An International Survey to Better Understand the Current Incidence, Diagnosis, and Management of Transplant-associated Thrombotic Microangiopathy (TA-TMA) in Clinical Practice

Introduction and Rationale
Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication of hematopoietic stem cell transplantation (HSCT), characterized by endothelial damage, thrombocytopenia, microangiopathic hemolytic anemia, and organ dysfunction. While thrombotic microangiopathies (TMAs) occur in several contexts like autoimmune disorders, malignancies, infections, and drug toxicities, TA-TMA is influenced by HSCT-related factors such as conditioning regimens, graft-versus-host-disease (GVHD), and immunosuppressive therapies. Advances in understanding the pathophysiology of TA-TMA, particularly the roles of complement activation and endothelial injury, have improved diagnostic and therapeutic options. However, significant variability remains in the diagnosis and management of TA-TMA across centers.

Survey Objectives
The primary objective of this survey is to assess, in real-world clinical practice, the incidence, diagnostic approaches including the evolving international criteria, and the management strategies for TA-TMA.

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* 1. What is your current role in the field of HSCT and TA-TMA?

Consultant clinical hematologist/HSCT physician

Laboratory work (diagnostic and/or research)

Intern/resident/trainee in hematology/HSCT

Nurse practitioner

Other specialty (please specify)

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* 2. How many years have you been practicing in this field?

Less than 5 years

5-10 years

11-20 years

More than 20 years

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* 3. What is the primary patient age group of your HSCT and TA-TMA practice?

Adults

Children and young adolescents

Both adults and pediatric patients

Other (please specify)

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* 4. How many allogeneic HSCT procedures does your center perform annually?

Less than 50

50–100

More than 100

Unknown / not sure

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* 5. Where is your primary practice or institution located?

North America

Europe

Asia

Australia/Oceania

Central/South America

Africa

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* 6. Do you routinely screen for TA-TMA in your practice?

I screen all autologous and allogeneic HSCT recipients

I screen all allogeneic HSCT recipients

I screen only allogeneic HSCT recipients with high-risk features or complications

I screen patients only when they present possible clinical features

I do not routinely screen for TA-TMA

Other (please specify)

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* 7. Which of the following features do you use to screen for TA-TMA in your practice? (Select all that may apply)

Anemia and/or thrombocytopenia

Refractory hypertension

Schistocytes

Haptoglobin

Increased LDH

Proteinuria

Increased sC5b9

Other (please specify)

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* 8. Which of the following TA-TMA diagnostic criteria do you use in your practice?

Cho 2010

City of Hope 2013

Jodele 2014

Li 2019

Schoettler 2023 Harmonization criteria

Our own clinical judgment or institutional standard operating procedures

Others (please specify)

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* 9. Do you do kidney, intestinal or other tissue biopsies for diagnosis of TA-TMA?

Routinely, in a majority of suspected cases

Often, whenever clinically feasible

Rarely, only in very selected cases

Never

Other (please specify)

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* 10. How often do you diagnose TA-TMA in your practice?

Rarely (less than 1 case per year)

Occasionally (1–5 cases per year)

Frequently (6–15 cases per year)

Very frequently (more than 15 cases per year)

Other (please specify)

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* 11. To the best of your knowledge, TA-TMA diagnosis is:

Greatly overdiagnosed

Somewhat overdiagnosed

Appropriately diagnosed

Somewhat underdiagnosed

Greatly underdiagnosed

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* 12. Beyond anemia, thrombocytopenia, elevated LDH and schistocytes, which are universally included as diagnostic features in all international criteria to date, and according to your experience and practice, please select and score the following features based on their importance to diagnose TA-TMA, as follows: (1) very important/required; (2) important but not required; (3) neutral; (4) unimportant; (5) negligible

