Thrombotic Thrombocytopenic Purpura (TTP)

Life-threatening, multisystem disease manifested by thrombocytopenia, microangiopathic hemolytic anemia, fever, neurologic changes and renal abnormalities.

A micro angiopathic syndrome characterized by a pentad of thrombocytopenia, microangiopathic hemolytic anemia, renal insufficiency, fever, waxing/waning neurologic symptoms.

Characterized by widespread thrombosis in the arterioles and capillaries many organs and tissues.

Only a minority of patients present with all the symptoms outlined above.

Caused by a germline predisposition or acquired autoantibodies.

An auto immune disease caused by a autoantibody to the ADAMST13 protease resulting in an accumulation of abnormally large vwF in plasma capable of causing platelet micro thrombi in the microcirculation.

ADAMST13 is the plasma metalloproteinases that cleaves ultra large von Willebrand factor multimers down to physiologic size.

Normally von Willebrand Factor mediates platelet binding to subendothelial collagen at sites of vascular injury; during this process, activated endothelial cells releasenvon Willebrand factor in multimerized forms that are then cleaved by the Adamts 13 metalloproteinase.

When large von Willebrand factor multimers are not cleaved they spontaneously bind platelets, which aggregate and cause the formation of micro thrombi leading to microvascular occlusion that  result in end-organ ischemia and dysfunction.

Plasma exchange attempts to remove inhibitory antibodies and replenish the missing ADAMTS 13.

With plasma exchange the efficiency in removing ADAMTS13 antibodies varies and for platelet counts to normalize the time ranges from a few days to more than one month.

In patients with intense ADAMTS13 autoimmunity or advanced organ dysfunction, plasma exchange may be inadequate to induce remission and prevent death.

Plasma exchange to remove the inhibitory antibodies and replenish the missing ADAMTS 13 efficiency varies not only by diffusion from their extravascular pool but also by newly synthesized anybody molecules from plasma.

The intensity of ADAMTS13 auto immunity varies during the course of the disease in the same individual.

Patients may have exacerbations before remission is achieved.

ADAMTS13 immunity varies during the course of the disease and may lead to exacerbation before remission is achieved, or reoccur after the plasma exchange is discontinued.

ADAMTS 13 activity levels are usually above 50% and if the activity below falls below 10% the diagnostis is likely TTP, whereas levels exceeding 20% indicate the diagnosis is unlikely.

Manifests by acute episodes of systemic microvascular thrombosis.

Most patients eventually achieve remission without plasma exchange as ADAMTS13 autoimmunity becomes quiescent.

Microvascular thrombi are comprised of von Willebrand factor and platelets and little fibrin.

Initial symptoms are fatigue and headache, and or non-specific.

Patients come to medical attention when findings of neurologic deficits, petechiae, confusion, or seizures occur.

Abdominal pain is not uncommon and may be the predominant complaint in patients with TTP.

Rarely, the patient may present with a stroke, acute myocardial infarction, or sudden death with no or mild thrombocytopenia and microangiopathic hemolytic anemia.

Hemolytic uremic syndrome (HUS) considered as the same entity i.e. TTP-HUS.

Many patients have only thrombocytopenia and microangiopathic hemolysis.

Patients with TTP show that the platelet count offer begins to decrease before the patient becomes symptomatic.

Occasionally micro vascular thrombosis can cause a stroke or myocardial infarction before it becomes physically widespread to cause thrombocytopenia.

Thrombocytopenia in general does not occur until the plasma ADAMTS13 activity level is less than 10% of normal.

Approximately 2-7 cases per million person years, with more frequency and in females, with nearly 3 to 1 female to male ratio.

The incidence is seven times as high among Black people.

Most patients are 20-60 years of age.

New diagnoses in children and elderly are uncommon.

Viral infections, pregnancy, obesity, African-American race and certain drugs are risk factors.

Microvascular thrombi the hallmark of pathologic diagnosis.

Von Willebrand factor-cleaving protease (ADAMS-13) deficient in patients with TTP resulting in abnormally large von Willebrand factor multimers to circulate.

The largest multimers promote platelet adhesion by binding to the platelet glycoprotein Ibalpha- IX-V surface receptors.

