Includes: Thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, and c3 glomerulonephritis/dense deposit disease
Ramy M. Hanna MD FASN FACP 1, Umut Selamet FASN 1
UCLA David Geffen School of Medicine, division of medicine department of nephrology
The human immune system is a complex mixture of old defensive proteins known as the innate immune system, and the newer adaptive immune system consisting of targeted antibodies. These two systems normally work together to eliminate bacterial and viral invaders of the human body. When antibodies target a human body’s own tissues “autoimmune diseases” result. When the innate immune system malfunctions, diffuse clotting disorders occur that can have dramatically negative impacts on the kidneys amongst other target organ systems.
The complement system is an evolutionary ancient set of proteins that attack bacterial and viral proteins. Once the initial complement proteins recognize the foreign bacterial surface protein a chain of reactions occur that result in damaging the bacterial cell’s membrane leading to its death. There are some identifying proteins that protect human cells from destruction but this system does not always work properly-leading to disease.
Most patients with complement system disorders usually present with features that may include hemolysis (or destruction of red blood cells), low platelet counts, and kidney failure. Bleeding, clotting, strokes, seizures, and other catastrophic events can be associated with these disorders. These disorders can be difficult to diagnose, but timely diagnosis and treatment can be life-saving.
Thrombotic Thrombocytopenic Purpura (TTP)
TTP is one of the classically described complement diseases though the cause of it is not directly related to the complement protein directly. It is due to an abnormal level of a protein that prevents platelet clumping or aggregation called ADAMTS13 (ADAM Metallopeptidase with Thrombospondin Type 1 Motif 13). ADAMTS13 prevents abnormal platelet clumping by processing another protein called Von-Willebrand Factor (vWF). Conceptually long strings of platelets form with abnormally processed vWF protein and shear apart red blood cells resulting in inflammation, pigment damage to kidneys, and greatly increased risk of clotting despite a very low platelet count. The causes of low ADAMTS13 (<10%) activity could include genetic absence of protein (Upshaw-Shulman syndrome), consumption of ADAMTS13 in classic TTP due to various causes, or existence of an inhibitor.
Once this diagnosis is made by finding a very low level activity level of ADAMTS13, the treatment of choice is plasma exchange (also known as plasmapheresis). This is a procedure where blood is removed from the body through a catheter and separated into compartments based on the weight by spinning the blood rapidly around a cylinder. The filter then removes the portion of blood called plasma that contains all the antibodies in the blood. This has effect of removing specific antibodies in the blood against ADAMTS13 present in some cases of TTP. Part of the treatment process also involves giving back fresh frozen plasma instead of removed plasma, and this replaces the depleted ADAMTS13 with fresh co-factor that helps reduce the severity of the disease. The onset of this disease can be very rapid resulting in catastrophic events if immediate plasma exchange is not done.
Typical Hemolytic Uremic Syndrome (HUS)
HUS is another syndrome that can result in a TTP like picture, namely red cell hemolysis, drop in number of platelets, and organ damage like kidney failure. In this syndrome however, the cause is not reduced ADAMTS13 activity (>10%), but disruption of the complement system by a bacterial toxin. This bacterial toxin is the same one found in Shigella and the entero-hemorrhagic E.Coli (O157H7 strain) that has been reported to cause fatal cases of food poisoning. Treatment usually involves supportive care, antibiotics only in very serious cases of food poisoning with evidence of bacterial sepsis in the blood. It is usually seen in children but can be seen in adults as well. This syndrome occurs rapidly after infection with gram negative bacteria (a certain type of bacterial designation based on cell membrane), and often resolves after the infection is controlled.
Atypical Hemolytic Uremic Syndrome (aHUS)
This syndrome appears very similar to TTP and typical HUS clinically including features of low platelets, hemolysis, and kidney failure; but the root cause is quite different. This is a syndrome generally caused by a self-activated complement system (auto-activation). This can be due to medications, cancer, auto-immune disease, or a variety of genetic mutations. The complement system activates itself in a continual loop resulting in ongoing cellular damage to the patient. The ADAMTS13 level mentioned above is generally not reduced (>10%). The damage done to the body by this disease is usually rapid in onset.
Though this disease appears similar to the ones discussed above the drop in platelet count tends to be less severe, and the kidney failure tends to be more rapid in onset and more severe. However, it is important to mention that clinical features of this disease can vary widely between different patients. The management of this disease is generally ineffective with plasma-exchange. Complement inhibiting medications are available and are highly effective for treatment of this disease, though they do come with some risks of certain infections. It is vitally important to distinguish this disease from HUS and TTP since treatment is different very and the cause is more likely genetic in HUS. Genetic testing in generally helpful in predicting recurrence risk, but only 50-70% of these tests reveal a mutation, mostly since all mutations of the different proteins of the complement system are not known yet.
Paroxysmal nocturnal hemoglobinuria (PNH)
Paroxysmal Nocturnal Hemoglobinuria (PNH) is a very rare and complex blood disorder that results in hemolysis (destruction of red blood cells), a greatly increased risk of clotting (thrombophilia), and free heme pigment protein that floats in blood and ends up in urine (hemoglobinuria) resulting in kidney damage. Other cell lines (platelets and white blood cells) can be low in this disorder as well, and pancytopenia (decrease in all three blood cell lines) can sometimes be seen. Typically people with other bone marrow disorders that involve abnormal production of red blood cells, white blood cells, and platelets are at higher risk for the acquired form of the disease.
The mechanism that causes red cell destruction in PNH is an inborn or acquired mutation of a self-protecting complex sugar structure (poly-saccharide) known as the GPI anchor on red blood cells. Other proteins that protect red and white cells from lysis may also be affected in this disorder. This disease is identified by a specific test (flow cytometry) that identifies if cells have functional or dysfunctional GPI anchor sugar structures.
C3 Glomerulonephritis and Dense Deposit Disease (DDD)
In contrast to the rapid onset of the disease mentioned above, this disease is slowly progressive presenting more as spilling of protein and blood in urine. There are usually no blood count abnormalities. The chief findings include a low C3 (complement protein 3) level that is usually isolated, kidney failure, protein in urine, and blood in urine. The cause maybe due to a genetic mutation in complement or an antibody that binds and changes the proper function of the C3 protein- called a C3 nephritic factor.
The treatment for this disorder is controversial and there are no established firm guidelines. Complement binding medications may eventually be found to have a role, but so far no firm guidelines exist about treating this disorder. Transplantation maybe done but does pose some risk, especially if the patient has a mutation, as recurrence rate of disease can be rather high.
Conflict of interest report: Dr. Ramy M. Hanna is a member of the Alexion speaker’s bureau, Alexion is a pharmaceutical company that manufactures medications that are approved by the Food and Drug Administration (FDA) to treat the complement disorders aHUS and PNH.
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