A Young Woman With an Unprovoked Deep Vein Thrombosis

AUTHOR:
Ronald N. Rubin, MD^1,2—Series Editor

AFFILIATIONS:
¹Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
²Department of Medicine, Temple University Hospital, Philadelphia, Pennsylvania

CITATION:
Rubin RN. A young woman with an unprovoked deep vein thrombosis. Consultant. 2020;60(9):17-19. doi:10.25270/con.2020.09.00002

DISCLOSURES:
The author reports no relevant financial relationships.

CORRESPONDENCE:
Ronald N. Rubin, MD, Temple University Hospital, 3401 N Broad St, Philadelphia, PA 19140 (blooddocrnr@yahoo.com)

A 31-year-old woman is seen in the office several weeks after having sustained a Doppler ultrasonography–confirmed deep vein thrombosis (DVT) of her left popliteal vein with some extension proximally. She had been treated with apixaban and currently is on maintenance anticoagulation with that agent. Otherwise, her health is excellent, without chronic conditions or major medical diagnoses.

There had been no obvious provoking factor for this DVT. She simply had noticed pain in her leg behind her knee and a degree of unilateral edema on the affected side. She works as an executive in an office and spends much of her time at a desk but is also on her feet many times during the course of the day. And she works out at least 3 times per week at the local fitness gym. She takes no medications other than occasional nonsteroidal anti-inflammatory drugs. She is married and uses a hormonal intrauterine device for contraception and has done so for more than a decade, except when she wished to become pregnant. She has a 2-year-old son and reports a history of a miscarriage 3 years ago, “almost exactly at 12 weeks,” since she considered that the time after which a pregnancy was “safe and confirmed” and likely to proceed.

Her physical examination findings are totally within normal limits, save for residual 1+ edema in the left ankle, which she says is improving daily.

Review of her laboratory test results obtained several weeks ago at her initial DVT presentation revealed a totally normal complete blood cell count and metabolic and biochemical panels, with a creatinine level of 0.9 mg/dL. Coagulation study findings prior to therapy showed an international normalized ratio (INR) of 1.0 and a partial thromboplastin time (PTT) of 36 s (reference range, 22-36 s). Just prior to this office visit, her INR was again 1.0 and her PTT was 38 s. Her creatinine level remains normal. She is here for evaluation of possible antiphospholipid (aPL) syndrome (APS).

Answer: A, when testing for APS, IgG and IgM antibodies are most specific for the diagnosis.

The patient presented is an example of findings encountered in APS. Clinically, this syndrome is a set of findings involving a variety of thrombotic events and/or obstetric complications and morbidity, with both groups also manifesting the presence of certain aPL antibodies demonstrable by blood testing.

The revised Sapporo classification criteria for diagnosis of the syndrome requires the presence of venous and/or arterial thrombotic events and/or occurrence of a variety of adverse pregnancy outcomes in the presence of persistent (at least 6 weeks and usually at least 12 weeks, according to most authorities) evidence of positive aPL antibodies on blood tests. APS can be primary or can be associated with known underlying disease (usually systemic lupus erythematosus, or SLE).^1,2

A more specific delineation of the syndrome’s attributes is as follows: Thrombotic clinical events, most commonly DVTs, can be venous or arterial or both—the latter is an unusual scenario, since most hypercoagulation syndromes affect only the venous system. Stroke and thrombotic microangiopathy are examples of such conditions. Both venous and arterial thrombotic presentations are seen in a younger patient population than is typically seen, which therefore often launches a “hypercoagulable workup” that demonstrates laboratory test abnormalities (discussed below). The obstetric complications include unexplained fetal death beyond 10 weeks of gestation, eclampsia, preeclampsia, births at less than 34 weeks, and more than 3 unexplained miscarriages at less than 10 weeks of gestation.¹ Such patients often find themselves in high-risk obstetric care settings, which then triggers blood testing for APS.

These APS blood tests usually probe for the presence of abnormal antibodies of 3 varieties. One is the so-called lupus anticoagulant antibody (first described in a cohort containing many SLE cases, hence the name). This antibody interferes with in vitro PTT testing, with results showing subsequent prolongation to variable degrees, as seen in our patient. The second is IgG, IgM, and IgA antibodies demonstrable by enzyme-linked immunosorbent assay (ELISA). There is a hierarchy of specificity for the presence of the syndrome, with IgG more specific than IgM for the presence of the syndrome and its severity.^2,3 IgA seems not related to either. Thus, Answer A is a correct statement. Answer B, however, is not correct as stated, since although the lupus anticoagulant test is indeed helpful as one of the required serological findings to confirm the APS diagnosis, in fact, a positive result seems most predictive of the incidence of morbidity and clinical events in patients with APS. The third serologic test is directed at β₂-glycoprotein I antibodies, again either in IgG or IgM variants. Any one of these 3 discussed aPL antibody variants, when persistently present in a patient with either clinical thrombotic or obstetric findings, confirms the presence and diagnosis of APS.¹