Acquired disease due to the development of inhibitory antibodies against von Willebrand factor, cleaving protease ADAMTS13, which is a disintegrin and metalloprotease with thromboplastin motif-13, which cleaves multimeric VWF at the Tyr MET peptide bond of the A2 domain.

In acquired TTP severe ADAMTS 13 deficiency is the result of circulating auto antibodies inhibiting ADAMTS 13 function or increasing ADAMTS 13 clearance (iTTP).

In congenital ADAMTS 13 deficiency hereditary TTP is caused by biallelic ADAMST 13 mutations.

Inherited variance in the gene encoding ADAMTS 13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif 13, known as hereditary TTP.

ADAMTS13 cleaves ultra large multimers , preventing inappropriate platelet adhesion and thrombosis.

ADAMTS13 cleaves ultra large multimers that are secreted from vascular endothelial cells.

Pathophysiology is presence of large von Willebrand factor multimers and low levels of ADAMTS13.

Large vWF multimers easily accumulate and cause intravascular vWF platelet aggregation and microvascular thrombosis.

Ultra large von Willebrand secretion from endothelial cells is stimulated by inflammatory cytokines TNF-alpha, IL-8,, IL-6, Shiga toxin, estrogen and other agonists.

It is caused by a deficiency of A Disintegrin-like And Metalloprotease with a ThromnoSpondin type 1 motif 13 (ADAMTS13), which may be an inherited disorder, but more commonly it is an acquired disease due to autoantibodies directed against ADAMTS13.

Inhibitory antibodies most commonly IgA and they target ADAMTS13.

Low ADAMTS13 levels result in increased ultra large von Willebrand factor multimers, which induce platelet adhesion and thrombosis.

AdamsTS13 deficiency results in large von Willebrand factor multimers and platelet thrombi in small vessels with high shear rates.

Patients may have characteristic clinical features without severe ADAMS-13 deficiency.

Decreased ADAMTS 13 activity is associated with an increased size of von Willebrand factor multimers and increased risk of microvascular thrombosis.

Large von Willebrand factor multimers cause disseminated platelet clumping in the microcirculation.

Ultra large von Willebrand factor multimers are no longer cleaves by the protease and accumulate within the microcirculation causing shear stress dependent platelet aggregation, and red blood cell damage.

Damage caused by ultra large von Willebrand factor multimers resulted in a thrombi formation, thrombocytopenia, microangiopathic hemolysis and neurologic symptoms.

More than 40% of patients present with severe neurologic abnormalities, the majority of which are a transient focal abnormalities.

Almost 70% of patients had gastrointestinal symptoms and greater than 50% of bleeding, purpura, or hematuria.

95% of patients have a normal kidney function or mildly acute kidney injury.

90% mortality rate when left untreated.

Plasma exchange standard treatment with survival rates of 75-92%.

Responds to plasma exchange secondary to the removal of inhibitory antibodies and restoration of ADAMS-13 activity from infused donor plasma.

Nearly all cases with severe ADAMS-13 deficiency are secondary to an autoantibody inhibitor.

Congenital deficiency of ADAMS13 causing TTP is also known as  Upshaw Schulman syndrome.

Congenital TTP is an ultra rare thrombotic microangiopathy with a prevalence of 0.5 cases per million population.

Congenital TTPResults from severe hereditary deficiency with less than 10% of normal activity of ADAMTS 13, leading to accumulation of ultralarge von Willebrand  factor, multimers with high platelet binding activity.

The spontaneous formation of platelet rich micro thrombi, and organ ischemia, cause acute symptoms and long-term organ damage and premature death.

Platelet consumption manifest as thrombocytopenia, which is a hallmark of congenital TTP.

Congenital TTP has a clinical presentation that ranges from life-threatening, acute events to milder manifestations, including thrombocytopenia, hemolytic anemia, abdominal pain, headache, and neurologic symptoms.

End-organ damage due to recurrent TTP such as stroke, chronic kidney disease or cardiac involvement can also occur.

Acute TTP events are triggered by infections, trauma and, pregnancy.

Hereditary TTP (Upshaw-Schulman syndrome) is caused by homozygous or compound heterozygous ADAMTS13.

TTP rarely causes severe acute kidney injury.

Diagnosis of hereditary TTP requires documentation of ADAMSTS13 deficiency and in absence of ADAMSTS13 auto antibody inhibitor and confirms documentation of ADAMSTS13 mutations.

