At a Glance

Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening, multisystem disorder with an estimated incidence of 2-10 cases per million/year. This hematologic emergency affects all racial groups and both sexes, two- to three-fold higher among females.

TTP is characterized by five features (pentad) consisting of thrombocytopenia, microangiopathic hemolytic anemia (MAHA), fever, variable neurological abnormalities (mostly confusion or severe headache), and renal failure.

The key pathogenesis of TTP is the circulating excessive amounts of ultra-large von Willebrand factor (UL-vWF) multimers, which are mostly due to the deficiency of an important cleavage protease (i.e., ADAMTS13). These UL-vWF multimers bind to and activate platelets, causing spontaneous aggregation of platelets and activation of coagulation cascade. Consequently, multiple platelet thrombi are formed inside the capillaries and the small arterioles, resulting in the development of specific TTP clinical and laboratory manifestations.

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Although almost one-third of TTP are idiopathic, the other two-thirds are often associated with an underlying condition, such as autoimmune disease, AIDS, pregnancy and postpartum, drug toxicity (e.g., chemotherapy, Quinine), hematopoietic cell transplantation, or following bloody diarrhea (usually by E. coli O157:H7 series).

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

TTP patients usually present with a characteristic set of laboratory findings. This includes a negative direct antiglobulin test (DAT), microangiopathic hemolytic anemia (MAHA), and thrombocytopenia, which are considered major laboratory criterion of TTP.A normal to elevated white blood cell (WBC) count and increased reticulocytes percentage can also be detected.

Markedly decreased to undetectable levels of haptoglobin is very common, along with high levels of indirect bilirubin due to red blood cell (RBC) destruction while passing through the microscopic thrombi. This can often be detected on the peripheral blood smear, in up to 80% of TTP cases, as fragmented RBCs known as schistocytes. Helmet cells and nucleated RBCs can be seen as well.

Prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen levels are usually normal in TTP with elevated levels of fibrin degradation products (FDP). A significant increase in lactate dehydrogenase (LDH) levels is a very common finding in TTP.

Elevated levels of creatinine are usually an indication of renal involvement. Urinalysis is usually normal with mild proteinuria; however, RBCs and red cell casts can be detected in advanced cases of renal failure.

Although identifying ADAMTS13 activity and antibody levels is crucial in TTP diagnosis, studies have shown that the presenting features of patients who had severe ADAMTS13 deficiency were indistinguishable from patients who had low to almost normal levels. Therefore, utilization of these tests can be helpful in confirming and understanding the pathogenesis of this disorder (congenital versus acquired) and in disease monitoring and for prognostic evaluation but are not required initially as part of TTP diagnosis.

In general, it is very difficult to diagnose TTP because of the wide variations in patient presentations, which can also be nonspecific (e.g., fatigue, weakness). In addition, the pentad symptoms may not always emerge evenly and simultaneously. Therefore, since TTP has a high fatality rate if misdiagnosed or not treated promptly, a combination of any MAHA and thrombocytopenia without another clinically apparent etiology (e.g., disseminated intravascular coagulation, malignant hypertension, severe preeclampsia) is considered adequate for an immediate but tentative diagnosis so management (i.e., plasma exchange) can be instituted in a timely manner.(Table 1)

Table 1.
Test Name Result
PT, PTT, Fibrinogen Normal
Platelet Count Very Low (Average 30-50,000/micro L)
WBC Normal to Elevated
Fibrinogen Degradation Products (FDP) Elevated
DAT Negative
Haptoglobin Extremely low to undetectable
Indirect Bilirubin Elevated
Lactate dehydrogenase (LDH) Extremely Elevated
Reticulocytes Elevated
Creatinine Normal to High
Proteinuria Normal to High (depends on renal involvement)
WBC and RBC Casts Positive in Renal Failure
Peripheral Blood Smear Schistocytes, Helmet cells, and Nucleated RBCs

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

The presenting features of TTP and hemolytic uremic syndrome (HUS) are similar in most adult patients. Cases of dominant neurologic findings with minimum or no renal involvement are considered by some classical TTP, whereas HUS is considered in cases including acute renal involvement with or without neurologic findings.

Nevertheless, regardless of the primary diagnosis, the initial effective treatment of both disorders in all adult patients is plasma exchange.

Although 90% of TTP patients exhibit neurological findings (vs. 15% of HUS patients), 98% of HUS patients exhibit renal involvement (vs. 2% of TTP patients).

What Lab Results Are Absolutely Confirmatory?

ADAMTS13 activity and antibody assays are commonly used for TTP confirmation. However, they are not available in a timely manner in most cases. Furthermore, these assays are not well standardized, and results are often inconsistent.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Excessive amounts of ultra-large vWF multimers are released from damaged endothelial cells, causing the formation of massive platelet rich-microthrombi in the vessel lumina. The accumulation of these ultra-large vWF multimers in the circulation is primarily due to ADAMTS13 deficiency, which may result from either acquired or inherited causes.

Consequently, partial or complete obstruction of the blood vessel may develop affecting organ function (e.g., central nervous system (CNS) and kidney) and may result in end organ damage, which is one of the features of this disorder.

In addition, these characteristic microthrombi cause sheer stress effect on the circulating RBCs, resulting in schistocytes formation and intravascular hemolysis.

Clinically, there are two different types of TTP: congenital and acquired. Congenital TTP, also known as Upshaw-Schülman syndrome, is an extremely rare (1:1,000,000) autosomal recessive disorder caused by mutations in the ADAMTS13 gene and accounts for almost 5-10% of all TTP cases. This type is usually presented at birth or during childhood. Under normal conditions, the phenotype of this disorder is usually mild; TTP develops in clinical situations of acute phase reactions (e.g., infection) in which increased levels of vWF are seen.

Whether ADAMTS13 autoantibodies are present or not, the acquired type can be sub-classified into two forms: immune- and non-immune-mediated forms. The former is mostly seen in autoimmune disorders, drug-induced, or pregnancy with an ADAMTS13 activity less than 5% and detectable levels of inhibitor. This form is probably due to massive endothelial stimulation that results in the release of high concentrations of UL-vWF multimers that exceed the enzymatic capability of ADAMTS13. Slightly to moderately low levels of ADAMTS13 activity can also be detected in this form with no presence of inhibitor to ADAMTS13. This form can be seen in cancers, metastasis, organ transplantation, and during the use of certain drugs, such as cyclosporine, mitomycin, and alpha-interferon.

Following the routine use of plasma exchange, the survival rate of TTP improved significantly (from <10% to almost 98%). Classical TTP usually presents as a single random acute episode that can be cured with daily plasma exchange procedures for about 1 week. Chronic recurrent forms can be seen in about 20-30%, mostly in cases with a genetic basis or cases associated with autoantibodies. Relapse can be seen in almost one-third to one-half of all TTP patients in which intensive immunosuppressive therapy may be indicated. Overall, it was found that patients with detectable levels of ADAMTS13 at the time of first TTP diagnosis usually had a worse prognosis, including delayed platelet count recovery, a need for more intensive treatment, higher risk for relapse (about 30% vs. 9% in severe deficiency), and death.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

The combination of thrombocytopenia, MAHA, and renal failure can also be seen in a number of severe disorders, such as systemic vasculitis and other connective tissue diseases, catastrophic antiphospholipid syndrome, scleroderma renal crisis, disseminated intravascular coagulation (DIC), malignant hypertension, and disseminated malignancy. Low levels of ADAMTS13 have also been found in other conditions, such as DIC, idiopathic thrombocytopenic purpura, sepsis, autoimmune disorders, and heparin-induced thrombocytopenia, as well as in newborns.