Thrombotic thrombocytopenic purpura
Encyclopedia
Thrombotic thrombocytopenic purpura (TTP or Moschcowitz syndrome) is a rare disorder
of the blood-coagulation
system, causing extensive microscopic thromboses
to form in small blood vessels throughout the body (thrombotic microangiopathy). Most cases of TTP arise from inhibition of the enzyme
ADAMTS13
, a metalloprotease responsible for cleaving large multimers of von Willebrand factor
(vWF) into smaller units. A rarer form of TTP, called Upshaw-Schülman syndrome, is genetically inherited as a dysfunction of ADAMTS13. If large vWF multimers persist there is tendency for increased coagulation.
Red blood cells passing the microscopic clots are subjected to shear stress
which damages their membranes, leading to intravascular hemolysis
and schistocyte
formation. Reduced blood flow due to thrombosis
and cellular injury results in end organ damage
. Current therapy is based on support and plasmapheresis
to reduce circulating antibodies against ADAMTS13 and replenish blood levels of the enzyme.
Due to the high mortality of untreated TTP, a presumptive diagnosis of TTP is made even when only microangiopathic hemolytic anemia and thrombocytopenia is seen, and therapy is started.
The symptoms of TTP may at first be subtle - starting with malaise
, fever, headache and sometimes diarrhea. As the condition progresses clots (thrombi) form within blood vessels and platelets (clotting cells) are consumed. Bruising, and rarely bleeding, results and may be spontaneous. 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.
Clots formed within the circulation can temporarily disrupt local blood supply. TTP preferentially affects the blood vessels of the brain and kidneys. Thus a patient may experience headache, confusion, difficulty speaking, transient paralysis, numbness or even fits whilst high blood pressure (hypertension) may be found on examination.
Platelet associated IgG and complement levels are usually normal in TTP.
s (MAHAs), is caused by spontaneous aggregation of platelet
s and activation of coagulation
in the small blood vessel
s. Platelets are consumed in the coagulation process, and bind fibrin
, the end product of the coagulation pathway. These platelet-fibrin complexes form microthrombi which circulate in the vasculature and cause shearing of red blood cell
s, resulting in hemolysis
.
Roughly, there are two forms of TTP: idiopathic and secondary TTP. A special case is the inherited deficiency of ADAMTS13, known as the Upshaw-Schülman syndrome.
form of TTP was recently linked to the inhibition of the enzyme
ADAMTS13 by antibodies
, rendering TTP an autoimmune disease
. ADAMTS13 is a metalloproteinase
responsible for the breakdown of von Willebrand factor
(vWF), a protein that links platelets, blood clots, and the blood vessel wall in the process of blood coagulation
. Very large vWF multimers are more prone to lead to coagulation. Hence, without proper cleavage of vWF by ADAMTS13, coagulation occurs at a higher rate, especially in the part of the blood vessel system where vWF is most active due to high shear stress
: in the microvasculature.
In idiopathic TTP, severely decreased (<5% of normal) ADAMTS13 activity can be detected in most (80%) patients, and inhibitors are often found in this subgroup (44-56%). The relationship of reduced ADAMTS13
to the pathogenesis of TTP is known as the Furlan-Tsai hypothesis, after the two independent groups of researchers who published their research in the same issue of the New England Journal of Medicine
in 1998. This theory is seen as insufficient to explain the etiology of TTP, since many patients with hereditary lack of ADAMTS13
activity do not manifest clinical symptoms of TTP.
The mechanism of secondary TTP is poorly understood, as ADAMTS13 activity is generally not as depressed as in idiopathic TTP, and inihibitors cannot be detected. Probable etiology may involve, at least in some cases, endothelial damage.
levels, e.g. infection. Reportedly, 5-10% of all TTP cases are due to Upshaw-Schülman syndrome.
has become the treatment of choice for TTP. This is an exchange transfusion
involving removal of the patient's blood plasma
through apheresis
and replacement with donor plasma (fresh frozen plasma
or cryosupernatant
); the procedure has to be repeated daily to eliminate the inhibitor and abate the symptoms. If pheresis is not available, fresh frozen plasma can be infused, but the volume able to be given safely is limited due to the danger of fluid overload. Lactate dehydrogenase
levels are generally used to monitor disease activity. Plasmapheresis may need to be continued for 1–8 weeks before patients with idiopathic TTP cease to consume platelets and begin to normalize their hemoglobin. No single laboratory test (platelet count, LDH, ADAMTS13 level, or inhibitory factor) is indicative of recovery; research protocols have used improvement or normalization of LDH as a measure for ending plasmapheresis. Although patients may be critically ill with failure of multiple organ systems during the acute illness, including renal failure, myocardial ischemia, and neurologic symptoms, recovery over several months may be complete in the absence of a frank myocardial infarct, stroke, or CNS hemorrhage.
