Hi, my name is Allison Schaaf, my own fertility journey, including 5 miscarriages, inspired me to create this website to help YOU navigate your own fertility journey.
Here are my main takeaways I would share with you as a friend:
- Often times, APS is first diagnosed due to recurrent miscarriages
- There are specific protocols that can help with a successful pregnancy in someone with APS
Of course, I also recommend you do your own research! That is why I have coordinated these articles with the nitty-gritty details and links to research so you can best decide what works best for you, read on for more! And don’t miss my Action Steps at the bottom of the article!
Table of Contents
What is antiphospholipid syndrome?
Antiphospholipid syndrome and recurrent miscarriage
What causes antiphospholipid syndrome?
Other symptoms of antiphospholipid syndrome
Testing and diagnostic criteria for APS
Antiphospholipid syndrome contributes to about 7 – 25% of recurrent miscarriages (or recurrent pregnancy loss, RPL). 1 It may also cause other pregnancy complications and diseases of the blood vessels. Fortunately, if correctly diagnosed and treated, there is an 80 – 90% chance of successful pregnancy. This article will cover antiphospholipid syndrome as a potential cause of miscarriage, along with diagnosis and treatment.
What is antiphospholipid syndrome (APS)?
The antiphospholipid antibody syndrome (APS) or Hughes syndrome, is an autoimmune disorder often found in lupus. However, it is possible to have APS without lupus. APS causes blood clots (thrombosis), pregnancy complications, and miscarriages. 23 It is more common in women than men, particularly young women. 4
In APS patients, the immune system launches different antibodies against phospholipid-bound proteins on cell membranes, such as beta-2 glycoprotein 1 (aβ2GPI), prothrombin, or cardiolipin (aCL). 5 Lupus anticoagulant (LA) is also an antibody that may cause blood clots.
Antiphospholipid syndrome and recurrent miscarriages / recurrent pregnancy loss (RPL)
APS may cause pregnancy complications including, stillbirth, pre-eclampsia, intrauterine growth restriction, premature delivery, and miscarriage. 678 If you have two or more pregnancy losses that are not necessarily subsequent, you should request lab tests for APS antibodies from your doctor. 9
Like many other conditions that cause blood clots, APS may cause miscarriage or other pregnancy complications by causing blood clots or impairing blood flow in the placenta. Antiphospholipid antibodies may also interfere with normal development of the placenta, which prevents the pregnancy from progressing naturally. The autoimmunity may also interfere with natural immune system changes during pregnancy. 10
What causes antiphospholipid syndrome?
Loss of immune tolerance
A healthy immune system prevents autoimmune diseases with many checks and balances. For example, self-attacking immune cells commit suicide (apoptosis) and are suppressed by regulatory T cells. 12 When these checks and balances fail due to genetic susceptibility and environmental triggers, your immune system loses self-tolerance and may develop an autoimmune disease.
No one gene directly causes APS, but some genetic variants may increase your risk of developing APS. Certain genetic variants predispose you to produce antiphospholipid antibodies, more easily lose self-tolerance or generally increase inflammation and oxidative stress. 13
Molecular mimicry – Some immune triggers, such as infections or allergens, harbor parts that are very similar to your own cellular components. If the similarity is high enough, your antibodies against these immune triggers may also attack your own cells. 14
The gut flora or the composition of microorganisms in the large intestine is important for both self-tolerance and activating the immune system. In addition, many people with antiphospholipid syndrome have gut inflammation and reduced friendly gut bacteria. 1516 A small clinical study found that a certain common human gut bacteria, Roseburia intestinalis, may trigger antiphospholipid antibodies. 17
Loss of self-tolerance and immune triggers eventually cause the immune cells to launch antibodies that bind and block phospholipid-bound proteins. Because phospholipid-bound proteins such as aβ2GPI prevent the platelets from adhering to the blood vessels, blocking them increases the risk of blood clots. 18 However, many people with the antibodies have no symptoms until they encounter a second hit.
