Thrombotic microangiopathies

French national reference center for thrombotic microangiopathies

The thrombotic microangiopathies study network was labeled in August 2006, then re-labeled in 2017, as the national reference center for thrombotic microangiopathies.

The low incidence of thrombotic microangiopathies (TMA), the level of expertise required to manage them and their life-threatening severity in the short term fully justified the establishment of a dedicated reference center to facilitate access to diagnosis, organize the healthcare offer and optimize multidisciplinary patient follow-up while conducting clinical research.
Indeed, the severity of TMA puts at risk the vital and renal prognosis of patients in the short term; however, when optimally managed, these diseases can have an excellent prognosis. It is therefore necessary to know how to recognize them in order to quickly diagnose them and to institute specific treatment as a matter of urgency.

The Necker site of the reference center for thrombotic microangiopathies thus takes care of both children and adults. The pediatric and adult nephrology teams work closely together, allowing a transition of young patients to the adult sector and a continuum in the follow-up of these patients.

This reference center is affiliated with the MaRIH rare disease healthcare network and the ERKnet European reference network (ERN) .

bouton calculette Tension artérielle MARHEA anglais

Medical
team

Aude Servais Service Néphrologie Hôpital Necker à Paris.Avril 2016

Coordinating doctor
Dr Aude Servais

MD, PhD

Pr Olivia Gillion Boyer, néphrologue pédiatre

Pr Olivia Boyer
MD, PhD

Contact us
 

For a child :
Tel. +33 (0)1 44 49 44 67

Doctolib : prenez rendez-vous en ligne

 

 

For an adult patient :
Tel. +33 (0)1 44 49 54 16

Doctolib : prenez rendez-vous en ligne

In case of emergency

What is thrombotic microangiopathy (TMA)?

The term thrombotic microangiopathy (TMA) defines a group of diseases in which the body’s small blood vessels are clogged with platelet plugs. Different organs (kidneys, brain, digestive tract) can be affected depending on the cause of the TMA. The following occurence can be observed :

  1. A decrease in the number of platelets in the blood (or thrombocytopenia); platelets are the blood cells that help to clot during an injury ;
  2. A decrease in the number of red blood cells by destroying them on the platelet plugs (this is called mechanical hemolytic anemia) ;
  3. A dysfunction of the affected organs, variable according to the severity and the cause of the TMA. The organs most often affected are the kidney (kidney failure), the brain (thought or vision disorders, muscular deficit of a limb or even a stroke), the intestines or the heart.

Major therapeutic advances in recent years have considerably improved the long-term prognosis of TMA. Plasma exchanges, which consist in replacing plasma from patients with plasma from healthy donors, have been used since the 1970s and most often lead to remission of the disease. Very recently, better tolerated treatments, detailed in the « Treatment » tab, have proven their long-term efficacy (Rituximab in TTP, Eculizumab in atypical HUS). A rapid diagnosis allows the urgent implementation of an adapted treatment, guaranteeing the most favorable evolution possible. The field of knowledge of TMA has increased significantly in recent years.

What are the consequences?

The consequences are clinical (symptoms) and biological (abnormalities in blood or urine tests).

The common points of all TMAs are :

  1. Thrombocytopenia, i.e. a decrease in the number of platelets in the blood, which can cause bleeding ;
  2. Anemia, a decrease in the number of red blood cells in the blood, which can be responsible for fatigue and shortness of breath ;

Obstruction of small blood vessels has variable consequences, which may be asymptomatic or result in significant symptoms. The organs most frequently affected are the kidneys, the central nervous system, and more rarely the heart and intestines. The extent of organ damage varies; there may be no apparent suffering or, on the contrary, several organs may be affected at the same time.

All of these events justify the implementation of emergency treatment in a specialized service.

Are there several diseases?

Yes, the term TMA encompasses several diseases that have some commonalities, but whose mechanisms are different.
The 3 most common diseases are typical hemolytic uremic syndrome (typical HUS), atypical hemolytic uremic syndrome (atypical HUS) and thrombotic thrombocytopenic purpura (TTP). The mechanisms of occurrence of these diseases are distinct.
Hemolytic uremic syndrome :
There are two main types of HUS :
  1. In 90% of the cases, it is a typical HUS. Typical HUS is caused by bacteria secreting particular toxins called shiga toxins. Several bacteria have been identified, the best known is Escherichia coli O157:H7. Typical HUS is manifested by sometimes bloody diarrhea, associated with severe but transient acute renal failure, which may require dialysis. Bacterial contamination can typically occur through consumption of undercooked meat, contaminated water, or contaminated dairy products. In spring 2011, Germany experienced a major outbreak of typical HUS, linked to a particular strain of Escherichia coli (O104), responsible for nearly 855 cases. This outbreak was linked to the contamination of batches of sprouted seeds. Typical HUS preferentially affects children. Recovery is usually complete but requires long-term follow-up.
  2. HUS that are not associated with a bacterium are much rarer (10% of HUS), these are atypical HUS.
    – there are sometimes other cases in the family (hereditary HUS) ;
    – kidney damage is at the forefront, and may lead to dialysis and/or transplantation.
    – Genetic abnormalities have been highlighted on different genes involving molecules participating in the immune defenses: proteins of the alternative complement pathway, which are poorly regulated and attack the kidney.

Thrombotic thrombocytopenic purpura :

 What you need to know :
– It is not contagious,
– it can occur at any age,
– it is more common among women (3 women for 2 men),
– it can be promoted by pregnancy,
– the decrease in platelet count is generally very deep,
– kidney damage is usually moderate.
Most often, this disease is caused by the patient making antibodies that block the function of an enzyme, called ADAMTS13, which prevents the formation of excess platelet clots. It is exceptionally hereditary, and in this case most often diagnosed in the early years of life.
  1. Autoimmune TTP :

In the vast majority of cases, TTP is an autoimmune disease, i.e. patients make antibodies that recognize their own ADAMTS13 protein, instead of recognizing microbes (bacteria, viruses).