With hereditary TTP microangiopathic hemolytic anemia and thrombocytopenia may be apparent at birth, but they may not appear until adulthood when precipitated by a clinical process such as pregnancy.

Hereditary TTP has a pattern of autosomal recessive inheritance and environmental factors such as infections are often associated with acute episodes of thrombocytopenia and hemolysis.

Patients with hereditary TTP may appear to be in good health, but the increased risk of critical thrombosis is always present.

Incidence of acquired TTP is much greater in adulthood, 2.9 cases per 1 million per year, than in children, 0.1 cases per 1 million per year.

Patients with acquired TTP present with weakness, purpura , transient focal neurologic abnormalities, and gastrointestinal symptoms.

One third of patients with acquired TTP have no neurologic abnormalities.

Most patients with acquired TTP have normal or mildly elevated transiently elevated creatinine levels.

An ADAMTS13 level of less than 10% supports the diagnosis of acquired TTP.

This level of ADAMTS 13 is not sufficient to identify will patients with TTP.

Patients with ADAMS-13 inhibitors and severely deficient in functional activity are predisposed to relapse after plasma exchange treatment.

Inverse relationship exists between severe ADAMS-13 deficiency and TTP relapses or exacerbations.

A small fraction of patients are refractory to plasma exchange or unable to be independent from plasma exchange or plasma infusions and require immunosuppressive therapy.

Platelet transfusions may be dangerous precipitating deterioration and exacerbation of thromboses.

Chronic renal failure occurs in 25% of patients within 1 year of the diagnosis.

Red blood cell fragmentation occurs as blood circulates though abnormal microcirculation.

Laboratory findings include: thrombocytopenia, and hemolytic anemia manifested by fragmented red blood cells.

Most cases are idiopathic.

3.7 cases per million persons.

May result from infection with E.Coli strain 0157:H7, ticlopidine, clopidrogrel, bone marrow transplantation, cancer chemotherapy, HIV infection and pregnancy.

Fever and hemolytic anemia are the most common symptoms.

Cogulation studies and bone marrow biopsy are typically normal or mildly so.

Microagioathic hemolytic anemia resolves in an elevated LDH and indirect bilirubin values, and schistoctes are seen on peripheral blood smear.

Hyaline thrombi are present in terminal arterioles and capillaries is most commonly in the brain, spleen, heart, kidneys, pancreas, and adrenal glands.

No specific criteria set for diagnosis.

Remains a clinical diagnosis.

The PLASMIC score based on platelet count, combined hemolysis variable, mean corpuscular volume, international normalized ratio, and creatinine in the absence of active cancer or recent transplantation is a clinical tool used to estimate the likelihood of severe ADAMTS 13 deficiency in adults with thrombocytopenia and evidence of micro angiopathic hemolytic anemia on peripheral smear.

Kidneys are not usually affected, as is present in hemolytic uremic syndrome.

Only 51% of patients have the classic presentation of the pentad of fever, hemolytic anemia, thrombocytopenia, renal failure, and neurologic symptoms.

68% of patients have hemolytic anemia, thrombocytopenia, and neurologic deficits, and the differential diagnoses of patients with these three signs and symptoms must include TTP.

In a study of 70 consecutive patients there were 57 survivors with a median age of 39 years, 79% were women, 37% were black, prevalence of SLE was 7%, 40% experienced hypertension and 19% major depression, 11 patients (19%) died (Deford CC et al ).

TTP survivors are at greater risk for poor health and premature death.

Treatment for hereditary TTP is replacement of ADAMSTS 13 by plasma infusions.

Most patients with hereditary TTP require plasma infusions primarily when thrombocytopenia or other symptoms occur, others however may require prophylactic infusions.

Therapeutic plasma exchange allows the transfusion of a high volume of ADAMST13 in donor plasma, but also removes the circulating antibody inhibitor in more than 95% of patients with autoimmune TTP.

An acquired TTP plasma exchange is associated with the survival rate of approximately 80-90%.

Immediate objective in management in acquired TTPS to halt von Willebrand factor-platelet aggregation and to maintain ADAMTS13 levels above 10%, conventionally with plasma exchange.

Control of ADAMTS13 auto immunity helps achieve this goal for patients with inhibitory antibodies.