	1	2	3	4	5
Renal dysfunction (i.e. acute renal failure)	Renal dysfunction (i.e. acute renal failure) 1	Renal dysfunction (i.e. acute renal failure) 2	Renal dysfunction (i.e. acute renal failure) 3	Renal dysfunction (i.e. acute renal failure) 4	Renal dysfunction (i.e. acute renal failure) 5
Neurological dysfunction (e.g. seizures, PRES, stroke, etc.)	Neurological dysfunction (e.g. seizures, PRES, stroke, etc.) 1	Neurological dysfunction (e.g. seizures, PRES, stroke, etc.) 2	Neurological dysfunction (e.g. seizures, PRES, stroke, etc.) 3	Neurological dysfunction (e.g. seizures, PRES, stroke, etc.) 4	Neurological dysfunction (e.g. seizures, PRES, stroke, etc.) 5
Gastrointestinal dysfunction (e.g. bleeding, ischemia, refractory abdominal pain)	Gastrointestinal dysfunction (e.g. bleeding, ischemia, refractory abdominal pain) 1	Gastrointestinal dysfunction (e.g. bleeding, ischemia, refractory abdominal pain) 2	Gastrointestinal dysfunction (e.g. bleeding, ischemia, refractory abdominal pain) 3	Gastrointestinal dysfunction (e.g. bleeding, ischemia, refractory abdominal pain) 4	Gastrointestinal dysfunction (e.g. bleeding, ischemia, refractory abdominal pain) 5
Pulmonary hypertension	Pulmonary hypertension 1	Pulmonary hypertension 2	Pulmonary hypertension 3	Pulmonary hypertension 4	Pulmonary hypertension 5
Serositis (ascites, pleural or pericardial effusion)	Serositis (ascites, pleural or pericardial effusion) 1	Serositis (ascites, pleural or pericardial effusion) 2	Serositis (ascites, pleural or pericardial effusion) 3	Serositis (ascites, pleural or pericardial effusion) 4	Serositis (ascites, pleural or pericardial effusion) 5
New onset or refractory hypertension	New onset or refractory hypertension 1	New onset or refractory hypertension 2	New onset or refractory hypertension 3	New onset or refractory hypertension 4	New onset or refractory hypertension 5
Negative Coombs test	Negative Coombs test 1	Negative Coombs test 2	Negative Coombs test 3	Negative Coombs test 4	Negative Coombs test 5
Decreased haptoglobin	Decreased haptoglobin 1	Decreased haptoglobin 2	Decreased haptoglobin 3	Decreased haptoglobin 4	Decreased haptoglobin 5
Increased proteinuria	Increased proteinuria 1	Increased proteinuria 2	Increased proteinuria 3	Increased proteinuria 4	Increased proteinuria 5
Normal coagulation studies	Normal coagulation studies 1	Normal coagulation studies 2	Normal coagulation studies 3	Normal coagulation studies 4	Normal coagulation studies 5
Increased soluble C5b9	Increased soluble C5b9 1	Increased soluble C5b9 2	Increased soluble C5b9 3	Increased soluble C5b9 4	Increased soluble C5b9 5
Involved organ positive biopsy	Involved organ positive biopsy 1	Involved organ positive biopsy 2	Involved organ positive biopsy 3	Involved organ positive biopsy 4	Involved organ positive biopsy 5

Other features (please specify)

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* 13. Score the frequency of occurrence of the following features during the early post-HSCT period up to day 180 in your allogeneic HSCT practice, regardless of TA-TMA cases, as follows: (1) very common, >90% of cases; (2) common, >1/3 of cases; (3) uncommon, <1/3 of cases; (4) very rare, in <10% of cases; (5) I don’t know

	1	2	3	4	5
Anemia	Anemia 1	Anemia 2	Anemia 3	Anemia 4	Anemia 5
Thrombocytopenia	Thrombocytopenia 1	Thrombocytopenia 2	Thrombocytopenia 3	Thrombocytopenia 4	Thrombocytopenia 5
Elevated LDH	Elevated LDH 1	Elevated LDH 2	Elevated LDH 3	Elevated LDH 4	Elevated LDH 5
Schistocytes present in peripheral blood smear	Schistocytes present in peripheral blood smear 1	Schistocytes present in peripheral blood smear 2	Schistocytes present in peripheral blood smear 3	Schistocytes present in peripheral blood smear 4	Schistocytes present in peripheral blood smear 5
Refractory hypertension	Refractory hypertension 1	Refractory hypertension 2	Refractory hypertension 3	Refractory hypertension 4	Refractory hypertension 5
Increased proteinuria	Increased proteinuria 1	Increased proteinuria 2	Increased proteinuria 3	Increased proteinuria 4	Increased proteinuria 5
Renal dysfunction	Renal dysfunction 1	Renal dysfunction 2	Renal dysfunction 3	Renal dysfunction 4	Renal dysfunction 5
Neurologic dysfunction	Neurologic dysfunction 1	Neurologic dysfunction 2	Neurologic dysfunction 3	Neurologic dysfunction 4	Neurologic dysfunction 5
Increased soluble C5b9 or other complement tests	Increased soluble C5b9 or other complement tests 1	Increased soluble C5b9 or other complement tests 2	Increased soluble C5b9 or other complement tests 3	Increased soluble C5b9 or other complement tests 4	Increased soluble C5b9 or other complement tests 5

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* 14. What is the availability and turnaround time of soluble C5b9 testing in your institution?

Not available (not a validated laboratory diagnostic tool)

Available from an external provider, but only in selected cases and with long turnaround time that prevent its use in diagnostic and therapeutic decisions

Available from an external provider, with quick turnaround time to make clinical decisions

Readily available on-site as required with quick turnaround time to make clinical decisions

Other (please specify)

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* 15. How do you interpret the soluble C5b9 level when considering a diagnosis of TA-TMA?

