You Make the Call: How would you treat these patients with acute stroke who are positive for lupus anticoagulant or aCL antibodies?

This month Keith R. McCrae, MD, discusses anticoagulation for patients with antiphospholipid antibodies and a history of stroke.

And don’t forget to check out next month’s clinical dilemma – send in your responses for a chance to win an ASH Clinical News-themed prize!

I saw two patients in consultation from the neurology service; both had recently experienced a stroke and were positive for either lupus anticoagulant or anticardiolipin (aCL) antibodies. The tests were done at the time of the stroke in the first case and 2 days after the stroke in the other case. The neurologists would like to know if the patients should be anticoagulated. I am hesitant to take action as there is a lack of evidence that these were true positive tests and neither patient meets diagnostic criteria for antiphospholipid syndrome (APS). Can we start anticoagulation therapy in these patients? Also, can tissue plasminogen activator (t-PA) affect the results of antiphospholipid antibody tests?

Antiphospholipid antibodies (APLA) are strongly associated with stroke. In a 1,000-patient prospective series of patients with APLA, 19.8% and 11.1% of patients had a history of stroke or transient ischemic attack, respectively; the series also reported a 38.9% and 14.1% incidence of deep venous thrombosis (DVT) and pulmonary embolism.¹ Over a 10-year follow-period, 5.3% of patients experienced stroke compared with 4.3% who experienced DVT; the majority of these events occurred despite anticoagulation. The RATIO (Risk of Arterial Thrombosis In relation to Oral contraceptives) study also confirmed a strong association of APLA with stroke in young women.²

In terms of management of APLA, we suffer from a dearth of rigorous, controlled data, with a lack of standardized testing approaches and consistent laboratory inclusion criteria characterizing most reports. Moreover, the strongest association of APLA with stroke is in younger patients, generally less than 50 years of age, and the significance of APLA likely differs among younger versus older populations.

A 2003 study that used data from the National Institute of Neurological Disorders and Stroke (NINDS) tissue plasminogen activator (t-PA) trial, which evaluated the association of APLA with stroke outcomes and response to t-PA therapy but did not measure lupus anticoagulants, found no association of APLA with stroke outcomes or t-PA response.³ However, a more contemporary observational study that enrolled patients less than 55 years of age with acute stroke found an association of IgM anticardiolipin antibodies (aCL) with the NIH stroke scale (NIHSS) within 48 hours and a tendency toward a positive correlation of positive IgG anti-β2GPI levels within 48 hours with the 3-month Modified Rankin Scale score, a measure of stroke disability.⁴

Another retrospective study that pulled data from the Nationwide Inpatient Sample database from 2010-2012 found that patients with APS and stroke had longer and more expensive hospital stays as well as higher mortality. Patients with APS also had a higher risk of hemorrhagic transformation, but this was independent of recombinant t-PA (rt-PA).⁵ These results and other small series suggest that stroke severity and outcomes in younger patients with APLA may be worse that in those without APLA. Based on this, and the fact that multiple small reports of successful t-PA therapy in patients with APS and stroke, I would recommend t-PA be considered in the acute management plan for appropriate candidates in whom the stroke is thought be thrombotic in nature.

Whether, and how, to use anticoagulation in patients with APS and stroke remains another area of uncertainty. The study by Mehta et al., cited above, found no association of antithrombotic therapy with an increased risk of hemorrhagic transformation;⁵ thus, anticoagulation can presumably be used in appropriate patients with a risk similar to that in patients without APS.

In terms of management of APLA, we suffer from a dearth of rigorous, controlled data, with a lack of standardized testing approaches and consistent laboratory inclusion criteria characterizing most reports.

However, as hematologists, we are most often asked to comment on the value of long-term anticoagulation of patients with APS after stroke. The largest study addressing this is the Antiphospholipid Antibodies and Stroke Study (APASS), which was a prospective cohort within the Warfarin-Aspirin Recurrent Stroke Study (WARSS).⁶ The APASS study found no difference in the composite endpoint of death due to any cause, ischemic stroke, myocardial infarction, DVT, pulmonary embolism, or other thrombo-occlusive events in patients treated with warfarin or aspirin after an initial stroke; likewise, there was no difference in outcome between patients who were APLA positive or negative.

Despite concerns surrounding low cutoffs for aCL positivity, the APASS study informs current American Heart Association (AHA) guidelines that recommend aspirin therapy in patients with stroke and APLA levels that do not meet Sydney classification criteria for defining APLA syndrome.⁷ The AHA guidelines state that in patients with stroke who meet Sydney criteria but in whom anticoagulation has not begun, aspirin therapy is indicated. They also state that anticoagulation might be “considered” in patients with stroke and APS.⁸ However, with respect to the use of both warfarin and aspirin in patients with APS and stroke, it is worth mentioning a single small, randomized study of 20 patients that showed a significantly lower incidence of recurrent stroke in patients treated with both aspirin and anticoagulation, targeted to an International Normalized Ratio (INR) of 2.0-3.0.⁹