The second hit hypothesis states that the antibodies may be in circulation until another event tips the physiology towards forming blood clots, especially in the presence of antibodies. Second hits may include: 192021
- oxidative stress
- leaky gut, increasing bacterial toxins such as lipopolysaccharides in the blood
- high blood phospholipids due to infections
- concomitant connective tissue diseases, such as Sjogren’s, systemic sclerosis, and mixed connective tissue disease 22
- estrogen-containing contraceptives
- immobility or lack of movements, such as during long flights or bedrest
Other symptoms of antiphospholipid syndrome
Vascular APS symptoms may include blood clot-related complications, cardiovascular disease, and pregnancy complications.
Superficial vein clots (Thrombophlebitis) may inflame tissues around the vein, resulting in redness, warmth, and tenderness. 23 Livedo reticularis, another obvious sign of APS, is a web of purplish marks on the skin typically observed on the front of the arms and legs. 24 These are caused by clots in small blood vessels in the skin.
Deep vein blood clots (Deep vein thrombosis) may cause swelling, pain, and redness of the affected limb. Deep vein clots can migrate to the lungs, causing life-threatening pulmonary embolism. 25 Symptoms of pulmonary embolism include sudden chest pain that worsens with breathing, shortness of breath along with cough, and sometimes even bloody sputum. 26
Testing and diagnostic criteria for APS
Currently, the diagnosis criteria for APS are the same for both vascular and obstetric APS. To be diagnosed with APS, you must have antibodies and at least one clinical criterion, which could be thrombotic events or pregnancy complications (see below). 28
Thrombotic events consist of one or more confirmed clinical episodes of a blood clot occurring in an artery, vein, or small blood-vessel validated by imaging studies or tissue biopsy.
- One or more unexplained deaths of a physically normal fetus at or after the 10th week of pregnancy
- One or more premature births of a physically normal newborn at or before the 34th week of pregnancy due to pre-eclampsia, eclampsia, or placenta malfunction
- Three or more unexplained consecutive miscarriages before the 10th week of pregnancy
- Presence of Lupus anticoagulant (LA) in plasma
- Moderate to high levels of aCL (IgG or IgM) in serum or plasma ( > 40 IgG phospholipid units (GPL)/mL or IgM phospholipid units (MPL)/mL or > 99th percentile)
- Moderate to high levels of aβ2GPI antibodies (IgG or IgM) in serum or plasma (> 99th percentile)
- <15.0 MPL or GPL (negative)
- 15.0-39.9 MPL or GPL (weakly positive)
- 40.0-79.9 MPL or GPL (positive)
- > or =80.0 MPL or GPL (strongly positive)
*MPL- IgM Phospholipid Units. 1 MPL unit is 1 mg of IgM antibody.
**GPL – IgG Phospholipid Units. 1 GPL unit is 1 mg of IgG antibody.
Fortunately, with proper blood thinner and aspirin treatments, up to 80% of women with APS can have successful pregnancies. 3334 Of the remaining 20% of women, about 61% of them have successful pregnancies with anti-inflammatory treatments. 3536
Blood thinners or anticoagulants
Once your doctor diagnoses you with APS, they may prescribe anticoagulants and low-dose aspirin as prophylactic treatments during prenatal, pregnancy, and up to 6 weeks postpartum.
These anticoagulants used may include Low Molecular Weight Heparins, such as Clexane (fraxiparine at 0.6 mg daily) or Lovenox (enoxaparin between 0.5-1 mg/kg/day), given subcutaneously. 37 This family of drugs are the only anticoagulants that are safe for pregnancy.
Prophylactic (preventive) treatments involve using lower dosages of the medications to prevent blood clots up until 6 – 12 weeks postpartum. The prophylactic dose for Lovenox is 0.5 mg/kg/day.
Therapeutic treatments – if you’ve had blood clots or related symptoms, your doctor may advise a higher therapeutic dosage and to continue the medications indefinitely. The therapeutic dose for Lovenox is 1 mg/kg/day.
Your doctor may also prescribe low dose aspirin, 75-100 mg per day. In the case of allergy, Plavix (clopidogrel 75 mg daily) may be prescribed.
