• Information
  1. Definition
  2. Epidemiology
  3. Etiology of Anti-Phospholipid Antibodies
  4. Pathogenesis of Anti-ß2-GP1 Abs
  5. Symptoms
  6. Laboratory Evaluation
  7. Differential Diagnosis
  8. Treatment
  9. Prognosis

A. Definition [1]

1. Both clinical and laboratory criteria must be met
2. Clinical Criteria
   1. At least 1 Vascular Thrombosis in any organ or tissues OR
   2. At least 1 category of Pregnancy Complications:
   3. At least 1 unexplained death of morphologically normal fetus at least 10 weeks gestation
   4. At least 1 premature birth of morphologically normal neonate no more than 34 weeks gestation
   5. Three or more unexplained consecutive spontaneous abortions before 10 weeks gestation
3. Laboratory Criteria
   1. Anticardiolipin (ACL) Antibody (Ab) present at moderate or high levels in blood on 2 or more occasions at least 6 weeks apart OR
   2. Lupus anticoagulant as detected by Proglonged PTT or Prolonged Russel Viper Venom Time (RVVT) and appropriate inhibitor tests
4. ACL Abs
   1. Abs are directed against phospholipids, proteins which bind to phospholipids, or both
   2. Standard tests for ACL include immunoassays (ELISA)
   3. Measure ß2-glycoprotein I (ß2-GP1) dependent IgM and IgG ACL Abs (see below)
5. Thrombocytopenia or Livedo Reticularis are no longer part of definition
6. Primary APLS
   1. Rare syndrome with APLS and no connective tissue disease
   2. ANA Negative or Low titer positive (<1:160)
   3. No antibodies to extractable nuclear antigens or DNA
   4. Does not meet criteria for other autoimmune disease, especially systemic lupus (SLE)
   5. Patients with thromboembolism and ACL Ab are at high risk for recurrence [5]
   6. Peripheral vascular disease with IgG ACL Ab have poor prognosis compared to IgG negative patients, with ~2X increased mortality risk [6]
   7. Increased prevalance of ACL Ab in new onset localized seizure disorder patients than controls [7]
7. Secondary APLS [2]
   1. Usually associated with Systemic Lupus Erythematosus (SLE)
   2. 15-25% of SLE patients have actual APLS
   3. Defined by SLE + ACL Abs with at least 2 thrombotic events
   4. ~25% of patients with SLE have high titer Abs with some APL associated events
   5. These patients may or may not have an overall increased risk for thrombotic events [21]
   6. SLE patients with very high titer IgG anti-cardiolipin Abs have high thrombosis risk [15]
   7. Abs to platelet ß2-glycoprotein I correlate better with APLS than do APL Ab
   8. Usual presence of other SLE symptoms (absent in Primary APLS)
   9. APLS in SLE correlated well with thrombocytopenia, Coombs' positive hemolytic anemia, and prolonged APTT but not with livido reticularis [21]
   10. Presence of APL Abs is a predictor of central nervous system involvement in SLE [17]
   11. Increased incidence of APL Abs in APLS patients' relatives (but not spouses) [20]
   12. Patients with SLE and APL Abs do not have increased risk of myocardial infarction
   13. About 15% of rheumatoid arthritis patients have APL Abs [25]
8. Distinguishing Primary versus Secondary APLS is important for prophylaxis and treatment

B. Epidemiology

1. About 2-4% of general population have antiphospholipid (APL) antibodies (Abs) [25]
2. Most common in middle aged women: Female:Male ~ 4:1
3. Mean age ~40 years
4. Increased risk of thromboembolic events in APLS with oral contraceptives [26]
5. APL Abs and Other Diseases
   1. Infection, especially endocarditis
   2. Premature atherosclerosis
   3. Drug Induced APL Abs (see below)
   4. Positive APL Abs with mycoardial infarction is risk factor for recurrent MI [23]

