Expert Provides Guidelines for Diagnosis and Management of TA-TMA

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 = .0001).⁴

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:

1. LDH above normal for age,
2. Schistocytes on peripheral blood smear,
3. De novo thrombocytopenia/required platelet transfusions,
4. De novo anemia or required red blood cell transfusions
5. Hypertension >99% for age, 140/90, or antihypertensive therapy
6. Proteinuria ≥30 mg/dL (2 measurements) or urine protein creatinine ratio ≥2 mg/mg,
7. 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 <.01), and also had more pericardial effusion (P <.06), and pulmonary hypertension (P <.03).

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

Regarding TMA-cardiac complications, a recent prospective study monitored 79 (81%) patients who underwent HSCT that were admitted to pediatric intensive care for respiratory distress/hypoxia, symptoms consistent with shock, transplant-associated complications, or associated TMA. All patients underwent echocardiography (ECHO) screening, which identified 35% of patients with ≥1 actionable finding; 34% had elevated right ventricular pressure (of these, 14% had pulmonary hypertension; PH), 31% had ventricular systolic dysfunction (VSD), and 13% had moderate to large pericardial effusion. It was determined that there was no TMA association with left VSD; however TMA was found to be associated in 70% of the patients with PH and 77% of the pericardial effusion cases.⁷

Jodele outlined criteria for diagnosing HSCT-TMA lung injury, which includes;

• Initially clear lungs on x-ray,
• Unexplained hypoxia,
• Drop in hemoglobin without obvious bleeding in the airways, or interstitial bleeding,
• Increased vascular markings on x-ray or CT,
• Fast progression to acute respiratory distress syndrome,
• Difficulty oxygenating on mechanical ventilator,
• Response to empiric NO,
• Cardiac failure

A case of HSCT-TMA associated pulmonary hypertension was described in a patient who underwent and displayed elevated right ventricular pressure beginning on day 7, which increased through day 60, plus fast progression with both hypoxemia and PH. A consultation between cardiology and PH teams resulted in early initiation of treatment with eculizumab (Soliris), which resulted in an immediate and continued decrease in pressure.⁸

Jodele advised that HSCT-TMA PH should be suspected when a patient has shortness of breath, respiratory failure, or cardiovascular compromise after HSCT. Diagnosis entails reviewing the patient’s history and conducting a physical exam, followed by an electrocardiogram, chest x-ray, CT scan, or

echocardiogram to identify underlying etiology.

Findings concerning PH from an electrocardiogram include right axis deviation or right ventricular hypertrophy. On x-ray, pulmonary artery prominence, or enlarged hilar vessels would be detected. The CT scan would reveal dilation of the pulmonary artery, and an echocardiogram could provide information indicative of PH in adults, such as tricuspid regurgitant velocity >2.9 m/sec, estimated systolic pulmonary artery pressure estimated >35 mm of mercury. In children, the relevant echocardiogram finding is estimated pulmonary artery pressure >35% of systemic pressure. With the disease etiology determined, patients are referred to a specialist.⁹

Regarding HSCT-TMA polyserositis, Jodele remarked, “Pericardial effusions are often part of polyserositis syndrome and occur in approximately 70% of patients with HSCT-TMA; they may have a delayed presentation or progress to tamponade acutely. Often pericardiocentesis with prolonged drainage is required.”

TMA-associated CNS injury may be determined by changes in the patient’s mental state, CNS bleeding, or posterior reversible encephalopathy syndrome (PRES). Since CNS injury is associated with hypertension, good blood pressure control is essential.¹⁰

Clinical manifestations of bowel injury stemming from HSCT-TMA may include mucosal casts, severe pain, blood in stool, or ileus; radiologic evidence includes ileus and thick mucosal wall. By endoscopy, mucosal erosions and mucosal hemorrhages may be observed. Enterorrhaphy may lead to ileus, feeding intolerance, and bacterial seeding. Enterorrhaphy is also detected by radiological study and is managed by administering parenteral nutrition until the bowel heals and/or surgical resection. Bowel injury can proceed to necrotic bowel.¹¹ Histology of intestinal TMA is characterized by loss of glands, mucosal hemorrhage, intraluminal schistocytes, fibrin and microthrombi, endothelial swelling or separation, and total mucosal denudation.^12,13

TMA With MODS

Skin injury is a visually dramatic result of HSCT-TMA, with the affected area showing swelling and bright red coloration, and histology showing complement deposits in the tissue.¹⁴TMA with MODS, is defined by Jodele as evidence of TMA and at least one of these organ dysfuntions:

• Renal: 50% reduction of cystatin C GFR pre-HSCT or the lowest value prior to diagnosis of TMA, or whichever is lower,
• Pulmonary: Any need for invasive or non-invasive positive pressure for ≥24 hours,
• Cardiovascular: PH diagnosed by cardiac catheterization or PH criteria on echocardiogram, such as right ventricular pressure ≥of systemic pressure, ventricular septal flattening or right ventricular dysfunction,
• Pericardial effusion: Significant effusion requiring medical or surgical treatment.
• Severe hypertension: Hypertension requiring antihypertensive medication for ≥12 hours,
• CNS: Seizure clinically attributable to posterior reversible encephalopathy syndrome,
• GI: Bleeding and/or strictures attributable to TMA requiring surgical or medical intervention.

