author:
Chen Xianglei Department of Hematology, Yidu Central Hospital, Weifang City
Liu Daji Department of Rheumatology, Yidu Central Hospital, Weifang City
This article is authorized by the author to be published by Medical Pulse, please do not reprint without permission.
Antiphospholipid syndrome (APS) is an acquired autoimmune disorder that is generally associated with thrombotic events with rare bleeding. However, APS occasionally presents with bleeding events as the first manifestation, and sometimes with thrombosis and bleeding.
In this paper, the causes, mechanisms and treatment measures of APS bleeding are discussed from four aspects: platelets, coagulation factors, microvascular and anticoagulants.
1. Thrombocytopenia can cause bleeding
The incidence of thrombocytopenia in patients with APS is 20–53%1–3, and the risk of thrombocytopenia is 2 times higher than that of primary APS in patients with APS secondary to systemic lupus erythematosus4. Most patients with APS have mild to moderate thrombocytopenia, mostly above 50×109/L, and only about 10% of APS patients will develop severe thrombocytopenia, but this severe thrombocytopenia is often associated with the development of disseminated intravascular coagulation (DIC) and catastrophic antiphospholipid antibody syndrome (CAPS). Mild to moderate thrombocytopenia generally does not occur clinically significant bleeding; severe thrombocytopenia, such as CAPS-associated, can cause bleeding.
1. Pathogenesis
The mechanisms of thrombocytopenia in patients with APS mainly include 5:
1. Pathologically enhanced platelet activation and aggregation, resulting in platelet thrombosis and increased platelet consumption;
2. Immune-mediated pathological platelet clearance. Anti-β2GPI directly interacts with specific platelet membrane glycoproteins (GPIB/IX, GPIIb/IIIa, GPIV) by binding to the activated platelet surface or antiphospholipid antibodies (aPL) through β2GPI, eventually leading to platelet clearance. Special subtypes of APL and their number may play an important role in the pathogenesis of thrombocytopenia. These evidences include IgGs in anti-β2GPI antibodies, lupus anticoagulants (LA), high titers of IgG anticardiolipin antibodies (ACLs), and triple positive (referred to as LA, ACL, anti-β2GPI simultaneous positive) APS are more common in patients with thrombocytopenia;
3. Impair the production of megakaryocytes to reduce platelets;
4. Splenomegaly after thrombosis of the spleen or portal vein leads to aggregation and redistribution of platelets in circulation;
5. At the same time, there are 6 immune thrombocytopenia (ITP), drug-induced thrombocytopenia, heparin-induced thrombocytopenia, infection-related thrombocytopenia, thrombotic microangiopathy (TMAS) or pregnancy-related thrombocytopenia.
2. Targeted treatment
Treatments for thrombocytopenia are mainly as follows: glucocorticoids are selected first-line, with or without intravenous immunoglobulins (IVIG), but IVIG has an increased risk of thrombosis. For patients who do not respond well to treatment, other immunosuppressants or immunomodulatory drugs (chloroquine, rituximab, plasmapheresis, etc.) or splenectomy can be selected. Thrombopoietin receptor agonists are effective in enhancing platelets, but their safety, particularly the risk of thrombosis formation, has yet to be further defined.
Second, coagulation factor defects can also lead to bleeding
1. Lupus anticoagulant - hypothrombinogen syndrome
In patients with APS with bleeding, lupus anticoagulant-hypothrombin syndrome is the most common7,8, most common in children or adolescent women, occasionally reported in adults, most often secondary to systemic lupus erythematosus or viral infection, and also secondary to lymphoma or drug reactions that produce abnormal immunoglobulins. Bleeding ranges in severity from asymptomatic, mild mucocutaneous bleeding to severe, fatal gastrointestinal, urinary tract, and central nervous system bleeding.
Coagulation factor defects under APS do not produce neutralizing antibodies against coagulation factors. Antiphospholipid antibodies cross-react with the phospholipid epitope of prothrombin, accelerating prothrombin clearance, resulting in FII activity often dropping below 20%9, but joint coagulation factor deficiency may also occur.
The main treatment measures include discontinuation of anticoagulants and, if necessary, infusion of red blood cells and fresh frozen plasma, vitamin K, and antifibrinolytic drugs. Treatment aims to stop active bleeding, remove autoantibodies that cause FII deficiency, and prevent thrombotic events. Therapeutic measures such as glucocorticoids, rituximab, and plasmapheresis can be used for the clearance of autoantibodies.
2. Vascular hemophilia factor defect
Acquired von Willebrand syndrome (AWS) can also coexist with APS. However, this condition often also diagnoses diseases that are clearly associated with AWS, such as myeloproliferative tumors (MPNs), aortic stenosis, and SLE. Therefore, some researchers believe that the occurrence of APS at this time is used to balance the bleeding tendency of AWS.