C. Etiology of Anti-Phospholipid Antibodies

1. Both B and T cell abnormalities have been found
   1. Pathogenic Abs are clearly directed against various clotting proteins
   2. Most commonly directed against ß2-GP1 (apolipoprotein H) c ß2-GP1 is a member of complement control proteins
   3. Most of these Abs require combination of ß2-GP1 with phospholipid
   4. The combination between ß2-GP1 and lipid induces a conformational change in both
   5. Other Abs directed against prothrombin, oxidized LDL, and/or Protein S
   6. Prothrombin Abs are directed against prethrombin or (less commonly) Fragment-1 [24]
2. Blood T lymphocytes in APLS
   1. Peripheral T Cell abnormalities documented in Primary APLS
   2. Lower total lymphocyte count with expansion of naive (CD45RA+) CD4+ T cells
   3. Lower proportion of memory (CD45RO+) CD4+ T cells
3. Protein S Levels [14]
   1. Acquired free protein S deficiency associated with antiphosopholipid Abs in SLE patients
   2. These patients also generated increased thrombin in their serum
   3. These findings may provide insight into thrombosis in SLE/APLS
   4. Antibodies against Proteins S and/or C have been detected in some APLS patients
4. Drug Associated APLS
   1. Main associations are with drugs which cause false positive ANA
   2. Procainamide, Quinidine, Phenothiazines (Thorazine and Stelazine), Dilantin
   3. Valproate, amoxicillin, and propranolol are uncommonly associated with these Abs
   4. ANA and anti-histone antibody levels should be checked as well

D. Pathogenesis of Anti-ß2-GP1 Abs

1. Anti-ß2-GP1 Abs may have direct effects on:
   1. Platelets
   2. Endothelial Cells
   3. Complement Regulation
   4. Effects on endothelium may be direct or through other proteins such as annexin V
2. APL Ab Effects
   1. Newer data suggest that anticoagulant protein annexin V may be major target
   2. Annexin V also called placental anticoagulant protein 1, vascular anticoagulant alpha
   3. Anti-phospholipid Ab reduce levels of annexin V and accelerate plasma coagulation
   4. Platelets may be activated and/or destroyed by APL Abs
3. Anti-ß2-GP1 Abs correlate well with thrombosis in lupus patients [19]
   1. Levels are elevated in patients at risk for thrombosis (~5X risk)
   2. Drops in anti-ß2-GP-1 levels often occur with acute thrombosis in SLE patients
   3. Suggests pathogenic role of these autoantibodies in thrombotic events
4. ACL Ab after initial deep vein thrombosis (DVT) predicts recurrent DVT [5]

