Notes on Thrombotic Microangiopathy

1. TMA are of diverse etiologies but have unified manifestation

   1. MAHA (Coombs negative, increased LDH, schistocytes)
   2. Thrombocytopenia
   3. Organ injury (ischemic)

2. TMA has unified pathogenesis

   1. Endothelial dysfunction
   2. Microinfarcts

3. Approach to treatment

   1. Primary TMA syndromes (ADAMTS deficiency, HUS): treatment to be of the cause
   2. Secondary TMA syndromes: treat the precipitating cause

ADAMTS deficient TTP

1. Classification

   1. Hereditary (ADAMTS deficiency): homozygous or compound heterozygous mutations.
   2. Acquired (anti ADAMTS antibodies)

2. ADAMTS cleaves the ultra-large vWF polymers into smaller fragments, which lead to controlled platelet adhesion. In the absence of ADAMTS, the ultra-large vWF polymers leads to excess platelet plugs in high flow vascular beds, leading to clinical features of TTP.

3. Unique in that Renal Failure is rare complication. Lungs are not involved (Uptodate).

4. Recurrent MAHA, neurological deficits, organ injury

5. Clinical manifestation requires additional environmental and genetic factors

6. Weakness, GI symptoms, purpura, transient neurological symptoms

7. ADAMTS activity < 10% of normal is associated with high chances of recurrence. But, it is not adequately sensitive and specific to include or exclude patients.

8. Treatment

   1. Plasma replacement
   2. Plasma derived Factor VIII concentrate (contain ADAMTS)
   3. Without plasmapheresis, survival 10%, else 78%
   4. Glucocorticoid (standard), Rituximab and other immunosuppressives in complicated cases

9. Long term complications

   1. Relapse
   2. Dementia, cognitive impairment, major depression
   3. SLE
   4. Hypertension
   5. Early deaths

Complement mediated TMA

1. Predominant renal involvement (HUS)

2. Complement factor H (complement pathway inhibitor) deficiency

3. Multiple mutations leading to excessive activation of alternate complement pathway

4. Classification

   1. Hereditary
   2. Acquired (antibodies)

5. Alternate complement pathway is constitutively active due to spotaneous hydrolysis of C3 to C3b. Unregulated contued activation of complement pathway can lead to endothelial and platelet activation.

6. Mutation can be of two types

   1. Gain of function mutation of complement factors (C3, CFB)
   2. Loss of function mutation of complement inhibitors (CFH, CFI, CD46)

7. Heterozygous mutations are symptomatic

8. AKI and hypertension main features

9. ADAMTS < 5%, negative Shiga toxin

10. Genetic studies available

11. Normal complement levels do not exclude the diagnosis

12. Treatment

    1. Plasma replacement
    2. Anti complement treatment (Eculizumumab) (High cost, increased chances of meningococcal infections). Can be tried when antibodies against complement factor H present
    3. Immunosupression
    4. Liver transplantation

13. Long term outcomes

    1. Chronic Renal Failure
    2. Recurrence after renal transplantation

Shiga Toxin Mediated HUS

1. Shiga toxin producing E coli and S dysenteriae

2. ST binds to the CD 77 on the endothelial cells and renal mesangial cells and podocytes, leading to endothelial activation and proinflammatory and prothrombotic state (by inducing vWF secretion).

3. Acute bloody dysentry, recovers, followed by renal invovlement

4. ST detectable in stool during colitis phase, but not after that

5. Treatment

   1. Largely supportive
   2. Hydration is reno-protective
   3. Role of plasma replacement and anti complement therapy is doubtful

6. Long term complications

   1. Hypertension and neurological abnormalities may persists
   2. ESRD may rarely occur

Drug Mediated TMA (immune reaction)