The pathophysiology of APS is complex and continues to be slowly elucidated. APS is an autoimmune disease wherein B lymphocytes are producing the autoantibodies whose main target is β₂-microglobulin, a plasma protein that binds to phospholipid surfaces.^2,4 Such surfaces include vascular endothelium and platelet IIb/IIIa receptors, which likely accounts for the thrombotic morbidity, and the decidual cells in the placenta that, along with the observed microthrombi in that organ seen in patients with APS, results in the observed obstetric sequelae and morbidity.^2,4

Once a diagnosis of APS has been confirmed, therapy needs to be directed at prevention and treatment of the morbid clinical events. For venous thrombotic APS, the recurrence rate is high such that ongoing therapy is indicated as long as aPL antibodies are demonstrable. For venous disease, traditional warfarin with an INR target of 2.0 to 3.0 remains the best-tested and preferred treatment.^2,5,6 Despite anecdotal data supporting a higher INR goal (eg, 3.0-4.5), most agree that this strategy offers little if any further thrombosis reduction to balance the documented increased bleeding and difficulty in managing INRs associated with that scheme.⁷ The antiphospholipid effect in APS can interfere with coagulation studies both prothrombin time and PTT, with progressively more interference and monitoring difficulty as the INR increases.⁷ Thus, Answer D is not a correct response here. There may be a role for a more-intense warfarin strategy when the INR 2.0 to 3.0 regimen fails.

The DOACs are significantly replacing warfarin in so many thrombotic situations with at least equivalent efficacy and bleeding profiles and with so much more convenience for both patient and physician. It will be surprising if in time there is not an important role for them in APS thrombosis, as well. But for now, no confirmatory data exist, and the evidence is insufficient in support of their use in APS—an extremely high-risk hypercoagulation syndrome—such that Answer C is not correct, at least not yet.²

Prevention and therapy in obstetric APS is quite specialized and is in the domain of a high-risk obstetrics practice and will be addressed only briefly here. If there is an associated thrombotic part of the syndrome, as in our patient’s case, a thrombotic prevention scheme applies. Of course, heparin or low-molecular-weight heparin (LMWH) will be used instead of warfarin during pregnancy and continuing at least 6 to 12 weeks postpartum, which is perhaps the highest-risk situation in any patient at risk for thrombotic events. An additional treatment often added to the anticoagulant regimen is low-dose aspirin to reduce the incidence of obstetric complications and morbidity.

PATIENT FOLLOW-UP

The coexistence of obstetric findings (fetal loss after the 10th week of gestation) and thrombotic event (essentially unprovoked DVT) in the same patient prompted an evaluation for APS. A complete battery of appropriate testing revealed an APL IgG titer above 40 and IgG, IgM, and anti-β₂-glycoprotein I titers greater than the 99th percentile. Lupus anticoagulant antibodies also were present. Although the tests will be repeated in 12 weeks, the presence of (1) an obstetric morbidity, (2) a vascular thrombosis, and (3) positive ELISA IgG and IgM results for anticardiolipin antibodies,

and anti-β₂-glycoprotein I antibodies, and lupus anticoagulant antibodies, are quite confirmatory for the diagnosis of APS.

She was switched from apixaban to warfarin with an INR goal of 2.0 to 3.0 and has successfully attained this with good INR stability. This will be the mainstay of therapy for now, unless there is recurrence of DVT or until more definitive studies on efficacy and safety of DOACs are available. Of note, all serologic study results for SLE were negative.

TAKE-HOME MESSAGE

APS is an autoimmune disease characterized by thrombotic and/or obstetric events and the presence of persistent aPL antibodies. These antibodies have been shown to activate inflammatory and endothelial cells, activate platelet expression of IIb/IIIa receptors, and interfere with trophoblasts and decidual cells required to sustain pregnancy. The occurrence of a thrombotic event (usually in a younger patient in whom such an event is uncommon) and/or an obstetric event (fetal loss after week 10 or preeclampsia/eclampsia syndromes) are clues to the syndrome, which is confirmed by finding the persistent presence of one or more of the 3 anticardiolipin antibodies—aPL of IgG or IgM by ELISA, anti-β₂-microglobulin by ELISA, or a lupus anticoagulant, the latter of which may be the most clinically predictive of all. A variety of maneuvers for secondary prevention of vascular thrombosis exist in the literature, with warfarin and an INR goal of 2.0 to 3.0 having the most support. For prevention and therapy of obstetric APS, low-dose aspirin and therapeutic-dose heparin or LMWH during pregnancy are suggested, including prophylactic-dose LMWH for 6 to 12 weeks postpartum.

REFERENCES:

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6. Garcia D, Akl EA, Carr R, Kearon C. Antiphospholipid antibodies and the risk of recurrence after a first episode of venous thromboembolism: a systematic review. Blood. 2013;122(5):817-824. doi:10.1182/blood-2013-04-496257
7. Moll S, Ortel TL. Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med. 1997;127(3):177-185. doi:10.7326/0003-4819-127-3-199708010-00001