Microvascular Antiphospholipid Syndrome

1. What is antiphospholipid syndrome (APS)?
2. What is microvascular antiphospholipid syndrome (MAPS)?
3. Is MAPS different from CAPS?
4. What are the clinical problems related to MAPS?
5. Why is MAPS important in clinical practice?
6. Which antiphospholipid antibody-positive patients are at risk?
7. What is the general treatment strategy for MAPS?
8. What is HSS's treatment approach to microvascular lung disease?
9. What is HSS's treatment approach to microvascular kidney disease?
10. What is HSS's treatment approach to microvascular skin disease?

1. What is antiphospholipid syndrome (APS)?

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder in which the patient’s immune system makes antibodies (antiphospholipid antibodies [aPL]) that mostly increase the risk of blood clots (thickened blood) and pregnancy complications.

These antibodies (aPL) can also cause other clinical problems such as thrombocytopenia (low platelet counts) or heart valve disease.

Antiphospholipid antibodies occur in otherwise healthy individuals or in patients with other systemic autoimmune rheumatic disorders such as systemic lupus erythematosus (SLE and commonly called “lupus”) or rheumatoid arthritis (RA).

2. What is microvascular antiphospholipid syndrome (MAPS)?

In addition to developing blood clots in moderate- to large-size veins or arteries, APS patients can rarely develop clots in small blood vessels. This is called microvascular disease or microvascular APS (MAPS).

Microvascular refers to the small blood vessels in the body, including capillaries, arterioles, and venules. These tiny vessels are responsible for delivering oxygen and nutrients to tissues and removing waste. In MAPS, damage or blockage of small blood vessels can cause health problems related to various organs.

3. Is microvascular APS different from catastrophic APS (CAPS)?

Catastrophic APS, also referred to as CAPS, is the most severe form of APS and is very rare (less than 1% of APS patients). In CAPS, multiple blood clots in medium and large blood vessels (macrovascular) occur over a short period (usually within a week), and CAPS is generally associated with microvascular disease. Thus, CAPS patients are in critical condition and require hospitalization, mostly admitted to intensive care units, for multi-disciplinary management.

Microvascular APS, also referred to as MAPS, is rare (collectively approximately 10% of APS patients). In MAPS, active microvascular disease leads to microvascular thrombosis (clots in the small blood vessels), which can result in damage to specific organs like the kidneys, lungs, and skin. Accurately diagnosing MAPS can be challenging, since the condition often mimics other diseases with microvascular involvement – such as thrombotic thrombocytopenic purpura (a condition causing blood clots and low platelet count). Patients with aPL-related microvascular disease can present with: 

• CAPS (see above).
• Acute organ involvement without CAPS.
• More subtle or chronic symptoms that do not require hospitalization.

4. What are the clinical problems related to microvascular APS (MAPS)?

Microvascular involvement can affect multiple organs (alone or in combination), causing sometimes acute but generally subtle/chronic clinical problems. Selected microvascular APS clinical manifestations are listed below.

5. Why is microvascular APS important in clinical practice?

• Differentiating Microvascular Involvement: Unlike typical APS with large-vessel clots, such as deep venous thrombosis (a blood clot in a deep vein, usually in the leg) or stroke), MAPS  involves small-vessel clots across multiple organs. Early recognition is essential as symptoms can be subtle and sometimes progress rapidly.
• Risk of Catastrophic APS Progression: MAPS increases the risk of developing CAPS, which involves severe, multi-organ clots. Early treatment can prevent this progression.
• Organ-Specific Complications: MAPS can affect critical organs like the kidneys, lungs, heart, and brain, causing serious health problems such as acute respiratory distress syndrome (severe lung failure), kidney failure, or brain dysfunction.
• Challenges in Diagnosis: MAPS, especially if occurring together with low platelet counts and anemia, can mimic other conditions like thrombotic thrombocytopenic purpura (a condition causing blood clots and low platelet count) or sepsis (a life-threatening infection in the bloodstream), making diagnosis challenging. Testing for antiphospholipid antibodies is essential for confirmation.
• Complex Treatment Needs: Traditional APS medications used for prevention and treatment of blood clots (aspirin, vitamin K antagonists such as warfarin, and heparin) are usually not effective for MAPS (see below for further discussion).

