DR PRAKASH NAG
MD MEDICINE
NGMC
Thrombotic thrombocytopenic Purpura
$
Hemolytic Uremic Syndrome
TTP
INTRODUCTION
Thrombotic thrombocytopenic purpura (TTP) is a
rare blood disorder.
In TTP, blood clots form in small blood vessels
throughout the body.
The clots can limit or block the flow of oxygen-rich
blood to the body's organs, such as the brain, kidneys,
and heart.
As a result, serious health problems can develop.
In about half of cases a trigger is identified, while in
the remainder the cause remains unknown.
Known triggers include bacterial infections, certain
medications, autoimmune diseases such as lupus, and
pregnancy
Epidemiology
• Suspected TTP 11cases/million/yr
• SevereADAMTS13deficiency- 1.7 cases/million/yr
• Incidence rates were greater for women and African-
Americans
• Prior to plasma exchange, mortality rate was as high
as 90%, now less than 20%.
Diagnosis
TheClassicPentad of TTP
The classic presentation of TTP, which occurs in less than
10% of people , includes five medical signs. These are:
• Microangiopathic hemolytic anemia
• Thrombocytopenia
• Renal insufficiency or abnormalities
• Neurologic abnormalities that can be fluctuating
• Fever
• Most common symptoms at presentation are nonspecific
and include abdominal pain, nausea, vomiting and
weakness.
Signs and symptoms
The signs and symptoms of TTP may at first be subtle
and nonspecific. Many people experience an
influenza-like or diarrheal illness before developing
TTP
Neurological symptoms are very common and vary
greatly in severity. Frequently reported symptoms
include feeling very tired, confusion, and headaches
Seizures and symptoms similar to those of a stroke can
also be seen
Other signs and symptoms include:
Purplish bruises on the skin or mucous membranes
(such as in the mouth). ...
Pinpoint-sized red or purple dots on the skin known
as petechiae.
Paleness or jaundice (a yellowish color of the skin or
whites of the eyes).
Fatigue (feeling very tired and weak).
Fever.
A fast heart rate or shortness of breath.
The bruising often takes the form of purpura, while
the most common site of bleeding, if it occurs, is from
the nose or gums.
Larger bruises (ecchymoses) may also develop.
Petechiae are pinpoint, round spots that appear on
the skin as a result of bleeding.
The bleeding causes the petechiae to appear red,
brown or purple.
Petechiae (puh-TEE-kee-ee) commonly appear in
clusters and may look like a rash.
Usually flat to the touch, petechiae don't lose color
when you press on them
Purpura, also called blood spots or skin hemorrhages,
refers to purple-colored spots that are most
recognizable on the skin.
The spots may also appear on organs or mucous
membranes, including the membranes on the inside of
the mouth.
Purpura occurs when small blood vessels burst,
causing blood to pool under the skin.
What is the difference between petechiae and purpura?
Petechiae are small (1–3 mm), red, nonblanching
macular lesions caused by intradermal capillary
bleeding .
Purpura are larger, typically raised lesions resulting
from bleeding within the skin .
Similar to petechiae, purpura do not blanch and
may occur anywhere on the body
Neurologic symptoms
• most are subtle, such as transient confusion or severe
headache. Focal, objective abnormalities are less
common, but grand mall seizures and coma can occur.
Fever
• less frequent finding, but the presence of chills and
high spiking fever should suggest dx of sepsis or DIC. •
Cardiac involvement
Incidence is difficult to determine, but diffuse platelet
thrombi and associated hemorrhage in cardiac tissues
can lead to arrythmias, MIs, sudden death, shock, or
heart failure.
Mechanism (Pathophysiology )
The underlying mechanism typically involves
autoantibody-mediated inhibition of the enzyme
ADAMTS13, a metalloprotease responsible for cleaving
large multimers of von Willebrand factor (vWF) into
smaller units.
The increase in circulating multimers of vWF
increases platelet adhesion to areas of endothelial
injury, particularly where arterioles and capillaries
meet, which in turn results in the formation of small
platelet clots called thrombi.
As platelets are used up in the formation of thrombi, this
then leads to a decrease in the number of overall circulating
platelets, which may then cause life-threatening bleeds.
Red blood cells passing the microscopic clots are subjected
to shear stress, which damages their membranes, leading to
rupture of red blood cells within blood vessels, which in turn
leads to anaemia and schistocyte formation.
The presence of these blood clots in the small blood vessels
reduces blood flow to organs resulting in cellular injury and
end organ damage
What is adamts13 deficiency?
ADAMTS13 deficiency can be acquired or congenital
Congenital TTP (Upshaw-Shulman syndrome) is a rare
autosomal-recessive disease caused by compound
heterozygous or homozygous mutations of
the ADAMTS13 gene, producing
nonfunctional ADAMTS13 protein.
Causes
The two best understood causes of TTP are due to
autoimmunity and an inherited deficiency of
ADAMTS13 (known as the Upshaw-Schülman
syndrome).
The majority of the remaining cases are secondary to
some other factor.
