What are the causes and symptoms of Thrombotic Thrombocytopenic Purpura (TTP)?

Causes and Symptoms of Thrombotic Thrombocytopenic Purpura (TTP)

Thrombotic Thrombocytopenic Purpura (TTP) is characterized by severe ADAMTS13 deficiency leading to microangiopathic hemolytic anemia, severe thrombocytopenia, and microvascular thrombosis causing organ damage, with the classic pentad including fever, neurological abnormalities, and renal dysfunction.

Causes of TTP

TTP can be classified into two main types based on etiology:

1. Acquired TTP (immune-mediated)

• Autoantibodies against ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) 1
• More common in adults than children 1
• Higher incidence in:
  • Females (3.19 times higher than males) 1
  • Black individuals (7.09 times higher than non-Black individuals) 1
• Potential triggers:
  • Drugs (e.g., ticlopidine, which can cause drug-induced TTP) 2
  • Infections
  • Immune checkpoint inhibitor therapy (rare adverse effect) 3

2. Congenital TTP (hereditary)

• Caused by biallelic mutations in the ADAMTS13 gene 4
• Often detected in childhood or during pregnancy 4
• Less common than acquired TTP

Pathophysiology

1. ADAMTS13 deficiency leads to accumulation of ultra-large von Willebrand factor (vWF) multimers 1
2. These large vWF multimers bind platelets in high-shear microcirculation 1
3. Formation of platelet-rich microthrombi in small blood vessels 5
4. Resulting microvascular occlusion causes:
   • Mechanical destruction of red blood cells (schistocytes)
   • Consumption of platelets
   • Ischemic organ damage 4

Symptoms and Clinical Presentation

Classic Pentad (though less than 7% of cases present with all five features) 6

1. Microangiopathic hemolytic anemia

   • Pallor, fatigue, weakness
   • Jaundice (yellowing of skin/eyes) 2

2. Severe thrombocytopenia

   • Purpura (palpable or non-palpable) 7
   • Petechiae (pinpoint dots on skin) 2
   • Abnormal bleeding (gums, nose) 2
   • Bruising

3. Neurological abnormalities (39-80% of cases) 1

   • Headache
   • Confusion
   • Weakness on one side of the body 2
   • Seizures
   • Altered mental status

4. Renal dysfunction

   • Variable degrees of renal insufficiency 7
   • Hematuria
   • Proteinuria
   • Dark urine 2

5. Fever

   • Present in many but not all cases

Other Common Symptoms

• Abdominal pain (35-39% of cases) 1
• Excessive weakness and tiredness 2
• Chills or sore throat (may indicate neutropenia) 2

Laboratory Findings

1. Blood count abnormalities

   • Severe thrombocytopenia (platelet count often <30 × 10⁹/L) 1
   • Anemia

2. Peripheral blood smear

   • Schistocytes (fragmented RBCs) 2
   • Normal white blood cell morphology 3

3. Hemolysis markers

   • Elevated lactate dehydrogenase (LDH)
   • Decreased haptoglobin
   • Elevated reticulocyte count
   • Elevated indirect bilirubin 3

4. ADAMTS13 activity

   • Severely reduced (<10% of normal) in TTP 1
   • Presence of ADAMTS13 inhibitor or anti-ADAMTS13 IgG in acquired TTP 3

Diagnostic Workup

The American Society of Clinical Oncology recommends the following tests when TTP is suspected 3:

• Complete blood count with peripheral smear
• ADAMTS13 activity level and inhibitor titer
• LDH, haptoglobin, reticulocyte count, bilirubin
• Prothrombin time, activated partial thromboplastin time, fibrinogen
• Blood group and antibody screen, direct antiglobulin test
• Consider brain imaging (CT or MRI)
• Rule out other causes of thrombotic microangiopathy

Warning Signs Requiring Immediate Medical Attention

Patients should immediately seek medical care if they experience 2:

• Yellow skin or eye color
• Pinpoint dots (rash) on the skin
• Pale color
• Fever
• Weakness on one side of the body
• Dark urine

Differential Diagnosis

TTP must be differentiated from other thrombotic microangiopathies 3:

• Hemolytic uremic syndrome (HUS)
• Malignant hypertension-associated TMA
• Drug-induced TMA
• Complement-mediated TMA
• Disseminated intravascular coagulation (DIC)

TTP associated with malignant hypertension typically shows less severe thrombocytopenia and fewer schistocytes compared to primary TTP 3.

Early recognition and prompt initiation of appropriate treatment are critical, as untreated TTP has a mortality rate approaching 90%, while with proper treatment, survival rates exceed 90% 1.