In summary, MAPS is essential to recognize in clinical practice due to its unique presentation, risk of progression to CAPS, and complex treatment requirements. Early diagnosis and targeted therapy improve patient outcomes and prevent severe complications.

6. Which antiphospholipid antibody-positive patients are at risk for microvascular APS?

Even if microvascular APS (MAPS) is relatively rare, patients with triple antiphospholipid antibody positivity, which includes persistently positive lupus anticoagulant test (LA), anticardiolipin antibodies (aCL), and anti-Beta-2-glycoprotein-I (aβ2GPI) antibodies, are at increased risk of developing MAPS, especially if they have high levels of aCL and aβ2GPI Immunoglobulin G (IgG) antibody type. Additionally, individuals with a history of catastrophic APS (CAPS) are also at risk because CAPS involve severe, multi-organ thrombotic events that can lead to microvascular complications. Studies are ongoing to determine additional risk factors associated with MAPS development.

7. What is the general treatment strategy for microvascular APS?

There is no uniform approach to the management of MAPS due to heterogeneous organ involvement with different severity and the limited number of studies investigating treatment approaches. While blood thinners may be part of the treatment strategy, there is limited evidence supporting its effectiveness in MAPS specifically, and the decision to use blood thinners should be individualized.

Given that APS is an autoimmune disease in which the immune system attacks the body's own cells, immunosuppressive medications to control the immune response play a major role in the management of APS patients with microvascular disease. However, controlled studies are limited and the evidence for the use of immunosuppression in APS comes mostly from case reports or case series.

Some of the medications used in APS patients with microvascular involvement include (risks/benefits of these medications should be discussed with your physician as individualized treatment is required for APS patients with microvascular disease):

• Corticosteroids help reduce inflammation and suppress the immune system, which can be used in patients APS with some, but not all, microvascular manifestations.
• Mycophenolate Mofetil (MMF) helps control inflammation by slowing down the growth of certain immune cells and lowering immune responses.
• Rituximab is an infusion medication that targets and inhibits B cells, which are responsible for making antibodies. In a pilot prospective study of rituximab (RITAPS) for 19 APS patients, our group demonstrated that rituximab can be effective in APS patients with selected microvascular involvement.
• Intravenous Immunoglobulin (IVIG) blocks harmful antibodies and decreases the activation of inflammatory cells, which help stabilize the immune system and reduce inflammation.
• Sirolimus targets mTOR pathway (regulates cell growth and metabolism), which can be activated by antiphospholipid antibodies resulting in the blood vessel inner layer thickening. This thickening may lead to blood clot formation in small blood vessels such as in kidneys and skin. Sirolimus, also known as rapamycin, is a medication that blocks mTOR pathway activation.
• Eculizumab is a monoclonal antibody (specialized protein designed to attack specific targets) that blocks the complement protein C5 (part of the immune system), reducing inflammation and blood clot risk.
• Hydroxychloroquine (HCQ) is an antimalarial medication, which also has anti-inflammatory function and is used to treat systemic lupus erythematosus (SLE, also known as lupus). Hydroxychloroquine reduces the risk of blood clots in experimental APS mouse models, thus, HCQ, despite limited number of clinical APS studies, can be considered as add-on medications in difficult-to-treat APS patients.
• Statins are typically used to lower cholesterol levels. However, there is emerging evidence that these medications have anti-inflammatory effects on various cells. Two small APS studies demonstrated that statins improve clot promoting markers in aPL-positive patients, thus, similar to HCQ, statins can be considered as add-on medications in difficult-to-treat APS patients.

8. What is our treatment approach to microvascular lung disease (diffuse alveolar hemorrhage) at Hospital for Special Surgery?

Corticosteroids (CS) improve symptoms of most of the diffuse alveolar hemorrhage (DAH) patients. However, nearly half of patients develop flares without an immunosuppressive medication when CS is stopped or the dose is decreased. Thus, our initial treatment approach for DAH generally includes CS often combined with mycophenolate mofetil, with or without rituximab. For persistent cases, intravenous immunoglobulin (IVIG) may be used if there is insufficient response or ongoing need for CS. In APS patients presenting with DAH and who are on chronic blood thinners due to a history of thrombosis, the management of blood thinners is carefully evaluated, often discontinued in the setting of severe bleeding but reintroduced as soon as benefits outweigh risks.