One advantage of anticoagulation therapy in APS, even in those who present with stroke, is that warfarin is likely to provide better systemic protection against other systemic thrombi, specifically DVT or pulmonary embolism. If warfarin is used, there are no evidence-based data that establish that INR targets higher than 3.0 are superior to 2.0-3.010; however, some experts advocate for more aggressive anticoagulation in high-risk patients.¹¹

I would not recommend treatment of these patients with direct oral anticoagulants (DOACs) based on emerging evidence that DOAC therapy is not effective in APS, particularly in preventing recurrent arterial thrombosis in patients who are triple positive for lupus anticoagulants and aCL and anti-β2GPI antibodies.^12,13

Every patient with APS needs to be considered individually. My approach to a patient with a single positive APLA test might be less aggressive (e.g., aspirin alone) than to a patient who is young and triple-positive, in whom I might consider both warfarin and antiplatelet therapy, accepting the increased bleeding risk with the latter approach. For more severe patients, additional therapies such as hydroxychloroquine might also be considered.¹⁴ Of course, with a new diagnosis of antiphospholipid antibodies, confirmatory testing at a date at least 12 weeks after diagnosis is always indicated.

To my knowledge, the effect of t-PA on antiphospholipid antibody tests has not been directly studied, but it is unlikely that in the absence of a significant systemic fibrinolysis effect there would be any impact.

References

1. 1. Joly B, Stepanian A, Hajage D, et al. Evaluation of a chromogenic commercial assay using VWF-73 peptide for ADAMTS13 activity measurement. Thromb Res. 2014;134:1074-1080.
   2. Urbanus RT, Siegerink B, Roest M, et al. Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study. Lancet Neurol. 2009;8:998-1005.
   3. Tanne D, Levine SR, Brey RL, Lin H, Tilley BC. Antiphospholipid-protein antibodies and acute ischemic stroke in the NINDS rt-PA Stroke Trial. Neurology. 2003;61:1158-1159.
   4. Rodríguez-Sanz A, Martínez-Sánchez P, Prefasi D, et al. Antiphospholipid antibodies correlate with stroke severity and outcome in patients with antiphospholipid syndrome. Autoimmunity. 2015;48:275-281.
   5. Mehta T, Hussain M, Sheth K, Ding Y, McCullough, LD. Risk of hemorrhagic transformation after ischemic stroke in patients with antiphospholipid antibody syndrome. Neurol Res. 2017;39:477-483.
   6. Levine SR, Brey RL, Tilley BC, et al. Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. JAMA. 2004;291:576-584.
   7. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295-306.
   8. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:2160-2236.
   9. Okuma H, Kitagawa Y, Yasuda T, Tokuoka K, Takagi S. Comparison between single antiplatelet therapy and combination of antiplatelet and anticoagulation therapy for secondary prevention in ischemic stroke patients with antiphospholipid syndrome. Int J Med Sci. 2009;7:15-18.
   10. Crowther MA, Ginsberg JS, Julian J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003;349:1133-1138.
   11. Garcia D, Erkan D. Diagnosis and management of the antiphospholipid syndrome. N Engl J Med. 2018;378:2010-2021.
   12. Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018;132:1365-1371.

1. Ordi-Ros J, Sáez-Comet L, Pérez-Conesa M, et al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: a randomized noninferiority trial. Ann Intern Med. 2019;171:685–694.
2. Limper M, Scirè CA, Talarico R, et al. Antiphospholipid syndrome: state of the art on clinical practice guidelines. RMD Open. 2018;4:e000785.

How did readers respond? Check out You Make the Call – Readers’ Response.

I am caring for a 67-year-old man with stage 4B diffuse large B-cell lymphoma (DLBCL) transformed from follicular lymphoma. He presented with breathlessness and weight loss for 1 month. His malignant cells in the bone marrow were BCL2 positive on a fluorescence in situ hybridization (FISH) test, but negative for c-Myc and BCL6. A PET/CT scan showed diffuse marrow uptake in the axial and appendicular skeleton, increased uptake in his liver and spleen, and extensive hypermetabolic lymph nodes in his abdomen above and below the diaphragm. His lactic acid dehydrogenase (LDH) level at the time of diagnosis was above 700 U/L and his beta-2 microglobulin level is 3.5 times the upper limit of normal. His creatinine level was normal, alkaline phosphatase (ALP) level was 1,268 U/L, and his alanine transaminase (ALT) and aspartate aminotransferase (AST) levels were about 175 U/L. He had severe lactic acidosis and his uric acid level was 2 times the upper limit of normal.

After 3 cycles of RCHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone), a PET/CT scan shows resolution of all uptake with a score of 1 on the Deauville scale. His LDH remains normal but his beta-2 microglobulin level is still slightly elevated. The patient is clinically well and fit. He received 2 cycles of intrathecal chemotherapy, and there is no evidence of CNS involvement by the lymphoma. He was recently given high-dose methotrexate and cycle 4 of RCHOP therapy. We are planning to administer 6 cycles of RCHOP, of which 2 cycles will be with methotrexate. I would appreciate advice on management going forward. Is rituximab maintenance preferable? Is there any role for autologous transplant?

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