Dispelling Common Misperceptions in aHUS
Presented to The Western Pennsylvania-Allegheny Health System (WPAHS)
at Pittsburgh, PA on February 20,2013 (Revised Aug. 2013)
by Robert B. Kaplan, MD
Within the last two decades, major advances in our understanding of the thrombotic microangiopathies has greatly expanded the boundaries of our knowledge base and enabled us to view these disorders in a fresh perspective. Misconceptions existed concerning aspects of the disease relevant to securing the correct diagnosis and selecting the optimal treatment approach. A concise summary of the new disease concepts which have replaced previously held misperceptions should prove useful to both patients and their caretakers struggling to grapple with this perplexing disorder.
FACT: In the largest European cohort of aHUS patients, 41 % of patients were diagnosed after age 18. Age at diagnosis can range from infancy to the later decades of life.
FACT: aHUS is a systemic disorder which can affect the microvascular bed of every organ. The most commonly involved organ is the kidney. Many patients have involvement of the neurologic, cardiovascular and gastrointestinal systems, with other organs affected less frequently. The take away message is that no organ has true immunity to this disease. This is due to the fact that many of the complement regulatory proteins rendered dysfunctional by the disease play an important regulatory role in the various organs throughout the body.
FACT: Approximately 20% of patients may have no signs of renal dysfunction at diagnosis. Although all patients ultimately develop renal dysfunction, it may only be detectable by the presence of protein and/or blood in the urine in some patients when still in its early stages.
FACT: Although genetic mutations are estimated to be causal in approximately 90% of patients (10% acquired), in clinical trials, they have been documented in only about 50% of cases and are not necessary to establish the diagnosis. Testing requires several months to complete, is expensive, generally not reimbursed by health insurance, and only performed in a few facilities in the country. This is not to say that the genetic information will have no utility, but rather, at the current time, it is has no practical role in facilitating the diagnosis.
FACT: Eculizumab was purposefully designed to target only a specific (terminal) component of the complement pathway, i.e, the segment responsible for cell lysis, and does not affect the proximal aspects; therefore, the other functions of the complement system are left unaffected. For this reason, eculizumab should not be grouped in the same category with the more traditional and commonly used immunomodulatory drugs which are known to strongly suppress the immune system and have more dramatic side effects. Morover, surgery, in general, is known to be one of the major triggers of aHUS disease activity and, consequently, discontinuing the drug in the peri-operative period may allow the disease to flare at a very inopportune time. Although there are currently no evidence-based guidelines regarding the use of eculizumab in the surgical setting (only anecdotal evidence is available), those clinicians who have had significant clinical experience with the drug have not observed serious infections in their patients who stayed on treatment schedule and therefore, do not routinely advocate treatment interruption in this scenario.
FACT: aHUS and TTP do belong to the same family of diseases known as the thrombotic microangiopathies; however, despite having very similar clinical presentations (microangiopathic hemolytic anemia and organ injury), each of the major TMA’s (TTP, aHUS, and STEC-HUS) have a unique pathogenesis. While it is now clear that inherited derangements in complement regulatory proteins are the root cause of aHUS, TTP is believed to be driven by abnormalities in a distinct protein known as von Willbrand factor and, in most cases, is not hereditary. Historically, management did not require a strict distinction as TTP and HUS were commonly grouped as “TTP/HUS” and were treated with the same strategy, plasma-exchange. Today, differentiation is believed to be critical as currently recommended treatment strategies are divergent (eculizumab in aHUS/plasma-exchange in TTP), and the use of plasma-exchange in a substantial proportion of aHUS patients may prove to be wholly ineffective. In some aHUS cases, it is possible that the delay in implementation of eculizumab could potentially compromise outcomes.
Dr. Robert B. Kaplan, MD
Director, Hemostasis-Thrombosis Laboratory
The Western Pennsylvania Hospital
West Penn Allegheny Health System
Pittsburgh, PA 15224
Office PH: 412 -578-1605
Office FAX: 412-578-4391
This information was derived from a component of Dr. Kaplan's formal slide lecture entitled "Dispelling Common Myths in aHUS" presented at The Western Pennsylvania-Allegheny Health System (WPAHS) in Pittsburgh, PA, 02/20/2013, as part of the weekly Core Curriculum Conference within the health system's hematology-oncology fellowship program. The target audience included hematology-oncology fellows as well as key faculty members of the Division of Hematology and Cellular Therapy.
Dr Kaplan is a key faculty member within the Division of Hematology and Cellular Therapy of The Western Pennsylvania-Allegheny Health System and a member of Alexion's aHUS Speaker's Bureau.