Clinical Utility of Diagnostic Criteria for Hematopoietic Stem Cell Transplant (HSCT)-Associated Thrombotic Microangiopathy (TMA): A Prospective Single Center Study

Overview: Current diagnostic criteria for TMA proposed by the Blood and Marrow Transplant Clinical Trials Network and the International Working Group have limitations because the renal and hematologic findings are not specific for TMA after HSCT, as noted retrospectively by Cho et al (Transplantation 2010).

Methods: To prospectively assess the utility of current diagnostic TMA criteria we enrolled 100 pediatric HSCT patients at a single institution and evaluated clinical and laboratory markers of TMA during the first 100 days post-HSCT (Table).  Patients with a biopsy diagnosis of TMA or signs of hemolytic microangiopathy were assigned to the TMA group (n=37), with remaining HSCT recipients grouped as non-TMA controls (n=63).  The first lactate dehydrogenase (LDH) elevation was considered the start of TMA.

Results: 37% of patients were diagnosed with TMA at a median of 32 days (17, 43) (interquartile range)  after HSCT. The first LDH elevation was noted at a median of 14 days (10, 20) after HSCT.  The appearance of schistocytes and drop in haptoglobin lagged LDH by 10 (2, 21) and 13.5 (7,22) days ,  and was present in 95% and  89% patients with TMA, respectively. Proteinuria was an early sign of renal injury, detected 4 days (-7, 21)  after LDH elevation in 73% of patients with TMA, while acute kidney injury (AKI), defined as  a doubling of serum creatinine on ≥2 consecutive measures, occurred in 49% of patients with TMA 3 days (-8,16)  after LDH elevation. 

LDH elevation, low haptoglobin, schistocytosis, and number of platelet and red cell transfusions were significant clinical markers of TMA, manifesting over a 14 day period after LDH elevation. Patients with TMA required more antihypertensive medications and were more likely to have AKI and proteinuria early in the TMA course. Patients with TMA had a significantly higher incidence of respiratory failure, need for the intensive care unit, and a higher 100 day mortality (all <0.001) compared to the non-TMA controls.

Conclusion:  We prospectively determined that current clinical consensus criteria delay TMA diagnosis by at least by 2 weeks, potentially placing HSCT recipients at risk for higher morbidity and mortality from irreversible tissue injury.  Additional AKI biomarkers are needed to promptly diagnose TMA, even before proteinuria, increased creatinine and hypertension can be clinically detected.

Table

	Patients with TMA (n=37)	HSCT controls (n=63)	p-value
Elevated LDH	37 (100%)	31 (49%)	0.0001
Number of platelet transfusions	13 (10.5, 20) [2, 89]	7 (3, 15) [1, 63]	0.002
Number of red cell transfusions	5 (3, 8) [0, 48]	3 (2, 4) [0, 17]	0.0002
Schistocytes	35 (95%)	10 (16%)	0.0001
Haptoglobin below normal	33 (89%)	23/62 (37%)	0.0001
AKI	18 (49%)	20 (32%)	0.048
Proteinuria (≥30 mg/dL )	27 (73%)	31 (49%)	0.02
Number of antihypertensive medications	4 (2, 5) [1, 8]	2 (1, 3) [1, 5]	0.0001

Data presented as n (%) or median (25^th, 75^th percentile) [range]