Quiz on TTP – Part 1

Definitions

Which of the following statements is/are correct:

TTP is a type of thrombotic microangiopathy

Thrombotic microangiopathy (TMA) is a group of syndromes with different etiologies, including ADAMTS13 deficient and nondeficient states, that share clinical features of thrombocytopenia, microangiopathic hemolytic anemia, and organ injury and pathologic features of occlusive microvascular or macrovascular disease, often with intraluminal thrombus formation.

TTP is defined by deficiency of ADAMTS13 activity < 30% of normal

TTP is a TMA associated with severe deficiency of ADAMTS13 activity (< 10% of normal).

Epidemiology

The annual incidence of TTP 3.1 per million persons in the United States and 13 per million adults in France. TTP is more common in which of the following demographics:

Female adults

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Black persons

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Children vs adults

Classifications

TTP may be classified according to:

Congenital vs. acquired

Congenital TTP, also called Upshaw-Schulman syndrome, is caused by abnormal ADAMTS13 variants. Acquired TTP, also called immune TTP, is caused by autoantibodies to ADAMTS13. Immune TTP is reported to account for > 95% of all TTP cases.

Primary vs. secondary

In primary TTP, there are no underlying precipitating causes. Secondary TTP is triggered by an underlying cause. Examples include connective tissue disease, HIV, pregnancy, and certain drugs.

Low ADAMTS13 vs. normal ADAMTS13

ADAMTS13 activity < 10% required for the diagnosis of TTP. If it is higher, it is not considered TTP. ADAMTS13 is an acronym for “a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13”.

Pathogenesis

Which of the following statement is/are correct:

ADAMTS13 normally functions to cleave fibrinogen

ADAMTS13 cleaves ultra-large vWF multimers.

Deficiency in ADAMTS13 activity results in increased levels of ultra-large vWF multimers

ADAMTS13 is a metalloprotease that regulates the platelet-aggregating activity of the von Willebrand factor (vWF) by cleaving it at specific sites.

TTP is associated with thrombin-induced platelet aggregation

In TTP, deficiency in ADAMTS13 activity results in increased levels of ultra-large vWF multimers, resulting in vWF-induced platelet aggregation causes widespread formation of microthrombi, especially in the microvasculature, where shear rates are high.

The microvascular thrombi is composed of vWF and platelets, and extensive fibrin

The microvascular thrombi is composed of vWF and platelets, but little fibrin,

Acquired TTP is caused by a severe deficiency of ADAMTS13, due to circulating antibodies that inhibit ADAMTS13 activity or increase ADAMTS13 clearance

Clinical presentation

Which of the following represents the historically characterized clinical pentad of immune ITP:

Thrombocytopenia, microangiopathic, hemolytic anemia, neurologic symptoms, kidney impairment, fever

Thrombocytopenia, microangiopathic, hemolytic anemia, neurologic symptoms, liver impairment, fever

Thrombocytopenia, microangiopathic, hemolytic anemia, neurologic symptoms, kidney impairment, leukocytosis

The reported prevalence of signs and symptoms that make up the classic pentad (historically used for diagnosis) in a cohort identified in the Canadian Apheresis Group registry between 1982 and 1995:

Thrombocytopenia in 100%
Anemia in 100%
Neurologic signs in 64%
Fever in 22%
Renal involvement in 18%

Presenting findings in a cohort of 78 patients with TTP (ADMATS13 activity < 10%) enrolled in the Oklahoma TTP Registry between 1995 and 2015 included:

Thrombocytopenia and microangiopathic hemolytic anemia in 100%
Neurologic abnormalities in 53%
Fever in 10%
Severe acute kidney injury in 5%

Clinical presentation

Which of the following organ systems are often affected in TTP:

GI tract

Bowel ischemia may cause abdominal pain, nausea, vomiting or diarrhea. Patients may also present with pancreatitis.

Neurologic

Neurologic symptoms are reported in 70%-80% of the cases. The symptoms are typically fluctuating and include confusion, headaches, weakness, altered speech and visual changes.

Heart

Presentation includes chest pain, arrhythmias, and symptoms of heart failure.

Lung

Usually spared

Testing to assess for the presence and extent of specific organ damage:

Tests include:
- Serum creatinine and urinalysis (hematuria and/or proteinuria may indicate renal involvement)
- Cardiac troponin
- Electrocardiogram/echocardiogram
- Brain imaging (computed tomography/magnetic resonance imaging), if neurologic symptoms are present

Suspect diagnosis of immune TTP in adults with:

Isolated microangiopathic hemolytic anemia
Thrombocytopenia
New focal neurological symptoms, seizure, or acute myocardial infarction with unexplained microangiopathic hemolytic anemia
Prior history of TTP

Confirmation of diagnosis requires:

Elevated creatinine

Reduced plasma ADAMTS13 activity (< 10%)

MRI brain showing evidence of stroke

Change in plasma vWF levels

ADAMTS13 levels usually take several days to come back. TTP is a medical emergency and requires prompt treatment within hours of presentation. How is an initial tentative clinical diagnosis made for purposes of proceeding with management:

Expert opinion (gestalt)

Use of a clinical scoring system (pretest probability tool)

Degree of thrombocytopenia

Must wait for ADAMTS13 level before instiuting treatment

Two clinical scoring systems have been validated in TTP:

The PLASMIC score is the most commonly used tool for predicting the probability of a patient having TTP. Which of the following parameters is/are included in the PLASMIC score:

Thrombocytopenia

MCV < 90 fL

Creatinine >2.0 mg/dL

Creatinine <2.0 mg/dL

INR < 3

INR < 1.5

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