      2. Hereditary TTP :

In very rare cases, TTP is hereditary and results from mutations in the ADAMTS13 gene. There are currently a few dozen cases of hereditary TTP in France. Hereditary TTP is characterized by a permanent deficiency of ADAMTS13, which results in the patient being exposed to repeated relapses, requiring regular plasma infusions. These infusions effectively prevent relapses, which is important to prevent organ complications that may occur after years of evolution.
Patients with hereditary TTP should receive very specific follow-up during pregnancy, which includes plasma infusions throughout the pregnancy to prevent a relapse that would have serious consequences for the fetus and the mother.

Other situations in which a TMA may occur :

In some cases a TMA may be associated with another disease, such as cancer, human immunodeficiency virus (HIV) infection, or a marrow transplant. Some drugs (chemotherapy, some anti-rejection drugs) may be associated with TMA. The treatment is specific to each context.

What is the frequency of TMAs?

TMAs are rare diseases.

Their frequency is still rather poorly known, and it is estimated that between 5 and 10 new cases of TTPs occur per million inhabitants per year. The frequency of HUS is also very close to these values. It is estimated that 350 to 700 people may be affected each year in France.

Hereditary TTP is a very rare form of TMA, of which there are a few dozen identified cases in France.

When and how to think about it?

Symptoms are varied. Most often, they appear suddenly.

The most constant sign is a recent onset of fatigue, which is the consequence of a drop in red blood cells. Other symptoms that may be associated with it are red spots on the skin (purpura) related to the drop in platelets, dark urine, jaundice.

The triggering factor is often an infectious episode, most often diarrhea, a common cold, or flu-like illness. In early severe cases, there may be signs related to brain damage such as decreased vision, pins and needles, or decreased strength in one or more limbs (arms and/or legs). These manifestations are often transient.

The doctor seeing these manifestations will prescribe a blood test that will show anemia (low red blood cells), thrombocytopenia (low platelets) and sometimes kidney failure (high plasma creatinine).

In this case, the patient must be referred urgently to a specialized hospital in order to complete the assessment and start treatment early.

In patients who have already had one or more episodes of TMA, particular attention should be paid to the occurrence of these manifestations, which may indicate a relapse.

What is the treatment of TMAs?

The treatment depends on the type of TMA. It is a specialized treatment that must be administered in a reference center.

In the typical HUS associated with a shiga toxin occurring in children, treatment is symptomatic: rehydration, blood pressure control and dialysis sessions until renal function is recovered.

In atypical HUS and in TTP, the initial treatment is most often based on plasma exchanges.

Plasma exchanges are done with a machine that removes plasma from the patient and replaces it with fresh plasma obtained from voluntary donors. This machine is comparable to those used for blood donations. Plasma exchanges are efficient by bringing large volumes of plasma from voluntary donors that contain the ADAMTS13 protein (in TTP) or complement proteins (in HUS). By removing part of the patient’s plasma, plasma exchange also removes from the body substances involved in the MAT process such as autoantibodies and proteins that promote the formation of platelet plugs.

Corticosteroids can be combined.

Two molecules have proven their effectiveness in recent years in the treatment of TTP and atypical HUS :

1/ Rituximab prevents the production of antibodies by the patient by transiently destroying B lymphocytes. It is effective in TTP.

2/ Eculizumab blocks the terminal complement pathway activation involved in atypical HUS. Infusions carried out every 15 days make it possible to prevent a relapse of the disease.

How does the disease progress?

Although TMA remains a serious disease, considerable progress has been made in recent decades with a better suspicion of TMA diagnosis by all physicians and the establishment of reference centers that can be reached 7 days a week, 24 hours a day, allowing the rapid administration of an adapted treatment. The initial treatment is most often administered in intensive care units.

In the case of early and appropriate treatment, recovery can be complete. Chronic kidney disease is a frequent sequelae of HUS, whether typical or atypical. It requires regular long-term nephrology follow-up. It may progress to severe chronic kidney failure, requiring dialysis care and/or a kidney transplant. In atypical HUS, Eculizumab should limit the occurrence of chronic kidney disease.

How long do you need to be monitored?

Regular follow-up in a specialized environment is essential. Indeed, some patients may have a new episode of TMA after achieving remission.

Relapses occur most often in the case of TTP or atypical HUS with genetic complement abnormalities.

The risk of TTP recurrence during pregnancy is an important issue. Follow-up of the pregnancy of a patient with a history of TTP should be done in a specialized setting, in consultation with the referring physician and the obstetrics team, and in conjunction with the reference center.

In atypical HUS, monitoring is major because the risk of relapse is high, with each time renal failure that can lead to dialysis and/or transplantation. The use of Eculizumab should limit this unfavorable development in the future. For young children who have had an episode of HUS after diarrhea, the risk of TMA recurrence is almost nil. On the other hand, depending on the severity of the initial acute renal failure, nephrological surveillance is necessary over the very long term.

Post-diarrheal hemolytic uremic syndrome

What is post-diarrheal hemolytic uremic syndrome?

Hemolytic Uremic Syndrome (HUS) is a disease that affects both kidneys and other organs.

« Hemolytic » means that there is « destruction of red blood cells », which can lead to anemia with fragmented red blood cells (« schizocytes ») and decreased platelet counts (« thrombocytopenia »).

« Uremic » means that there is « urea in the blood ». Urea is a waste product of the body that is eliminated by the kidneys in the urine (see « kidney function » page). An increase in urea in the blood and other wastes such as creatinine is a sign of kidney failure, meaning that the kidneys cannot clean the blood properly or regulate the amount of water and other essential substances in the body.