Monitoring blood-thinning treatments
To ensure that the treatment is effective and prevent excessive bleeding, your doctor may monitor the anti-factor Xa and/or prothrombin time.
Anti-factor-Xa is the preferred test because Lovenox does not affect prothrombin time and INR. LMWH such as Lovenox inactivates factor Xa by binding to substances that inhibit blood clots in your blood. Therefore, the less amount of factor Xa remaining in the sample means the less clotting risk you have 39.
Anti-factor-Xa levels should be checked 4 hours after a dose 40.
Prophylactic ranges: 0.2-0.5 IU/mL 41
Therapeutic ranges: 0.5-1.2 IU/ml 42
In some cases, your doctor may also test for prothrombin time (PT), partial thromboplastin time (PTT), and international normalized (ratios) INR levels. These tests show how much time it takes you to bleed. Ideally, you should be tested every 4 weeks if the pregnancy is going well and your INR is optimal. However, if your doctor is monitoring your treatments or titrating your medications, they may order more frequent tests. If you are on anticoagulants, it is important to take precautions to prevent bleeding, such as avoiding bruising and using soft toothbrushes.
Reference ranges for prothrombin and partial prothrombin time
Obstetric vs. vascular APS
Obstetric APS may explain why some women continue to have miscarriages despite aspirin and blood-thinning treatments. Currently, this is a controversial topic and not all doctors agree that obstetric APS is different from vascular APS.
Most APS cases are vascular APS, where the patients have both blood clots and pregnancy complications. More recent studies described obstetric APS as a distinct form where autoimmunity and inflammation cause the miscarriage. Obstetric APS patients have no detectable blood clots in their bodies or placental tissues.
Obstetric APS explains why anticoagulants and aspirin treatments cannot help 20 – 30% of women with APS antibodies achieve full-term pregnancies 46. A few small clinical studies showed that ~61% of these women eventually delivered healthy babies after trying anti-inflammatory treatments. 4748
Currently, there is no specific test that can distinguish between obstetric and vascular APS, as both types of APS present with the same antibodies in the blood. 49 If you have APS antibodies with normal blood clot INR, no blood clot in a full-body CT, and placenta inflammation in a placenta examination, you may have obstetric APS.
A placenta histopathology exam can determine if your placenta has blood clots, tissue damage due to lack of blood flow (infarction), and/or signs of inflammation. Recurring miscarriages or multiple miscarriages is an indication for placenta pathology exam if it is possible to retrieve examinable placental tissues after eight weeks of pregnancy. The placenta may not fully form until past eight weeks of pregnancy, and samples may need to be collected in a clinical setting. Typically, your OB/GYN collects the placenta samples and sends it to the lab after a dilatation and curettage (D&C). However, you can also bring your product of conceptus to the clinic for an examination.
In obstetric APS or cases that still have miscarriages despite aspirin and blood thinners, anti-inflammatory treatments have had some success in small clinical studies. Many of these promising experimental treatments for APS are pre-existing autoimmune or anti-inflammatory drugs. However, we still need larger clinical trials to confirm that these treatments are safe and effective.
Intravenous immune globulins (IVIG), which are antibodies that tie up APS antibodies, were as safe and effective as anticoagulants for APS pregnancies. 50 These studies were based on single case studies with promising results during the pregnancy and follow up. 51
Hydroxychloroquine is a standard treatment for lupus, a condition similar to APS. Currently, there is a large clinical trial to test whether hydroxychloroquine may prevent pregnancy complications due to obstetric APS. 52
Prednisone is a steroid that is typically contraindicated for pregnancy as it can contribute to gestational diabetes and hypertension. However, in small clinical studies of women who had miscarriage despite aspirin and blood thinners, low-dose prednisone up until 14 weeks were somewhat helpful. ~61% of these women overcame early miscarriage and achieved successful pregnancies, although rates of complications remained high. 5354
TNF-⍺ blockers Because obstetric APS is caused by placental inflammation, anti-inflammatory drugs such as TNF-⍺ blockers may help with obstetric APS. 55 In animal studies, APS antibodies attack placental tissue, increasing placental and systemic TNF-⍺, leading to inflammation and fetal loss. 56 Although TNF-⍺ blockers have been successfully used in 12 refractory APS cases, a larger study would be necessary to demonstrate its safety and effectiveness in pregnant women. 5758
Antihistamine Some women may believe that antihistamines such as Benadryl may help because allergic symptoms often precede their miscarriages. Animal studies have suggested that histamines and mast cell activation may contribute to blood clotting in deep vein thrombosis. 5960 However, to date, there is no evidence that over the counter antihistamines help with recurrent miscarriage. Antihistamines have also been linked to birth defects in small clinical studies, but these results were not confirmed in larger studies. 61 Although antihistamines are available over the counter, you should consult your physician before taking them during pregnancy.
