Table of Contents
Definition of Hemolytic Anemia
There are various forms of hemolytic uremic syndrome (HUS), but for ease of clinical management, they are often categorized into the following two types:
- Classical, typical, or diarrhea-positive or D+ or STEC HUS
- Atypical or genetic or diarrhea-negative or D- HUS
Epidemiology of Hemolytic Anemia
HUS is a cause of community-acquired acute renal injury in the pediatric population. It can occur at any age but is more common in children under 6 years. It occurs in all races and both sexes. Shiga toxin-producing E. coli or STEC is responsible for 90% of cases of HUS in children.
Etiology of Hemolytic Anemia
HUS has several etiologies:
Infection (STEC, HIV, Streptococcus pneumonia)
- Medications (Anti-VEGF, calcineurin inhibitors cyclosporine and tacrolimus [particularly in the setting of organ transplantation], clopidogrel, gemcitabine, mitomycin, oral contraceptives, quinidine, and ticlopidine)
- Genetic diseases (complementary gene mutation, vitamin B12 metabolic disorders, a congenital vWF deficiency)
STEC is found in the intestinal tracts of domesticated animals, so it is transmitted via undercooked meat or raw (unpasteurized) milk. Apple cider is another source of disease transmission. Rarely, STEC epidemics can occur due to contaminated vegetables (e.g., spinach and lettuce). Associations have been found with bathing in contaminated swimming pools, lakes, and ponds.
Pathophysiology of Hemolytic Anemia
The verotoxin produced by STEC is absorbed from the intestines. It causes endothelial injury, especially to the kidney (also brain and other organs), which results in clotting/thrombi formation as well as damage to red blood cells and platelets, especially when they pass through the kidney’s damaged microvasculature. The damaged cells and increased platelet activation cause the hematological signs of hemolysis and thrombocytopenia. Endothelial injury, directly or due to fibrin deposition, causes renal injury, leading to renal insufficiency and failure.
Mechanism of cytotoxic effects
The Shiga toxin binds to cells containing Gb3 receptors, which are abundant in human endothelial cells, podocytes, and proximal tubular cells. The toxin’s binding to the cells causes apoptosis.
Pneumococci-associated HUS has similar pathophysiology of toxin-induced damage. However, the toxin is n-acetyl neuraminidase, released by streptococcus pneumoniae. Here, n-acetyl neuraminidase damages the endothelial cells and exposes the hidden T antigen, which is acted upon by endogenous IgM, thereby triggering microvascular angiopathy.
In patients with atypical HUS, the pathophysiology is not related to the Shiga toxin. Most patients seem to have excessive activation of the alternative complement pathway. This is often triggered by an infection; however, the underlying predisposition stems from genetic defects, such as defects of von Willebrand factor–cleaving protease (ADAMTS13) or of complement factors H, I, or B.
There may be many focal ischemic sequelae resulting from the aforementioned pathophysiological changes. These can cause seizures in the central nervous system and similar changes in the other organ systems, sometimes leading to severe multisystem disease.
Symptoms of Hemolytic Anemia
Patients with pneumococcal respiratory disease have empyema, bacteremia, and/or pneumonia during acute-phase HUS. In cases of atypical HUS, the onset is more insidious. A mild respiratory or gastrointestinal disease may be present before the onset of HUS symptoms.
On physical examination, the child may have dehydration, hepatomegaly, and splenomegaly. Petechiae on the skin may be found, which is due to thrombocytopenia.
Most patients with HUS have some, usually mild, central nervous system involvement in the form of irritability and lethargy. In rare instances, patients may have seizures and other symptoms and signs of severe disease.
Diagnosis of Hemolytic Anemia
In addition to clinical signs and symptoms, laboratory test results are required for an accurate diagnosis.
- Elevated white blood cells: up to 30,000/mm3
- Low hemoglobin level (anemia): 5–9 g/dL
- Low platelets (thrombocytopenia): 20,000–100,000/mm3
- Peripheral blood smear (PBS) may show helmet cells, schistocytes, and burr cells—all evidence of hemolysis
- Urinalysis: microscopic hematuria and mild proteinuria
- Signs of renal insufficiency—oliguria, increased blood urea nitrogen levels and increased serum creatinine
Although the anemia is hemolytic, the Coombs test is negative. (However, it is positive in patients with pneumococci-associated HUS.)
The diagnosis is mainly clinical, so biopsies are rarely needed. Also, the risks of biopsy often outweigh the benefits.
Differential Diagnoses of Hemolytic Anemia
(Idiopathic) Thrombotic thrombocytopenic purpura is the main differential diagnosis of HUS. There are many overlaps in the presentation. Both diseases can present with the classical triad of HUS, although thrombocytopenic purpura usually has central nervous system involvement than renal involvement, and is somewhat more common in young women.
Some authors report that activity levels of ADAMTS13 can help differentiate between the two. Extremely low activities, i.e., < 10% (or < 5% by some authors) of that in normal plasma, is indicative of thrombotic thrombocytopenic purpura, whereas normal levels or those reduced to not less than 30% – 40% are more indicative of HUS or other thrombotic microangiopathies [Bianchi et al., Scully & Goodship].
Other differential diagnoses include the following:
- (Bilateral) renal vein thrombosis
- Malignant hypertension
Especially in the setting of atypical HUS, differentiating HUS from other causes of renal thrombotic microangiopathy can be difficult. Some of the tests that can help differentiate the two are as follows [Scully & Goodship]:
|Antiphospholipid antibody syndrome||Antiphospholipid antibodies|
|Cobalamin C disease||Homocysteine levels (plasma)
Methylmalonic acid levels (plasma and urine)
Treatment of Hemolytic Anemia
The treatment against HUS is mainly supportive (and also aimed at the prevention of complications). Oliguria and anuria should be monitored if not already present, and early intravenous volume expansion should be initiated; this may considerably reduce kidney injury/complications. For hemolysis, red cell transfusions should be given, at least until the acute phase of the disease is over.
However, the red cells must be washed before transfusion in patients with pneumococci-associated HUS to remove residual plasma. Platelets are generally not administered because they are rapidly used by the coagulative process. Serious bleeding is rare in HUS patients despite a low platelet count. Some therapies targeted against the pathogenetic processes have been found to worsen the disease instead.
Patients with atypical HUS should undergo a trial of plasma exchange, although only a small number of them respond to this, and often long-term therapy is required. However, besides being supportive, the treatment can be aimed at complement inhibition. The US FDA has approved eculizumab as a complement inhibitor in atypical HUS, in which it is very effective [Scully & Goodship].
Progression and Prognosis of Hemolytic Anemia
Early diagnosis and treatment have a very favorable outcome. HUS usually resolves after the acute phase, and most patients regain normal kidney function. Mortality is often less than 5%. The prognosis of atypical or diarrhea-negative HUS is somewhat more severe. There can be the following complications, and monitoring them is essential for improving the prognosis:
- Diabetes mellitus
- Heart failure
- Late-onset chronic renal disease (up to 30% of patients can have some extent of chronic renal insufficiency)
Patients with atypical HUS usually have poorer prognoses, with disease recurrence and longer-term renal insufficiency. The risk of relapse is as high as 40%. There is a very high chance of relapse in the first year, so meticulous follow-up is necessary. Nevertheless, there is considerable variation in prognoses depending on the genetic profile and other factors.
Some forms can have a graver prognosis, e.g., complement factor H deficiency almost always requires transplantation and has close to a 100% recurrence rate, even in transplanted kidneys. On the other hand, membrane cofactor protein mutation carriers tend to have a good prognosis [Fremeaux-Bacchi et al.].