Summary
- Antiphospholipid syndrome is characterized by recurrent thrombosis (arterial, venous, microvascular) and/or pregnancy complications in the presence of persistent antiphospholipid antibodies (lupus anticoagulant, anti-β2-glycoprotein 1, and anticardiolipin).
- It may be a primary disease or be associated with another autoimmune disease (especially systemic lupus erythematosus).
- Antiphospholipid antibody testing should be considered in patients < 50 years of age with unprovoked venous or arterial thromboembolism, thrombosis at unusual sites, or pregnancy complications.
- The mainstay of treatment is antithrombotic therapy and recommendations vary depending on arterial, venous, or pregnancy complications.
- If associated with systemic lupus erythematosus, hydroxychloroquine is recommended as primary and secondary prophylaxis.
- Antithrombotic treatment is the gold standard and effective.
Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by vascular thrombosis or pregnancy complications associated with persistent antiphospholipid antibodies. In general, its prevalence in the population is estimated to be 40-50/100,000.
Although the association with individual antiphospholipid antibodies is controversial, these antibodies are believed to be related to 10-15% of recurrent pregnancy losses.
APS is frequently associated with systemic lupus erythematosus (SLE) and other autoimmune diseases but, in many cases, occurs in the absence of other autoimmune diseases (primary APS). In autoimmune disease, particularly SLE, the prevalence reaches 30%.
The prothrombotic state of this syndrome is largely due to the 3 characteristic anticoagulant antibodies: lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein 1. The risk of thrombosis increases with:
• Lupus anticoagulant or the action of anti β2-glycoprotein 1 alone (greater risk of thrombosis than with the presence of anticardiolipin alone).
• High antibody titers (particularly IgG).
• Multiple antibody positivity (associated with the highest risk of thrombosis).
• Additional risk factors for thrombosis at the time of diagnosis (eg, thrombosis in hypertension, smoking, and diabetes mellitus, and venous thrombosis due to hyperlipidemia).
The most commonly observed hematologic abnormalities in APS are prolonged activated partial thromboplastin time (which is not corrected by mixing with normal plasma due to the presence of a lupus anticoagulant) and mild to moderate thrombocytopenia.
Less common hematologic abnormalities are hemolytic anemia and thrombotic microangiopathies (eg, thrombotic thrombocytopenic purpura).
Other features of APS include cognitive dysfunction (even in the absence of stroke), kidney disease, heart valve disease, and skin manifestations such as severe ulcers and necrosis. Rarely, patients with APS can simultaneously present with thrombosis in multiple organs, called catastrophic APS, which is fatal in up to 50% of patients if not treated in time.
| Diagnosis |
There are no diagnostic criteria for APS, so caution is required when extrapolating the classification criteria developed for research to clinical practice, as they have not been validated for clinical use. The less common manifestations of the disease also do not meet the research criteria.
The diagnosis of APS is suspected in patients with recurrent or unexplained thrombotic events or pregnancy complications, particularly in young patients or with an autoimmune disease (e.g., SLE).
Other clinical features may support the diagnosis, such as the existence of L ivedo reticularis or an otherwise unexplained prolonged activated partial thromboplastin time). However, other causes of thrombosis should also be considered, such as malignancy, thrombocytopenia (including that caused by heparin, and thrombophilias).
The diagnosis of APS is established by the presence of any of the aforementioned antiphospholipid antibodies and the appropriate clinical presentation.
Antibodies must be present in the repeated test with an interval of no less than 12 weeks since, in other conditions, they may appear transiently (e.g., infections). Testing for other antiphospholipid antibodies directed against other antigens (e.g., antiphosphatidylserine/prothrombin antibodies) remains controversial and is not recommended for routine use.
False positive results may occur. Antiphospholipid antibodies can be present in up to 12% of the general population while their prevalence increases with age. In the absence of APS, antiphospholipid antibodies may be seen in infections, medication use, and malignancy.
Although antiphospholipid antibodies are thought to be critical for the development of thrombosis in APS, the majority of people considered healthy who have antiphospholipid antibodies do not develop APS, particularly when the antibodies are observed in isolation, or in low titers, or are absent in the repeat test.
| Treatment |
A hematologist must intervene in the treatment of APS. If it is associated with an autoimmune disease (such as SLE), it may also be managed by a rheumatologist. Furthermore, the obstetrician will participate in the management of pregnancy-related complications associated with APS.