Diet, lifestyle, and alternative therapies
Diet and nutrition therapy may be beneficial in managing autoimmune conditions like APS. 63 Obesity, metabolic syndrome, high cholesterol, and diabetes are diet-related conditions that significantly increase the risks of blood clots. Vitamin D deficiency is linked to autoimmunity. 64 Foods that are high in vitamin K, such as leafy greens, may increase thrombosis or interact with anticoagulant medications. Some small clinical studies have shown that the Autoimmune Paleo Protocol and probiotic therapy may help with autoimmune conditions such as Hashimoto’s thyroiditis and rheumatoid arthritis. 6566 As evidence supporting these treatments is still limited and there are many possible contraindications, you should work with a qualified dietician and physician for appropriate nutrition advice.
Next Steps to Consider
- If you have recurring miscarriages/ recurrent pregnancy loss (RPL) and have not been tested for Antiphospholipid Syndrome (APS), work with your doctor to do so
- If you have been diagnosed with APS, work with your doctor on a protocol for your next pregnancy
- To read more about my personal story that includes an APS diagnosis, click here.
|⇧1||Vinatier D, Dufour P, Cosson M, Houpeau JL. Antiphospholipid syndrome and recurrent miscarriages. Eur J Obstet Gynecol Reprod Biol. 2001;96: 37–50. Available: https://pubmed.ncbi.nlm.nih.gov/11311759/|
|⇧2||Antiphospholipid Antibody Syndrome (APS) – Hematology and Oncology – MSD Manual Professional Edition. In: MSD Manual Professional Edition [Internet]. MSD Manuals; [cited 18 May 2020]. Available: https://www.msdmanuals.com/professional/hematology-and-oncology/thrombotic-disorders/antiphospholipid-antibody-syndrome-aps?query=antiphospholipid%20antibody|
|⇧3||Abrahams VM, Chamley LW, Salmon JE. Emerging Treatment Models in Rheumatology: Antiphospholipid Syndrome and Pregnancy: Pathogenesis to Translation. Arthritis Rheumatol. 2017;69: 1710–1721. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575987/|
|⇧4||Antiphospholipid syndrome – Symptoms and causes – Mayo Clinic. 10 Oct 2019 [cited 18 May 2020]. Available: https://www.mayoclinic.org/diseases-conditions/antiphospholipid-syndrome/symptoms-causes/syc-20355831|
|⇧5||Rose NR. Prediction and Prevention of Autoimmune Disease in the 21st Century: A Review and Preview. Am J Epidemiol. 2016;183: 403–406. Available: https://pubmed.ncbi.nlm.nih.gov/26888748/|
|⇧6||Santos T da S, Ieque AL, de Carvalho HC, Sell AM, Lonardoni MVC, Demarchi IG, et al. Antiphospholipid syndrome and recurrent miscarriage: A systematic review and meta-analysis. J Reprod Immunol. 2017;123: 78–87. Available: https://pubmed.ncbi.nlm.nih.gov/28985591/|
|⇧7||Chaturvedi S, McCrae KR. Diagnosis and management of the antiphospholipid syndrome. Blood Rev. 2017;31: 406–417. Available: https://pubmed.ncbi.nlm.nih.gov/28784423/|
|⇧8||Kemp M, Thomas W. Antiphospholipid syndrome in obstetrics. Lupus. 2018;27: 28–31. Available: https://pubmed.ncbi.nlm.nih.gov/30452326/|
|⇧9||Tulandi T. Recurrent pregnancy loss: Definition and etiology. In: Lockwood CJ, Eckler K, editors. UpToDate. Waltham, MA: UpToDate; 2020. Available: https://www.uptodate.com/contents/recurrent-pregnancy-loss-definition-and-etiology|
