An unusual cause of bruising

Cleveland Clinic Journal of Medicine. 2019 August;86(8):535-542 | 10.3949/ccjm.86a.18119
August 1, 2019|Cleveland Clinic Journal of Medicine
Tahani Atieh, DO;Alan Lichtin, MD
Author and Disclosure Information

Tahani Atieh, DO
Department of Internal Medicine, Cleveland Clinic; Clinical Instructor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Alan Lichtin, MD
Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic; Associate Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Alan Lichtin, MD, Department of Hematology and Medical Oncology, CA-60, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; lichtia@ccf.org

Release date: August 1, 2019
Expiration date: July 31, 2020
Estimated time of completion: 1 hour

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LGL LEUKEMIA AND AUTOIMMUNE DISEASE

Patients with LGL leukemia commonly have or develop autoimmune conditions. Immune-mediated cytopenias including pure red cell aplasia, aplastic anemia, and autoimmune hemolytic anemias can occur. Neutropenia, the most common cytopenia in LGL leukemia, is thought to be at least partly autoimmune, as the degree of neutropenia is often worse than would be expected solely from bone-marrow infiltration of LGL cells.10,14,15

Rheumatoid arthritis is the most common autoimmune condition associated with LGL leukemia, with a reported incidence between 11% and 36%.13–15

Felty syndrome (rheumatoid arthritis, splenomegaly, and neutropenia) is often associated with LGL leukemia and is thought by some to be part of the same disease process.15

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Treat with immunosuppressives if needed

Indications for treating LGL leukemia include the development of cytopenias and associated autoimmune diseases. Immunosuppressive agents, such as methotrexate, cyclophosphamide, and cyclosporine, are commonly used.10,11,14 Most evidence of treatment efficacy is from retrospective studies and case reports, with widely variable response rates that overall are around 50%.10

ACQUIRED HEMOPHILIA A AND HEMATOLOGIC MALIGNANCY

A systematic review found 30 cases of AHA associated with hematologic malignancies.16 The largest case series17 in this analysis had 8 patients, and included diagnoses of chronic lymphocytic leukemia, erythroleukemia, myelofibrosis, multiple myeloma, and myelodysplastic syndrome. In 3 of these patients, the appearance of the inhibitor preceded the diagnosis of the underlying malignancy by an average of 3.5 months. In 1 patient with erythroleukemia and another with multiple myeloma, the activity of the inhibitor could be clearly correlated with the underlying malignancy. In the other 6 patients, no association between the two could be made.

In the same series, complete resolution of the inhibitor was related only to the level of Bethesda titer present at diagnosis, with those who achieved resolution having lower mean Bethesda titers.17 Similarly, in EACH2, lower inhibitor Bethesda titers and higher factor VIII levels at presentation were associated with faster inhibitor eradication and normalization of factor VIII levels.7

Murphy et al18 described a 62-year-old woman with Felty syndrome who developed a factor VIII inhibitor and was subsequently given a diagnosis of LGL leukemia. Treatment with immunosuppressive agents, including cyclophosphamide, azathioprine, and rituximab, successfully eradicated her factor VIII inhibitor, although the LGL leukemia persisted.

Case conclusion: Eradication of factor VIII inhibitor

Our patient, similar to the patient described by Murphy et al18 above, had eradication of the factor VIII inhibitor despite persistence of LGL leukemia. Between the time of diagnosis at our clinic, when she had 54% LGLs, and eradication of the inhibitor 3 months later, the LGL percentage ranged from 45% to 89%. No clear direct correlation between LGL and factor VIII inhibitor levels could be detected.

Given the strong association of LGL leukemia with autoimmune disease, it is tempting to believe that her factor VIII inhibitor was somehow related to her malignancy, although the exact mechanism remained unclear. The average age at diagnosis is 60 for LGL leukemia11 and over 70 for AHA,5,6 so advanced age may be the common denominator. Whether or not our patient will have recurrence of her factor VIII inhibitor or the development of other autoimmune diseases with the persistence of her LGL leukemia remains to be seen.

At last follow-up, our patient was off all therapy and continued to have normal aPTT and factor VIII levels. Repeat flow cytometry after treatment of her factor VIII inhibitor showed persistence of a clonal T-cell population, although reduced from 72% to 60%. It may be that the 2 entities were unrelated, and the clonal T-cell population was simply fluctuating over time. This can be determined only with further observation. As the patient had no symptoms from her LGL leukemia, she continued to be observed without treatment.

TAKE-HOME POINTS

  • The coagulation assay is key to initially assessing a bleeding abnormality; whether the prothrombin time and aPTT are normal or prolonged narrows the differential diagnosis and determines next steps in evaluation.
  • Mixing studies can help pinpoint the responsible deficient factor.
  • Acquired factor VIII deficiency, also known as AHA, may be caused by autoimmune disease, malignancy, or medications, but it is usually idiopathic.
  • AHA treatment is focused on achieving hemostasis and reducing factor VIII inhibitor.
  • Lymphocytosis should be evaluated with a peripheral blood smear and flow cytometry to determine if the population is polyclonal (associated with infection) or clonal (associated with malignancy).
  • LGL leukemia is usually a chronic, indolent disease, although an uncommon subtype has an aggressive course.
  • The association between AHA and LGL leukemia is unclear, and both conditions must be monitored and managed.