Most patients with refractory or relapsing TTP receive additional immunosuppressive therapy, with glucocorticoid
steroid
s (e.g. prednisolone
or prednisone
), vincristine
, cyclophosphamide
, splenectomy
, rituximab
or a combination of the above.
Children with Upshaw-Schulman syndrome receive prophylactic plasma every two to three weeks; this maintains adequate levels of functioning ADAMTS13.
Measurements of LDH, platelets and schistocytes are used to monitor disease progression or remission.
.
in New York City
in 1925. Moschcowitz ascribed the disease (incorrectly, as now known) to a toxic cause. Moschcowitz noted that his patient, a 16 year-old girl, had anemia, petechiae (purpura), microscopic hematuria
, and, at autopsy, disseminated
microvascular thrombi. In 1966, a review of 16 new cases and 255 previously reported ones led to the formulation of the classical pentad of symptoms and findings; in this series, mortality rates were found to be very high (90%). While response to blood transfusion had been noted before, a 1978 report and subsequent studies showed that blood plasma was highly effective in improving the disease process. In 1991 it was reported that plasma exchange provided better response rates compared to plasma infusion. In 1982 the disease had been linked with abnormally large von Willebrand factor multimers, and the late 1990s saw the identification of a deficient protease
in people with TTP. ADAMTS13 was identified on a molecular level in 2001.
Rare disease
A rare disease, also referred to as an orphan disease, is any disease that affects a small percentage of the population.Most rare diseases are genetic, and thus are present throughout the person's entire life, even if symptoms do not immediately appear...
of the blood-coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
system, causing extensive microscopic thromboses
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
to form in small blood vessels throughout the body (thrombotic microangiopathy). Most cases of TTP arise from inhibition of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
ADAMTS13
ADAMTS13
ADAMTS13 —also known as von Willebrand factor-cleaving protease —is a zinc-containing metalloprotease enzyme that cleaves von Willebrand factor , a large protein involved in blood clotting...
, a metalloprotease responsible for cleaving large multimers of von Willebrand factor
Von Willebrand factor
von Willebrand factor is a blood glycoprotein involved in hemostasis. It is deficient or defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly hemolytic-uremic syndrome...
(vWF) into smaller units. A rarer form of TTP, called Upshaw-Schülman syndrome, is genetically inherited as a dysfunction of ADAMTS13. If large vWF multimers persist there is tendency for increased coagulation.
Red blood cells passing the microscopic clots are subjected to shear stress
Shear stress
A shear stress, denoted \tau\, , is defined as the component of stress coplanar with a material cross section. Shear stress arises from the force vector component parallel to the cross section...
which damages their membranes, leading to intravascular hemolysis
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
and schistocyte
Schistocyte
A schistocyte or schizocyte is a fragmented part of a red blood cell. Schistocytes are typically irregularly shaped, jagged, and asymmetrical. A true schistocyte does not have central pallor...
formation. Reduced blood flow due to thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
and cellular injury results in end organ damage
End organ damage
End organ or target organ damage usually refers to damage occurring in major organs fed by the circulatory system which can sustain damage due to uncontrolled hypertension, hypotension, or hypovolemia....
. Current therapy is based on support and plasmapheresis
Plasmapheresis
Plasmapheresis is the removal, treatment, and return of blood plasma from blood circulation. It is thus an extracorporeal therapy...
to reduce circulating antibodies against ADAMTS13 and replenish blood levels of the enzyme.
Signs and symptoms
Classically, the following five features ("pentad") are indicative of TTP; in most cases, some of these are absent.- ThrombocytopeniaThrombocytopeniaThrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
(low plateletPlateletPlatelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
count), leading to bruising or purpuraPurpuraPurpura is the appearance of red or purple discolorations on the skin that do not blanch on applying pressure. They are caused by bleeding underneath the skin... - Microangiopathic hemolytic anemiaMicroangiopathic hemolytic anemiaIn medicine microangiopathic hemolytic anemia is a microangiopathic subgroup of hemolytic anemia caused by factors in the small blood vessels. It is identified by the finding of anemia and schistocytes on microscopy of the blood film.-Presentation:It is referred as Runner's anemia...
(anemiaAnemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, jaundiceJaundiceJaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
and a blood filmBlood filmA blood film or peripheral blood smear is a thin layer of blood smeared on a microscope slide and then stained in such a way to allow the various blood cells to be examined microscopically...
featuring evidence of mechanical fragmentation of red blood cells) - NeurologicNeurologyNeurology is a medical specialty dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue,...
symptoms (fluctuating), such as hallucinations, bizarre behavior, altered mental status, strokeStrokeA stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
or headacheHeadacheA headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
s - Kidney failureAcute renal failureAcute kidney injury , previously called acute renal failure , is a rapid loss of kidney function. Its causes are numerous and include low blood volume from any cause, exposure to substances harmful to the kidney, and obstruction of the urinary tract...
- FeverFeverFever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
Due to the high mortality of untreated TTP, a presumptive diagnosis of TTP is made even when only microangiopathic hemolytic anemia and thrombocytopenia is seen, and therapy is started.
The symptoms of TTP may at first be subtle - starting with malaise
Malaise
Malaise is a feeling of general discomfort or uneasiness, of being "out of sorts", often the first indication of an infection or other disease. Malaise is often defined in medicinal research as a "general feeling of being unwell"...
, fever, headache and sometimes diarrhea. As the condition progresses clots (thrombi) form within blood vessels and platelets (clotting cells) are consumed. Bruising, and rarely bleeding, results and may be spontaneous. 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.
Clots formed within the circulation can temporarily disrupt local blood supply. TTP preferentially affects the blood vessels of the brain and kidneys. Thus a patient may experience headache, confusion, difficulty speaking, transient paralysis, numbness or even fits whilst high blood pressure (hypertension) may be found on examination.
Platelet associated IgG and complement levels are usually normal in TTP.
Causes and pathogenesis
TTP, as with other microangiopathic hemolytic anemiaMicroangiopathic hemolytic anemia
In medicine microangiopathic hemolytic anemia is a microangiopathic subgroup of hemolytic anemia caused by factors in the small blood vessels. It is identified by the finding of anemia and schistocytes on microscopy of the blood film.-Presentation:It is referred as Runner's anemia...
s (MAHAs), is caused by spontaneous aggregation of platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
s and activation of coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
in the small blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s. Platelets are consumed in the coagulation process, and bind fibrin
Fibrin
Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....
, the end product of the coagulation pathway. These platelet-fibrin complexes form microthrombi which circulate in the vasculature and cause shearing of red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s, resulting in hemolysis
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
.
Roughly, there are two forms of TTP: idiopathic and secondary TTP. A special case is the inherited deficiency of ADAMTS13, known as the Upshaw-Schülman syndrome.
Idiopathic TTP
The idiopathicIdiopathic
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...
form of TTP was recently linked to the inhibition of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
ADAMTS13 by antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
, rendering TTP an autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
. ADAMTS13 is a metalloproteinase
Metalloproteinase
Metalloproteinases constitute a family of enzymes from the group of proteases, classified by the nature of the most prominent functional group in their active site. These are proteolytic enzymes whose catalytic mechanism involves a metal. Most metalloproteases are zinc-dependent, but some use...
responsible for the breakdown of von Willebrand factor
Von Willebrand factor
von Willebrand factor is a blood glycoprotein involved in hemostasis. It is deficient or defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly hemolytic-uremic syndrome...
(vWF), a protein that links platelets, blood clots, and the blood vessel wall in the process of blood coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
. Very large vWF multimers are more prone to lead to coagulation. Hence, without proper cleavage of vWF by ADAMTS13, coagulation occurs at a higher rate, especially in the part of the blood vessel system where vWF is most active due to high shear stress
Shear stress
A shear stress, denoted \tau\, , is defined as the component of stress coplanar with a material cross section. Shear stress arises from the force vector component parallel to the cross section...
: in the microvasculature.
In idiopathic TTP, severely decreased (<5% of normal) ADAMTS13 activity can be detected in most (80%) patients, and inhibitors are often found in this subgroup (44-56%). The relationship of reduced ADAMTS13
ADAMTS13
ADAMTS13 —also known as von Willebrand factor-cleaving protease —is a zinc-containing metalloprotease enzyme that cleaves von Willebrand factor , a large protein involved in blood clotting...
to the pathogenesis of TTP is known as the Furlan-Tsai hypothesis, after the two independent groups of researchers who published their research in the same issue of the New England Journal of Medicine
New England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...
in 1998. This theory is seen as insufficient to explain the etiology of TTP, since many patients with hereditary lack of ADAMTS13
ADAMTS13
ADAMTS13 —also known as von Willebrand factor-cleaving protease —is a zinc-containing metalloprotease enzyme that cleaves von Willebrand factor , a large protein involved in blood clotting...
activity do not manifest clinical symptoms of TTP.