|⇧10||Vinatier D, Dufour P, Cosson M, Houpeau JL. Antiphospholipid syndrome and recurrent miscarriages. Eur J Obstet Gynecol Reprod Biol. 2001;96: 37–50. Available: https://pubmed.ncbi.nlm.nih.gov/11311759/|
|⇧11||Rose NR. Prediction and Prevention of Autoimmune Disease in the 21st Century: A Review and Preview. Am J Epidemiol. 2016;183: 403–406. Available: https://pubmed.ncbi.nlm.nih.gov/26888748/|
|⇧12||Perl A. Pathogenesis and spectrum of autoimmunity. Methods Mol Biol. 2012;900: 1–9. Available: https://pubmed.ncbi.nlm.nih.gov/22933062/|
|⇧13||Iuliano A, Galeazzi M, Sebastiani GD. Antiphospholipid syndrome’s genetic and epigenetic aspects. Autoimmun Rev. 2019;18: 102352. Available: https://europepmc.org/article/med/31323355|
|⇧14||Oldstone MB. Molecular mimicry and autoimmune disease. Cell. 1987;50: 819–820. Available: https://pubmed.ncbi.nlm.nih.gov/3621346/|
|⇧15||Ruff WE, Dehner C, Kim WJ, Pagovich O, Aguiar CL, Yu AT, et al. Pathogenic Autoreactive T and B Cells Cross-React with Mimotopes Expressed by a Common Human Gut Commensal to Trigger Autoimmunity. Cell Host Microbe. 2019;26: 100–113.e8. http://dx.doi.org/10.1016/j.chom.2019.05.003l|
|⇧16||De Luca F, Shoenfeld Y. The microbiome in autoimmune diseases. Clin Exp Immunol. 2019;195: 74–85. Available: https://pubmed.ncbi.nlm.nih.gov/29920643/|
|⇧17||Ruff WE, Dehner C, Kim WJ, Pagovich O, Aguiar CL, Yu AT, et al. Pathogenic Autoreactive T and B Cells Cross-React with Mimotopes Expressed by a Common Human Gut Commensal to Trigger Autoimmunity. Cell Host Microbe. 2019;26: 100–113.e8. http://dx.doi.org/10.1016/j.chom.2019.05.003|
|⇧18||Viard JP, Amoura Z, Bach JF. Anti-beta 2-glycoprotein I antibodies and thrombosis. Clin Rev Allergy Immunol. 1995;13: 67–72. Available: https://pubmed.ncbi.nlm.nih.gov/7648351/|
|⇧19||Schreiber K, Sciascia S, de Groot PG, Devreese K, Jacobsen S, Ruiz-Irastorza G, et al. Antiphospholipid syndrome. Nat Rev Dis Primers. 2018;4: 17103. Available: https://pubmed.ncbi.nlm.nih.gov/29321641/|
|⇧20||Antovic A, Sennström M, Bremme K, Svenungsson E. Obstetric antiphospholipid syndrome. Lupus Sci Med. 2018;5: e000197. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195166/|
|⇧21||Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid syndrome. N Engl J Med. 2013;368: 1033–1044. Available: https://pubmed.ncbi.nlm.nih.gov/23484830/|
|⇧22||Rai R, Swetha T. Association of anti-phospholipid antibodies with connective tissue diseases. Indian Dermatol Online J. 2015;6: 89–91. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375772/|
|⇧23||Nasr H, Scriven JM. Superficial thrombophlebitis (superficial venous thrombosis). BMJ. 2015;350: h2039. Available: https://pubmed.ncbi.nlm.nih.gov/26099257/|
|⇧24||Sajjan VV, Lunge S, Swamy MB, Pandit AM. Livedo reticularis: A review of the literature. Indian Dermatol Online J. 2015;6: 315–321. Available: http://www.idoj.in/article.asp?issn=2229-5178;year=2015;volume=6;issue=5;spage=315;epage=321;aulast=Sajjan|
|⇧25||Deep Venous Thrombosis (DVT): Practice Essentials, Background, Anatomy. 10 Nov 2019 [cited 18 May 2020]. Available: https://emedicine.medscape.com/article/1911303-overview|