In children, hemolytic uremic syndrome most often results from an infection of the intestines with a bacteria called Escherichia coli (E. coli). Certain types of E. coli can be very dangerous by producing toxins called « shiga toxins » or « STEC » which are responsible for hemolytic uremic syndrome.

These toxins cause damage to small vessels in the body which can be blocked by blood clots in the kidneys and sometimes other organs: brain, heart, liver, pancreas …

HUS is a serious disease. With appropriate care, the clinical course is favorable in a majority of patients.

How often is post-diarrheal HUS found in the population?

It is a rare disease that affects both boys and girls, especially small children and the elderly. It is the leading cause of acute kidney failure in children under 3 years of age. Approximately 100 to 120 children present a hemolytic uremic syndrome every year in France. The majority of reported cases are isolated. More rarely, epidemics may occur.

A national surveillance network set up in 1996 by the « Institut de veille sanitaire » (health watch institute) in collaboration with the pediatric nephrology society, makes it possible to record cases throughout metropolitan France.

What are the causes and means of transmission of post-diarrheal HUS?

Post-diarrheal » or « typical » or « STEC » hemolytic uremic syndrome

In children, hemolytic uremic syndrome most often follows an intestinal infection with toxin-secreting bacteria called Escherichia coli (E. Coli). These bacteria can withstand the cold well (they can survive several days in a refrigerator), but are destroyed by cooking.

We can contaminate ourselves :

  • By eating contaminated foods eaten raw or undercooked: beef (especially ground), unpasteurized milk or dairy products, apple juice, raw vegetables, or contaminated drinking water ;
  • By putting your soiled hands to your mouth, after touching animals carrying the bacteria or their contaminated environment ;
  • By contact with a sick person who excretes the bacteria in his or her stool.

Some types of E. coli can be very dangerous by producing toxins called « shiga toxins » or « STEC » which are responsible for hemolytic uremic syndrome.

A majority of people who get this bacteria will have gastroenteritis, which is diarrhea sometimes with mucus and blood in the stool, stomach pain and vomiting. Anyone can get E. coli gastroenteritis, but it is more serious in children and the elderly. About one in 10 children who have shigatoxin-producing E. coli gastroenteritis will develop HUS within days.

Some forms of HUS are unrelated to diarrhea.

Atypical HUS or HUS without diarrhea is another form of HUS. It is a more serious disease that sometimes has a genetic origin. All the genetic causes of hemolytic uremic syndrome are not yet known.

What are the symptoms of post-diarrheal HUS?

Hemolytic uremic syndrome manifests itself at any age but mainly affects young children. In 95% of cases, it occurs in the days following gastroenteritis due to E. Coli. Diarrhea can be mucus or bloody in half of the cases. The symptoms and laboratory abnormalities of HUS are often a few days later than the diarrhea. They are linked to the build-up of wastes, fluids and solutions in the blood that are no longer properly eliminated by the kidneys, low red blood cells and platelets, and damage to small vessels.

Symptoms of HUS may include the following :

  • Dark or red urine (« tea » or « Coca-Cola » colored pee)
  • A decrease in the volume of urine
  • Puffiness of the eyelids and swelling of the ankles (edema)
  • A pallor of the face
  • Bruises that are not caused by blows or falls, nosebleeds, bleeding gums
  • Excessive fatigue, drowsiness, irritability
  • Shortness of breath
  • Headaches
  • Epileptic seizures
  • High blood pressure

What tests should be taken for the diagnosis?

The diagnosis is confirmed by a blood test and urinalysis which detects a decrease in red blood cells (anemia) and in platelets (thrombocytopenia), the presence of fragmented red blood cells (schizocytes), as well as the accumulation of wastes in blood related to kidney malfunction (renal failure).

The bacterium that causes hemolytic uremic syndrome is also tested for by stool analysis in a specialized laboratory. Stools should be taken as soon as possible after the onset of symptoms (less than 6 days).

If there is any doubt about the diagnosis, specialized examinations may be necessary. Thus, a renal biopsy may be indicated at the time of diagnosis if there are clinical symptoms or laboratory findings suggesting that the symptoms are related to another disease. It may also be indicated some time later to assess kidney sequelae.

How does post-diarrheal HUS progress?

Most children recover from post-diarrheal HUS.

The length of your child’s hospitalization will depend on symptoms, on how your child responds to treatment and on how quickly his or her kidneys improve. The length of hospitalization varies greatly from patient to patient, ranging from a few days to several weeks.

However, in all cases, long-term nephrological monitoring will be offered. In fact, secondary HUS kidney scars may not be evident on laboratory tests until several years after the acute episode. Long-term follow-up in nephrology is therefore particularly important. In children, 5 to 10% of HUS progress to end-stage renal failure requiring the initiation of treatment such as long-term dialysis or kidney transplantation. The death rate is currently 1% in France.

Which organs are affected?

The toxins produced by bacteria cause damage to small vessels which can be blocked by blood clots in the kidneys and sometimes other organs: brain, heart, liver, pancreas … These complications are rare but potentially serious.

  • Kidney :
    Both kidneys are affected. Kidney damage can be manifested by dark or red urine ( « tea » or « Coca-cola » colored pee), less urine, edema : puffiness of the eyelids and swelling of the ankles, high blood pressure, abnormalities in the blood test.
  • Red blood cells and platelets :
    Anemia (low red blood cells) and thrombocytopenia (low platelets) can cause the following symptoms : shortness of breath, fatigue, facial paleness, bruises that are not caused by blows or falls, nosebleeds, bleeding gums. Jaundice of the eyes may occur and, more rarely, jaundice of the skin(icterus).
  • Brain :
    All symptoms can occur and should be warning : intense headaches, drowsiness, irritability, disorientation, double vision, visual or auditory hallucinations, epilepsy, difficulty to move a limb… They can be linked to abnormalities induced on the cerebral vessels but also secondary to renal dysfunction leading to the accumulation of toxins (urea) or to disorders of ions and water in the blood. A brain scan or MRI is then carried out as an emergency and a blood test is performed.
  • Heart :
    Angina pectoris, shortness of breath, palpitations… This condition is systematically investigated by a blood test and an electrocardiogram.
  • Liver :
    Jaundice, increased liver enzymes on the blood test.
  • Pancreas :
    Abdominal pain, elevation of pancreatic enzymes on blood tests, diabetes, chronic diarrhea…

What are the treatments to follow?