Secondary TTP
Secondary TTP is diagnosed when the patient's history mentions one of the known features associated with TTP. It comprises about 40% of all cases of TTP. Predisposing factors are:- CancerCancerCancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
- Bone marrow transplantation
- PregnancyPregnancyPregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
- MedicationMedicationA pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
use:- QuinineQuinineQuinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...
- Platelet aggregation inhibitors (ticlopidineTiclopidineTiclopidine is an antiplatelet drug in the thienopyridine family. Like clopidogrel, it is an adenosine diphosphate receptor inhibitor. It is used in patients in whom aspirin is not tolerated, or in whom dual antiplatelet therapy is desirable...
and clopidogrelClopidogrelClopidogrel is an oral, thienopyridine class antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It is marketed by Bristol-Myers Squibb and Sanofi-Aventis under the trade name Plavix. The drug works by irreversibly...
) - Immunosuppressants (cyclosporine, mitomycinMitomycinThe mitomycins are a family of aziridine-containing natural products isolated from Streptomyces caespitosus or Streptomyces lavendulae. One of these compounds, mitomycin C, finds use as a chemotherapeutic agent by virtue of its antitumour antibiotic activity. It is given intravenously to treat...
, tacrolimusTacrolimusTacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection...
/FK506, interferon-αInterferonInterferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
)
- Quinine
- HIV-1 infection
The mechanism of secondary TTP is poorly understood, as ADAMTS13 activity is generally not as depressed as in idiopathic TTP, and inihibitors cannot be detected. Probable etiology may involve, at least in some cases, endothelial damage.
Upshaw-Schülman syndrome
A hereditary form of TTP is called the Upshaw-Schülman syndrome; this is generally due to inherited deficiency of ADAMTS13 (frameshift and point mutations). Patients with this inherited ADAMTS13 deficiency have a surprisingly mild phenotype, but develop TTP in clinical situations with increased von Willebrand factorVon Willebrand factor
von Willebrand factor is a blood glycoprotein involved in hemostasis. It is deficient or defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly hemolytic-uremic syndrome...
levels, e.g. infection. Reportedly, 5-10% of all TTP cases are due to Upshaw-Schülman syndrome.
Treatment
Since the early 1990s, plasmapheresisPlasmapheresis
Plasmapheresis is the removal, treatment, and return of blood plasma from blood circulation. It is thus an extracorporeal therapy...
has become the treatment of choice for TTP. This is an exchange transfusion
Exchange transfusion
An exchange transfusion is a medical treatment in which apheresis is used to remove one person's red blood cells or platelets and replace them with transfused blood products...
involving removal of the patient's blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
through apheresis
Apheresis
Apheresis is a medical technology in which the blood of a donor or patient is passed through an apparatus that separates out one particular constituent and returns the remainder to the circulation...
and replacement with donor plasma (fresh frozen plasma
Fresh frozen plasma
The term fresh frozen plasma refers to the liquid portion of human blood that has been frozen and preserved after a blood donation and will be used for blood transfusion...
or cryosupernatant
Cryosupernatant
The term cryosupernatant refers to plasma from which the cryoprecipitate has been removed.-Components:...
); the procedure has to be repeated daily to eliminate the inhibitor and abate the symptoms. If pheresis is not available, fresh frozen plasma can be infused, but the volume able to be given safely is limited due to the danger of fluid overload. Lactate dehydrogenase
Lactate dehydrogenase
Lactate dehydrogenase is an enzyme present in a wide variety of organisms, including plants and animals.Lactate dehydrogenases exist in four distinct enzyme classes. Two of them are cytochrome c-dependent enzymes, each acting on either D-lactate or L-lactate...
levels are generally used to monitor disease activity. Plasmapheresis may need to be continued for 1–8 weeks before patients with idiopathic TTP cease to consume platelets and begin to normalize their hemoglobin. No single laboratory test (platelet count, LDH, ADAMTS13 level, or inhibitory factor) is indicative of recovery; research protocols have used improvement or normalization of LDH as a measure for ending plasmapheresis. Although patients may be critically ill with failure of multiple organ systems during the acute illness, including renal failure, myocardial ischemia, and neurologic symptoms, recovery over several months may be complete in the absence of a frank myocardial infarct, stroke, or CNS hemorrhage.
Most patients with refractory or relapsing TTP receive additional immunosuppressive therapy, with glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
s (e.g. prednisolone
Prednisolone
Prednisolone is the active metabolite of prednisone, which is also used as a drug.-Uses:Prednisolone is a corticosteroid drug with predominant glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and auto-immune conditions such as...
or prednisone
Prednisone
Prednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...
