Antiphospholipid Syndrome and Organ Damage – Top 10 Series

1. What is APS?
2. What does “organ damage” mean?
3. What tools are used to assess organ damage in APS?
4. What are the components of Damage Index for Antiphospholipid Syndrome (DIAPS)?
5. What are the strengths and limitations of Damage Index for Antiphospholipid Syndrome (DIAPS?)
6. What percentage of antiphospholipid antibody-positive patients have organ damage?
7. Which organs or systems are most commonly damaged in antiphospholipid syndrome?
8. What factors increase the risk of organ damage in APS?
9. Is it possible to prevent organ damage in APS?
10. If I have lupus in addition to APS, am I at increased risk for organ damage?

1. What is APS?

Antiphospholipid syndrome (APS) is an autoimmune disorder associated with increased risk of blood clotting in vessels and/or pregnancy complications. Clinical problems in APS are caused by circulating antiphospholipid antibodies (aPL), which are generated by body’s immune system in order to fight autoantigens (self-proteins) that are misidentified as foreign substances. Antiphospholipid syndrome may present alone (primary APS) or together with another autoimmune disorders, mostly with systemic lupus erythematosus (SLE).

2. What does “organ damage” mean?

Organ damage means permanent (not reversible) complete or partial loss of the normal function of an organ system due to a clinical manifestation or treatment of a disease. Depending on the affected organ, an acute problem can result in permanent tissue injury (“damage”), for instance, stroke with loss of motor function, myocardial infarction with heart failure, or blood clots leading to blockage of blood flow in kidney vessels and chronic kidney disease.

3. What tools are used to assess organ damage in APS?

Originally, the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) damage index (SDI) was used to measure organ damage in APS. However, SDI is an instrument specifically developed to measure the damage in SLE (lupus) and does not include some key features of APS. Given the concerns about overestimating lupus-related, and underestimating aPL-related damage when SDI is used in APS, “Damage Index for APS” (DIAPS) was developed in 2015 as a tool for assessing damage in APS patients.

4. What are the components of Damage Index for Antiphospholipid Syndrome (DIAPS)?

Damage Index for APS includes 37 different clinical problems covering 10 organ systems, and each item may receive up to two points if present in a patient. The total index score may range from 0 to 74 (the higher the number, the higher the damage score). Clinical problems counted as “damage” that are included in DIAPS are:​​​​

1. Peripheral vascular
   1. Deep vein thrombosis (blockage of veins, usually in the leg, by a blood clot due to damaged inner lining of veins and propensity to clotting)
   2. Intermittent claudication (pain affecting the calf caused by too little blood flow to muscles during exercise, and relieves by rest)
   3. Tissue loss: minor
   4. Tissue loss: major
   5. Vascular venous insufficiency (the veins have problems sending blood back to the heart)
2. Lungs
   1. Pulmonary infarction (dead tissue in the lung)
   2. Pulmonary arterial hypertension
   3. Chronic thromboembolic Pulmonary hypertension (high blood pressure in the small blood vessels of the lungs due to chronic blood clot)
   4. Respiratory insufficiency
3. Heart
   1. Coronary artery bypass
   2. Myocardial infarction (dead tissue in the heart)
   3. Cardiomyopathy (heart muscle becomes enlarged, thick, or rigid)
   4. aPL-associated heart valve disease: Asymptomatic, symptomatic
   5. aPL-associated heart valve disease requiring valvular replacement
4. Nervous system
   1. Cognitive impairment (memory deficit, poor concentration, difficulty with calculation, difficulty in spoken or written communications)
   2. Seizures
   3. Ischemic stroke with hemiparesia (weakness on the one side of the body caused by a blockage cutting off the blood supply to the brain)
   4. Ischemic stroke with hemiplegia (paralysis on the one side of the body caused by a blockage cutting off the blood supply to the brain)
   5. Multi-infarct dementia (series of strokes that damage or destroy brain tissue)
   6. Cranial neuropathy (inflammation of the nerves in brain)
   7. Sudden sensorineural hearing loss (rapid onset of hearing loss over a 72-hour period)
   8. Transverse myelitis (inflammation of the spinal cord)
   9. Optic neuropathy (inflammation of eye nerves)
   10. Peripheral neuropathy (inflammation of the nerves outside of the brain or spinal cord)
   11. Abnormal movements
5. Eye
   1. Retinal vaso-occlusive disease (a blockage in a small blood vessel that carries blood away from retina)
   2. Blindness
6. Kidney
   1. Chronic renal failure (decreased kidney function)
   2. Proteinuri (protein in the urine due to impaired kidney function)
   3. Renal thrombotic microangiopathy (blood clot leading blockage of blood flow in multiple small vessels of kidney)
7. Musculoskeletal
   1. Avascular necrosis (death of bone tissue due to a loss of blood supply)
8. Skin
   1. Chronic cutaneous ulcers (skin ulcers are not healing more than six weeks)
9. Gastrointestinal (digestive tract)
   1. Mesenteric thrombosis (blood clot in vessels of intestines)
   2. Budd-Chiari syndrome (blood clot in veins of liver which carrying blood out of the liver)
   3. Cirrhosis of the liver
10. Endocrine (hormonal system)
    1. Suprarenal (adrenal) insufficiency (In case of decreased blood supply, adrenal glands are not able to produce enough amount of hormones)
    2. Hypopituitarism (In case of decreased blood supply, pituitary gland is not able to produce enough amount of hormones)
    3. Infertility