E. Symptoms

1. Recurrent Venous Thrombosis
   1. Deep Vein Thrombosis (DVT)
   2. Increased risk for pulmonary embolism (PE)
   3. Other venous thrombosis with organ failure (such as adrenal vein thrombosis [4])
2. Arterial Thrombosis
   1. Transient ischemic attack (TIA) and stroke (CVA) most common
   2. APL Abs are not a risk for recurrent stroke or other thrombo-occlusive events after initial stroke [3]
   3. MI may occur, but APL Ab does not include increased risk for MI in most studies
   4. Peripheral embolic disease is more common: renal [9], mesentary, others
   5. Case report of bone marrow necrosis probably due to thrombosis with APL Ab [16]
3. Fetal Loss
   1. Typically midtrimester
   2. Placental circulation thrombosis leads to spontaneous abortion
   3. Correlates only with increased IgG anticardiolipin Ab (relative increased risk ~3.5X)
   4. APL Abs reduce levels of annexin V which increases coagulation in placental area
   5. Antiprothrombin APL were found in 11 of 19 women with spontaneous abortion [24]
   6. These Abs are typically directed against prethrombin-1, not fragment-1 [24]
4. ACL Ab does not predict:
   1. Low Apgar scores
   2. Maternal complications
   3. Decreased birth weight
5. Thrombocytopenia
   1. APL Abs bind to platelets, activate them, and then lead to their clearance
   2. Increased risk of bleeding correlates with platelet count
   3. Use of heparin in APLS patients is associated with high risk of thrombocytopenia [18]
   4. Thrombosis may also be increased, despite low platelet counts, due to activation
   5. Antiprothrombin Abs also associated with severe preeclampsia, which can include low platelets (HELLP Syndrome) [24]
6. Livedo reticularis
   1. May be seen in cholesterol emboli syndrome and other diseases as well as APLS
   2. Violaceous net-like discoloration, blanches with pressure
   3. Sneddon's Syndrome = livedo reticularis + anticardiolipin antibodies + CNS symptoms
7. Endocarditis (Libman-Sacks)
   1. Atypical non-bacterial verrucous endocarditis, up to 30% of patients
   2. Mitral and aortic valve lesions most common (usually with regurgitation)
   3. More common in secondary APLS
8. CNS Symptoms
   1. CNS Vasculitis
   2. Stroke Syndromes (including multi-infarct dementia)
   3. Transverse Myelitis
   4. Migraines
   5. Low grade memory problems
9. Primary Antiphospholipid Syndrome requires the absence of:
   1. Vasculitic rash
   2. Arthritis and Serositis
   3. Presence of these symptoms strongly suggests SLE or Primary Vasculitis
10. Catastrophic APLS [1,8,12]
    1. Rapidly progressive, acute severe APL symptoms
    2. Usually with digital necrosis, strokes, and thrombocytopenia
    3. Renal failure may occur [12]
    4. Ocular disease, vision loss, due to APL is usually inflammatory not thrombotic [12]
    5. History or presence of DVT
    6. Very uncommon, but may be fatal
    7. Aggressive therapy with glucocorticoids, cytotoxic agents, plasma exchange recommended
11. Antiprothrombin (mainly anti-fragment-1) Abs associated with severe preeclampsia [24]

F. Laboratory Evaluation

1. Prolonged PTT
   1. Phospholipids are required for activation of Factors VII, IX and X
   2. Inhibitor studies positive - usually only for "lupus" anti-coagulant
   3. Prolongation of Russel Viper Venom Time (RVVT)
   4. PT should be normal (unless on coumadin)
2. Anti-Phospholipid Antibodies (APL Abs; See Below)
   1. Most commonly against cardiolipin in general population
   2. Lupus anti-coagulant is commonly found in patients with true SLE (will prolong PTT)
   3. Lupus anticoagulant is usually directed against prothrombin (prethrombin or fragment 1)
   4. IgG APL Ab is more common than IgM and is better associated with vascular events
   5. IgG APL Abs >40 GPL units has ~4 fold increased risk for vascular events [22]
   6. These Abs will also cause a false positive test for syphilis (RPR, usually low titer)
3. Anticardiolipin Abs (ACL Ab)
   1. ß2-Glycoprotein I (ß2-GP I) is an apolipoprotein coagulation inhibitor
   2. ß2-GP I interacts with negatively charged phospholipids
   3. Anti-cofactor or ß-glycoprotein I Abs are detected with ELISA test
4. Other
   1. Immune thrombocytopenic purpura (ITP)
   2. Depressed levels of protein C and/or S due to Abs against these proteins
   3. Anti-mitochondrial Abs, Type 5, may associated with APLS
   4. Some Abs cross react with oxidized LDL cholesterols or prothrombin
5. Assays for RPR and Coombs' direct Abs are usually also done
6. Should assess for high titers of ANA, Anti-Sm, and other autoantibodies

