Thrombotic thrombocytopenic purpura

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2]

Thrombotic thrombocytopenic purpura (TTP or Moschcowitz disease) is a rare disorder of the blood-coagulation system, causing multiple blood clots to form in blood vessels around the body.^[1] Most cases of TTP arise from deficiency or inhibition of the enzyme ADAMTS13, which is responsible for cleaving large multimers of von Willebrand factor.^[2] This leads to hemolysis and end-organ damage, and may require plasmapheresis therapy.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2]

In 1924, Eli Moschcowitz first describe TTP. In 1960, plasma infusion was introduced as a part of the treatment of a 8-year old patient with chronic anemia and thrombocytopenia by Schulman and colleagues.In 1966, the new criteria for the diagnosis of TTP. In 1978, Upshaw first described the hereditary aspect of the disease which lacked an enzyme in the blood and responded to plasma transfusion. Moschcowitz ascribed the disease.

• In 1924, Eli Moschcowitz first describe TTP with a pentad of presentation (petechiae, anemia, and pallor followed by paralysis and coma) ^[1].
• In 1960, plasma infusion was introduced as a part of the treatment of a 8-year old patient with chronic anemia and thrombocytopenia by Schulman and colleagues ^[2].
• In 1966, the new criteria for the diagnosis of TTP as the “pentad” of clinical and laboratory features was suggested. The criteria included thrombocytopenia, microangiopathic hemolytic anemia (fragmentation of RBCs or schistocytes) in the peripheral blood smear, neurological signs and symptoms, renal failure, and fever .
• In 1978, Upshaw first described the hereditary aspect of the disease which lacked an enzyme in the blood and responded to plasma transfusion ^[3].
• In 1979, Rennard & Abe proposed the use of the name Upshaw-Schulman syndrome to define the disease with these clinical features who responded to plasma infusion ^[4].
• In 1982, the pathogenesis of TTP was fully understood by Moake and colleagues ^[5].
• Moschcowitz ascribed the disease (incorrectly) to a toxic cause. Moschcowitz noted that his 16 year-old patient had anemia; petechiae; microscopic hematuria; and at autopsy, disseminated microvascular thrombi. Since that time, the pathophysiology, etiology, and medical management of TTP has expanded.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2]

TTP may be classified according to ADAMTS13 gene mutations and autoantibody against ADAMTS13 into two subtypes: herditary syndromes, aquired syndromes.

TTP may be classified into several subtypes based on ADAMTS13 gene mutations(herditary syndromes) and autoantibody against ADAMTS13(aquired syndromes):^[1][2]

1.Hereditary:

• Congenital TTP
• Inherited TTP
• Familial TTP
• Upshaw-Schulman syndrome (USS) is an autosomal recessive disease of ADAMTS13 gene on chromosome 9q34 .

2.Acquired

• Existence of an inhibitory antibody against ADAMTS13 due to the variety of conditions.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2]

The exact pathogenesis of thrombotic thrombocytopenic purpura (TTP) is not fully understood. It is thought that TTP is caused by the deficiency of a plasma metalloprotease, ADAMTS13.

• The exact pathogenesis of TTP is not completely understood.^[1]
• It is understood that TTP is caused by either deficiency of a plasma metalloprotease, ADAMTS13( (A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13).
• ADAMTS13 is member of human family the ADAMTS.^[2]
• ADAMTS13 is a plasma reprolysin-like metalloprotease divides von Willebrand factor (VWF).^[3]
• The von Willebrand factor (VWF) is produced by the endothelial cells as an ultra-high-molecular-weight multimers. Normally, VWF is sliced by a plasma metalloproteinase called ADAMTS13 into smaller multimers. When the activity or the amount of the protease is not enough, the ultra-high-molecular-weight multimers of VWF commence platelet aggregation and thrombosis in small vessels.^[1]
• Autoantibodies against the von Willebrand factor (VWF) cleaving metalloprotease ADAMTS-13. Severe deficiency of plasma ADAMTS-13 activity with or without detectable inhibitory autoantibodies against ADAMTS-13 supports the diagnosis of TTP.
• Deficiency of ADAMTS13 is caused by gene mutations or acquired. Autoantibodies is main to the pathophysiology of TTP. Ultra-large VWF multimers are breaking down by ADAMTS13 enzyme .
• In ADAMTS13 deficiency, large von willebrand factor (VWF) multimers collect leading to platelet aggregation, hemolysis and microthrombi formation. Organs are damaged by microthrombi that it cause ischemia is leading to damage to end organs.
• The most common organs being damaged are central nervous system (CNS) and kidneys.
• Thrombocytopenia results from platelet consumption during thrombus formation.
• Anemia results from hemolytic destruction of red blood cells as they pass through small vessels that are partially occluded by thrombi.