Your child will need to be hospitalized. The duration is very variable, from a few days to several weeks.
Currently there is no cure for hemolytic uremic syndrome. The purpose of treatments is to limit the consequences of HUS while waiting for the child to naturally eliminate toxins.

Children with HUS often need :

  • Transfusions of red blood cells (very rarely platelets)
  • A limitation on the amount of drinks allowed during the day. Take note of the entire amount drunk and do not give more water to the child than the allowable amount.
  • A diet low in salt, potassium (fruits and vegetables), phosphorus and proteins (meats, dairy products). Meals will be determined by a dietician and other foods should not be given without the consent of the medical team.
  • An infusion or tube feeding if he is too tired or nauseous to eat on his own.
  • Treatments to lower the level of potassium and phosphorus in the blood, and balance other solutes.
  • Treatments for high blood pressure. Blood pressure will be checked several times a day.
  • Dialysis if the kidneys are not working well. Dialysis removes excess water and waste products from the blood. Typically, half of children who report post-diarrheal HUS will need dialysis. For the majority of patients, this dialysis will only be temporary.

There are two types of dialysis: hemodialysis and peritoneal dialysis. If your child needs dialysis, you will receive appropriate information when the time comes. The doctor will tell you what type of dialysis is best for the patient.

Your child’s blood pressure, blood tests, urine and stools will be monitored regularly. Blood tests will be done regularly to assess the progression of the disease and help doctors adapt the different treatments needed for the patient.

If the patient is still a carrier of the bacteria that causes HUS, they will be isolated to avoid passing the germ to another person who may in turn develop HUS.

Here are some tips to prevent passing HUS to others, such as your other children :

  • Wash your hands thoroughly before touching your child and after touching him.
  • Do not eat or drink in your child’s room.
  • Check other family members for symptoms of gastroenteritis or HUS and tell the nurse or doctor as soon as possible if you or others have any suggestive symptoms.
  • Visitors who want to see the patient should register at the nursing station.

How to prevent post-diarrheal HUS?

Contaminating foods are mainly ground meats and products made from raw milk. To prevent HUS :

  • The cold chain must be respected. Meat minced by the butcher on demand must be consumed during the day, and frozen hamburger steaks must not have undergone a cold chain break or thawing.
    Red (rare) meat should not be fed to children up to the age of 5 years. Make sure that the meat is cooked in the center and that it is no longer pink.
  • It is not recommended to give raw milk to a child under 5 years old.
    This recommendation also applies to products made from raw milk : butter, crème fraîche and cheeses made from raw milk.
  • For children, you should prefer : Cooked pressed cheeses such as Gruyère, Emmental, Comté, etc… and cheeses made from pasteurized milk.
  • Avoid seafood (oysters, mussels) in children under 5 years old
    Some animals, especially cattle, can be healthy carriers of this type of bacteria. Hygienic rules (hand washing …) must be applied during contact with animals in children under 5 years old (farm visit etc …)

More broadly, the prevention of hemolytic uremic syndrome in children, as with any food poisoning, involves following simple actions :

  • Hand washing should be done routinely before preparing meals, when leaving the toilet or after changing an infant’s diaper.
  • Vegetables, fruits and herbs should be washed thoroughly, especially when eaten raw.
  • Prepared meals and leftover food must be sufficiently reheated and consumed quickly.
  • Children should not drink untreated water (well water …)
  • Raw foods should be stored separately from cooked or ready-to-eat foods.
  • Kitchen utensils and the worktop must be washed thoroughly, especially when they have been in contact with raw meat.

Atypical hemolytic uremic syndrome

What is atypical hemolytic uremic syndrome?

Hemolytic uremic syndrome corresponds to the haematological association of :

  • a hemolytic anemia with the presence of schizocytes (debris of fragmented red blood cells)
  • a thrombocytopenia (decrease in the number of platelets)
  • and  a kidney failure (kidney function defect).

How are hemolytic uremic syndromes (HUS) classified?

The HUS classification reviewed in 2016 distinguishes :

  • the typical or post diarrhea hemolytic uremic syndrome which represents 85% of pediatric HUS cases.
  • secondary HUS linked to other infectious causes (pneumococcus, influenza, HIV, etc.)
  • so-called secondary HUS occurring in the context of a prior disease (post-bone marrow transplant, lupus, vasculitis) or secondary to certain drugs (anticalcineurins, some antimalarials such as quinine)
  • secondary HUS linked to a metabolic abnormality (cobalamin C deficiency)
  • the so-called atypical HUS. They represent nearly 10% of pediatric HUS cases. They include HUS with an anomaly in the regulation of the complement alternate pathway, HUS with DGKE mutation and untyped HUS.

How often is atypical HUS found in the population?

This is a rare disease. Its incidence is estimated between 0.2 to 0.4 cases / 1,000,000 inhabitants. There is no predominance of gender or ethnicity.

An international register collating all cases of atypical HUS has been set up. More than 1,750 patients have been included to date.

In 2013, the French register listed 89 pediatric patients and 125 adult patients.

What are the causes of atypical HUS?

Atypical HUS are mostly secondary to a lack of regulation of complement activity. The complement is a set of proteins forming part of the immune system whose role is to promote the destruction of microbes. This activity must be regulated in order to avoid an excessive response which could lead to damage to the patient. Several regulatory factors have been demonstrated: factor H, factor I, C3 convertase, factor B and CD46. Loss of complement regulation due to dysfunction of any of these factors can lead to HUS.