G. Differential Diagnosis

1. Several prothrombotic states with both venous and arterial thrombosis
2. Heparin-induced thrombocytopenia
3. Homocysteinemia
4. Myeloproliferative syndromes (including polycythemia vera)
5. Hyperviscosity (including Waldenstrom's Macroglobulinemia)
6. Nephrotic Syndrome
7. Sickle cell anemia
8. Acute leukemia
9. Paroxysmal nocturnal hemoglobulinuria (venous >> arterial thromboses)

H. Treatment [1]

1. Eliminate and/or control any contributing factors
   1. Smoking
   2. Diabetes
   3. Hypertension
   4. Hyperlipidemia
   5. Atherosclerosis
   6. Oral contraceptives should not be used in patients with APLS [26]
2. Aspirin
   1. Recommended as prophylaxis for asymptomatic patients only
   2. Not effective for secondary prevention in patients with symptomatic APLS [13]
   3. Combination of ASA and heparin is used to prevent fetal loss [2]
   4. Usual dose is 325mg po qd
   5. May also be combined with warfarin in low doses (81mg ASA qd + Warfarin)
3. Warfarin [2,10,11,26]
   1. Warfarin is strongly recommended to patients who have had symptoms and/or events
   2. INR of 2-3 is sufficient for most patients [1,2,26]
   3. INR 3.1-4.0 not superior to INR 2.0-3.0 for preventing recurrent thrombosis [10]
   4. Arterial thromboses may be better treated with INR >3.0, but no longer recommended [11]
   5. Aspirin provides little additional benefit when given with high dose coumadin
4. Sub-Cutaneous Heparin
   1. IV heparin may be acutely in thromboembolic events
   2. Heparin prophylaxis in pregnancy is usually 5000 U bid sc
   3. Low molecular weight heparins (LMWH) are safer and at least as effective
   4. Women on standard heparin prophylactically are at high risk for osteoporosis
5. Hydroxychloroquine - may be useful in patients with SLE and secondary APL Abs
6. Severe Cases
   1. Heparin anticoagulation therapy, followed by warfarin with high INR
   2. Glucocorticoids - may actually worsen risk of thrombosis [26]
   3. Cytotoxic Agents: cyclophosphamide (preferred), azathioprine
   4. Cyclophosphamide may decrease titer of Antiphospholipid antibodies
   5. Temporizing: Intravenous immunoglobulin (IVIg)
   6. Plasma exchange generally added, particularly for renal dysfunction [12]
7. Thrombocytopenia
   1. Prednisone initially very effective (20-40mg with taper)
   2. Frequent relapse with discontinuation
   3. Low dose aspirin or heparin may reverse thrombocytopenia as well
   4. Danazol (400-800mg initial, 200-400mg qd) has apparent efficacy and is well tolerated
   5. Intravenous Immunoglobulin (IVIg) can have temporizing effects
   6. IVIg is generally effective but temporary in thrombocytopenia
8. Recurrent Fetal Loss [2,26]
   1. Treatment with aspirin or prednisone alone or in combination not effective [27]
   2. Prednisone+aspirin increased risk of prematurity, maternal hypertension and diabetes
   3. Subcutaneous heparin appears to be effective, but osteoporosis can develop
   4. Heparin is strongly recommended; low molecular weight heparin is preferred
   5. Combination aspirin+heparin reduces risk of subsequent fetal loss by 50% [2]
   6. Fetal survival in treated patients is increased from 40% to 80%
   7. Heparin induced thrombocytopenia is another concern
   8. IVIg may also be used in high risk pregnancy with some success (history of fetal loss)
   9. Hydroxychloroquine in SLE is generally considered safe
9. Catastrophic APLS
   1. Emergent therapy in intensive care unit generally required
   2. Immediate plasmapheresis ± IVIg administration should be used
   3. Severe thromboses may be treated with thrombolytic therapy
   4. Generally poor prognosis