|⇧26||Website NHS. Pulmonary embolism. [cited 18 May 2020]. Available: https://www.nhs.uk/conditions/pulmonary-embolism/|
|⇧27||Antiphospholipid Syndrome Clinical Presentation: History, Physical, Causes. 12 Nov 2019 [cited 18 May 2020]. Available: https://emedicine.medscape.com/article/333221-clinical|
|⇧28||Antiphospholipid Syndrome | Lab Tests Online. [cited 18 May 2020]. Available: https://labtestsonline.org/conditions/antiphospholipid-syndrome|
|⇧29||Satta R, Biondi G. Antiphospholipid syndrome and pregnancy. G Ital Dermatol Venereol. 2019;154: 277–285. Available: https://pubmed.ncbi.nlm.nih.gov/30375212/|
|⇧30||Joste V, Dragon-Durey M-A, Darnige L. [Laboratory diagnosis of antiphospholipid syndrome: From criteria to practice]. Rev Med Interne. 2018;39: 34–41. Available: https://pubmed.ncbi.nlm.nih.gov/28302338/|
|⇧31||CLPMG – Clinical: Phospholipid (Cardiolipin) Antibodies, IgG and IgM, Serum. [cited 18 May 2020]. Available: https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/82976|
|⇧32||Antiphospholipid Syndrome | Allergy & Autoimmune Disease. In: Allergy & Autoimmune Disease [Internet]. [cited 18 May 2020]. Available: https://www.thermofisher.com/diagnostic-education/hcp/wo/en/tests/autoimmune-diseases/aps.html|
|⇧33||Schreiber K, Sciascia S, de Groot PG, Devreese K, Jacobsen S, Ruiz-Irastorza G, et al. Antiphospholipid syndrome. Nat Rev Dis Primers. 2018;4: 17103. Available: https://pubmed.ncbi.nlm.nih.gov/29321641/|
|⇧34||Antiphospholipid Antibody Syndrome (APS) – Hematology and Oncology – MSD Manual Professional Edition. In: MSD Manual Professional Edition [Internet]. MSD Manuals; [cited 18 May 2020]. Available: https://www.msdmanuals.com/professional/hematology-and-oncology/thrombotic-disorders/antiphospholipid-antibody-syndrome-aps?query=antiphospholipid%20antibody|
|⇧35||Bramham K, Thomas M, Nelson-Piercy C, Khamashta M, Hunt BJ. First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood. 2011;117: 6948–6951. Available: https://ashpublications.org/blood/article/117/25/6948/24351/First-trimester-low-dose-prednisolone-in|
|⇧36||Mekinian A, Alijotas-Reig J, Carrat F, Costedoat-Chalumeau N, Ruffatti A, Lazzaroni MG, et al. Refractory obstetrical antiphospholipid syndrome: Features, treatment and outcome in a European multicenter retrospective study. Autoimmun Rev. 2017;16: 730–734. Available: https://pubmed.ncbi.nlm.nih.gov/28478081/|
|⇧37||Lockshin MD. Anticoagulation in management of antiphospholipid antibody syndrome in pregnancy. Clin Lab Med. 2013;33: 367–376. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664954/|
|⇧38||Website NHS. Side effects. [cited 18 May 2020]. Available: https://www.nhs.uk/conditions/anticoagulants/side-effects/|
|⇧39||Anti-Xa Assay (Heparin Assay). 4 Mar 2020 [cited 22 Aug 2020]. Available: https://emedicine.medscape.com/article/2085000-overview|
|⇧40||Smythe MA, Priziola J, Dobesh PP, Wirth D, Cuker A, Wittkowsky AK. Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism. J Thromb Thrombolysis. 2016;41: 165–186. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715846/|
|⇧41||Silberstein L, Anastasi J. Hematology – 6th Edition. Hoffman R, Benz E, Heslop H, Weitz J, editors. Churchill Livingstone; 2012.|