Genes involved in the pathogenesis of TTP include:^[4]

• Mutations in the ADAMTS13 gene.

• The development of TTP is the result of inherited ADAMTS13 deficiency but mild phenotype with increased von Willebrand factor level. Upshaw–Schulman syndrome is hereditary of TTP.
• Among some patients with severe, hereditary ADAMTS13 deficiency do not have signs or symptoms of TTP until their adulthoods .^[5]

On microscopic histopathological analysis findings of TTP include:

• Granular (muddy brown) casts
• Characteristic fibrin thrombi in glomerular and interstitial capillaries
• Slough into tubular lumen

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2]

TTP may be caused by decreasing function or amount of von Willebrand factor(vWF) cleaving protease ADAMTS13 .

Decrease function or amount of von Willebrand factor cleaving protease ADAMTS13 causes TTP.

Hereditary: Insertions, deletions, missense, nonsense point mutations and splice site mutations ^[1][2] of both alleles of ADAMTS13 genes on chromosome 9q34 cause decrease in the amount or activity of the enzyme.

Acquried:

• Diseases: Lupus, cancer, HIV, and infections(influenza)^[3]
• Conditions: Pregnancy, surgery, blood and marrow stem cell transplant

• Drugs: Mitomycin, cyclosporin A, cisplatin, bleomycin, quinine, ticlopidine, clopidogrel, estrogen, HRT

ADAMTS13 is a zinc and calcium requiring 190,000 Dalton glycosylated protein that is encoded on chromosome 9q34. It is a disintegrin and a metalloprotease with 8 thrombospondin 1-like domains composed of an aminoterminal metalloprotease followed by a disintegrin domain; a thrombospondin 1-like domain; a cysteine-rich domain and an adjacent spacer portion; seven additional thrombospondin 1-like domains and 2 other different types of domains that resemble each other at the carboxyl-terminal end of the molecule. It cleaves a tyrosine 1605-1606 methionine peptide bond of VWF. This protease is 13 in a family of 19 distinct ADAMTS-type metalloprotease enzymes. It is produced predominantly in endothelial cells for slow, constitutive release into the circulation. Endothelial cells can be stimulated to secrete long vWF strings by inflammatory cytokines (TNF, IL8 & IL6, shiga toxins or estrogen). ADAMTS13 is inhibited by EDTA and therefore functional assays of the enzyme are usually performed using plasma anticoagulated with citrate (a weaker divalent cation binder than EDTA).

TTP, as with other microangiopathic hemolytic anemias (MAHAs), is caused by a spontaneous aggregation of platelets and activation of coagulation in the small blood vessels. When stimulated, endothelial cells secrete the ultra-large VWF multimers in long strips that remain anchored to the cell membrane. The long VWF multimeric strings are sticky to the glycoprotein Iba components of platelet GPIb-IX-V surface receptors. The initial adherence of platelets via the GPIb receptors to the long vWF strings and the subsequent coherence of additional platelets to each other (aggregation) via activated GPIIb/IIIa receptors produces potentially occlusive platelet thrombi. 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 cells, resulting in hemolysis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2] Anum Ijaz M.B.B.S., M.D.[3]

The main differential diagnosis of TTP is hemolytic-uremic syndrome. TTP should be diffrential from the other disaeses such as TMA syndromes, disseminated intravascular coagulation ,hypertension, immune thrombocytopenic purpura (ITP)

• Malignant hypertension
• Hematological abnormalities
• Ischemic manifestations linked to autoimmune diseases