This deficit in regulation of the alternative complement pathway is most often of genetic origin. It can also be acquired with the presence of anti-factor H antibodies which neutralize the latter.

It is important to note that 85% of atypical HUS linked to a genetic anomaly in the regulation of the alternative complement pathway are said to be sporadic (only 1 case in the family), whereas the family genetic investigation makes it possible to find several subjects carrying the mutation. We speak of variable penetrance to translate that being a carrier of the mutated gene does not systematically lead to the onset of the disease.

Atypical HUS evolves by flare and a patient is therefore likely to have several flares of HUS in his life. Flare-ups can be triggered by any type of infectious agent. The influenza virus, for example, is recognized as one of the triggers for outbreaks of atypical HUS. Pregnancy is also a triggering factor in predisposed patients.

In 2013, atypical HUS linked to a DGKE mutation (diacyl glycerol Kinase epsilon) was demonstrated. It is a genetic HUS that first outbreaks before the age of 1 year. The progression to end-stage renal failure is gradual (20 years on average). The pathophysiology remains poorly understood but seems independent of the complement, which results in ineffective treatment with Eculizumab.

What are the symptoms of atypical HUS and which organs are affected?

Clinically

Atypical HUS is accompanied by non-specific signs such as pallor, icterus (jaundice), fatigue, difficulty breathing, a decrease in urine output (urine volume) with sometimes hematuria (presence of blood in the urine) and finally edema .

Biologically

HUS is characterized by hemolytic anemia of mechanical origin; (which means that the red blood cells are destroyed) with the presence of schizocytes (debris of red blood cells) and acute renal failure (kidney failure) which may lead to the setting up of dialysis. Thrombocytopenia (lower platelet count) is classically associated with it but may be missing in 15% of cases. Neurological damage can be present, manifested by convulsions, an alteration of consciousness which can lead to coma as well as cardiac, hepatic, pancreatic damage…

Digestive damage is particularly rare in atypical HUS. Rarely, lesions with necrosis of the extremities or skin ulcers may be present.

What are the specific treatments offered?

The care of atypical HUS differs in adults and children.

The current recommendations argue for the use of Eculizumab as a first-line treatment in children with suspected atypical HUS. The only indication for carrying out plasma exchanges remains the demonstration of atypical HUS with anti-factor H antibodies. In this case, the exchanges are associated with immunosuppressive treatment (corticosteroids, mycofenolate mofetil or endoxan).

In adults, the first-line use of Eculizumab is only offered in the event of a family history of atypical HUS or in the event of a recurrence of HUS after renal transplant. In the majority of cases, patients have first-line plasma exchanges due to the frequency of occurrence of thrombotic thrombocytopenic purpura, the clinical presentation of which is similar to HUS.

How does atypical HUS evolve over the long term and what treatments are offered?

Atypical HUS is a disease whose prognosis has dramatically changed since the advent of complement pathway inhibitors.

Before using this treatment, the death rate was particularly high; between 8 and 10% in children and 3% in adults. Progression to end-stage renal disease was very common: 36% of children and 64% of adults had end-stage renal disease within 5 years of being diagnosed with atypical HUS.

Complement pathway inhibitors have significantly changed the prognosis of this disease with a mortality rate of around 1% and a rate of progression to end-stage chronic renal disease only of 10 to 12% in adults and children.

The use of complement pathway inhibitors has also made it possible to modify the outcome of patients with atypical HUS requiring kidney transplantation. The risk of post-transplant recurrence in atypical HUS with an abnormality in the regulation of the complement pathway was particularly high.

While initially it was envisaged that complement pathway inhibitors would be continued for life, treatment may have been discontinued in some patients meeting specific criteria. However, there is a risk of a new outbreak of HUS. This risk is particularly marked in patients with a factor H mutation, with nearly 60% of patients relapsing.

Education of patients and their families, for pediatric patients, is essential to detect a possible outbreak of HUS and to start treatment as quickly as possible if one occurs. Complement pathway inhibitors carry a risk of bacterial infections, and should be combined with specific vaccination of the patient and family and preventive antibiotic treatment.

Any patient with atypical HUS requires specialist lifelong monitoring.

Thrombotic thrombocytopenic purpura

What is thrombotic thrombocytopenic purpura (TTP)?

Thrombotic thrombocytopenic purpura (TTP) is a particular form of thrombotic microangiopathy (TAM) characterized in its typical form by the combination of five manifestations :

  • a neurological damage,
  • a fever,
  • a kidney failure
  • a mechanical hemolytic anemia,
  • a consumer thrombocytopenia.

This clinical picture is variable since it can be severe from the outset with multiple organ failures that are life-threatening, or on the contrary amount to bicytopenia. In all cases, TTP must be quickly diagnosed in order to organize specialized emergency care.

What you need to know

  • It is not contagious,
  • it can occur at any age,
  • it is more common in women (3 women for 2 men),
  • it can be favored by pregnancy,
  • the drop in the platelet count is generally very deep,
  • kidney involvement is usually moderate,
  • Most often, the cause of this disease is the production by the patient of antibodies which block the function of an enzyme, called ADAMTS13, which is necessary to maintain good blood circulation and which prevents the formation of platelet clots;
  • it is exceptionally hereditary, and in this case most often diagnosed in the first years of life.

Autoimmune TTP

In the vast majority of cases, TTP is an autoimmune disease, i.e. patients make antibodies that recognize their own ADAMTS13 protein, instead of recognizing microbes (bacteria, viruses).

Hereditary TTP

In very rare cases, TTP is inherited and results from mutations in the ADAMTS13 gene. There are currently a few dozen cases of hereditary TTP in France. Hereditary TTP is characterized by a permanent deficit in ADAMTS13, which has the consequence of exposing the patient to recurrent relapses, which necessitates the establishment of regular plasma infusions. These infusions are effective in preventing relapses, which is important in preventing the onset of organ complications, which can occur after years of development.