|⇧42||Silberstein L, Anastasi J. Hematology – 6th Edition. Hoffman R, Benz E, Heslop H, Weitz J, editors. Churchill Livingstone; 2012.|
|⇧43||Partial Thromboplastin Time, Activated: Reference Range, Interpretation, Collection and Panels. 4 Mar 2020 [cited 18 May 2020]. Available: https://emedicine.medscape.com/article/2085837-overview|
|⇧44||Partial Thromboplastin Time, Activated: Reference Range, Interpretation, Collection and Panels. 4 Mar 2020 [cited 18 May 2020]. Available: https://emedicine.medscape.com/article/2085837-overview|
|⇧45||Shikdar S, Bhattacharya PT. International Normalized Ratio (INR). StatPearls. Treasure Island (FL): StatPearls Publishing; 2020. Available: https://www.ncbi.nlm.nih.gov/pubmed/29939529|
|⇧46||Tabacco S, Salvi S, De Carolis S, Botta A. Predictors-of-pregnancy-outcome-in-antiphospholipid-syndrome-a-review-2155-6121-1000239.pdf. J Allergy Ther. 2016. Available: https://www.longdom.org/open-access/predictors-of-pregnancy-outcome-in-antiphospholipid-syndrome-a-review-2155-6121-1000239.pdf|
|⇧47||Bramham K, Thomas M, Nelson-Piercy C, Khamashta M, Hunt BJ. First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood. 2011;117: 6948–6951. Available: https://ashpublications.org/blood/article/117/25/6948/24351/First-trimester-low-dose-prednisolone-in|
|⇧48||Mekinian A, Alijotas-Reig J, Carrat F, Costedoat-Chalumeau N, Ruffatti A, Lazzaroni MG, et al. Refractory obstetrical antiphospholipid syndrome: Features, treatment and outcome in a European multicenter retrospective study. Autoimmun Rev. 2017;16: 730–734. Available: https://pubmed.ncbi.nlm.nih.gov/28478081/|
|⇧49||Meroni PL, Borghi MO, Grossi C, Chighizola CB, Durigutto P, Tedesco F. Obstetric and vascular antiphospholipid syndrome: same antibodies but different diseases? Nat Rev Rheumatol. 2018;14: 433–440. Available: https://pubmed.ncbi.nlm.nih.gov/29891914/|
|⇧50||Branch DW, Peaceman AM, Druzin M, Silver RK, El-Sayed Y, Silver RM, et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group. Am J Obstet Gynecol. 2000;182: 122–127. Available: https://pubmed.ncbi.nlm.nih.gov/10649166/|
|⇧51||Arnout J, Spitz B, Wittevrongel C, Vanrusselt M, Van Assche A, Vermylen J. High-Dose Intravenous Immunoglobulin Treatment of a Pregnant Patient with an Antiphospholipid Syndrome: Immunological Changes Associated with a Successful Outcome. Thromb Haemost. 2018;71: 741–747. Available: https://pubmed.ncbi.nlm.nih.gov/7974342/|
|⇧52||Schreiber K, Breen K, Cohen H, Jacobsen S, Middeldorp S, Pavord S, et al. HYdroxychloroquine to Improve Pregnancy Outcome in Women with AnTIphospholipid Antibodies (HYPATIA) Protocol: A Multinational Randomized Controlled Trial of Hydroxychloroquine versus Placebo in Addition to Standard Treatment in Pregnant Women with Antiphospholipid Syndrome or Antibodies. Semin Thromb Hemost. 2017;43: 562–571. Available: https://pubmed.ncbi.nlm.nih.gov/28609801/|
|⇧53||Bramham K, Thomas M, Nelson-Piercy C, Khamashta M, Hunt BJ. First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood. 2011;117: 6948–6951. Available: https://ashpublications.org/blood/article/117/25/6948/24351/First-trimester-low-dose-prednisolone-in|