The main differential diagnosis of TTP is hemolytic-uremic syndrome (HUS, which has neurosymptoms, renal failure, hypertension and fever). Note that ADAMTS13 activity is normal in HUS.^[1]

The table below helps differentiate TTP from other thrombotic microangiopathies.^[2]

Abbreviation: ADAMTS13, a disintegrin and metallopeptidase with thrombospondin type 1 motif 13.

a Common etiologies are listed, although the list is not meant to be exhaustive.

b Hemolysis: low hemoglobin level, high reticulocyte count/serum lactate dehydrogenase level/indirect bilirubin, low haptoglobin levels.

c Common laboratory values at presentation, although patients may differ.

d All thrombotic microangiopathies can have neurologic, cardiac, and abdominal features due to involvement of microvasculature.

SI conversion factor: To convert creatinine values to μmol/L, multiply by 88.4.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2] Anum Ijaz M.B.B.S., M.D.[3]

The most proportion of TTP cases occurred after 40 years, black race and femal sex. Congenital forms occur in children.

• Thrombotic thrombocytopenic purpura (TTP) is a rare disorder with a worldwide annual incidence of approximately 2–6 cases per million population.^[1],^[2],^[3]
• Data suggests the increased risk of TTP in black race and femal sex.^[4]
• In adults, more than 95% of TTP cases are immune-mediated (iTTP), while only 3%–5% represent congenital ADAMTS13 deficiency.^[1]

• In 2005, the prevalence of TTP was estimated to be 3 cases per 1000,000 individuals worldwide.^[5]

• Patients of all age groups may developTTP.
• The incidence of TTP increases with age; the median age at diagnosis is 40 years. TTP often occurs after 40 years.
• The incidence of immune TTP is substantially higher in adults than in children, with an incident rate ratio (IRR) of 31.62 per 100 000 person-years.^[2]

• iTTP disproportionately affects Black individuals, who have an incident rate ratio of 7.09 per 100,000 years as compared with non-Black populations.^[2]

• Females are more commonly affected by iTTP than men.
• The females to men ratio is approximately 2 to 1.^[6][2] and the incident rate ratio is 3.19 per 100,000 person-years as compared to males.

• The majority of TTP cases are reported in black african and caribbean people.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2]

The most potent risk factor in the development of TTP is black ethnicity. Other risk factors include famale gender, pregnancy, obseity, chemotherapy, infection and etc.

Common risk factors in the development of TTP include:^[1][2][3]

• Black ethnicity
• Female gender
• SLE
• Obesity
• Pregnancy (third trimester)
• Cancer therapies
• Infection (HIV)
• Surgery (bone marrow stem cell transplant)
• Medicines :chemotherapy, hormone replacement therapy(estrogens)

Less common risk factors in the development of TTP include:^[1][4][5][6]

• HIV infection
• Bone marrow transplantation
• Antiplatelet agents
• Quinine

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2]

There is no insufficient evidence to recommend routine screening for TTP.

• There is no insufficient evidence to recommend routine screening for TTP.^[1]
• First test to be screening for ADAMTS13 activity. ADAMTS13 activity < 10%, TTP diagnosis is confirmed.
• In sever deficiency of ADAMTS13 second screening is detection of anti-ADAMTS13 IgG

• Gene sequencing of ADAMTS13 is a third test is used.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2] Anum Ijaz M.B.B.S., M.D.[3]

If left untreated, >90% of patients with TTP may progress to develop renal dysfunction, neurological disorders (mild headache, onset of behavioural anomalies, transient sensory and motor deficits, coma), ischaemic gastrointestinal complications (abdominal pain) and retinal detachment.