For both the immediate and post discharge treatment TTP, therapeutic plasma exchange must be accomplished by immunosuppression.

glucocorticoids, or typically started alongside therapeutic plasma exchange.

Anti-von Willebrand factor drugs may control thrombotic complications before the plasma ADAMTS 13 level is stably above 10%.

Immunosuppressive treatments such as rituximab, cyclosporine vincristine, cyclophosphamide and intravenous immunoglobulin reported to induce remissions in patients with relapsing or refractory forms of disease.

Rituximab increases plasma level of ADAMTS13 by decreasing the synthesis of ADAMTS 13 inhibitors.

Rituximab is effective in preventing a recurrence of the disease in patients with multiple recurrences.

Rituximab  treatments limitation includes a lag time for response as it depletes B- cells leaving existing plasma cells to decrease by attrition and the response may take days to weeks or longer.

The median duration of remission to rituximab is  approximately 30 months in patients treated for persistent disease or multiple recurrences.

Retreatment before ADAMTS13 decreases below 10% may prevent recurrence.

Glucocorticoids or standard treatment for acquired TTP, but no efficacy of corticosteroids in treatment of TTP or for prevention of relapses has been found although a rare patient reportedly responds.

Mortality previous to effective therapy with plasma exchange was 90% and is now decreased to 20%.

The aim of plasma exchange is to replenish deficient stores of ADAMST13 and to remove autoantibodies against ADAMST13.

However, with normal or slightly decreased ADAMST13 levels plasma exchange provides normal vWF diminishing the effect of large vWF multimers and removes the large multimers themselves.

Recovery from acute episodes is complete except for risk of recurrent acute episodes.

Surviving patients frequently report problems with memory, concentration, and endurance.

Acquired TTP is associated with a risk of relapse, increased cognitive impairment, depression, SLE, hypertension, and death.

Covid-19 vaccines have been implicated in the pro thrombotic disorder, TTP: intravenous IV IgG is efficacious.

Caplacizumab approved for use in combination with plasma exchange and immunosuppression is a nanobody that binds to the A1 domain of vonWillebrand’s factor and prevents it from binding platelets.

Caplacizumab Is an anti-von Willebrand factor immunoglobulin fragment that reduces microthrombus formation and end organ damage by antagonizing von Willebrand factor platelet interactions.

Caplacizumab is associated with increased frequency of bleeding related adverse events and should be avoided in patients who have substantial bleeding, or at a risk of bleeding.

Long-term monitoring of blood counts in ADAMTS 13 activity is important with immune TTP as this is a lifelong auto immune disorder.

Even without relapse, patients who have had TTP have long-term consequences including: cognitive impairment, hypertension, depression, and stroke.

The estimated risk of relapse at 7.5 years is 41%.

Hereditary TTP is a rare process with an estimated prevalence of 0.5 to 2 cases per million population worldwide.

Biallelic mutations in the Gene ADAMTS13 lead to a severe ADAMTS 13 deficiency with activity less than 10% of normal plasma.

In the absence of ADAMTS 13 size regulation of the Von Willebrand factor  is lacking.

Platelets bonding to ultra large von Willebrand factor multimers, resulting in microvascular thrombosisbrosis with end organ damage, consumptive thrombocytopenia, and microangiopathic hemolytic anemia with schistocytes on the peripheral blood smear during acute episodes.

More than 300 mutations have been identified in patients with hereditary TTP.

Plasma is the primary source of exogenous ADAMTS13 for treatment and prophylaxis in patients with hereditary TTP.

Recombinant ADAMTS 13 is promising therapy for this process.

Current therapy involves ADAMTS 13 replacement through prophylactic or on-demand infusions of fresh frozen plasma, plasma that has been treated with a solvent detergent process or ADAMTS 13 containing plasma derived factor VIII von Willebrand factor concentrates.

Such products rely on donor plasma and provide limited ADAMTS 13 replacement.

The mainstay of therapy for TTP his plasma exchange, which remove the inhibitor and provides exogenous ADAMTS 13.

Plasma exchange induces a clinical response, the most patients, despite it best replaying only approximately half of the normal ADAMTS 13 activity levels.

Prophylactic therapy is lengthy, burdensome and associated with allergic reactions to plasma.

Recombinant ADAMTS13 studies are underway, and show efficacy.


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