The treatment of APS includes primary prophylaxis to avoid the first thrombotic and obstetric events, secondary prophylaxis for venous and arterial thrombotic events, management of recurrent thromboses and obstetric complications.
> Primary prophylaxis
Aspirin remains a controversial treatment to prevent a first thrombotic event in the presence of antiphospholipid antibodies . However, it may be considered in patients who have high-risk antiphospholipid antibodies (i.e., triple or multiple positivity, lupus anticoagulant, medium- to high-titer persistent antibodies), and if they have other thrombotic risk factors (e.g., hypertension , smoking, diabetes, hyperlipidemia, recent surgery).
For patients with APS associated with SLE, hydroxychloroquine is recommended, as it has been shown to be beneficial as primary prophylaxis, inducing the reduction of thromboembolic episodes. However, the use of hydroxychloroquine in primary APS is not currently recommended.
> Prevention of venous thrombosis
In patients with APS who developed unprovoked venous thrombosis, anticoagulation with unfractionated heparin or low molecular weight heparin followed by a vitamin K antagonist (warfarin) is recommended, with a target INR (International Normalized Ratio) of 2-3. .
In 2 randomized controlled trials, high doses of warfarin (INR 3-4) have not been shown to reduce the risk of recurrence of venous thrombotic events, but were also associated with a higher rate of bleeding.
Anticoagulation should be continued long term, since its discontinuation is accompanied by a high risk of recurrent thrombosis. Long-haul air travel may require additional measures to prevent venous thromboembolism (e.g., compression stockings).
> Prevention of arterial thrombosis.
There is no consensus due to the lack of high-quality evidence for the optimal management of APS with arterial thrombosis. Because of higher rates of recurrent arterial thrombosis in APS, experts recommend anticoagulation with warfarin, with a target INR of >3.0, or a combination of aspirin and warfarin, with a target INR of 2–3.
Although cohort studies suggest a rate of recurrent thrombosis with an INR >3 achieved with warfarin, two randomized controlled studies showed no difference in the recurrence rate with warfarin at higher INR values.
Two other studies, one prospective and one retrospective, showed a lower rate of recurrent arterial thrombosis with aspirin and warfarin combined. Other studies found that monotherapy with warfarin or aspirin was equally effective in preventing ischemic stroke in patients with a history of stroke and only 1 antiphospholipid antibody. Therefore, some experts have suggested that patients can be treated with aspirin alone, as long as there are no other indications for anticoagulation.
> Recurrent thrombosis in the anticoagulated patient
A recurrent thrombotic episode despite therapeutic anticoagulation is a well-recognized but relatively uncommon scenario.
There is no high-quality evidence to support a therapeutic strategy. Potential options include intensifying warfarin treatment to achieve a target INR of 3-4, adding aspirin (although this is associated with an increased risk of bleeding), adding hydroxychloroquine, or a statin, using a different anticoagulant such as low-weight heparin. molecular or their combination. Statins have pleiotropic immunomodulatory, anti-inflammatory and antithrombotic properties, but clinical trials are lacking.
> Obstetric antiphospholipid syndrome
When pregnancy presents obstetric and thrombotic complications, the currently recommended treatment is low-dose aspirin and low-molecular-weight heparin in therapeutic doses. However, up to 20% of pregnancies are unsuccessful despite treatment. Risk factors for an unsuccessful pregnancy are: triple positivity of antiphospholipid antibodies, associated autoimmune disease and thrombotic manifestations.
Obstetric APS is treated with hydroxychloroquine, low doses of prednisolone up to 14 weeks of gestation, immunoglobulin, plasma exchange and immunoadsorption. Asymptomatic antiphospholipid antibody carriers are candidates for postpartum thromboprophylaxis, given the increased risk of thrombosis in this period. Low-dose aspirin has been used as primary prophylaxis in patients with antiphospholipid antibodies, but there are no clear data on this.
> Catastrophic antiphospholipid syndrome
Catastrophic APS is characterized by multiple thrombi with a systemic inflammatory response and high mortality rate. Due to the rarity of this condition and the high mortality rate, there are no controlled trials evaluating optimal treatment.