9. What is our treatment approach to microvascular kidney disease (aPL-nephropathy) at Hospital for Special Surgery?

Our initial treatment approach to aPL-nephropathy involves controlling blood pressure with antihypertensive medications (which also help improve protein in the urine), and immunosuppressive therapy, which include mycophenolate mofetil and/or rituximab. In selected patients with significant disease activity, corticosteroids (CS) are also used. For patients who are unresponsive to these treatments or cannot tolerate them, based on a small number of case reports, sirolimus is considered. Complement inhibition, for example, eculizumab, may be an option in patients with systemic thrombotic microangiopathy (TMA), defined as low platelet counts, anemia, and organ failure (mostly kidney) due to blood clots in small vessels.

10. What is our treatment approach to microvascular skin disease (livedoid vasculopathy) at Hospital for Special Surgery?

Our first line of treatment for livedoid vasculopathy-related skin ulcers is rituximab. Additionally, antiplatelet agents (for example, low-dose aspirin, clopidogrel) can be used as add-on therapy based on case reports. Corticosteroids are less preferable in livedoid vasculopathy given the risk of infection.

Posted: 12/30/2024

Authors

Related articles

References

1. Ambati A, Knight JS, Zuo Y. Antiphospholipid syndrome management: a 2023 update and practical algorithm-based approach. Curr Opin Rheumatol. 2023 May 1;35(3):149-160. doi: 10.1097/BOR.0000000000000932. Epub 2023 Mar 2. PMID: 36866678; PMCID: PMC10364614. https://pubmed.ncbi.nlm.nih.gov/36866678/
2. Bahar Keleşoğlu Dinçer A, Erkan D. The ABCs of antiphospholipid syndrome. Arch Rheumatol. 2023 Jun 5;38(2):163-173. doi: 10.46497/ArchRheumatol.2023.41875. PMID: 37680521; PMCID: PMC10481699. https://pubmed.ncbi.nlm.nih.gov/37680521/
3. Barbhaiya M, Zuily S, Naden R, Hendry A, Manneville F, Amigo MC, Amoura Z, Andrade D, Andreoli L, Artim-Esen B, Atsumi T, Avcin T, Belmont HM, Bertolaccini ML, Branch DW, Carvalheiras G, Casini A, Cervera R, Cohen H, Costedoat-Chalumeau N, Crowther M, de Jesus G, Delluc A, Desai S, De Sancho M, Devreese KM, Diz-Kucukkaya R, Duarte-Garcia A, Frances C, Garcia D, Gris JC, Jordan N, Leaf RK, Kello N, Knight JS, Laskin C, Lee AI, Legault K, Levine SR, Levy RA, Limper M, Lockshin MD, Mayer-Pickel K, Musial J, Meroni PL, Orsolini G, Ortel TL, Pengo V, Petri M, Pons-Estel G, Gomez-Puerta JA, Raimboug Q, Roubey R, Sanna G, Seshan SV, Sciascia S, Tektonidou MG, Tincani A, Wahl D, Willis R, Yelnik C, Zuily C, Guillemin F, Costenbader K, Erkan D; ACR/EULAR APS Classification Criteria Collaborators. The 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria. Arthritis Rheumatol. 2023 Oct;75(10):1687-1702. doi: 10.1002/art.42624. Epub 2023 Aug 28. PMID: 37635643. https://pubmed.ncbi.nlm.nih.gov/37635643/
4. Barbhaiya M, Taghavi M, Zuily S, Domingues V, Chock EY, Tektonidou MG, Erkan D, Seshan SV; New APS Classification Criteria Steering Committee and APS ACTION Collaborators. Efforts to Better Characterize "Antiphospholipid Antibody Nephropathy" for the 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria: Renal Pathology Subcommittee Report. J Rheumatol. 2024 Feb 1;51(2):150-159. doi: 10.3899/jrheum.2022-1200. PMID: 37399462. https://pubmed.ncbi.nlm.nih.gov/37399462/  
