Thrombotic Microangiopathies

Bourbon-Street

Thrombotic microangiopathies (or TMA for the cool kids or the occasional phonetically-challenged fellows like myself) have always been a little tricky so I decided to do a quick review today to help clear things up a bit. First I’ll start with some questions and try to jump into the meat of things.

Question 1

A 49 year female with a past medical of possible sickle cell, hypertension, sciatica and cervical radiculopathy comes in complaining of 2 hours of facial drop, right arm weakness/numbness, and slurred speech. The patient is found to have unremarkable metabolic panel, but blood count shows platelets of 16,000 and mild anemia with hemoglobin of Hgb of 8.9. LFTs show total bilirubin of 1.7. CT of the head is unremarkable and vitals show mildly elevated BP.

What other test would be useful in further evaluating this patient?

A.Peripheral smear
B.EKG
C.LDH
D.Haptoglobin
E.EMG
F.A,C and D
G.All of the above

 

Answer: F
A peripheral smear would be useful here to evaluate for schistocytes. An elevated LDH and total bilirubin, in addition to decreased haptoglobin and hemoglobin raise the suspicion of hemolytic anemia.

Question 2

The patient is diagnosed with worsening of her cervical neuropathy and discharged home with gabapentin and pain medication. Two days she is found down at home with seizure like symptoms. She is transferred to nearest ED and found to have platelets of 10,000, hemoglobin of 6.4, schistocytes on peripheral smear and creatinine of 1.2 with no urine output. On exam she febrile, euvolemic, but is altered with a GCS of 8.

What intervention will most likely be most effective in this patient?

A.Hemodialysis
B.IVIG
C.ACE Inhibitor
D.Plasma Exchange
E.Fish Oil

 

Answer: D

This This patient likely has TTP (thrombotic thrombocytopenic purpura) given MAHA, severe thrombocytompenia, fever, AKI, CNS manifestations. Whether genetically determined ADAMTS13 deficiency or immune-mediated deficiency may benefit from exchange.

  • Genetically determined ADAMTS13 may benefit from both plasma infusion and exchange because both may replace the defective activity.
  • Immune mediate ADAMTS13 deficient patients tend to do well with just exchange as auto-antibodies are removed.

 


Intro

Thrombotic Microangiopathies pathologically results in thrombosis in capillaries and arterioles due to endothelial injury. Classically Hemolytic Uremic Syndrome (HUS) and Thrombotic Thrombocytopenic Purpura (TTP). Other conditions where you can have TMA (pathologically):

  • DIC
  • Scleroderma Renal Crisis
  • Malignant Hypertension
  • AntiPhospholipid Antibody Syndrome
Picture1

Picture1. TMA

As seen in the picture above you see thrombocytopenia and microangiopathic hemolytic anemia (MAHA, finally a 4 letter acronym to break up the 3 letter monotony). The coombs doesn’t always have to be ordered in this work-up, unless there is concern for autoimmune hemolytic anemia.

Picture 2.

Picture 2.

Renal Pathology

Question 3: What is seen below in the following EM?

EM1

 

A.Electron-dense subepitheial deposits
B.Electron-lucent subendothelial deposits
C.Fibrin clot
D.All of the above

 

Answer: B

Glomerular capillary in hemolytic-uremic syndrome (HUS). The endothelium is detached from the glomerular basement membrane (GBM); the subendothelial space is widened and occupied by electron-lucent fluffy material and cell debris (arrow). Beneath the endothelium is a thin layer of newly formed GBM.

 


Question 4: What is seen in the EM below?

EM2
A.Electron-dense subepitheial deposits
B.Electron-lucent subendothelial deposits
C.Lumen Occlusion
D.All of the above

 

Answer: C

Renal arteriole in hemolytic-uremic syndrome (HUS). The vascular lumen is completely occluded by thrombi. There is marked intimal edema with consequent separation of myointimal cells.

Characteristic Findings in TMA

1.Widening of the subendothelial space

2. Microvascular thrombosis.

3. Detachment of the endothelial cells from the basement membrane. (with the accumulation of fluffy electro-lucent material in the subendothelium)

 


Differential Diagnosis

Picture3


TTP

A

Disintegrin

And

Metalloprotease with

Thrombo-

Spondin

13 (domain)

Picture 4

Picture 4

ULvWF (ultra largevWF) multimers are synthesized in endothelial cells but are rapidly degraded by ADAMTS13. Therefore if ADAMTS13 is low ULvWF is left in circulation where it can attach to platelets and promote aggregation.

Treatment

Genetic
  • Plasma exchange or infusion
  • Steroids
Acquired
  • Plasma exchange only
  • Steroids
Refractory or Recurrent
  • Rituximab
  • Vincristine


HUS

HUS comes in two flavors: the well known shiga toxin-associated HUS (Stx-associated) and Atypical HUS (aHUS). StxHUS is the commonly thought of cause of HUS in which E. coli O157:H7 or shigella dysenteriae. Atypical HUS is largely due to one or several genetic mutations that cause chronic activation of complement. This results in platelet activation and endothelial damage which sparks the cycle seen in picture 2.

Treatment

Stx-associated:
  • Adults plasma exchange (up to 16 days) lowers risk of ESRD and mortality.
  • Children no plasma exchange and no steroids
aHUS:
  • Eculizumab if factor H mutation
  • Liver transplant to cure complement genetic defect (factor H)

 



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You now have 30 beans.
Use them wisely, my friend.

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