Genetic :This condition may also be congenital. Such
cases may be caused by mutations in the ADAMTS13
gene.This hereditary form of TTP is called the
Upshaw–Schulman syndrome.[
Secondary
Secondary TTP is diagnosed when the person's history
mentions one of the known features associated with
TTP. It comprises about 40% of all cases of TTP.
Predisposing factors are:
Cancer
Bone marrow transplantation
Pregnancy
Medication use:
Antiviral drugs (acyclovir)
Certain chemotherapy medications such as gemcitabine
and mitomycin C
Quinine
Oxymorphone
Quetiapine
Bevacizumab
Sunitinib
Platelet aggregation inhibitors (ticlopidine, clopidogrel,
and prasugrel)
Immunosuppressants (ciclosporin, mitomycin,
tacrolimus/FK506, interferon-α)
Hormone altering drugs (estrogens, contraceptives,
hormone replacement therapy)
HIV-1 infection
Types:
1. Congenital
2. Acquired
• Autoimmune forms, due to autoantibodies against
ADAMTS– 13
• secondary to massive endothelial activation with
release of ultra - large VWF multimers in large
amounts.
Congenital TTP
• Congenital TTP is very rare (1 in 1 million) and
represents 5% of all TTP cases.
• usually occurs immediately after birth or during
childhood, although may present later in life
• Congenital TTP is caused by homozygous or double
heterozygous mutations in theADAMTS13gene(located
on chromosome 9q34) that affect protein secretion or
function; it is inherited in autosomal recessive manner
Acquired TTP
• The acquired form accounts for >99% of the adolescent
and adult cases.
• Pathophysiology
• Autoimmune TTPis due to anti - ADAMTS- 13antibodies
that inhibit the proteolytic activity of ADAMTS- 13 and/or
bind the protease to accelerate its clearance from plasma
• Anti - ADAMTS–13 antibodies are usually of IgGtype,
although in few casesautoantibodies of IgAand/orIgM
isotype were also found.
• Thehigher incidence of autoimmune idiopathic TTPin
specific ethnic groups suchas Afro –Caribbeans.
Treatment
Due to the high mortality of untreated TTP, a
presumptive diagnosis of TTP is made even when only
microangiopathic hemolytic anemia and
thrombocytopenia are seen, and therapy is started.
Transfusion is contraindicated in thrombotic TTP, as it
fuels the coagulopathy.
Since the early 1990s, plasmapheresis has become the
treatment of choice for TTP
This is an exchange transfusion involving removal of
the person's blood plasma through apheresis and
replacement with donor plasma (fresh frozen plasma
or cryosupernatant); the procedure must be repeated
daily to eliminate the inhibitor and abate the
symptoms.
If apheresis is not available, fresh frozen plasma can
be infused, but the volume that can be given safely is
limited due to the danger of fluid overload
Apheresis
Apheresis is a medical procedure that involves
removing whole blood from a donor or patient and
separating the blood into individual components so
that one particular component can be removed.
The remaining blood components then are re-
introduced back into the bloodstream of the patient or
donor.
Corticosteroids (prednisone or prednisolone) are
usually given.
Rituximab, a monoclonal antibody aimed at the CD20
molecule on B lymphocytes, may be used on
diagnosis; this is thought to kill the B cells and thereby
reduce the production of the inhibitor.
A stronger recommendation for rituximab exists
where TTP does not respond to corticosteroids and
plasmapheresis.
Caplacizumab is an alternative option in treating TTP
as it has been shown that it induces a faster disease
resolution compared with those people who were on
placebo.
However, the use of caplacizumab was associated with
increase bleeding tendencies in the studied subjects.
People with refractory or relapsing TTP may receive
additional immunosuppressive therapy, e.g.
vincristine, cyclophosphamide, cyclosporine A, or
splenectomy
Children with Upshaw-Schülman syndrome receive
prophylactic plasma every two to three weeks; this
maintains adequate levels of functioning ADAMTS13.
Some tolerate longer intervals between plasma
infusions.
Additional plasma infusions may be necessary for
triggering events, such as surgery; alternatively, the
platelet count may be monitored closely around these
events with plasma being administered if the count
drop
Measurements of blood levels of
lactate dehydrogenase, platelets, and schistocytes are
used to monitor disease progression or remission.
ADAMTS13 activity and inhibitor levels may be
measured during follow-up, but in those without
symptoms the use of rituximab is not recommended
Prognosis
The mortality rate is around 95% for untreated cases,
but the prognosis is reasonably favorable (80–90%
survival) for people with idiopathic TTP diagnosed
and treated early with plasmapheresis.
Differential diagnosis
TTP is characterized by thrombotic microangiopathy
(TMA), the formation of blood clots in small blood
vessels throughout the body, which can lead to
microangiopathic hemolytic anemia and
thrombocytopenia.
This characteristic is shared by two related
syndromes, hemolytic-uremic syndrome (HUS) and
atypical hemolytic uremic syndrome (aHUS
HUS
Definition
HUS, is a disease characterized by :
Hemolytic anemia
Uremia
Low platelet count
It predominantly, but not exclusively, affects children.
