A 75-year-old with abdominal pain, hypoxia, and weak pulses in the left leg

Cleveland Clinic Journal of Medicine. 2018 February;85(2):145-154 | 10.3949/ccjm.85a.16069
February 1, 2018|Cleveland Clinic Journal of Medicine
Maya Serhal, MD;Natalie Evans, MD, RPVI;Heather L. Gornik, MD, RVT, RPVI
Author and Disclosure Information

Maya Serhal, MD
Vascular Medicine Section, Department of Cardiovascular Medicine, Cleveland Clinic

Natalie Evans, MD, RPVI
Vascular Medicine Section, Department of Cardiovascular Medicine, Cleveland Clinic; Clinical Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Heather L. Gornik, MD, RVT, RPVI
Medical Director, Non-Invasive Vascular Laboratory, Vascular Medicine Section, Department of Cardiovascular Medicine, Cleveland Clinic; Associate Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Maya Serhal, MD, Department of Vascular Medicine, J3-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195; Serhalm@ccf.org

Dr. Gornik has disclosed she was a site principal investigator in the Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial, funded by AstraZeneca.

WHAT CAN CAUSE BOTH ARTERIAL AND VENOUS THROMBOSIS?

5. Given that the patient had both arterial thrombosis (renal artery, lower-extremity arteries) and venous thromboembolism (deep vein thrombosis and pulmonary embolism), which of the following would be included in the differential diagnosis?

  • Antiphospholipid antibody syndrome
  • Protein C or protein S deficiency
  • Malignancy
  • Paradoxical embolization
  • Factor V Leiden mutation

Correct answers include antiphospholipid antibody syndrome, malignancy, and paradoxical embolization.

The differential diagnosis for concomitant venous and arterial thrombosis is broad,12 and includes the following:

  • Structural factors: patent foramen ovale, popliteal artery aneurysm
  • Malignancy
  • Inflammatory diseases: Behçet disease, Buerger disease, inflammatory bowel disease, antiphospholipid antibody syndrome, elevated lipoprotein(a), elevated homocysteine
  • Hematologic diseases: myelodysplastic syndrome, disseminated intravascular coagulation, paroxysmal nocturnal hemoglobinuria, heparin-induced thrombocytopenia.

Traditional risk factors for venous thromboembolism include protein C deficiency, protein S deficiency, factor V Leiden mutation, the prothrombin G20210A gene mutation, and others. These are relatively minor risk factors for venous thrombosis and do not pose a risk for arterial thrombosis.12 In contrast, antiphospholipid antibody syndrome and malignancy pose a risk for both venous and arterial thrombosis. Paradoxical embolism is a mechanism by which arterial thrombosis (emboli) can develop in the setting of existing venous thrombosis.12

Our patient underwent testing for antiphospholipid antibodies and lupus anticoagulant, and he was encouraged to undergo age-appropriate cancer screening as an outpatient.12

ANTIPHOSPHOLIPID ANTIBODY SYNDROME

Antiphospholipid antibody syndrome is defined by both clinical and laboratory criteria. Clinical symptoms include vascular thrombosis (arterial, venous, or both) and pregnancy-related complications.13

Laboratory criteria require the presence of antiphospholipid antibodies or lupus anticoagulant. These must be confirmed with repeat testing in 12 weeks. Antiphospholipid antibodies are detected by an enzyme-linked immunosorbent assay; laboratory assessment for the presence of lupus anticoagulant is a stepwise process and relies on 4 criteria:

  • There should be prolongation of a phospholipid-dependent clotting test (eg, activated partial thromboplastin time, dilute Russell viper venom time test).
  • There must be evidence of an inhibitory activity with mixing study.
  • The inhibitor must exhibit phospholipid dependence; that is, with more phospholipid there is shortening of clotting time.
  • Specific inhibitors must be excluded, including factor VIII and anticoagulant drugs such as heparin.14–17

Antiphospholipid antibody tests and terminology.
From Houghton DE, Moll S. Antiphospholipid antibodies. Vasc Med 2017; 22:545–550.
Figure 5. Antiphospholipid antibody tests and terminology.
Diagnostic criteria for antiphospholipid antibody syndrome were updated in 2006. In the past, repeat testing at 6 weeks was sufficient, but this period has been lengthened to 12 weeks.15 Antiphospholipid antibodies include lupus anticoagulant, anticardiolipin antibody immunoglobulin G (IgG), anticardiolipin antibody IgM, anti-beta-2-glycoprotein I IgG, and anti-beta-2-glycoprotein I IgM, as well as other less common antibodies (Figure 5).15,18

Clinically, one should consider antiphospholipid antibody syndrome in patients who have arterial thrombosis, a history of pregnancy morbidity, or unexplained prolongation of activated partial thromboplastin time.13

Antiphospholipid antibodies may be present in up to a quarter of patients with venous thromboembolism, but it is persistent positivity of antibody assays that is associated with increased future risk of venous thromboembolism.19 Of note, the risk of venous thromboembolism in patients with confirmed antiphospholipid antibody syndrome is 10 times higher than in the general population.20

ANTIPHOSPHOLIPID ANTIBODIES ARE NOT ALL THE SAME

6. Which of the following antiphospholipid antibodies have not been associated with an increased thrombotic risk?

  • Anti-beta-2-glycoprotein I IgG
  • Lupus anticoagulant
  • Antiphosphatidylserine
  • Anticardiolipin IgM
  • Anticardiolipin IgG

The correct answer is antiphosphatidylserine.15

Antiphospholipid antibodies are directed against a portion of select plasma proteins that are uncovered upon phospholipid binding. While lupus anticoagulant, anti-beta-2-glycoprotein I, and anticardiolipin antibodies are associated with thrombosis, antiprothrombin antibodies (including antiprothrombin and antiphosphatidylserine antibodies) are not.15,21