5. Cohen H, Cuadrado MJ, Erkan D, Duarte-Garcia A, Isenberg DA, Knight JS, Ortel TL, Rahman A, Salmon JE, Tektonidou MG, Williams DJ, Willis R, Woller SC, Andrade D. 16th International Congress on Antiphospholipid Antibodies Task Force Report on Antiphospholipid Syndrome Treatment Trends. Lupus. 2020 Oct;29(12):1571-1593. doi: 10.1177/0961203320950461. PMID: 33100166; PMCID: PMC7658424. https://pubmed.ncbi.nlm.nih.gov/33100166/  
6. Erkan D. Expert Perspective: Management of Microvascular and Catastrophic Antiphospholipid Syndrome. Arthritis Rheumatol. 2021 Oct;73(10):1780-1790. doi: 10.1002/art.41891. Epub 2021 Sep 7. PMID: 34114366. https://pubmed.ncbi.nlm.nih.gov/34114366/
7. Erkan D, Vega J, Ramón G, Kozora E, Lockshin MD. A pilot open-label phase II trial of rituximab for non-criteria manifestations of antiphospholipid syndrome. Arthritis Rheum. 2013 Feb;65(2):464-71. doi: 10.1002/art.37759. PMID: 23124321. https://pubmed.ncbi.nlm.nih.gov/23124321/
8. Erton ZB, Erkan D. Treatment advances in antiphospholipid syndrome: 2022 update. Curr Opin Pharmacol. 2022 Aug;65:102212. doi: 10.1016/j.coph.2022.102212. Epub 2022 May 27. PMID: 35636385. https://pubmed.ncbi.nlm.nih.gov/35636385/ 
9. Erton ZB, K Leaf R, de Andrade D, Clarke AE, Tektonidou MG, Pengo V, Sciascia S, Ugarte A, Belmont HM, Gerosa M, Fortin PR, Lopez-Pedrera C, Atsumi T, Zhang Z, Cohen H, Ramires de Jesús G, Branch DW, Wahl D, Andreoli L, Rodriguez-Almaraz E, Petri M, Barilaro G, Zuo Y, Artim-Esen B, Willis R, Quintana R, Vendramini MB, Barber MW, Bertolaccini ML, Roubey R, Erkan D. Immunosuppression use in primary antiphospholipid antibody-positive patients: Descriptive analysis of the AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository ("Registry"). Lupus. 2022 Dec;31(14):1770-1776. doi: 10.1177/09612033221128742. Epub 2022 Oct 7. PMID: 36206383. https://pubmed.ncbi.nlm.nih.gov/36206383/
10. Gaspar P, Sciascia S, Tektonidou MG. Epidemiology of antiphospholipid syndrome: macro- and microvascular manifestations. Rheumatology (Oxford). 2024 Feb 6;63(SI):SI24-SI36. doi: 10.1093/rheumatology/kead571. PMID: 38320589; PMCID: PMC10846913. https://pubmed.ncbi.nlm.nih.gov/38320589/ 
11. Okunlola AO, Ajao TO, Sabi M, Kolawole OD, Eweka OA, Karim A, Adebayo TE. Catastrophic Antiphospholipid Syndrome: A Review of Current Evidence and Future Management Practices. Cureus. 2024 Sep 19;16(9):e69730. doi: 10.7759/cureus.69730. PMID: 39429267; PMCID: PMC11490264. https://pubmed.ncbi.nlm.nih.gov/39429267/
12. Parepalli A, Sarode R, Kumar S, Nelakuditi M, Kumar MJ. Antiphospholipid Syndrome and Catastrophic Antiphospholipid Syndrome: A Comprehensive Review of Pathogenesis, Clinical Features, and Management Strategies. Cureus. 2024 Aug 10;16(8):e66555. doi: 10.7759/cureus.66555. PMID: 39252716; PMCID: PMC11381965. https://pubmed.ncbi.nlm.nih.gov/39252716/
13. Tektonidou MG. Antiphospholipid Syndrome Nephropathy: From Pathogenesis to Treatment. Front Immunol. 2018 May 31;9:1181. doi: 10.3389/fimmu.2018.01181. PMID: 29904380; PMCID: PMC5990608. https://pubmed.ncbi.nlm.nih.gov/29904380/

(Return to top.)