Refractory Hypertension Post-BMT: TMA is a Critical Diagnostic Consideration
Yes, you should strongly suspect transplant-associated thrombotic microangiopathy (TMA) in this 5-year-old with refractory hypertension following bone marrow transplant, especially given the presence of GVHD and immunosuppressive therapy with calcineurin inhibitors and steroids.
Why TMA Should Be at the Top of Your Differential
Key Risk Factors Present in This Case
This patient has multiple established risk factors for post-BMT TMA:
- GVHD (grades II-IV) is the strongest predictor of TMA development, with multivariate analysis showing it as the primary correlative factor 1
- Calcineurin inhibitor exposure (tacrolimus or cyclosporine) causes renal vasoconstriction and long-term vascular structural changes that trigger TMA 2, 3
- Corticosteroid therapy contributes to hypertension through multiple mechanisms including sodium retention and vascular changes 2
- CNS involvement (HLH with CNS disease) may indicate higher risk for microvascular complications 3
The TMA-Hypertension Connection
Severe uncontrolled hypertension in post-BMT patients triggers a vicious cycle: pressure-induced renal natriuresis leads to autoregulation failure, increased vascular resistance, and renin-angiotensin system activation, causing further microcirculatory damage 4. This creates refractory hypertension that responds poorly to standard antihypertensive regimens 5.
Immediate Diagnostic Workup Required
Laboratory Tests to Order Now
- Peripheral blood smear looking specifically for schistocytes (fragmented RBCs) 4, 6
- LDH level (expect elevation >2x normal if TMA present) 4, 6
- Haptoglobin (expect decreased or undetectable) 4, 6
- Platelet count (thrombocytopenia is critical diagnostic criterion, often severe) 4, 6
- Hemoglobin/hematocrit (assess for microangiopathic hemolytic anemia) 6
- Serum creatinine and eGFR (renal involvement is common) 1, 5
- Direct Coombs test (should be negative in TMA) 6
- ADAMTS13 activity level (to distinguish TTP from other TMA forms, though post-BMT TMA typically has normal ADAMTS13) 6
Critical Diagnostic Criteria
TMA diagnosis requires the triad of 6:
- Thrombocytopenia
- Microangiopathic hemolytic anemia (negative Coombs, elevated LDH, reduced haptoglobin, schistocytes)
- Organ involvement (renal impairment, hypertension, neurological symptoms)
What You May Be Missing
Intestinal TMA Mimicking GVHD
A critical pitfall: Intestinal TMA can present identically to progressive GVHD with severe refractory diarrhea 7. In a series of 16 patients, 6 were misdiagnosed with progressive GVHD and received intensified immunosuppression—all died 7. The 9 patients correctly diagnosed with intestinal TMA who had immunosuppressants reduced (not increased) showed gradual improvement, with 6 surviving beyond 12 months 7.
The Sirolimus Connection
If this patient received sirolimus as GVHD prophylaxis or treatment, this significantly increases TMA risk. In the BMT CTN 1501 trial, sirolimus caused TMA in 10% of patients versus only 1.6% with prednisone alone 2.
Management Algorithm
Step 1: Confirm or Exclude TMA (Within 24-48 Hours)
- Send all laboratory tests listed above immediately 6
- Do not wait for ADAMTS13 results to act 6
- Consider colonoscopic biopsy if severe GI symptoms present to differentiate intestinal TMA from GVHD 7
Step 2: If TMA Confirmed
Immediately modify immunosuppression 7:
- Discontinue or reduce calcineurin inhibitors (tacrolimus/cyclosporine) as these are primary triggers 3, 5
- Reduce corticosteroid dose if clinically feasible 7
- Stop sirolimus if being used 2
Aggressive blood pressure control 4:
- Target BP <130/80 mmHg in this transplant patient 2
- Use combination antihypertensive therapy with complementary mechanisms 2
- Consider adding spironolactone if not already on board (provides substantial BP reduction in resistant hypertension) 2
- Monitor creatinine and potassium closely with any medication changes 2
Consider complement blockade therapy:
- Eculizumab may be appropriate for complement-mediated TMA 4, 6
- Requires meningococcal vaccination and penicillin prophylaxis 6
- FDA-approved for atypical HUS with demonstrated efficacy 8
Step 3: If TMA Excluded
Evaluate for other causes of refractory hypertension in transplant patients 2:
- Transplant-related renal artery stenosis
- Chronic kidney disease from conditioning regimen (especially if TBI used) 5
- Medication effects (calcineurin inhibitors cause hypertension independent of TMA) 2
- Volume overload from renal dysfunction
Common Pitfalls to Avoid
Do not intensify immunosuppression if intestinal symptoms worsen without confirming this is GVHD and not TMA—this mistake is fatal 7
Do not transfuse platelets unless life-threatening bleeding present, as this can worsen TMA 6
Do not delay diagnosis waiting for complete workup—TMA mortality remains high (up to 70% in some series) despite treatment 3
Do not assume normal platelet count excludes TMA—early or mild TMA may have only modest thrombocytopenia 4
Monitor for TMA even without CNI exposure—TBI-based conditioning alone increases TMA risk significantly 5
Prognosis and Monitoring
Post-BMT TMA carries high mortality despite aggressive therapy 3. However, early recognition and appropriate management (particularly reduction of offending immunosuppressants rather than escalation) significantly improves outcomes 7.
Long-term monitoring is essential: Even if acute TMA resolves, this patient remains at risk for chronic kidney disease, with 2-year cumulative incidence approaching 50% in TBI-exposed patients 5. The combination of TBI exposure, TMA diagnosis, and older age are independent risk factors for CKD development 5.
The presence of grades II-IV acute GVHD, female recipient/male donor mismatch (if applicable), TBI >1200 cGy, and viral infections (particularly adenovirus) all increase TMA risk and should prompt heightened surveillance 1.