All TA-TMA cases have increased sC5b9 levels

All cases with increased sC5b9 levels have TA-TMA

sC5b9 levels above the upper limit of normal range associate with high-risk TA-TMA only in children

sC5b9 levels above the upper limit of normal range associate with high-risk TA-TMA in children and in adults

I don’t know

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* 16. Clinical Scenario I: an 18 year-old matched sibling allogeneic HSCT recipient presents 7 weeks after transplant with mild upper respiratory symptoms without a fever. The patient has normal O2 saturation and examinations other than high blood pressure for several weeks since on calcineurin inhibitors that persists despite several lines of therapy. The patient has normal full blood count other than mild neutropenia (1078/uL), and isolated schistocytes in the blood smear. Basic electrolytes, renal, liver function tests and haptoglobin are normal, other than a moderately increased LDH (317 IU/L). Chest X Ray is normal. Urine antigen tests for respiratory infections are negative, but urine shows proteinuria with increased rUPCR (1.2 mg/mg). Respiratory samples for viral PCRs and cultures are pending. Which would be your working diagnosis?

Possible upper respiratory infection and confirmed TA-TMA

Possible upper respiratory infection and probable TA-TMA

Possible upper respiratory infection and possible TA-TMA

Possible upper respiratory infection (I didn’t even think of TA-TMA)

I don’t know

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* 17. Clinical Scenario II: If the case above, everything else unchanged, had concomitantly developed an inflammatory maculopapular erythematous skin rash in approximately two thirds of the body surface area, with no bullous formations and no liver or gastrointestinal abnormalities, which would be your working diagnosis?

Cutaneous stage 3, overall grade II acute GVHD and severe TA-TMA

Cutaneous stage 3, overall grade II acute GVHD and moderate TA-TMA

Cutaneous stage 3, overall grade II acute GVHD and mild TA-TMA

Cutaneous stage 3, overall grade II acute GVHD with no TA-TMA

I don’t know.

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* 18. Diagnostic criteria for severe HSCT complications, including TA-TMA, often offer definitions for different diagnostic levels (possible vs probable vs proven) to reconcile the needs for early diagnosis with those for diagnostic certainty. Please, select the following statements about the current 2023 harmonization criteria. (Select all that apply)

They improve early TA-TMA diagnosis and diagnostic accuracy without a need for further refinement

They improve early TA-TMA diagnosis but at the cost of reducing specificity and diagnostic certainty

They would benefit from the inclusion of levels of diagnostic certainty (e.g. possible vs probable vs proven) to improve accuracy and patient management

Other considerations (please specify)

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* 19. The current 2023 harmonization definition of high-risk TA-TMA requires the presence of any one of the following: peak LDH >2 times ULN, spot rUPCR ≥1 mg/mg, any organ dysfunction (renal except KDIGO stage I AKI, pulmonary, cardiovascular, serositis, CNS, and/or GI),
sC5b-9 > ULN, concurrent acute GVHD grade II-IV, and/or concurrent systemic bacterial or viral infection. Given this definition, what percentage of your TA-TMA patients would you categorize as high-risk?

0-20%

21-40%

41-60%

61-80%

81-100%

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* 20. Select the correct statements on therapeutic TA-TMA management based on your usual practice. (Select all that apply)

I always do supportive treatment of concomitant complications and manifestations

I generally withdraw or modify immunosuppressants

I generally do not modify immunosuppressants as their continuation does not impact TA-TMA resolution in my patients

I often use plasma exchange

Other (please specify)

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* 21. Which of the following statements would best reflect your decision-making regarding TA-TMA directed therapy?

Proximal complement inhibition preserving the lytic arm of the classical pathway of complement and formation of the membrane attack complex (i.e. MASP-2, Factor D, etc.) would be best in such heavily immunosuppressed patients

Terminal complement activation preventing function of the lytic arm of the classical pathway of complement and formation of the membrane attack complex (i.e. C3/C5) would be best in these patients

The point at which complement inhibition takes place is not relevant in terms of treatment safety or efficacy for these patients

TA-TMA goes beyond a complement-mediated disease, and therapies directed towards other targets should be sought

Other (please specify)

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* 22. Regarding TA-TMA directed therapy, despite no drugs being currently approved in this indication, what would be your first therapeutic option of choice for a patient with TA-TMA that has not responded to initial supportive care?

Eculizumab for C5 inhibition

Defibrotide targeting the endothelium

Narsoplimab for MASP-2 inhibition

Pegcetacoplan for C3 inhibition

Ravulizumab for C5 inhibition

Other (please specify)

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* 23. Please, provide any additional relevant comments that may have not been addressed by the prior questions:

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* 24. To be eligible to win one of 30 complimentary registrations and a 300 Euro travel grand to the 8th Annual Meeting of IACH taking part with COMydAL, COLYM and MPNCo&D in Paris France, please provide your email.