MD Notes

creation date: 2026-04-05 23:45
tags: Pathologies

Thrombotic Thrombocytopenic Purpura

Background

Definitions

Thrombotic thrombocytopenic purpura (TTP) is a type of microangiopathic hemolytic anemia.

TTP is a medical emergency with an untreated mortality of 90%.

Etiology

TTP occurs due to the decrease or absence of the enzyme ADAMTS13.

Acquired TTP (more common, 30x more likely than congenital) is due to autoantibodies targeting the enzyme. Commonly listed triggers include:

  • Antiplatelet drugs
  • Immunosuppressive drugs
  • HIV
  • Estrogen-containing birth control
  • Pregnancy

Congenital TTP results from mutations. In cases of hereditary ADAMTS13 deficiency, patients remain asymptomatic until a triggering event occurs such as infection or pregnancy. It should be noted that cTTP should remain on the differential if it presents during first pregnancy.

Pathophysiology

The ADAMTS13 enzyme is the von Willebrand factor-cleaving protease. As von Willebrand factor is involved in clot formation, a deficiency of ADAMTS13 results in spontaneous coagulation and microthrombi formation. This typically requires enzyme activity <10%.

Microthrombi circulate and result in end-organ ischemia and damage. The central nervous system and kidneys are most commonly affected.

Due to thrombus formation, platelets are consumed and manifests as thrombocytopenia. Small vessels occluded by thrombi results in hemolytic destruction of RBCs resulting in anemia, referred to as microangiopathic hemolytic anemia. The destruction of RBCs results in schistocyte morphology seen on smear.

Clinical Presentation

Signs & Symptoms

TTP is classically characterized by pentad of fever, thrombocytopenia, hemolytic anemia, renal dysfunction, and neurologic dysfunction.

Initial typical symptoms include:

  • Fatigue
  • Dyspnea
  • Petechiae (spots of bleeding under skin)
  • Bleeding
  • Neurologic symptoms

Organ involvement include:

  • CNS system (weakness, coma, stroke, seizure, focal abnormalities, headache, confusion)
  • Gastrointestinal symptoms (abdominal pain, nausea/vomiting, diarrhea)
  • Kidney involvement (AKI is uncommon but seen on biopsy)
  • CVS (elevated serum troponin)

Older patients may present atypically:

  • More organ involvement
  • Less severe thrombocytopenia

History & Physical Exam

Owing to nonspecific findings, history and physical is unlikely to reveal much beyond signs and symptoms.

The PLASMIC score can be used to predict the likelihood of TTP. A finding of peripheral schistocytes is required to apply this score. One point is given for each of the following:

  • Platelet <30,000/mcL
  • Presence of hemolysis (reticulocyte count >2.5%, undetectable haptoglobin, or indirect bilirubin >34 mcmol/L
  • MCV <90 fL
  • INR <1.5
  • Creatinine <176.8 mcmol/L
  • No active cancer
  • No solid organ or stem cell transplant

Probability of TTP with a score ≤4 is low, 5 is intermediate, and 6-7 is high. Note that a score ≥5 is enough for empiric treatment.

Risk Factors

  • Autoimmune diseases

Diagnosis

Criteria

A definitive diagnosis requires a severe deficiency in ADAMTS13 (<10%) with supportive clinical findings (MAHA and thrombocytopenia without another obvious cause).

Note that an activity level of 10-20% does not rule out TTP.

A presumptive diagnosis can be made with a PLASMIC score ≥5.

Work-up

Laboratory studies
Presence of microangiopathic hemolytic anemia (MAHA) and thrombocytopenia should raise suspicion for TTP. Tests immediately useful for risk stratification include:

  • CBC
  • Peripheral blood smear
  • Coagulation panel
  • Kidney function tests
  • Liver function tests

Other tests for evaluation include:

  • Lactate dehydrogenase
  • Serum haptoglobin
  • Direct antiglobulin (Coombs test) - for immune hemolysis
  • ADAMTS13 activity and inhibitor testing

Post-diagnostic evaluation
Further workup may be performed by a hematologist following diagnosis. This may include:

  • Medication review
  • Genetic testing

Differential

Other causes of thrombotic microangiopathies (eval: typically greater kidney impairment):

  • Drug-induced TMA
  • Shiga toxin-associated HUS

Systemic causes of MAHA and thrombocytopenia (eval: ADAMTS13 activity, resolution with delivery, response to treatment):

Other conditions include:

  • Vascular lesions causing MAHA
  • Heparin-induced thrombocytopenia
  • Other blood conditions

Red Flags / Complications

Untreated TTP have high mortality.

Management

Management is initiated with a PLASMIC score ≥5. This is typically deferred to hematology or a clinician with expertise in TTP.

Mainstay management consist of therapeutic plasma exchange (TPE). Donor plasma serves to:

  • Provide ADAMTS13
  • Removes the autoantibody against ADAMTS13

All plasma products are equally effective. It is insufficient to perform plasmapheresis and use other replacement fluids.

Immunosuppression is used to improve outcomes and decrease duration of TPE.

  • Glucocorticoid (prednisone PO or methylprednisolone IV for high risk features)
  • Rituximab once ADAMTS13 activity <10% confirmed.

References

Tools / Guidelines

Additional Reading

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