Table 3.

Clinical Manifestations, Diagnostic Workup, and Considerations in TA-TMA

Organ System	Clinical Manifestations	Diagnostic Workup	Supportive of TA-TMA Diagnosis	Clinical Considerations
Hematologic	Bleeding, fatigue	Complete blood count	Anemia, defined as (1) failure to achieve RBC transfusion independence despite evidence of neutrophil engraftment (in absence of AIHA or PRCA from donor recipient major ABO mismatch); (2) hemoglobin decline from baseline by ≥1 g/dL; or (3) new onset of transfusion dependence Thrombocytopenia, defined as (1) failure to achieve platelet engraftment with greater than expected platelet transfusion needs; (2) refractory to platelet transfusions; or (3) a 50% reduction in baseline platelet count after initial platelet engraftment	In the early post-HCT period, there are multiple etiologies for protracted cytopenias including conditioning regimen, engraftment failure, sinusoidal obstructive syndrome, GVHD, severe infections, GI bleeding, etc. Because TA-TMA often develops in the early post-HCT period, it may overlap with these complications. TA-TMA should be considered in the context of these multiple etiologies, and additional testing should be performed to support or rule out its presence.
		LDH	Above ULN for age on ≥2 occasions	Elevated LDH is not specific and needs to be interpreted within the context of other laboratory test results. However, serum LDH is almost always persistently elevated in TA-TMA.
		Haptoglobin	Below lower limit of normal for age	Low haptoglobin is consistent with hemolysis. However, haptoglobin is an acute-phase reactant, and in HCT recipients with ongoing inflammation, haptoglobin may be falsely elevated. Thus, low haptoglobin is helpful to confirm hemolysis, but normal or elevated haptoglobin does not rule out hemolysis.
		Direct Coombs test	Negative	A positive direct Coombs test can occur in patients after receipt of i.v. immunoglobulin and certain medications or can be present in ABO-mismatched donors and recipients. A positive test does not rule out TA-TMA, but the diagnosis should be questioned and additional testing performed.
		Manual review of peripheral blood smear	Schistocytes (any presence)	Although there are published guidelines defining pathologic schistocyte numbers, these are derived from the healthy population. Whether these data can be extrapolated to the HCT population is unknown. The presence of more than 2 schistocytes per HPF is highly supportive of a microangiopathic process; however, the absence of schistocytes does not rule out TA-TMA.
		ADAMTS-13 Activity	≥10%	<10% ADAMTS-13 activity is diagnostic of TTP. Although ADAMTS-13 should be checked as part of the TMA evaluation, we do not recommend delaying TA-TMA treatment for this laboratory result, as TTP (<10% activity) is extremely rare in the HCT setting.
		Coagulation studies	Normal coagulation studies	Coagulation studies are recommended to rule out disseminated intravascular coagulation when considering a diagnosis of TA-TMA. However, it is important to recognize that PT/PTT could be abnormal in the setting of poor nutrition and/or liver dysfunction as well, and that abnormal coagulation tests from other causes can coexist in TA-TMA.
Renal	Hypertension	Serum creatinine	≥2 times pretransplantation baseline or a ≥50% decrease in eGFR using serum creatinine or cystatin C	AKI is not necessary for the diagnosis of TA-TMA and can be absent in earlier stages. However, TA-TMA should always be included in the differential diagnosis in patients who develop AKI after HCT.
		rUPCR	≥1 mg/mg	De novo proteinuria can be an early sign of developing renal TA-TMA, often occurring before AKI becomes apparent. In patients with concurrent hemorrhagic cystitis/hematuria, urine protein may be difficult to interpret; however, viral infections (including BK virus and adenovirus) are themselves known risk factors for TA-TMA.
		Hypertension	Age <18 yr, BP ≥99th percentile; Age ≥18 yr, BP ≥140/90 mmHg	Hypertension is relatively common among adults as a baseline medical condition and is often exacerbated by calcineurin inhibitors or steroids after allogeneic HCT. TA-TMA should be considered if the hypertension is out of proportion to expected, and there is need for additional antihypertensive agents (especially 2 or more agents) to maintain control of BP.
Cardiopulmonary	Shortness of breath, hypoxia, hemoptysis, or diffuse alveolar hemorrhage	Echocardiogram	Elevated right ventricular pressure concerning for pulmonary hypertension, right-sided heart failure	Patients with respiratory symptoms should undergo echocardiography to evaluate for pulmonary hypertension.
		Chest imaging	Pleural effusion or pericardial effusion on chest X-ray	Serositis leading to pericardial and/or pleural effusions is a known manifestation of TA-TMA. Effusions also can occur in the context of volume overload from VOD/SOS or heart failure.
		Bronchoscopy/BAL	Alveolar hemorrhage	If clinically indicated, bronchoscopy and BAL analysis can identify alveolar hemorrhage and evaluate for infectious organisms. Patients with pulmonary TMA can manifest with diffuse alveolar hemorrhage, with associated poor outcomes.
GI	Abdominal pain, bloody stools	EGD/colonoscopy	Biopsy results consistent with TA-TMA	Acute GVHD and intestinal TA-TMA symptoms overlap, Intestinal TMA should be considered in patients with existing intestinal acute GVHD who develop severe pain, GI bleeding, or evidence of bowel ischemia. GI pathologists should be alerted to specifically assess for evidence of TA-TMA in the GI biopsies of patients with acute GVHD.
Central nervous system	Seizures, altered mental status, visual changes/cortical blindness	MRI/A	Imaging findings consistent with PRES, hemorrhage, or thrombosis	MRI/A findings with or without evidence of PRES or other focal findings may be seen but are not required for the diagnosis of neurologic TA-TMA. Neurologic involvement of TA-TMA should be strongly considered in patients with altered mental status and known TA-TMA regardless of imaging results. Consider CSF analysis to rule out infectious organisms.
		Lumbar puncture	CSF negative for leukocytosis or infection; may have elevated CSF protein
		EEG	Seizures
Miscellaneous	—	Complement studies	Elevated sC5b-9	Elevated sC5b-9 alone is not diagnostic of TA-TMA but is very helpful in supporting the diagnosis if other clinical parameters consistent with TMA are present. Normal C5b-9 levels do not rule out TA-TMA.
		Biopsy	Kidney or GI biopsy with characteristic TA-TMA features	Regardless of clinical criteria, tissue evidence of TA-TMA is sufficient for diagnosis. There is insufficient evidence of histology of other organs, including skin, liver, etc, or of stains (ie, complement deposition) to diagnose TA-TMA in tissue.

eGFR indicates estimated glomerular filtration rate; TTP, thrombotic thrombocytopenia purpura; VOD/SOS, veno-occlusive disease/sinusoidal obstruction syndrome; BAL, bronchoalveolar lavage; EGD, esophagogastroduodenoscopy; MRI/A, magnetic resonance imaging/angiography; PRES, posterior reversible encephalopathy; CSF, cerebrospinal fluid; EEG, electroencephalography., GI; gastrointestinal