Types HUS
Typical HUS
Atypical HUS
HUS due to Complement abnormalities
ETIOPATHOGENESIS
Typical/Diarrhea associated/Shiga Toxin associated HUS
Enterohaemorrhagic E. coli
Shigella dysenteriae type 1
Rarely, HUS can occur with E. coli UTI
The common serotype of E coli:0157:H7
However, only about 10-15% patients with E. coli
0157:H7 infection will develop HUS
Sources of infection are :
Milk and animal products (incompletely cooked beef,
pork, poultry, lamb)
Human feco-oral transmission
Vegetables, salads and drinking water may be
contaminated by bacteria shed in animal wastes
Atypical/Non-Diarrhea Related HUS
Pneumococcal HUS
HUS due to Complement abnormalities
Miscellaneous Causes of HUS / TTP
Abnormalities in intracellular vitamin B12 metabolism
HIV
Systemic lupus erythromatosus
Malignancies
Radiation
Certain drugs
Other infections associated with HUS
Include viruses like :
Influenza
Cytomegalovirus
Infectious mononucleosis
Bacteria like:
Streptococcii
Salmonella
Pathophysiology
The typical pathophysiology involves the shiga-toxin
binding to proteins on the surface of glomerular
endothelium and inactivating a metalloproteinase
called ADAMTS13, which is also involved in the closely
related TTP
The arterioles and capillaries of the body become
obstructed by the resulting complexes of activated
platelets which have adhered to endothelium via large
multimeric vWF
The growing thrombi lodged in smaller vessels destroy
RBCs as they squeeze through the narrowed blood
vessels, forming schistocytes, or fragments of sheared
RBCs.
The consumption of platelets as they adhere to the
thrombi lodged in the small vessels typically leads to
mild or moderate thrombocytopaenia
However, in comparison to TTP, the kidneys tend to be
more severely affected in HUS, and the central nervous
system is less commonly affected
CLINICAL FEATURES
The commonest clinical presentation of HUS is :
Acute pallor
Oliguria
Diarrhea or dysentery
It occurs commonly in children between 1-5 years of
age
HUS develops about 5-10 days after onset of diarrhea
Hematuria and hypertension are common.
Complications of fluid overload may present with:
Pulmonary edema
Hypertensive encephalopathy
Neurological symptoms like:
Irritability
Encephalopathy
Seizures
INVESTIGATIONS
CBC
Peripheral blood smears
Reticulocyte count
LDH
Bilirubin unconjigated
Cr & BUN
Urine analysis
Hemoglobinuria
Hematuria
Proteinuria
Investigations to Identify Cause
In patients with dirrhea, the identification of
pathogenic EHEC or Shigella is performed by:
Stool culture
Further serotyping by agglutination or enzyme
immunoassay
Rarely HUS can occur with E. coli UTI:
Urine cultures are indicated in non-diarrheal
patients
Bacteriological cultures of body fluids are indicated in
suspected pneumococcal disease.
Sputum
CSF
Blood
Pus
Diagnosis
Clinically, HUS can be very hard to distinguish from
TTP
The laboratory features are almost identical, and not
every case of HUS is preceded by diarrhea
HUS is characterized by the triad of:
Hemolytic anemia
Thrombocytopenia
Acute renal failure
The only distinguishing feature is that in TTP, fever
and neurological symptoms are often present, but this
is not always the case
A pericardial friction rub can also sometimes be
heard on auscultation
The two conditions are sometimes treated as a single
entity called TTP/HUS.
MANAGEMENT
Supportive Therapy
Antibiotics
Plasma Therapy
Miscellaneous
Supportive Therapy
In all patients, supportive treatment is primary.
Close clinical monitoring of :
Fluid status
Blood pressure
Neurological
Ventilatory parameters
Blood levels of glucose, electrolytes, creatinine and
hemograme need frequent monitoring.
The use of antimotility therapy for diarrhea has been
associated with a higher risk of developing HUS
With the onset of acute renal failure :
Fluid restriction
Diuretics
Antibiotics
E. coli
Shigellosis
pneumococcal HUS
Plasma Therapy
In a HUS due to :
complement factor abnormality
ADAMTS13 deficiency
The replacement of the deficient factor with FFP
Daily plasma infusions (10 to 20 mL/kg/day)
Exchange of 1.5 times plasma volume ( 60 to 75
mL/kg/day) using FFP
Miscellaneous
In infants with HUS associated with cobalamin
abnormalities:
Treatment with hydroxycobalamin
Oral betaine
Folic acid
Normalizes the metabolic abnormalities can help to
prevent further episodes.
In patients with persistent ADAMTS13 antibodies and
poor response to plasma exchange:
Immunosuppressive therapy with high dose
steroids/cyclophosphamide/ cyclosporin/rituximab
Splenectomy
Prognosis
With aggressive treatment, more than 90% survive the acute
phase.
About 9% may develop end stage renal disease.
About one-third of persons with HUS have abnormal kidney
function many years later, and a few require long- term dialysis.
Another 8% of persons with HUS have other lifelong
complications, such as :
High blood pressure
Seizures
Blindness
Paralysis
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