|⇧54||Mekinian A, Alijotas-Reig J, Carrat F, Costedoat-Chalumeau N, Ruffatti A, Lazzaroni MG, et al. Refractory obstetrical antiphospholipid syndrome: Features, treatment and outcome in a European multicenter retrospective study. Autoimmun Rev. 2017;16: 730–734. Available: https://pubmed.ncbi.nlm.nih.gov/28478081/|
|⇧55||Comarmond C, Cacoub P. Antiphospholipid syndrome: from pathogenesis to novel immunomodulatory therapies. Autoimmun Rev. 2013;12: 752–757. Available: https://pubmed.ncbi.nlm.nih.gov/23282546/|
|⇧56||Berman J, Girardi G, Salmon JE. TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss. J Immunol. 2005;174: 485–490. Available: https://pubmed.ncbi.nlm.nih.gov/15611274/|
|⇧57||Alijotas-Reig J, Esteve-Valverde E, Llurba E, Gris JM. Treatment of refractory poor aPL-related obstetric outcomes with TNF-alpha blockers: Maternal-fetal outcomes in a series of 18 cases. Semin Arthritis Rheum. 2019;49: 314–318. Available: https://pubmed.ncbi.nlm.nih.gov/30824278/|
|⇧58||Alijotas-Reig J, Esteve-Valverde E, Ferrer-Oliveras R, Llurba E, Gris JM. Tumor Necrosis Factor-Alpha and Pregnancy: Focus on Biologics. An Updated and Comprehensive Review. Clin Rev Allergy Immunol. 2017;53: 40–53. Available: https://pubmed.ncbi.nlm.nih.gov/28054230/|
|⇧59||Budnik I, Brill A. Immune Factors in Deep Vein Thrombosis Initiation. Trends Immunol. 2018;39: 610–623. Available: https://pubmed.ncbi.nlm.nih.gov/29776849/|
|⇧60||Ponomaryov T, Payne H, Fabritz L, Wagner DD, Brill A. Mast Cells Granular Contents Are Crucial for Deep Vein Thrombosis in Mice. Circ Res. 2017;121: 941–950. Available: https://pubmed.ncbi.nlm.nih.gov/28739590/|
|⇧61||Li Q, Mitchell AA, Werler MM, Yau W-P, Hernández-Díaz S. Assessment of antihistamine use in early pregnancy and birth defects. J Allergy Clin Immunol Pract. 2013;1: 666–74.e1. Available: https://pubmed.ncbi.nlm.nih.gov/24565715/|
|⇧62||Magro-Malosso ER, Saccone G, Di Tommaso M, Roman A, Berghella V. Exercise during pregnancy and risk of gestational hypertensive disorders: a systematic review and meta-analysis. Acta Obstet Gynecol Scand. 2017;96: 921–931. Available: https://pubmed.ncbi.nlm.nih.gov/28401531/|
|⇧63||Constantin M-M, Nita IE, Olteanu R, Constantin T, Bucur S, Matei C, et al. Significance and impact of dietary factors on systemic lupus erythematosus pathogenesis. Exp Ther Med. 2019;17: 1085–1090. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327661/|
|⇧64||Yang C-Y, Leung PSC, Adamopoulos IE, Gershwin ME. The implication of vitamin D and autoimmunity: a comprehensive review. Clin Rev Allergy Immunol. 2013;45: 217–226. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047889/|
|⇧65||Abbott RD, Sadowski A, Alt AG. Efficacy of the Autoimmune Protocol Diet as Part of a Multi-disciplinary, Supported Lifestyle Intervention for Hashimoto’s Thyroiditis. Cureus. 2019;11: e4556. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592837/|
|⇧66||Khanna S, Jaiswal KS, Gupta B. Managing Rheumatoid Arthritis with Dietary Interventions. Front Nutr. 2017;4: 52. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682732/|
|⇧67||Antiphospholipid Antibodies: Reference Range, Collection and Panels, Background. 4 Mar 2020 [cited 18 May 2020]. Available: https://emedicine.medscape.com/article/2116457-overview|