Thrombotic Microangiopathies & Rheumatology

Updates from the ACR Convergence 2023 Review Course, part 3

SAN DIEGO—The one-day Review Course, held before ACR Convergence 2023 officially kicked off on on Saturday, Nov. 11, covered a plethora of important topics under the leadership of moderators Noelle Rolle, MBBS, assistant professor in the Division of Rheumatology, associate program director of the Rheumatology Fellowship at the Medical College of Georgia, Augusta University, and Julia Schwartzmann-Morris, MD, associate professor, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, N.Y.

Thrombotic Microangiopathies

Dr. Thomas Ortel

Thomas Ortel, MD, PhD, chief, Division of Hematology, Department of Medicine, Duke University School of Medicine, Durham, N.C., discussed thrombotic microangiopathies (TMA). TMA is a group of clinical syndromes defined by the presence of hemolytic anemia, thrombocytopenia and organ damage that results from endothelial damage and microvascular occlusion.

TMAs are relevant to rheumatologists because systemic lupus erythematosus (SLE), scleroderma renal crisis (SRC) and catastrophic antiphospholipid syndrome (CAPS) can all manifest with TMA. Although these associations clearly exist, the precise pathophysiologic mechanisms that explain why these diseases cause TMA are not entirely clear.¹

About TMA

Two primary forms of TMA include thrombotic thrombocytopenic purpura (TTP) and complement-mediated TMA, also known as atypical hemolytic uremic syndrome (aHUS). TTP can be congenital or acquired and results from antibodies directed against ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). aHUS is a rare, hereditary, progressive and life-threatening disorder that results from a disruption in regulation of the alternative complement pathway.

A key point made by Dr. Ortel is that it is essential to identify primary TMAs, such as TTP and aHUS, because targeted therapies for these conditions now exist.

Dr. Ortel also noted that primary TMA can occur with other disorders that sometimes cause a secondary TMA; even in these cases, the primary TMA must be specifically treated.

In explaining the pathogenesis of TTP, Dr. Ortel stated there is systemic deposition of platelet thrombi with abundance of von Willebrand factor (vWF) in the arterioles and capillaries. This can occur when ADAMTS13, which is a vWF protease, is deficient and vWF levels can rise. This explains why low ADAMTS13 activity level is a defining feature of TTP.

Various assays exist to measure ADAMTS13 activity level, but Dr. Ortel noted that many of them take a long time to result, thus clinical decisions may need to be made before these levels return.

The PLASMIC score is an algorithm that can be used to calculate the likelihood of TTP in patients who are awaiting the results of the ADAMTS13 activity level assay. Developed in 2017, the name PLASMIC refers to the score’s seven components: Platelet count; combined hemoLysis variable; absence of Active cancer; absence of Stem-cell or solid-organ transplant; MCV; INR; Creatinine. When applied to the appropriate patient population, the score accurately distinguishes between TMA patients with and without severe ADAMTS13 deficiency (defined as ADAMTS13 activity level ≤10%). It can also be used to judge if the assay should be sent to begin with.

The treatment of acute TTP primarily involves plasma exchange. Caplacizumab, a vWF-directed antibody fragment, is a newer treatment for TTP that can be used as well. Upshaw-Schulman syndrome is a rare autosomal recessive cause of hereditary TTP, and the U.S. Food & Drug Administration recently approved Adzynma (ADAMTS13, recombinant-krhn) for treatment of the condition. This same medication is also being evaluated for the treatment of acute TTP.

For HUS, many clinicians are familiar with Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS). In contrast to this condition, aHUS is not associated with an underlying infection; rather, this is a complement-mediated process that frequently demonstrates hypocomplementemia and there is often a family history of the condition. Eculizumab and ravulizumab, both of which are inhibitors of C5, have become the standard of care in treatment of complement-mediated HUS.

Diagnosing aHUS with certainty remains challenging because there is no specific test for this condition. When acute aHUS is suspected, the ADAMTS13 activity level assay should be sent to rule out TTP. Ultimately, aHUS is a diagnosis of exclusion.

A number of other conditions can result in TMA. These conditions include the pregnancy-related forms of TMA, such as pre-eclampsia, eclampsia and the HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome. Although these conditions typically improve with delivery of the baby, about one-third of patients can present with TTP in the post-partum period. About 10% of all adult TTP cases are pregnancy-related, and even the first presentation of Upshaw-Schulman syndrome can be with the appearance of TTP in pregnancy.² HUS can present in the post-partum period.

An important cause of TMA is catastrophic antiphospholipid syndrome (CAPS), which is a rare, life-threatening form of APS that entails severe thrombotic complications (both microvascular and large-vessel thrombosis) that affects multiple organs simultaneously or in a short period of time. Identifying CAPS is important because patients should receive treatment with anticoagulation, corticosteroids and plasma exchange. In some cases, intravenous immunoglobulin (IVIG) and eculizumab may potentially be used as well.

Jason Liebowitz, MD, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.

References

1. Babar F, Cohen SD. Thrombotic microangiopathies with rheumatologic involvement. Rheum Dis Clin North Am. 2018 Nov;44(4):635–649.
2. Ferrari B, Peyvandi F. How I treat thrombotic thrombocytopenic purpura in pregnancy. Blood. 2020;136(19):2125–2132.