A retrospective review of the International Registry of Patients with Catastrophic APS found that anticoagulation, high doses of steroids, plasmapheresis and/or immunoglobulins (triple therapy) had the highest survival rate and therefore, this is the recommended treatment for the catastrophic SAF, although with little certainty,
| Novel therapies |
> Direct oral anticoagulants
There is insufficient evidence to make recommendations on the use of direct oral anticoagulants in APS.
Two randomized controlled trials evaluated its use in APS. One of them compared rivaroxaban with warfarin, using the mean percent change in thrombin generation, a marker of hypercoagulability, as the primary outcome measure, and found that rivaroxaban is inferior to warfarin in inhibiting thrombin generation.
Examination of venous thromboembolism rates as a secondary outcome measure showed no difference between the 2 interventions, nor any difference in adverse events.
The other trial, which examined thrombosis as a primary outcome in a high-risk population (triple positivity of antiphospholipid antibodies), was stopped early due to a higher rate of arterial thrombotic events in the rivaroxaban group. There are ongoing trials evaluating other direct oral anticoagulants, such as apixaban.
| Immunomodulatory therapy |
Research on immunomodulatory therapies is increasing due to the immune-based mechanisms involved in APS. Results from trials in mice suggest that B cell inhibition is involved.
An open-label phase 2 pilot case series of 19 participants receiving rituximab suggested that the drug may be the treatment of nonthrombotic manifestations (e.g., skin ulcers, cognitive dysfunction).
Another case series review of 24 patients receiving rituximab also noted variable improvements in skin ulcers, thrombocytopenia, cardiac valvular dysfunction, and cognitive dysfunction, as well as in 2 patients with thrombosis. The main adverse events included infectious complications. Complement activation has also been shown to initiate and amplify SAF.
There are case reports describing the use of eculizumab, a C5-monoclonal antibody, for the treatment of APS. It was successfully used as a treatment of thrombotic microangiopathy after renal transplantation in patients with a history of SLE and renal thrombotic microangiopathy, and as prophylaxis of recurrent thrombotic microangiopathy after transplantation. The main risk is infection with encapsulated organisms and therefore patients must be immunized against Neisseria meningitidis .
| Clinical vignette and advice for doctors |
Clinical vignette • A 62-year-old man with antiphospholipid syndrome with previous deep vein thrombosis and pulmonary embolism complicated by chronic thromboembolism. Due to pulmonary hypertension he was transferred to a tertiary center for a pulmonary endarterectomy. He was positive only for lupus anticoagulant. The patient was receiving long-term warfarin with a target INR of 2-3. • He underwent a successful pulmonary endarterectomy, but recurred a few weeks after discharge with ulceration and necrosis of the abdominal skin; The skin biopsy showed necrosis of the epidermal and dermal connective tissues with microthrombosis in small and medium-sized vessels with panniculitis in the surrounding dermis. If this was due to warfarin-induced skin necrosis, he was transitioned to danaparoid but the skin necrosis and thrombocytopenia (platelet nadir of 18 × 109 /L) progressively worsened. The presumptive diagnosis was relapse of antiphospholipid syndrome, precipitated by surgery, with manifestations that did not meet the criteria, such as skin necrosis and thrombocytopenia. He was treated with an immunosuppression regimen with pulsed methylprednisolone, 1 g/day, for 3 days; intravenous immunoglobulin; 3 doses of rituximab 500 mg/week, as well as hyperbaric oxygen therapy. After treatment, his platelet count improved to 50 × 109/l and his abdominal lesions also improved. He was safely discharged home after a 4-week hospital stay. |
| Explain antiphospholipid syndrome to patients |
• Antiphospholipid syndrome is a condition caused by the immune system that can lead to bleeding disorders and pregnancy complications. • Clots can occur anywhere in the body, but particularly in the heart, brain, legs, and lungs. • Pregnancy problems include recurrent miscarriages and premature births. • It is most commonly managed by a hematologist along with an obstetrician (if associated with pregnancy) and a rheumatologist (if associated with another immune system disease). • The condition can be easily treated with blood-thinning medications that are usually given long-term. |
