A 57-year-old woman presents for follow-up several months after a series of thrombotic episodes. Four days after she underwent ankle fusion to relieve pain and edema associated with a leg fracture that had occurred 40 years earlier, she sustained a massive myocardial infarction (MI).
A 57-year-old woman presents for follow-up several months after a series of thrombotic episodes. Four days after she underwent ankle fusion to relieve pain and edema associated with a leg fracture that had occurred 40 years earlier, she sustained a massive myocardial infarction (MI). She required support with a left ventricular assist device and will eventually need cardiac transplantation. Later in the perioperative period, she sustained 2 strokes and was found to have bilateral below-the-knee deep venous thromboses (DVTs).
Six months after the MI, while she was receiving prophylactic anticoagulation, a proximal DVT developed and a splenic infarct occurred, necessitating a splenectomy. Since then, she has been receiving low molecular weight heparin (LMWH).
The patient has never smoked or abused alcohol or drugs. Her father died of an MI in his 60s. She has no other family history of cardiovascular or hematological disease. She has 3 healthy children and had 1 spontaneous abortion. She is a disabled bookkeeper.
Vital signs are normal. Results of cardiac and pulmonary examinations are normal, and no lymphadenopathy is noted. On her abdomen, well-healed surgical scars and ecchymotic areas secondary to LMWH injections are evident. Her calves are large in diameter and her ankles show hemosiderin deposition, but there is no pitting edema. She has a normal gait but a mild expressive aphasia.
A hemogram and biochemistry profile are normal. Her international normalized ratio (INR) is 2.6. Partial thromboplastin time is 67 seconds (normal, 25 to 35 seconds).
Which of the following is the most likely diagnosis in this patient?
A. Factor V Leiden mutation.
B. Prothrombin gene mutation.
C. Lupus anticoagulant and anticardiolipin antibody syndrome.
D. Antithrombin III deficiency.
CORRECT ANSWER: C
The pathology that may underlie clotting in the venous or combined venous and arterial vascular beds can be subdivided into defects in coagulation inhibitors, defects in clot lysis, hyperviscosity, and defects in the vascular endothelium. Of venous and arterial clotting, venous thrombosis has by far the larger differential diagnosis. Possible causes of venous thrombosis include anticoagulation factor inhibitor abnormalities, such as resistance to activated protein C (the factor V Leiden mutation [choice A]); the prothrombin gene mutation (choice B); and inhibitor deficiencies-notably deficiencies in proteins C, S, and antithrombin III (choice D). Acquired risk factors for venous thromboembolism include the use of estrogens, stasis, trauma, and immobilization. Sole arterial thromboses tend to result from traditional cardiac risk factors, such as hypertension, diabetes, cigarette smoking, and hyperlipemic states.
Clinical entities that can produce both arterial and venous clotting include anticardiolipin antibodies, lupus anticoagulants, heparin-induced thrombocytopenia/ thrombosis, homocystinemia, and vasculitis. Of these, anticardiolipin antibodies and lupus anticoagulants are the most likely causes of both arterial and venous thrombosis.1
Both anticardiolipin antibodies and lupus anticoagulants are autoantibodies known as antiphospholipid antibodies. Antiphospholipid antibodies can have various antigenic targets. Those whose antigen is the phospholipid-binding protein β2 glycoprotein I have a strong association with thrombotic episodes. The antigens of many others are components of coagulation (eg, prothrombin, activated protein C, and activated protein S), which further explains the in vivo procoagulant properties of these entities.2
Diagnosis of antiphospholipid antibody syndrome. Both sufficient titers of the antibody and specific clinical findings are required to diagnose antiphospholipid antibody syndrome (choice C) (Table). The presence of antiphospholipid antibodies does not necessarily imply causality.3 Many studies have documented antiphospholipid antibodies in persons without thrombosis-both in patients with infectious diseases such as syphilis and AIDS and in healthy controls. Even in patients with systemic lupus erythematosus, the presence of anticardio- lipin antibodies does not universally predict clinical thrombosis. Moreover, profound interlaboratory variability makes it difficult to compare results among multiple trials and makes treatment guideline determinations even more complex.
Extensive variations in the presentation of the antiphospholipid antibody syndrome also make diagnosis challenging. Large-vessel thrombosis, thrombotic microangiopathy, and embolic events have been reported, with effects in nearly every organ system; the latter range from retinitis to aortic thrombosis.1
Therapy. Because anticoagulation is not without risk, the potential benefit must be determined for each patient before such therapy is initiated. The annual risk of thrombosis is low in healthy persons who have antiphospholipid antibodies.3 Low-dose aspirin, which is relatively low risk and has other potential health benefits, is reasonable in these patients.
Patients with antiphospholipid antibodies who experience a first venous event require long-term anticoagulation with warfarin to standard goal INR, following an extended heparin bridge. Stroke and transient ischemic attack are the most common events in patients with antiphospholipid antibodies. In those who have experienced such an ischemic event, treatment with standard-dose warfarin and treatment with aspirin, 325 mg/d, seem equally effective.
In patients who have recurrent thrombosis in either the arterial or vascular bed while they are receiving appropriate anticoagulation, results have been variable and good studies somewhat sparse. Recommendations include LMWH, unfractionated heparin, and the addition of an antiplatelet agent to a warfarin regimen.
For women with recurrent pregnancy losses and antiphospholipid antibodies, recommendations include low-dose aspirin before conception with prophylactic doses of heparin added after conception and continued until just before delivery.
Outcome of this case. The patient had elevated levels of IgG and IgA anticardiolipin antibodies. Results of special coagulation testing for the presence of a lupus anticoagulant were positive. Levels of activated protein C and S were normal. Because of the patient's history of life-threatening arterial and venous clotting, indefinite anticoagulation therapy with warfarin was recommended (with a goal INR of 2 to 3), along with aspirin, 81 mg/d.
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Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).
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