Patients with hereditary TTP should benefit from very specific monitoring during pregnancy, which includes infusions of plasma throughout the pregnancy to prevent a relapse which would have serious consequences for the fetus and the mother.

Other pathologies

  • Post-shigatoxin hemolytic uremic syndrome
  • Thrombotic microangiopathies associated with cancer
  • Thrombotic microangiopathies associated with chemotherapy
  • Thrombotic microangiopathies associated with HIV
  • Thrombotic microangiopathies associated with stem cells transplantation
  • Thrombotic microangiopathies associated with pregnancy
En savoir +

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Dany Anglicheau

Adult nephrologist
Pr Dany Anglicheau
MD, PhD

Photo Dominique Joly

Adult nephrologist
Pr Dominique Joly
MD, PhD

Julien Zuber

Adult nephrologist
Dr Julien Zuber
MD, PhD

photo-identite-femme magec2

Adult nephrologist
Dr Myriam Dao
MD

photo-identite-femme magec2

Adult nephrologist
Dr Aurélie Hummel
MD

photo-identite-femme magec2

Adult nephrologist
Dr Rebecca Sberro-Soussan
MD

Constituent site research program

  • ECULISHU: Hospital clinical research program (HCRP) whose inclusions have been completed and analyses in progress
  • ZITHROSHU: HCRP in progress
  • Long-term prognosis of atypical HUS in children since the marketing authorization of Eculizumab
  • National, European (ERKReg) and international (M11-001) registers of atypical HUS in children.
  • BAXALTA: Therapeutic trial of recombinant ADAMTS13 in congenital thrombotic thrombocytopenic purpura
  • Effect of Eculizumab in atypical HUS in renal transplanted and non-transplanted patients,
  • Study of kidney transplant patients treated with Eculizumab in prophylaxis of atypical HUS relapse,
  • Pregnancy in patients with atypical HUS,
  • Malignant arterial hypertension and TMA,
  • Secondary TMAs,
  • Study of the French series of C3 glomerulonephritis,
  • Forms of passage between TMA and glomerulonephritis with C3 deposits.

Former research programs of the constituent site

  • STOPECU; 2015
  • MATRISK: predictive factors of cardiac and cerebral damage during TMA; 2012
  • An open-label, multi-center clinical trial of eculizumab in adult patients with atypical hemolytic-uremic syndrome; 2011
  • PTTRITUX2: Dose adjustment of rituximab based on residual B-cell count in TTP; 2010
  • Multicenter, open-label, controlled clinical trial of eculizumab in adult patients with atypical hemolytic uremic syndrome (aHUS) resistant to plasma therapy (PT); 2009

2021

Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis.
Idris Boudhabhay, Victoria Poillerat, Anne Grunenwald, Carine Torset, Juliette Leon, Marie V Daugan, Francesca Lucibello, Khalil El Karoui, Amandine Ydee, Sophie Chauvet et al.
Kidney Int, 2021 Mar, PMID: 33137339 DOI: 10.1016/j.kint.2020.09.033

Impact of pre-eclampsia on renal outcome in sickle cell disease patients.
Idris Boudhabhay, Emmanuelle Boutin, Pablo Bartolucci, Marie-Isabelle Bornes, Anoosha Habibi, François Lionnet, Alexandre Hertig, Philippe Grimbert et al.
Br J Haematol, 2021 Sep, PMID: 34131893 DOI: 10.1111/bjh.17606

Ravulizumab for the Treatment of aHUS in Adults: Improving Quality of Life.
Christophe Legendre, Rebecca-Sberro-Soussan, Julien Zuber
Kidney Int Rep, 2021 May 12, PMID: 34169186 PMCID: PMC8207465 DOI: 10.1016/j.ekir.2021.04.036

Case Report: Adult Post-COVID-19 Multisystem Inflammatory Syndrome and Thrombotic Microangiopathy.
Idris Boudhabhay, Marion Rabant, Lubka T Roumenina, Louis-Marie Coupry, Victoria Poillerat, Armance Marchal, Véronique Frémeaux-Bacchi, Khalil El Karoui, Mehran Monchi, Franck Pourcine
Front Immunol, 2021 Jun 23, PMID: 34248962 PMCID: PMC8260674 DOI: 10.3389/fimmu.2021.680567

Complement factor H: a guardian within?
Idris Boudhabhay, Lubka T Roumenina
Kidney Int, 2021 Oct, PMID: 34556298 DOI: 10.1016/j.kint.2021.07.023

Immune Checkpoint Inhibitors in Transplantation-A Case Series and Comprehensive Review of Current Knowledge.
Julie Delyon, Julien Zuber, Richard Dorent, Armelle Poujol-Robert, Marie-Noelle Peraldi, Dany Anglicheau, Celeste Lebbe
Transplantation, 2021 Jan 1, PMID: 32355121 DOI: 10.1097/TP.0000000000003292

Importance of clinical practice guidelines to practicing pediatric nephrologists and IPNA survey.
Pankaj Hari, Khalid Alhasan, Arvind Bagga, Melvin Bonilla-Felix, Paula Alejandra Coccia, Ali Duzova, Ill-So Ha, Giovanni Montini, Koichi Nakanishi, Susan Samuel, Hong Xu, Olivia Boyer, Dieter Haffner
Pediatr Nephrol, 2021 Nov, PMID: 34014394 DOI: 10.1007/s00467-021-05105-9

Complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients.
Jignesh K Patel, Guillaume Coutance, Alexandre Loupy, Deanna Dilibero, Michele Hamilton, Michelle Kittleson, Evan Kransdorf, Babak Azarbal, Osamu Seguchi, Xiaohai Zhang, David Chang, Dael Geft, Lawrence Czer, Shaida Varnous, Jon A Kobashigawa
Am J Transplant, 2021 Jul, PMID: 33251691 DOI: 10.1111/ajt.16420

