Thrombotic Thrombocytopenic Purpura (TTP)

A 35 year old female presents with a 3-day history of fatigue, headache, and confusion. She also reports petechiae on her legs. On examination, she has pallor, petechiae, and mild jaundice. Vital signs show blood pressure of 130/80 mm Hg, pulse rate of 98 beats per minute, respiratory rate of 18 breaths per minute, and temperature of 99.9 F. Laboratory studies reveal hemoglobin of 8.0 g/dL, platelet count of 30,000/µL, elevated LDH, elevated indirect bilirubin, low haptoglobin, and serum creatinine of 1.8 mg/dL. Peripheral blood smear shows schistocytes. Coombs test is negative. ADAMTS13 activity is severely reduced (<10%). Diagnosis?

Diagnosis is Thrombotic Thrombocytopenic Purpura (TTP).

1. Definition

Thrombotic thrombocytopenic purpura (TTP) is a microangiopathic hemolytic anemia (MAHA) caused by severe deficiency of ADAMTS13, leading to platelet-rich microvascular thrombosis and end-organ ischemia, especially involving the central nervous system and kidneys.

2. Pathophysiology

2.1 Core Mechanism

1. ADAMTS13 activity <10%
2. Accumulation of ultra-large von Willebrand factor multimers
3. Platelet aggregation and microthrombi formation

2.2 Consequences

1. Thrombocytopenia due to platelet consumption
2. Hemolytic anemia due to mechanical RBC destruction
3. Microvascular ischemia affecting multiple organs

2.3 Etiology

1. Acquired autoimmune inhibition of ADAMTS13, most common
2. Congenital ADAMTS13 deficiency
3. Clinical disease is often triggered by infection, pregnancy, or medications

3. Clinical Features

3.1 Core Features

1. Microangiopathic hemolytic anemia
2. Thrombocytopenia

These two findings are sufficient to suspect TTP

3.2 Additional Features

1. Neurologic symptoms, most prominent, such as confusion, seizures, or focal deficits
2. Acute kidney injury, typically less severe than in HUS
3. Fever, present in a minority of cases

Note: The classic pentad is rarely seen in full (<5%)

4. Diagnostic Evaluation

4.1 Hematology

1. Low hemoglobin
2. Low platelet count
3. Increased reticulocyte count

4.2 Hemolysis Markers

1. Elevated LDH
2. Elevated indirect bilirubin
3. Low haptoglobin
4. Coombs negative hemolysis

4.3 Peripheral Blood Smear

1. Schistocytes

4.4 Coagulation Profile

1. Normal PT and aPTT

4.5 Renal Function

1. Elevated creatinine

4.6 ADAMTS13 Testing

1. Activity <10% is highly suggestive in the appropriate clinical context
2. May detect anti-ADAMTS13 antibodies

4.7 Clinical Scoring

1. PLASMIC score helps estimate probability of severe ADAMTS13 deficiency

5. Key Diagnostic Insight

MAHA + thrombocytopenia with normal coagulation profile = presume TTP and treat immediately

6. Differential Diagnosis

1. Hemolytic uremic syndrome (HUS) with more severe renal involvement
2. Disseminated intravascular coagulation (DIC) with abnormal coagulation profile
3. Drug induced or cancer associated thrombotic microangiopathy
4. Autoimmune hemolytic anemia, Coombs positive

7. Management

7.1 Emergency Treatment

1. Immediate plasma exchange (PEX) is life saving
2. Do not delay treatment while awaiting ADAMTS13 results

7.2 First Line Therapy

1. Plasma exchange combined with corticosteroids

7.3 Adjunct Therapy

1. Rituximab to reduce relapse and for severe or refractory disease
2. Caplacizumab used in combination with PEX and immunosuppression to inhibit vWF platelet interaction

7.4 Supportive Care

1. Platelet transfusion should be avoided unless life threatening bleeding
2. Packed red blood cell transfusion if clinically indicated

7.5 Alternative

1. Plasma infusion if PEX is not immediately available

8. Complications

1. Multiorgan ischemia
2. Stroke, seizures, or coma
3. Cardiac ischemia
4. Death if untreated, mortality up to 90%

9. Key Clinical Insight

TTP is a hematologic emergency and early plasma exchange reduces mortality from about 90% to 10–15%

10. Exam Level Pearls

1. Schistocytes indicate microangiopathic hemolysis
2. Normal PT and aPTT distinguish TTP from DIC
3. ADAMTS13 activity <10% is diagnostic in the right clinical setting
4. Neurologic symptoms are more prominent than renal involvement
5. Classic pentad is rare
6. Never delay plasma exchange