After the level of vascular hemophilia factor is normal, thrombosis prevention and treatment should be carried out in time, and immunosuppressive therapy for AWS combined with thromboprophylaxis therapy can often achieve good clinical results.
3. Other coagulation factor defects
Deficiencies in FVII,FVIII,FX.,FX., and FXI have all been reported in cases10–12, with varying levels of bleeding severity. Treatment is similar to AWS.
3. Thrombotic microangiopathy causes bleeding
1. Diffuse alveolar hemorrhage syndrome
Diffuse alveolar hemorrhage syndrome is an inflammatory destruction of the pulmonary microcirculation and is rare. It is more common in people with catastrophic antiphospholipid syndrome (CAPS).
High-dose glucocorticoids are the treatment of choice, with combinations preferring monotherapy. Rituximab and cyclophosphamide work well, but mycophenolate mofetil and azathioprine are not effective. Plasmapheresis and IVIG therapy may be done with CAPS.
2. Adrenal bleeding
Adrenal hemorrhage is rare and relatively common in CAPS, occurring in 10 to 16% 13. Often precipitated by trauma, invasive procedures, infection, and discontinuation of warfarin. Its mechanism is considered to be related to the adrenal gland having three blood supply arteries and one drainage vein. Once a blood clot forms in a drainage vein, bleeding can easily occur. Bleeding is often accompanied by adrenal cortex failure.
Adrenal bleeding may require hormone replacement therapy while preventing blood clots. Unless severe and extensive systemic bleeding occurs, try not to discontinue anticoagulant drugs.
3. Catastrophic antiphospholipid syndrome (CAPS)
Infection, malignancy, trauma, invasive procedures, activity of underlying autoimmune diseases, pregnancy complications, use of drugs such as oral contraceptives, and cessation of anticoagulation or inadequate anticoagulation are causes of CAPS. Pathological complement activation plays a key role in CAPS14. The causes of CAPS bleeding are complex15,16, mainly related to platelet hyperactivation and depletion leading to secondary thrombocytopenia, coagulation factor depletion, endothelial cell damage and power failure, TTP-like coagulation abnormalities, and may develop into DIC.
Treatment includes suppressing the immune system and reducing the production of antiphospholipid antibodies, preventing thrombotic events, and treating precipitating factors. Corticosteroids, IVIG, plasmapheresis, cyclophosphamide, rituximab, and eculizumab can all be used for treatment.
4. Antithrombotic therapy induces bleeding
Serious adverse events such as bleeding of the central nervous system and bleeding of the gastrointestinal tract occur in antithrombotic therapy. The bleeding probability of anticoagulants is 3-6 people/100 people/year17, and the bleeding probability of antiplatelet preparations is 3-4 people/1000 people/year18. Warfarin indirestr 4.0 or higher, combination antithrombotic therapy, older adults over 75 years of age, history of major bleeding (mostly gastrointestinal), malignancy, poorly controlled hypertension, leukopenia, poor patient compliance are all high risk factors for the development of antithrombotic therapy-related bleeding19–21.
5. Summary
Bleeding is a rare and often severe comorbidity of APS. The causes are related to thrombocytopenia, acquired coagulation factor deficiency (mainly hypothrombinogen), thrombotic microangiopathy, and adverse reactions to antithrombotic therapy (mainly warfarin). The management of bleeding is challenging and requires balancing the relationship between hemostasis and antithrombosis. Controlling bleeding while removing bleeding is key to treatment.
bibliography:
1.Uthman I, Godeau B, Taher A, Khamashta M. The Hematologic Manifestations of the Antiphospholipid Syndrome. Blood Rev. 2008;22(4):187-194. doi:10.1016/j.blre.2008.03.005
2.Artim-Esen B, Diz-Küçükkaya R, İnanç M. The Significance and Management of Thrombocytopenia in Antiphospholipid Syndrome. Curr Rheumatol Rep. 2015;17(3). doi:10.1007/s11926-014-0494-8
3.Gómez-Puerta JA, Martín H, Amigo MC, et al. Long-term follow-up in 128 patients with primary antiphospholipid syndrome: Do they develop lupus? Medicine (Baltimore). 2005;84(4):225-230. doi:10.1097/01.md.0000172074.53583.ea
4.Cervera R, Boffa MC, Khamashta MA, Hughes GRV. The Euro-Phospholipid project: Epidemiology of the antiphospholipid syndrome in Europe. Lupus. 2009;18(10):889-893. doi:10.1177/0961203309106832
5.Abreu MM, Danowski A, Wahl DG, et al. The relevance of “non-criteria” clinical manifestations of antiphospholipid syndrome: 14th International Congress on Antiphospholipid Antibodies Technical Task Force Report on Antiphospholipid Syndrome Clinical Features. Autoimmun Rev. 2015;14(5):401-414. doi:10.1016/j.autrev.2015.01.002
6.Deucher A, Wool GD. How I investigate bone marrow necrosis. Int J Lab Hematol. 2019;41(5):585-592. doi:10.1111/ijlh.13091
7.Chan EYH, Leung KFS, Soo ETL, Ma ALT. A Chinese Boy with Lupus Anticoagulant-hypoprothrombinemia Syndrome: A Case Report and Review of the Literature. J Pediatr Hematol Oncol. 2021;43(3):e445-e447. doi:10.1097/MPH.0000000000001805
8.Mulliez SMN, De Keyser F, Verbist C, et al. Lupus anticoagulant-hypoprothrombinemia syndrome: report of two cases and review of the literature. Lupus. 2015;24(7):736-745. doi:10.1177/0961203314558859
9.Bajaj SP, Rapaport SI, Fierer DS, Herbst KD, Schwartz DB. A mechanism for the hypoprothrombinemia of the acquired hypoprothrombinemia-lupus anticoagulant syndrome. Blood. 1983;61(4):684-692.