), vincristine
Vincristine
Vincristine , formally known as leurocristine, sometimes abbreviated "VCR", is a vinca alkaloid from the Catharanthus roseus , formerly Vinca rosea and hence its name. It is a mitotic inhibitor, and is used in cancer chemotherapy.-Mechanism:Tubulin is a structural protein that polymerizes to...
, cyclophosphamide
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
, splenectomy
Splenectomy
A splenectomy is a surgical procedure that partially or completely removes the spleen.-Indications:The spleen, similar in structure to a large lymph node, acts as a blood filter. Current knowledge of its purpose includes the removal of old red blood cells and platelets, and the detection and fight...
, rituximab
Rituximab
Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
or a combination of the above.
Children with Upshaw-Schulman syndrome receive prophylactic plasma every two to three weeks; this maintains adequate levels of functioning ADAMTS13.
Measurements of LDH, platelets and schistocytes are used to monitor disease progression or remission.
Epidemiology
The incidence of TTP is about 4-6 per million people per year. Idiopathic TTP occurs more often in women and black/African-American people, while the secondary forms do not show this distribution. Pregnant women and women in the postpartum period accounted for a notable portion (12-31%) of the cases in some studies; TTP affects approximately 1 in 25,000 pregnancies.Prognosis
The mortality rate is approximately 95% for untreated cases, but the prognosis is reasonably favorable (80-90% survival) for patients with idiopathic TTP diagnosed and treated early with plasmapheresisPlasmapheresis
Plasmapheresis is the removal, treatment, and return of blood plasma from blood circulation. It is thus an extracorporeal therapy...
.
History
TTP was initially described by Dr Eli Moschcowitz at the Mount Sinai HospitalMount Sinai Hospital, New York
Mount Sinai Hospital, founded in 1852, is one of the oldest and largest teaching hospitals in the United States. In 2011-2012, Mount Sinai Hospital was ranked as one of America's best hospitals by U.S...
in New York City
New York City
New York is the most populous city in the United States and the center of the New York Metropolitan Area, one of the most populous metropolitan areas in the world. New York exerts a significant impact upon global commerce, finance, media, art, fashion, research, technology, education, and...
in 1925. Moschcowitz ascribed the disease (incorrectly, as now known) to a toxic cause. Moschcowitz noted that his patient, a 16 year-old girl, had anemia, petechiae (purpura), microscopic hematuria
Hematuria
In medicine, hematuria, or haematuria, is the presence of red blood cells in the urine. It may be idiopathic and/or benign, or it can be a sign that there is a kidney stone or a tumor in the urinary tract , ranging from trivial to lethal...
, and, at autopsy, disseminated
Disseminated disease
Disseminated disease refers to a diffuse disease process, generally either infectious or neoplastic, but sometimes also referring to connective tissue disease....
microvascular thrombi. In 1966, a review of 16 new cases and 255 previously reported ones led to the formulation of the classical pentad of symptoms and findings; in this series, mortality rates were found to be very high (90%). While response to blood transfusion had been noted before, a 1978 report and subsequent studies showed that blood plasma was highly effective in improving the disease process. In 1991 it was reported that plasma exchange provided better response rates compared to plasma infusion. In 1982 the disease had been linked with abnormally large von Willebrand factor multimers, and the late 1990s saw the identification of a deficient protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
in people with TTP. ADAMTS13 was identified on a molecular level in 2001.
External links
- Thrombotic thrombocytopenic purpura from MedlinePlusMedlinePlusMedlinePlus is a free Web site that provides consumer health information for patients, families, and Health care providers. The site brings together information from the United States National Library of Medicine, the National Institutes of Health , other U.S. government agencies, and...
- What is TTP? from the National Heart, Lung, and Blood InstituteNational Heart, Lung, and Blood InstituteThe National Heart, Lung, and Blood Institute is a division of the National Institutes of Health, located in Bethesda, Maryland...
- Platelets on the Web from University of Oklahoma Health Sciences CenterUniversity of Oklahoma Health Sciences CenterThe University of Oklahoma Health Sciences Center is the health sciences branch of the University of Oklahoma. Located in Oklahoma City, it serves as the primary place of instruction for many of Oklahoma's health professions...
- TTP in the Merck Manual of Diagnosis and TherapyMerck Manual of Diagnosis and TherapyThe Merck Manual of Diagnosis and Therapy, often called simply The Merck Manual, is the world's best-selling medical textbook. First published in 1899, it is now in its 19th edition.-Professional Edition:...