Eculizumab discontinuation in children and adults with atypical hemolytic-uremic syndrome: a prospective multicenter study.
Fadi Fakhouri, Marc Fila, Aurélie Hummel, David Ribes, Anne-Laure Sellier-Leclerc, Simon Ville, Claire Pouteil-Noble, Jean-Philippe Coindre, Moglie Le Quintrec, Eric Rondeau et al.
Blood, 2021 May 6, PMID: 33270832 DOI: 10.1182/blood.2020009280

Feasibility and safety of tailored dosing schedule for eculizumab based on therapeutic drug monitoring: Lessons from a prospective multicentric study.
Christophe Passot, Rebecca Sberro-Soussan, Dominique Bertrand, Sophie Caillard, Betoul Schvartz, Camille Domenger, Cécile Contin-Bordes, Gilles Paintaud, Jean-Michel Halimi, David Ternant, Philippe Gatault
Br J Clin Pharmacol, 2021 May, PMID: 33118186 DOI: 10.1111/bcp.14627

Pediatric publications

  • Niaudet P, Boyer O. Overview of hemolytic uremic syndrome in children
  • Niaudet P, Boyer O. Complement-mediated hemolytic uremic syndrome
  • Niaudet P, Boyer O. Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children
  • Sana G, Dragon-Durey MA, Charbit M, […] Frémeaux-Bacchi V, Niaudet P, Boyer O. Long-term remission of atypical HUS with anti-factor H antibodies after cyclophosphamide pulses. Pediatr Nephrol 2014;29:75-83.
  • Krid S, Roumenina L, Beury D, Charbit M, Boyer O, Frémeaux-Bacchi V, Niaudet P. Renal transplantation under eculizumab prophylactic therapy in atypical hemolytic and uremic syndrome with CFH/CFHR1 hybrid protein. Am J Transplant 2012;12 :1938-44.
  • Boyer O, Niaudet P. Hemolytic and uremic syndrome. Int J Nephrol 2011;2011:908407.
  • Boyer O, Balzamo E, Charbit M, Biebuyck N, Salomon R, Frémeaux-Bacchi V, Dragon-Durey MA, Niaudet P. Cyclophosphamide pulses lead to sustained remission of atypical hemolytic uremic syndrome with anti-Factor H autoantibodies. Am J Kidney Dis 2010;55:923-927.
  • Koehl B, Boyer O, Biebuyck-Gouge N, Kossorotoff M, Fremeaux-Bacchi V, Boddaert N, Niaudet P. Neurological involvement in a child with atypical HUS. Pediatr Nephrol 2010;25:2539-42.
  • Boyer O, Noël LH, Balzamo E, Guest G, Biebuyck N, Guest G, Salomon R, Frémeaux-Bacchi V, Niaudet P: Post-transplant glomerulonephritis with isolated C3 deposits in two children with factor H deficiency and atypical HUS on native kidneys. Am J Kidney Dis 2008;51:671-677.