Jodele’s group investigated whether there may be a genetic predisposition to the development of TMA. They found that patients following HSCT having >3 genetic variants of a specific complement gene showed a higher cumulative incidence (CI) of TMA compared with patients with 3 genetic variants (P = .0154).¹⁵

Complete guidelines for the complex procedure of diagnosing and monitoring HSCT-TMA have been formulated by Jodele and published.¹⁶ At the conference, she summarized the process, placing screening for TMA as the first step. When TMA is suspected, it is important to rule out thrombotic thrombocytopenic purpura (TTP) by ADAMTS13 activity (<10% = TTP). TA-TMA is suspected with ADAMTS13 activity ≥10% and may be confirmed by tissue histology, laboratory, and clinical markers.

Once high risk for TMA is established, patients may be treated with complement blockers, with low-risk patients monitored closely. All patients with TMA must be monitored for signs of TA-TMA associated organ injury.

“The take-home message is that HSCT-TMA has high risk disease features and must be detected by screening that may provide early recognition allowing for early intervention,” said Jodele, adding that a multidisciplinary approach to treating these patients are crucial. “The most important elements are awareness of TMA and establishing a collaborative effort between departments to identify and treat TMA-associated organ injury.”

References

1. Chansirikulchai S, Myerson D, Guthrie KA, McDonald GB, Aplers CE, Hingorani SR. et al. Renal thrombotic microangiopathy after hematopoietic cell transplant: role of GVHD in pathogenesis. Clin J Am Soc Nephrol. 2009;4(2):345-353. doi: 10.2215/CJN.02070508.
2. Jodele S, Davies SM, Lane A, et al. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 2014;124:645-653. doi: 10.1182/blood-2014-03-564997.
3. Kraft S, Bollinger N, Bodenmann B, et al. High mortality in hematopoietic stem cell transplant-associated thrombotic microangiopathy with and without concomitant acute graft-versus-host disease. Bone Marrow Trans. 2018. doi: 10.1038/s41409-018-0293-3.
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8. Dandoy CE, Linscott LL, Davies SM, et al. Clinical utility of computed tomography and magnetic resonance imaging for diagnosis of posterior reversible encephalopathy syndrome after stem cell transplantation in children and adolescents. Biol Blood Marrow Transplant. 2015;21(11):2028-2032. doi: 10.1016/j.bbmt.2015.07.023.
9. Dandoy CE, Linscott LL, Davies SM, et al. Clinical utility of computed tomography and magnetic resonance imaging for diagnosis of posterior reversible encephalopathy syndrome after stem cell transplantation in children and adolescents. Biol Blood Marrow Transplant. 2015;21(11):2028-2032. doi: 10.1016/j.bbmt.2015.07.023.
10. Laskin BL, Goebel J, Davies SM, et al. Early clinical indicators of transplant-associated thrombotic microangiopathy in pediatric neuroblastoma patients undergoing auto-SCT. Bone Marrow Transplant. 2011 May;46(5):682-9. doi: 10.1038/bmt.2010.182.
11. E-Bietar J, Warren M, Dandoy CE, et al. Histologic Features of Intestinal Thrombotic Microangiopathy in Pediatric and Young Adult Patients after Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2015;21(11):1994-2001.
12. Warren M, Jodele S, Dandoy CE, et al. A complete histologic approach to gastrointestinal biopsy from hematopoietic stem cell transplant patients with evidence of transplant-associated gastrointestinal thrombotic microangiopathy. Arch Pathol Lab Med. 2017;141:1558-1566.
13. Warren M, Jodele S, Dandoy CE, et al. A complete histologic approach to gastrointestinal biopsy from hematopoietic stem cell transplant patients with evidence of transplant-associated gastrointestinal thrombotic microangiopathy. Arch Pathol Lab Med. 2017;141:1558-1566.
14. Laskin BL, Maisel J, Goebel J, et al. Renal Arteriolar C4d Deposition: A Novel Characteristic of Hematopoietic Stem Cell Transplantation—Associated Thrombotic Microangiopathy. Transplantation. 2013 Jul 27; 96(2): 217—223. doi: 10.1097/TP.0b013e31829807aa.
15. Jodele S, Zhang K, Zou F, et al. The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy. Blood. 2016;127:989-996. doi: 10.1182/blood-2015-08-663435.
16. Jodele S. Complement in Pathophysiology and Treatment of Transplant-Associated Thrombotic Microangiopathies. Sem in Hematol. 2018;55(3):159-166. doi: 10.1053/j.seminhematol.2018.04.003.

Photo Credit: Sonata Jodele headshot. Children’s Hospital Los Angeles.