10.Cao X-Y, Li M-T, Zhang X, et al. Characteristics of Acquired Inhibitors to Factor VIII and Von Willebrand Factor Secondary to Systemic Lupus Erythematosus: Experiences From a Chinese Tertiary Medical Center. J Clin Rheumatol Pract reports Rheum Musculoskelet Dis. 2021;27(5):201-205. doi:10.1097/RHU.0000000000001284
11.Gupta D, Chatterjee T, Sharma A, Ganguli P, Das S, Sharma S. Rare case of acquired haemophilia and lupus anticoagulant. Indian J Hematol blood Transfus an Off J Indian Soc Hematol Blood Transfus. 2014;30(3):197-200. doi:10.1007/s12288-012-0204-5
12.da Silva VA, Silva SS, Martins FFM. Acquired deficiency of coagulation factor VII. Rev Bras Hematol Hemoter. 2015;37(4):269-271. doi:10.1016/j.bjhh.2015.05.002
13.Ogata Y, Fujieda Y, Sugawara M, et al. Morbidity and mortality in antiphospholipid syndrome based on cluster analysis: A 10-year longitudinal cohort study. Rheumatol (United Kingdom). 2021;60(3):1331-1337. doi:10.1093/rheumatology/keaa542
14.Sacks D, Baxter B, Campbell BC V, et al. Multisociety Consensus Quality Improvement Revised Consensus Statement for Endovascular Therapy of Acute Ischemic Stroke. Int J stroke Off J Int Stroke Soc. 2018;13(6):612-632. doi:10.1177/1747493018778713
15.Skoczynska M, Crowther MA, Chowaniec M, Ponikowska M, Chaturvedi S, Legault K. Thrombotic microangiopathy in the course of catastrophic antiphospholipid syndrome successfully treated with eculizumab: case report and systematic review of the literature. Lupus. 2020;29(6):631-639. doi:10.1177/0961203320917460
16.Soe MH, Agarwal KA, Akough-Weir A. The Wolf Hidden behind the Clots: Catastrophic Antiphospholipid Antibody Syndrome. Case Rep Med. 2018;2018:4693037. doi:10.1155/2018/4693037
17.Adeboyeje G, Sylwestrzak G, Barron JJ, et al. Major Bleeding Risk During Anticoagulation with Warfarin, Dabigatran, Apixaban, or Rivaroxaban in Patients with Nonvalvular Atrial Fibrillation. J Manag care Spec Pharm. 2017;23(9):968-978. doi:10.18553/jmcp.2017.23.9.968
18.García Rodríguez LA, Martín-Pérez M, Hennekens CH, Rothwell PM, Lanas A. Bleeding Risk with Long-Term Low-Dose Aspirin: A Systematic Review of Observational Studies. PLoS One. 2016;11(8):e0160046. doi:10.1371/journal.pone.0160046
19.Bala MM, Celinska-Lowenhoff M, Szot W, et al. Antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with antiphospholipid syndrome. Cochrane database Syst Rev. 2020;10(10):CD012169. doi:10.1002/14651858.CD012169.pub3
20.Ruiz-Irastorza G, Khamashta MA, Hunt BJ, Escudero A, Cuadrado MJ, Hughes GR V. Bleeding and recurrent thrombosis in definite antiphospholipid syndrome: analysis of a series of 66 patients treated with oral anticoagulation to a target international normalized ratio of 3.5. Arch Intern Med. 2002;162(10):1164-1169. doi:10.1001/archinte.162.10.1164
21.Cervera R, Serrano R, Pons-Estel GJ, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. 2015;74(6):1011-1018. doi:10.1136/annrheumdis-2013-204838