Adult publications

  • Servais A, Devillard N, Frémeaux-Bacchi V, Hummel A, Salomon L, Contin-BordesC, Gomer H, Legendre C, Delmas Y. Atypical haemolytic uraemic syndrome andpregnancy: outcome with ongoing eculizumab. Nephrol Dial Transplant. 2016 Dec;31(12):2122-2130. doi: 10.1093/ndt/gfw314. Epub 2016 Sep 1. PMID: 27587606.
  • Zuber J, Frimat M, Caillard S, Kamar N, Gatault P, Petitprez F, Couzi L,Jourde-Chiche N, Chatelet V, Gaisne R, Bertrand D, Bamoulid J, Louis M, SberroSoussan R, Navarro D, Westeel PF, Frimat L, Colosio C, Thierry A, Rivalan J,Albano L, Arzouk N, Cornec-Le Gall E, Claisse G, Elias M, El Karoui K, ChauvetS, Coindre JP, Rerolle JP, Tricot L, Sayegh J, Garrouste C, Charasse C, Delmas Y, Massy Z, Hourmant M, Servais A, Loirat C, Fakhouri F, Pouteil-Noble C,Peraldi MN, Legendre C, Rondeau E, Le Quintrec M, Frémeaux-Bacchi V. Use of Highly Individualized Complement Blockade Has Revolutionized Clinical Outcomes after Kidney Transplantation and Renal Epidemiology of Atypical Hemolytic Uremic Syndrome. J Am Soc Nephrol. 2019 Dec;30(12):2449-2463. doi: 10.1681/ASN.2019040331. Epub 2019 Oct 1. PMID: 31575699; PMCID: PMC6900783.
  • Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, Bingham C, Cohen DJ, Delmas Y, Douglas K, Eitner F, Feldkamp T, Fouque D, Furman RR, Gaber O, Herthelius M, Hourmant M, Karpman D, Lebranchu Y, Mariat C, Menne J, Moulin B, Nürnberger J, Ogawa M, Remuzzi G, Richard T, Sberro-Soussan R, Severino B, Sheerin NS, Trivelli A, Zimmerhackl LB, Goodship T, Loirat C.Legendre CM, et al. N Engl J Med. 2013 Jun 6;368(23):2169-81. doi: 10.1056/NEJMoa1208981. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.
  • Zuber J, Fakhouri F, Roumenina LT, Loirat C, Frémeaux-Bacchi V; French Study Group for aHUS/C3G.Zuber J, et al. Nat Rev Nephrol. 2012 Nov;8(11):643-57. doi: 10.1038/nrneph.2012.214. Epub 2012 Oct 2. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies.
  • Fakhouri F, Hourmant M, Campistol JM, Cataland SR, Espinosa M, Gaber AO, Menne J, Minetti EE, Provôt F, Rondeau E, Ruggenenti P, Weekers LE, Ogawa M, Bedrosian CL, Legendre CM. Terminal Complement Inhibitor Eculizumab in Adult Patients With Atypical Hemolytic Uremic Syndrome: A Single-Arm, Open-Label Trial. Am J Kidney Dis. 2016 Jul;68(1):84-93. doi: 10.1053/j.ajkd.2015.12.034. Epub 2016 Mar 21. PMID: 27012908.
  • Legendre CM, Campistol JM, Feldkamp T, Remuzzi G, Kincaid JF, Lommelé Å, Wang J, Weekers LE, Sheerin NS. Outcomes of patients with atypical haemolytic uraemic syndrome with native and transplanted kidneys treated with eculizumab: a pooled post hoc analysis. Transpl Int. 2017 Dec;30(12):1275-1283. doi: 10.1111/tri.13022. Epub 2017 Sep 8. PMID: 28801959.
  • Levi C, Frémeaux-Bacchi V, Zuber J, Rabant M, Devriese M, Snanoudj R, Scemla A, Amrouche L, Mejean A, Legendre C, Sberro-Soussan R. Midterm Outcomes of 12 Renal Transplant Recipients Treated With Eculizumab to Prevent Atypical Hemolytic Syndrome Recurrence. Transplantation. 2017 Dec;101(12):2924-2930. doi: 10.1097/TP.0000000000001909. PMID: 28858176.
  • Zuber J, Le Quintrec M, Morris H, Frémeaux-Bacchi V, Loirat C, Legendre C. Targeted strategies in the prevention and management of atypical HUS recurrence after kidney transplantation. Transplant Rev (Orlando). 2013 Oct;27(4):117-25. doi: 10.1016/j.trre.2013.07.003. Epub 2013 Aug 12. PMID: 23937869.
  • Zuber J, Le Quintrec M, Sberro-Soussan R, Loirat C, Frémeaux-Bacchi V, Legendre C. New insights into postrenal transplant hemolytic uremic syndrome. Nat Rev Nephrol. 2011 Jan;7(1):23-35. doi: 10.1038/nrneph.2010.155. Epub 2010 Nov 23. PMID: 21102542.
  • Legendre CM, Licht C, Loirat C. Eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013 Oct 3;369(14):1379-80. doi: 10.1056/NEJMc1308826. PMID: 24088105.
  • Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaimé F, Dragon-Durey MA, Ngo S, Moulin B, Servais A, Provot F, Rostaing L, Burtey S, Niaudet P, Deschênes G, Lebranchu Y, Zuber J, Loirat C. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol. 2013 Apr;8(4):554-62.
  • Frémeaux-Bacchi V, Legendre CM.Frémeaux-Bacchi V, et al. Kidney Int. 2015 Nov;88(5):967-73. doi: 10.1038/ki.2015.253. Epub 2015 Sep 16.The emerging role of complement inhibitors in transplantation.
Liste contact MAT

Consult and download the brochure of the adult nephrology department

National congresses

  • Réunion NEPHEMA;2016; Paris; Servais
  • Actualités Roche en néphrologie; 2016; Paris; Servais
  • Séminaire Pierre Royer de néphrologie pédiatrique, Paris, 2015; néphrologues; 16 hours per year
  • Séminaire Pierre Royer de néphrologie pédiatrique, Paris, 2014; néphrologues; 16 hours per year
  • Séminaire universitaire de néphrologie de la Pitié Salpêtrière;2013; Paris; Servais
  • Séminaire Pierre Royer de néphrologie pédiatrique, Paris, 2013; néphrologues; 16 hours per year
  • Séminaire Pierre Royer de néphrologie pédiatrique, Paris, 2012; néphrologues; 16 hours per year
  • Société de néphrologie pédiatrique; 2012; Paris ; Salomon
  • Séminaire Pierre Royer de néphrologie pédiatrique, Paris, 2011; néphrologues; 16 hours per year

European congresses

  • Franco-British paediatric nephrology meeting, 1-3 December 2016, Paris; néphrologues, 20 hours
  • European Dialysis and Transplantation congress; 2012; Paris; Legendre

International congresses

  • Actualités néphrologiques Jean Hamburger , Paris, 2015; néphrologues, 16 hours per year
  • Renal grand rounds at Brigham and women’s hospital, held jointly with Massachusetts general hospital, Harvard university; 2014; Boston USA; Zuber
  • Actualités néphrologiques Jean Hamburger , Paris, 2014; néphrologues, 16 hours per year
  • ERA-EDTA Congress, 2016; Vienna, Austria; Zuber
  • Actualités néphrologiques Jean Hamburger , Paris, 2013; néphrologues, 16 hours per year
  • University of Missouri women’s and children’s hospital; 2013; Columbia, USA; Zuber
  • Société francophone de néphrologie pédiatrique; 2013; Genève; Boyer
  • American Society Nephrology; 2012; San Diego; Legendre
  • American transplant congress; 2012; Chicago; Legendre
  • American Transplant congress; 2012; Boston; Zuber
  • Société Française de Néphrologie; 2012; Genève; Legendre
  • ERA-EDTA congress; 2012; Paris ; Zuber
  • Actualités néphrologiques Jean Hamburger , Paris, 2012; néphrologues, 16 hours per year
  • Actualités néphrologiques Jean Hamburger , Paris, 2011; néphrologues, 16 hours per year

Contact information

Necker-Enfants malades university hospital
Adult nephrology-dialysis department

149 rue de Sèvres
75743 PARIS Cedex 15

> Pediatric welcome booklet

> Adult patients welcome booklet

In Necker, the reference center for thrombotic microangiopathies in brief …

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patients followed at least once a year*
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medical consultations*
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day hospitalizations*
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patients in full hospitalization*
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authorized therapeutic education programs*
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patients trained in therapeutic education*
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ongoing research projects*
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university courses*
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publications*
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teleconsultation procedures*

* data valid for 2021