1. Quinine, Quiteapine, Gemcitabine

2. Caused by: Drug dependent antibodies leading to endothelial activation

3. Sudden onset systemic symptoms, with anuric acute kidney injury, within hours after drug intake

4. Treatment: Supportive care and avoidance of drug

5. Long term complications: CKD and hypertension common. ESRD may occur.

Drug Mediated TMA (toxic dose related)

1. Immunosuppressive, chemotherapeutic agents, VEGF inhibitors

2. Evidence supporting causal role limited

3. CNI: direct endothelial injury and platelet aggregation due to inhibition of prostacyclin

4. VEGF inhibitors: decreased endothelial and podocytes VEGF lead to TMA

5. Gradual loss of kidney function with hypertension

6. Treatment: Supportive care and drug avoidance. For CNI, drug dose reduction may suffice

Metabolism mediated TMA (Uptodate)

1. Exclusively hereditary

2. Mutations in the MMACHC gene

3. Elevated homocysteine and low methionine levels are seen in plasma. Methylmalonic aciduria.

4. Treatment: High-dose vitamin B12, betaine, and folinic acid.

Coagulation mediated TMA

Secondary TMA (MAHA and thrombocytopenia)

1. Systemic Infection

   1. Viral: CMV, EBV, HIV
   2. Fungal: Aspergillus, Mucor
   3. Bacterial infections, Rickettsial, Malaria, IE

2. Systemic Malignancies

3. Autoimmune diseases (SLE, APS, SS)

4. Pre-ecclampsia, HELLP (D/D Pregnancy associated TTP, Complement mediated TMA can lead to post partum AKI)

5. DIC

6. Severe Hypertension (Can cause AKI or AKI can lead to severre hypertension. Rapid normalisation of BP is the key to management)

7. Post Hematopoeitic Stem Cell Transplantation

8. Acute graft rejection post renal transplantation

Important practical guidelines

1. A lack of improvement within several hours to three days after delivery of a pregnant patient decreases confidence that the symptoms were due to a pregnancy syndrome (preeclampsia/HELLP).

2. A longer duration of severe back pain (eg, weeks) or pulmonary symptoms increases suspicion for a malignancy and decreases confidence in a primary TMA.

3. High fever with chills increases suspicion for a systemic infection and decreases confidence in a primary TMA.

4. Severe hypertension with MAHA, thrombocytopenia, kidney failure, and neurologic abnormalities, even with documentation of TMA on a kidney biopsy, may be most effectively managed by treatment of the hypertension rather than PEX for a suspicion of TTP.

5. An established diagnosis of systemic lupus erythematosus (SLE) with MAHA, thrombocytopenia, and nephritis, even with documentation of TMA on a kidney biopsy, may be most effectively managed by treatment of the SLE rather than PEX for a suspicion of TTP.

6. A lack of early response to PEX (eg, first three or four days) for suspected TTP encourages us to continue to seek other causes of the patient’s symptoms.

Urgency of PEX (Definite role is there for TTP and complement mediated TMA)

1. A patient who walks into the primary care office after several days of not feeling well with severe anemia, thrombocytopenia, fragmented red blood cells (RBCs), and no or negligible kidney failure must be suspected to have TTP, and urgent initiation of PEX is appropriate. This is a common presentation of TTP.

2. If there is a history consistent with a drug-induced TMA (DITMA; eg, abrupt onset of nausea and anuria hours after a quinine-containing beverage, or after intravenous drug use, or if there is the gradual development of hypertension and kidney failure after several weeks or longer of treatment with a calcineurin inhibitor or chemotherapy), it may be possible to avoid PEX.

3. Following delivery in a pregnant patient, if there is rapid development of acute kidney injury with anticipated need for dialysis, postpartum complement-mediated TMA is likely; anti-complement treatment should occur promptly, without PEX.

Nature of renal involvement

1. Minimal or no kidney injury: TTP

2. Sudden, severe kidney injury: Immune mediated DITMA

3. Onset of kidney injury over days: Complement mediated TMA, ST-HUS

4. Onset of kidney injury over weeks and months: Toxic DITMA