• The symptoms of TTP(acquired) usually develop in the 4th decade of life, and start with no specificity of the signs, symptoms and laboratory findings; symptoms such as fever, renal dysfunction, neurological disorders (mild headache, onset of behavioural anomalies, transient sensory and motor deficits, coma), ischaemic gastrointestinal complications (abdominal pain) and retinal detachment.^[1]
• Neurological symptoms at onset do not occur approximately more than 35% of patients.
• Fever and renal dysfunction are present among only a small minority of patients.
• The symptoms of TTP typically develop after 40 years.
• Early morbidity and mortality in iTTP are primarily caused by microvascular thrombosis leading to ischemic organ injury such as myocardial infarction and stroke.^[2]
• A clinical response to acute iTTP treatment is characterized by normalization of platelet count, reduction in serum lactate dehydrogenase, and absence of new or progressive ischemic organ injury.^[2]
• Patients who achieve a clinical response may still have persistent ADAMTS13 activity below 10% due to circulating anti-ADAMTS13 autoantibodies. Up to 38% of patients experience disease exacerbation within 30 days after stopping therapy (plasma exchange and caplacizumab).^[3],^[4]

• Clinical remission is defined as sustained normalization of platelet count (150 x 10⁹/L) for at least 30 days without therapeutic plasma exchange or caplacizumab. and ADAMTS13 activity of 20% or greater.^[2]
• During remission, regular laboratory monitoring including complete blood count,LDH level, and basic metabolic panel ( every 1 to 3 months) and ADAMTS13 ( once monthly in first year of first episode and then every 3-6 months thereafter) activity has been suggested to detect recurrence early.^[5]
• Symptoms such as fatigue, petechiae, and neurologic complaints may signal impending relapse and require urgent evaluation.^[5]
• During clinical remission, patients should have periodic ADAMTS13 monitoring, and preemptive rituximab is recommended when ADAMTS13 activity falls (commonly <20%) to restore enzyme levels and reduce the risk of relapse. ^[6],^[5],^[7]

• Clinical relapse is defined by thrombocytopenia after remission with or without new ischemic organ injury and severe ADAMTS13 deficiency.^[2]
• Approximately 16% of patients experience clinical relapse within 6 months after the initial episode.^[7]
• Approximately one-third of patients experiencing a TTP episode have a relapse within 10 years following their first attack.

• Exacerbation refers to recurrence of iTTP symptoms within 30 days of discontinuing therapeutic plasma exchange or caplacizumab therapy.^[2]
• Exacerbation occurs because therapeutic plasma exchange and caplacizumab do not eliminate the underlying autoimmune process causing ADAMTS13 deficiency.^[2]
• Patients with persistent severe ADAMTS13 deficiency (<10%) remain at risk for recurrence after discontinuation of therapy.^[2]
• In an exacerbation of iTTP, therapeutic plasma exchange should be restarted.^[8]
• Caplacizumab initiated at the time of exacerbation (if not previously given) shows a high response rate of approximately 93%.^[9]

• Refractory iTTP is defined by failure of platelet recovery or persistent thrombocytopenia (<50 × 10⁹/L) with elevated lactate dehydrogenase after at least five plasma exchange treatments.^[2]
• Refractory disease occurs in approximately 4%–14% of patients.^[9]

• Acute iTTP may cause ischemic complications including stroke, myocardial infarction, and organ dysfunction due to microvascular thrombosis.^[10]

• Common complications of TTP(restrict blood flow to organs such as the brain, kidneys, and heart) include:^[1][11]
  • Early death in approximilaty of patients are not diagnosed.
  • Neurological problems(personality changes,mild headaches, confusion and slurred speech, coma)
  • Abnormal kidney function

• Cardiovascular disease is the leading non-TTP cause of death among survivors.^[12]

• The mortality rate is approximately 90% for untreated cases, but the prognosis is reasonably favorable (80-90%) for patients with idiopathic TTP diagnosed and treated early with plasmapheresis.^[11]
• Approximately one-third of patients experiencing a TTP episode have a relapse within 10 years following their first attack.
• Secondary TTP still has a dismal prognosis, with mortality rates despite treatment being reported as 59% to 100%.
• Current treatment has reduced 30-day mortality to approximately 6.6%.^[10]
• Predictors of 30-day mortality include neurologic manifestations (headache, stupor, seizure, or focal deficit) on presentation, advanced age (≥60 years), and markedly elevated lactate dehydrogenase levels ( >10 times of upper limit of normal).^[13]
• Elevated troponin or impaired consciousness ( GCS ≤14) at presentation is associated with higher mortality risk.^[14]
• Survivors have higher long-term mortality than an age- and sex-matched population.^[12]

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