I. Prognosis

1. Risk Factors for Events with APL Syndrome
   1. Titer of Antibody (Ab)
   2. Ab Isotype: IgG may have greater risk than IgM for fetal loss (but also more common)
   3. High titer IgG ACL Ab (but not IgM or IgA) are strongly correlated with events [15,22]
   4. Prolonged duration of Ab Presence increases risk of events
   5. History of vascular events is strongest predictor for recurrent events
2. No prior events
   1. ACL Ab (>95th %tile) in healthy men increase risk ~5X for DVT ± PE
   2. Stroke incidence does not appear to be increased by APL Ab in this study
   3. Results are independent of age and smoking
   4. Note, however, that if primary event is stroke, then risk is increased for 2nd stroke
3. Second events [10,13]
   1. Site of first event tends to predict site of recurrences (91% of recurrent events)
   2. Of 70 patients with initial event, 37 had 54 recurrent events
   3. Warfarin therapy with INR 2-3 now recommended; INR>3 of no overall benefit [2]
   4. Aspirin (80-325mg/d) also be of benefit [2]
   5. Combination ASA+Heparin in preganancy after initial fetal loss is recommended

References

1. Levine JS, Branch DW, Rauch J. 2002. NEJM. 346(10):752
2. D'Cruz DP, Khamashta MA, Hughes GR. 2007. Lancet. 369(9561):587
3. 32. APASS Investigators. 2004. JAMA. 291(5):576
4. Vlot AJ, van der Molen AJ, Muis MJ, Fijnheer R. 2001. Lancet. 358(9279):382 (Case Report)
5. Schulman S, Svenungsson E, Granqvist S. 1998. Am J Med. 104(4):332
6. Puisieux F, de Groote P, Masy E, et al. 2000. Am J Med. 109(8):635
7. Peltola JT, Haapala AM, Isojarvi JI, et al. 2000. Am J Med. 109(9):712
8. Coggins CH and McCluskey RT. 2001. NEJM. 344(15):1152 (Case Record)
9. Rennke HG and Laposata M. 1999. NEJM. 340(24):1900 (Case Record)
10. Crowther MA, Ginsberg JS, Julian J, et al. 2003. NEJM. 349(12):1133
11. Lockshin MD and Erkan D. 2003. NEJM. 349(12);1177
12. Magee CC. Coggins MP, Foster CS, et al. 2008. NEJM. 358(3):275 (Case Record)
13. Khamashta MA, Cuadrado MJ, Mujic F, et al. 1995. NEJM. 332(15):993
14. Ginsburg JS, Demers C, Brill-Edwards P, et al. 1995. Am J Med. 98(4):379
15. Escalante A, Brey RL, Mitchell BD Jr, Dreiner U. 1995. Am J Med. 98(6):559
16. Bulvik S, Aronson I, Ress S, Jacobs P. 1995. Am J Med. 98(6):572
17. Toubi E, Khamashta M, Panarra A, Hughes GR. 1995. Am J Med. 99(4):392
18. Auger WR, Permpikul P, Moser KM. 1995. Am J Med. 99(4):392
19. Gomez-Pacheco L, Villa AR, Drenkard C, et al. 1999. Am J Med. 106(4):417
20. Goldberg SN, Conti-Kelly AM, Greco TP. 1995. Am J Med. 99(5):473
21. Abu-Shakra M, Gladman DD, Urowitz MB, Farewell V. 1995. Am J Med. 99(6):624
22. Finazzi G, Brancaccio V, Moia M, et al. 1996. Am J Med. 100(5):530
23. Zuckerman E, Toubi E, Shiran A, et al. 1996. Am J Med. 101(4):381
24. Akimoto T, Akama T, Saitoh M, et al. 2001. Am J Med. 110(3):188
25. Merkel PA, Chang Y, Pierangeli S, et al. 1997. Am J Med. 101(6):576
26. Krnic-Barrie S, O'Connor CR, Looney SW et al. 1997. Arch Intern Med. 157(18):2101
27. Laskin CA, Bombardier C, Hannah ME, et al. 1997. NEJM. 337(3):148