TTP-aHUS

 Causes of thrombotic microangiopathies beyond TTP and HUS

1. Sepsis
2. DIC
3. Malignant hypertension
4. Pregnancy
5. Drug induced
6. Cancer associated
7. Hematopoietic Stem cell transplant TMA
8. Cobalamin C defect
9. DGKE deficiency

Reference: ASH education TTP HUS and beyond

Approach- pearls

1. In a patient who responds poorly to PEX with no other clear explanation for the TMA findings, a diagnosis of aHUS might then become more plausible on the differential diagnosis as an explanation for the TMA.

2. In many of these disorders, the ADAMTS13 activity will be below “normal” or even very low (10%-20%) but not severely deficient (<10%), which typically characterizes acquired TTP

Let us look at the uncommon ones first:

a. DGKE deficiency presents in the first year of life and PEX does not work.

b. Cobalamin C defect: Extremely rare but important to identify.

Patients present with pulmonary artery hypertension, kidney failure, hyperhomocysteinemia, decreased methionine, and normal vitamin B₁₂ levels. Recovery is typically complete after starting treatment, which includes high-dose hydroxycobalamin, betaine, and folinic acid.

c. Hematopoietic stem cell transplant-associated TMA--> TA-TMA

TA-TMA commonly affects the kidneys and results in transfusion-dependent anemia and thrombocytopenia; however, it can also present with multisystem organ injury that includes: pulmonary hypertension, intestinal TMA, posterior reversible encephalopathy syndrome (secondary to uncontrolled hypertension), and polyserositis. Proteinuria and elevated LDH.

Trigger for complement activation ( could be a board question)-copy number variants in genes CFHR3-CFHR1 and acquired complement dysregulation through the formation of neutralizing autoantibodies to Factor H.

Treatment: Eculizumab, supportive care, discontinue calcineurin inhibitors

PEX not very effective <50%

d. Atypical HUS: Complement mediated disorder due to  either

-loss of function mutations in factor H ( board question)

-gain-of-function mutations in factor B or C3 that are potentially pathologic in aHUS

e. TMA in cancer: chemo induced, or bm involvement. Gastric, breast and mucinous adenoca at highest risk.

Compared with patients with acquired TTP, patients with cancer-associated TMA may have new or exacerbated hypertension, greater pulmonary involvement (dyspnea, cough, abnormal chest radiograph), or a leukoerythroblastic reaction on peripheral smear

Rx: treat cancer, no role for PEX, stop any offending drugs.

Common drugs in cancer associated with TMA: different immunotoxins, immunotherapy, anti-VEGF therapy (appears to be a class effect), and imatinib

f. Drug induced TMA- commonest drug is quinine. Ask for OTC anticramp tonics.

2 mechanisms- immune mediated and direct endothelial injury.

Quinine induces TMA by immune mechanism.

Direct toxicity- sirolimus and tacrolimus reduce VEGF on endothelial cells

Rare case report of bortezomib and carfilzomib induced TMA. 

Diagnosis: can be made by drug dependent antibodies

 The most common drugs associated with immune-mediated DI-TMA are quinine, oxaliplatin, and quetiapine, 

Direct toxic mechanism are cyclosporine, tacrolimus, sirolumus, bevacizumab, interferons α and β, and mitomycin. 

Gemcitabine is the only medication that has been associated with both immune-mediated³⁷  and toxic mechanisms.  Illicit drugs, specifically cocaine and IV use of oxymorphone (OPANA ER), have also been reported to cause a DI-TMA

Treatment:

1. Avoid the drug, renal recovery is the slowest, CBC improves faster

2. With immune toxicity, never rechallenge, with direct toxicity ok to rechallenge

3. PEX no use

4. Can consider eculizumab for gemcitabine TMA

HELLP syndrome- treatment --> delivery of baby, control BP

Atypical HUS is common post partum; 1/3 of HELLP can be post partum, otherwise mostly in weeks 28-36.

ddx fatty liver of pregnancy-- often indistinguishable from  HELLP. the only diagnosis to rule out is infectious hepatitis and if this is negative, plan to deliver the baby and maximize supportive care.

Clinical pearl--> in acute fatty liver of pregnancy-DO NOT do a liver bx

Liver biopsy should not be performed to confirm a diagnosis of AFLP or to distinguish AFLP from severe pre-eclampsia, because management of both conditions are the same.