5. What are the strengths and limitations of Damage Index for Antiphospholipid Syndrome (DIAPS?)

Damage Index in APS is the first organ damage assessment tool developed specifically for APS patients. The tool is able to capture damage in APS patients and also significantly correlates with health-related quality of life measurement tools. However, DIAPS was developed and initially validated for APS patients with blood clots only, thus does not cover all aPL-related manifestations or some potential APS treatment-related damage, for instance bleeding. Finally, scoring system is binary, which means there is no weighting regarding the severity of findings. Efforts and studies are ongoing to develop an updated version of DIAPS.

6. What percentage of antiphospholipid antibody-positive patients have organ damage?

Prior to DIAPS, a limited number of studies was conducted using different definitions of “damage” in different subgroups of aPL-positive patients.  For instance, one Hospital for Special Surgery study describing the long-term outcomes of primary APS patients found that approximately one-third of patients developed organ damage 10 years after the onset of the disease. Similar results were found by other researchers:

1. One study including APS patients both with or without other systemic autoimmune disease found that 29% had organ damage after 7.5 years of follow-up
2. Another study found that 20% of primary APS patients had organ damage after a median follow-up of 21 years.

Based on different studies conducted using DIAPS, the frequency of organ damage in APS patients with no other systemic autoimmune diseases varies between 15% to 66% and 96% to 99%, at the beginning and end of the follow-up, respectively. This variance is because of differences in the study designs (retrospective: 4; and cross-sectional: 1), patient sub-groups studied, and follow-up period (10 to 15 years).

Recently, APS-ACTION (www.apsaction.org) researchers analyzed organ damage in the largest number (586 patients) of multiethnic international primary aPL-positive patients with or without APS classification. Antiphospholipid antibody-positive patients without blood clots were also included in the analysis. It was reported that 85% of aPL-positive patients with history of blood clots and 20% aPL-positive patients without blood clots had some type of damage at the baseline evaluation and the mean DIAPS score was higher in patients with blood clots compared to patients without blood clots. About one-fourth of aPL-positive patients with history of blood clots presented with high damage (defined as DIAPS score of greater than or equal to 3 [≥3]).

7. Which organs or systems are most commonly damaged in antiphospholipid syndrome?

Based on the studies above, in APS damage occurs most frequently in two systems: the peripheral vascular system and nervous system. Therefore, the most commonly affected organs are venous structures in the legs and  some parts of the brain. The heart and lungs are other affected organs less commonly from these two systems. Kidneys may rarely be affected, but its frequency increases especially in APS associated with lupus. 

8. What factors increase the risk of organ damage in APS?

The most common reason for organ damage in APS is history of blood clots. Additionally, older age, male gender, long-term illness, delay in diagnosis, being positive for all three aPL tests (lupus anticoagulant, anticardiolipin antibodies, and anti-beta-2 glycoprotein-I antibodies), corticosteroid use, traditional cardiovascular risk factors (such as hypertension, higher cholesterol levels, and obesity), and inadequate use of blood thinner are contributing factors for damage.

9. Is it possible to prevent organ damage in APS?

It is possible to prevent organ damage especially if diagnosed early and appropriate treatment is started. Compliance with treatment and regular follow-ups are of utmost importance. It is necessary to measure laboratory values at regular intervals to determine whether blood thinning treatments used in patients with blood clots are effective or not, and to closely monitor patients with a high risk of progression of damage. Additionally, optimal management of additional cardiovascular disease risk factors such as hypertension, high cholesterol levels, obesity, and eliminating other thrombosis risk factors such smoking, oral contraceptives or hormone replacement therapies, staying inactive for a long period, are also critical to prevent further clots and damage.

