Alright, this is totally complicated. What is the best way to approach this?

Slowly. And my way of understanding it.

Ok, let’s start with what TMA actually is: thrombosis in capillaries and arterioles, due to an endothelial injury.

Clinical features?

  1. Thrombocytopenia
  2. MAHA
  3. Organ injury

Simply put, TMA can be subcategorised MANY different ways.

They include HUS, TTP,disseminated intravascular coagulation, scleroderma renal crisis, malignant hypertension, antiphospholipid antibody syndrome, and drug toxicities, e.g. calcineurin inhibitor toxicity

For the purpose of this entry, I will focus on HUS (typical and atypical), TTP, aHUS and just very quickly, because it is renal – TMA in transplant rejection.

Haemolytic Uraemic Syndrome

The syndrome of:

  • MAHA (shearing of RBC through platelet micro thrombi)
    • Tests: Coombs (will be negative), haemolytic screen, blood film, LDH
  • Thrombocytopenia
  • AKI (normally hypertensive)

Causes:

Typical/Secondary:

  • Infection
    • Shiga toxin-producting E. Coli (STEC)/verotoxin 0157
    • Shigella
    • Strep Pneumonia
    • HIV
  • Drugs
  • Preganancy
  • Other autoimmune conditions

Other organs affected:

  • Central nervous system – Manifestations of central nervous system (CNS) involvement include seizures, coma, stroke, hemiparesis, and cortical blindness.In addition, severe hypertension may result in CNS symptoms and require emergent therapy to decrease blood pressure. The presence of severe hypertension and the response to antihypertensive therapy differentiates CNS involvement due to elevated blood pressure.
  • Gastrointestinal tract – Any area from the esophagus to the perianal area can be involved. The more serious manifestations include severe hemorrhagic colitis (which may be misdiagnosed as ulcerative colitis), bowel necrosis and perforation, rectal prolapse, peritonitis, and intussusception. Transmural necrosis of the colon may lead to subsequent colonic stricture.
  • Cardiac dysfunction – Cardiac dysfunction can be due to cardiac ischemia detected by elevated levels of troponin and fluid overload.
  • Pancreas – During the acute phase, up to 10 percent of patients develop glucose intolerance. Transient diabetes mellitus may occur, and rarely permanent diabetes mellitus, which may develop years later.
  • Liver – Hepatomegaly and/or increased serum transaminases are frequent findings.
  • Hematology – In addition to anemia and thrombocytopenia, leukocytosis is common in diarrhea-induced HUS; the prognosis is worse with increased white blood cell counts

 

Thrombotic Thrombocytopenic Purpura

Slide1

  • Severe AKI is unusual in TTP
  • Hereditary TTP (also called Upshaw–Schulman syndrome) is caused by homozygous or compound heterozygous ADAMTS13 mutations.
  • Acquired TTP is an autoimmune disorder caused by autoantibody inhibition of ADAMTS13 activity
    • ADAMTS13 is a von Willebrand Factor cleaving protease
    • Inhibition leads to large multimers of vWF, increasing risk of platelet thrombi leading to damage to endothelium
    • This leads to TMA and organ failureADAMTS13

 

  • In a nutshell, if you suspect TTP, TREAT! but send ADAMTS13 assay. If it is negative, it generally rules out TTP.

 

TMA in Transplant Rejection

  • Antibody mediated rejection
  • C4d + : Acute humoral rejection(AHR); C4d – : Acute cellular rejection (ACR)
  • Risk of graft loss is greater in AHRSlide2
    The Ab-Ag complex in AHR activates C1 which starts the pathway. C4d is a by product of this

 

Renal histology findings:

  • thrombosis of vessels
  • fibrinoid necrosis of arterioles
  • oedematous expansion of arteries – double contouring

Treatment

  1. Plasma exchange
  2. Eculizumab, an a monoclonal antibody to C5 that blocks the terminal complement cascade
  3. Renal +/- hepatic transplant
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