and pregnancy morbidity (severe pre-eclampsia, miscarriages, and late foetal loss).

APS is classified based on clinical and laboratory criteria (Sydney classification criteria for antiphospholipid syndrome). Treatment of APS can be preventive and long-term.

 

APS Related Antibodies and Assays

 Antiphospholipid antibodies include:

1.     Lupus anticoagulant (LA)

2.     Anticardiolipin (ACL)

3.     Anti-beta 2 glycoprotein I (B2GP1)

 Lupus anticoagulant being the most important of the above three with regards to symptoms and outcome.

 Three steps should be taken to determine the presence of a lupus anticoagulant:

1.     High sensitivity screening assays should be performed:

-       DRVVT (Dilute Russell Viper Venom Time)

-       APTT (partial thromboplastin time)

2.     A mixing study to exclude any factor deficiencies. The patient’s sample is mixed 1:1 or 2:1 with normal plasma.

3.     Tests to prove the existence of a phospholipid dependent inhibitor:

-       Anticardiolipin and anti-beta 2 glycoprotein 1 (IgG and IgM)

-       Anti-phosphatidylserine/prothrombin.

 

Mechanism of Action (MOA):

Targets of Lupus Anticoagulants

There are two subtypes of lupus anticoagulant. One subtype has beta 2 glycoprotein I as a target, while the other subtype has prothrombin as a target.

Another MOA is through annexin 5.

Thrombocytopenia

Platelets have beta 2 glycoprotein I receptors which antiphospholipid antibodies bind to causing activation and aggregation of platelets and subsequent platelet depletion (thrombocytopenia).

 Inflammatory Targets

Signs of inflammatory targets regarding antiphospholipid antibodies are the occurrence of neurologic syndromes, such as chorea and myelitis.

 Role of Complement

Both thrombotic and obstetric APS seem to rely on complement activation. Animal models of both conditions seem to reveal that thrombosis was prevented when complement activation was blocked.

 

Classification Criteria - Sydney Classification Criteria

Sydney classification criteria is used (see below) to confirm diagnosis of APS.

“Sydney Classification Criteria for Antiphospholipid Syndrome:

Clinical Criterion

Clinical criteria have to be present within 5 years of positive antiphospholipid assays:

  1. Vascular thrombosis –

    arterial, venous or small vessel

  2. Pregnancy morbidity –

    One or multiple foetal losses after 10th week

    One or multiple premature births (<34 weeks) due to pre-eclampsia or placental insufficiency

    Multiple (three or more) consecutive spontaneous abortions

Laboratory Criterion

Positive (for the following antibodies) for over 3 months:

·      Lupus anticoagulant or anticardiolipin IgG, IgM (medium to high titre)

·      Anti-beta 2 glycoprotein I IgG and IgM”

Symptoms of APS not included in the classification criteria are as follows:

  1. Chorea

  2. Longitudinal myelitis

  3. Cardiac valvulitis

  4. Thrombocytopenia

  5. Hypertension

  6. Proteinuria

  7. Livedo racemosa

  8. Skin ulcers

IgA anti-cardiolipin not included in classification criteria while many studies have found that the IgA isotype is linked to thrombosis and common in SLE.

 

Epidemiology

Prevalence of Antiphospholipid Antibodies in the General Population

These antibodies are also found in the general population. 12% in older people, and 1-5% in younger people.

Prevalence of Infection Induced Antiphospholipid Antibodies

Many infections can lead to an increase in antiphospholipid antibodies. Infections such as HIV, hepatitis B, hepatitis C, leprosy, and syphilis. But this increase is not associated with thrombosis.

Prevalence of Antiphospholipid Antibodies in Systemic Lupus Erythematosus

About 30-40% of patients with SLE have antiphospholipid antibodies.

The probability of a patient with SLE and a baseline LA developing thromboembolism is 42% (over a 20-year period).

 

Subsets of Antiphospholipid Syndrome

 Thrombotic Antiphospholipid Syndrome

 Antiphospholipid antibodies are associated with

1.     Occurrence of stroke in patients under 50

2.     Occurrence of myocardial infarction in patients less than 50

3.     Deep vein thrombosis (20% of reported cases)

 Obstetric Antiphospholipid Syndrome

 Three types of pregnancy morbidity

1.     Recurrent early miscarriage (<10 weeks’ gestation)

2.     Late foetal death

3.     Severe preeclampsia (also in patients with SLE)

Catastrophic Antiphospholipid Syndrome

 This syndrome involves:

1.     Renal (73%)

2.     Pulmonary (60%)

3.     Cerebral (56%) e.g., encephalopathy

4.     Cardiac (50%)

5.     Skin (47%) e.g., cutaneous necrosis

Criteria for diagnosis with catastrophic antiphospholipid syndrome include:

1.     Three or more organs being involved

2.     Evidence of small vessel occlusion (via histopathology)

3.     Detection of antiphospholipid antibodies

Antiphospholipid Antibodies in SLE

There is a fluctuation in the detection of antiphospholipid antibodies in SLE.