10. If I have lupus in addition to APS, am I at increased risk for organ damage?

Few studies compared APS patients with and without lupus in terms of organ damage risk. Two of the studies (using DIAPS) found no increased risk of organ damage in APS patients with lupus, whereas two other studies (one using DIAPS and one using SDI) reported significantly increased  risk in APS patients with lupus. Prospective and larger studies are needed to better understand the effect SLE or other autoimmune diseases on organ damage in APS patients.

Posted: 3/5/2024

Authors

Related articles

References

• Amigo MC, Goycochea-Robles MV, Espinosa-Cuervo G, Medina G, Barragán-Garfias JA, Vargas A, Jara LJ. Development and initial validation of a damage index (DIAPS) in patients with thrombotic antiphospholipid syndrome (APS). Lupus. 2015 Aug;24(9):927-34.
• Balbi GGM, Ahmadzadeh Y, Tektonidou MG, Pengo V, Sciascia S, Ugarte A, Belmont HM, Lopez-Pedrera C, Fortin PR, Wahl D, Gerosa M, de Jesús GR, Ji L, Atsumi T, Efthymiou M, Branch DW, Nalli C, Almaraz ER, Petri M, Cervera R, Knight JS, Artim-Esen B, Willis R, Bertolaccini ML, Cohen H, Roubey R, Erkan D, Andrade D; AntiPhospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) Clinical Database and Repository (APS ACTION). Damage measured by damage index for antiphosphlipid syndrome in antiphospholipid antibody-positive patients included in APS ACTION Registry. Rheumatology (Oxford). 2023 Jun 12:kead292.​​​​​​
• Barbhaiya M, Erkan D. The optimal tool for assessment of organ damage in antiphospholipid syndrome. J Rheumatol. 2013 Jan;40(1):89.
• Dall'Ara F, Reggia R, Taraborelli M, Andreoli L, Taglietti M, Frassi M, Franceschini F, Tincani A. Patients with longstanding primary antiphospholipid syndrome: retrospective analysis of organ damage and mortality. Lupus. 2014 Oct;23(12):1255-8.
• Erkan D, Yazici Y, Sobel R, Lockshin MD. Primary antiphospholipid syndrome: functional outcome after 10 years. J Rheumatol. 2000 Dec;27(12):2817-21.
• Garcia D, Erkan D. Diagnosis and Management of the Antiphospholipid Syndrome. N Engl J Med. 2018 May 24;378(21):2010-2021.
• Gaspar P, Farinha F, Sayar Z, Efthymiou M, Cohen H, Isenberg DA. A one-point increase in the Damage Index for Antiphospholipid Syndrome (DIAPS) predicts mortality in thrombotic antiphospholipid syndrome. Clin Exp Rheumatol. 2023 Mar;41(3):605-612.
• Gladman D, Ginzler E, Goldsmith C, Fortin P, Liang M, Urowitz M, Bacon P, Bombardieri S, Hanly J, Hay E, Isenberg D, Jones J, Kalunian K, Maddison P, Nived O, Petri M, Richter M, Sanchez-Guerrero J, Snaith M, Sturfelt G, Symmons D, Zoma A. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum. 1996 Mar;39(3):363-9.​​​​​​​
• Grika EP, Ziakas PD, Zintzaras E, Moutsopoulos HM, Vlachoyiannopoulos PG. Morbidity, mortality, and organ damage in patients with antiphospholipid syndrome. J Rheumatol. 2012 Mar;39(3):516-23.
• Medina G, Cimé Aké EA, Vera-Lastra O, Saavedra MÁ, Cruz-Domínguez MDP, Amigo MC, Jara LJ. Damage index for antiphospholipid syndrome during long term follow-up: Correlation between organ damage accrual and quality of life. Lupus. 2021 Jan;30(1):96-102.​​​​​​​
• Radin M, Foddai SG, Cecchi I, Roccatello D, Sciascia S. Quality of life in patients with antiphospholipid antibodies differs according to antiphospholipid syndrome damage index (DIAPS). Eur J Intern Med. 2021 Oct;92:134-136.
• Torricelli AK, Ugolini-Lopes MR, Bonfá E, Andrade D. Antiphospholipid syndrome damage index (DIAPS): distinct long-term kinetic in primary antiphospholipid syndrome and antiphospholipid syndrome related to systemic lupus erythematosus. Lupus. 2020 Mar;29(3):256-262.
• Uludağ Ö, Çene E, Gurel E, Çetin Ç, Bektaş M, Yalçınkaya Y, Diz-Küçükkaya R, Gül A, Inanç M, Artim-Esen B. Description of damage in different clusters of patients with antiphospholipid syndrome. Lupus. 2022 Apr;31(4):433-442. doi: 10.1177/09612033221079781. Epub 2022 Feb 15. PMID: 35166607.

(Return to top.)