Sonata Jodele, MD
While complex, criteria for diagnosing transplant-associated thrombotic microangiopathy (TA-TMA) following hematopoietic stem cell transplantation (HSCT) should be closely followed and should begin with screening, according to a presentation during the 2019 European Society for Blood and Marrow Transplantation Annual Meeting.
“The goal of this lecture is to increase awareness of HSCT associated TMA as a potentially severe transplant complication and to provide criteria to aid in identifying patients requiring early clinical intervention,” said Sonata Jodele, MD, professor and medical director of the Blood and Marrow Transplantation Program at Children's Hospital Los Angeles, University of Southern California, Keck School of Medicine, in a presentation during the meeting.
Difficulties in diagnosing TMA arise due to overlap with graft-versus-host disease (GVHD), which is often a comorbidity, and grades 3/4 GVHD have also been identified as a predisposing factor for development of TMA.1
Jodele described the development of TMA as a result of activation of the complement pathway by GVHD, chemotherapy, infections, or disimmunity that results in inflammation, tissue ischemia and hypoxia, blood clots, and hemolysis, which may lead to the formation of thrombus-forming angiopathy or blood vessel injury. HSCT-TMA may also present as multi-organ dysfunction syndrome (MODS).
“TMA can range from a mild, self-limited form to uncontrolled fulminant disease leading to death, and it has been shown to affect HSCT outcomes,” according to Jodele, whose group previously conducted research demonstrating that pediatric patients with post–HSCT-TMA had higher non-relapse mortality (NRM) than patients without TMA.2
Higher NRM rates have also been shown in adult patients with TMA compared with those not developing TMA,3
and also by researchers who demonstrated significantly higher 3-year NRM in adult patients with TMA (P
The incidence of TMA varies; for example, incidence was 39%, 9.8%, and 33%, respectively, in the 3 above-mentioned studies. This is most likely due to the different diagnostic criteria that have been proposed, according to Jodele. In 2009, TMA was diagnosed on the presence of schistosome, elevated serum LDH and creatinine, and a negative Coombs test.5
These criteria changed somewhat until the current guidelines were accepted, which comprise:
- LDH above normal for age,
- Schistocytes on peripheral blood smear,
- De novo thrombocytopenia/required platelet transfusions,
- De novo anemia or required red blood cell transfusions
- Hypertension >99% for age, 140/90, or antihypertensive therapy
- Proteinuria ≥30 mg/dL (2 measurements) or urine protein creatinine ratio ≥2 mg/mg,
- Terminal complement activation elevated above normal (≥244 ng/mL).
Jodele proposed that diagnosis be based upon presence of 4 of the above 7 laboratory and clinical markers and noted that proteinuria and complement activation are high-risk markers for TMA. She commented that ADAMTS13 activity may be reduced in TMA but remains >10%, elevated haptoglobin is a poor prognostic marker, and serum creatinine is a late occurring marker that is only useful if elevated, especially in children.
HSCT-TMA is a multi-visceral disease that may affect blood vessels of the kidney, lung, CNS, skin, or intestine. Exemplifying the widespread effects of TMA, a prospective study of 90 transplant recipients showing that patients with TMA compared with non-TMA patients had more neurological symptoms (P
<.07), required more medications to control hypertension, admission to intensive
care, had respiratory failure, showed significant gastrointestinal (GI) bleeding, had higher NRM rates at 1 year post HSCT, higher overall mortality at 1 year following HSCT (all P
and also had more pericardial effusion (P
<.06), and pulmonary hypertension (P
Specifically focusing on TMA-kidney injury, Jodele proposed diagnosis of these patients be based on elevated serum creatinine, reduced glomerular filtration rate (GFR); hypertension requiring more than 2 medications in allogeneic HSCT, or any medication in allogeneic HSCT, and proteinuria ≥30 mg/dL x2 or urine protein creatinine ratio ≥2mg/mg.6