In SLE, the antibodies that do not fluctuate (e.g., anti-Smith, anti-Ro, anti-RNP and anti-La) are those that are created by plasma cells.

Thus, diagnosis of APS in SLE is difficult to make.

Link between Lupus Anticoagulant and Thrombosis/Immunothrombosis

For both pregnancy morbidity and SLE it is the presence of lupus anticoagulant that explains the risk of adverse outcomes the most.

Lupus anticoagulant is strongly associated with the risk of thrombosis is SLE.

Immunothrombosis is the involvement of interactions of complement, platelets, and coagulation. Immunothrombosis has a role in SLE.

Hopkins SLE Thrombosis Risk Equation:

Low C3, C4d attached to platelets and lupus anticoagulant, strongly connected with thrombosis.

Complement Mutations in Catastrophic Antiphospholipid Syndrome

It has been found that complement mutations are the major risk factor for catastrophic antiphospholipid syndrome.

Variants in germline complement regulatory genes were found in 60% of catastrophic antiphospholipid syndrome.

 

Treatment

Preventive and Prophylactic Treatment

A combination of hydroxychloroquine and low dose aspirin is recommended for SLE patients.

Vitamin D is recommended as a possible treatment against thrombosis as it has been found to reduce activation of tissue factor by antiphospholipid antibodies.

Thrombosis Treatment

Warfarin is the drug of choice for patients who have had a thrombotic episode.

Heparin is given to patients at the time of a thrombotic event as it blocks complement activation and is an anticoagulant. It is not given long-term due to the risk of patients experiencing osteopenia.

Long-term use of anticoagulants is recommended for patients as there is a high risk of APS recurring.

Treatment of Thrombocytopenia

Only when severe, patients with thrombocytopenia are treated with corticosteroids, intravenous immunoglobulin, and rituximab.

Treatment of Catastrophic Antiphospholipid Syndrome

The classical “triple therapy” of

1.     Intravenous heparin

2.     Intravenous methylprednisolone pulse

3.     Plasmapheresis or intravenous immunoglobulin

Some patients do not respond to the “triple therapy”. Other treatments such as rituximab and eculizumab have been useful.

Treatment in Pregnancy

For a woman without a history of late foetal demise, multiple early losses or severe preeclampsia prophylactic heparin and low dose aspirin is prescribed.

For a woman with a history of a thrombotic event, then full dose heparin and low dose aspirin is prescribed.

An anti-TNF biologic, that does not cross the placenta, is being trialled.

 

Conclusion

Four possible subsets of antiphospholipid syndrome:

1.     Thrombotic

2.     Obstetric

3.     Microvascular (catastrophic antiphospholipid syndrome)

4.     Inflammatory APS (that involves chorea, longitudinal myelitis, thrombocytopenia, or valvulitis).

 

References

Ferlič, J. (2018) Image of a pregnant woman, Unsplash.com. Available at: https://unsplash.com/photos/ZNVGL_Pcf74 (Accessed: 10 September 2023). 

Holm, J. (2019) Woman with reddened hands on floor, Unsplash.com. Available at: https://unsplash.com/photos/nH_AxCStABM (Accessed: 10 September 2023). 

Petri, M. (2020) ‘Antiphospholipid syndrome’, Translational Research, 225, pp. 70–81. doi:10.1016/j.trsl.2020.04.006. 

Simmer, J. (2021) A woman sitting in the dark, Unsplash.com. Available at: https://unsplash.com/photos/isVYj70Ar-E (Accessed: 10 September 2023). 

THAVIS 3D (2023a) Activated platelet, Unsplash.com. Available at: https://unsplash.com/photos/S1jBzQcr-eo (Accessed: 10 September 2023). 

THAVIS 3D (2023b) Thrombus, Unsplash.com. Available at: https://unsplash.com/photos/Vvj_PFLrmBQ (Accessed: 10 September 2023). 

Megan Gardner