Thrombotic thrombocytopenic purpura (TTP) is a life-threatening blood clotting disorder caused by a lack of the enzyme ADAMTS13. It leads to microclots throughout the body. TTP requires emergency treatment with plasma exchange (PEX) and steroids to remove antibodies and increase ADAMTS13 levels. A new treatment is the monoclonal antibody caplacizumab, which blocks clotting and reduces deaths and hospitalization time. TTP can recur and be refractory, requiring intensified treatment including rituximab and additional immunosuppressants. With prompt treatment, survival rates as high as 90% are now possible.

1. Thrombotic Thrombocytopenic
Purpura

2. Definitions:
• TTP is a thrombotic microangiopathy (TMA) caused by severely reduced activity of the
von Willebrand factor-cleaving protease ADAMTS13.
• TTP can be acquired, due to an autoantibody inhibitor, or hereditary, due to inherited
mutations in ADAMTS13.
• TTP is a medical emergency that is almost always fatal if appropriate treatment is not
initiated promptly.
• With appropriate treatment, survival rates of up to 90% are possible.

3. Epidemiology and Risk Factors:
• The incidence of acquired TTP is approximately 3 cases per 106 adults per year, based on
data from the Oklahoma TTP-HUS Registry.
• Demographic features associated with an increased risk of acquired TTP include female
sex and black race.
• Autoimmune diseases, such as SLE are common among patients with TTP.
• In the UK TTP Registry, 75% of cases occurred in females.
• In the Oklahoma TTP-HUS Registry, 76% of patients were women and 36% were black.

4. Pathophysiology:

5. Clinical Characteristics:
• Initial symptoms of MAHA and thrombocytopenia may include fatigue, dyspnea,
petechiae, or other bleeding.
• Organ involvement in TTP often affects the central nervous system and/or
gastrointestinal system.
• Renal involvement is seen on renal biopsy, but acute kidney injury is uncommon.
• Other organs such as the heart may also be affected. Pulmonary involvement is
rare.

6. Laboratory Findings:
• MAHA and thrombocytopenia are the hallmarks of TTP.
• MAHA is characterized by the presence of schistocytes on blood smear along with other findings such
as helmet and triangular cells, polychromasia (due to reticulocytosis), nucleated RBCs and
microspherocytes (more common with AIHA).
• A finding of two or more schistocytes per HPF in the appropriate clinical setting is suggestive of MAHA.
• Severe thrombocytopenia < 30,000/microL is common.
• Severely reduced ADAMTS13 activity (generally <10 percent) during an acute episode is a hallmark of
acquired TTP.
• Other lab findings of hemolysis: elevated indirect bilirubin, LDH and retic count, low haptoglobin,
and normal coomb's test.
• Other lab findings of organ damage: elevated Troponin (may correlate with early death), elevated Cr...

7. Diagnosis:
• Presumptive Diagnosis of TTP is made by the findings of MAHA and thrombocytopenia
without another obvious cause in the appropriate clinical setting.
• It is important to start treatment emergently and order ADAMST13.
• Confirmed Diagnosis of TTP is made by the finding of severe ADAMTS13 deficiency (eg,
activity <10% of normal) and the presence of an ADAMTS13 inhibitor (autoantibody) in
the appropriate clinical setting (a patient with MAHA and thrombocytopenia that
responds to treatment).

8. • PLASMIC Score predicts the likelihood of ADAMTS13 activity ≤10%
in adults with features of TMA (MAHA and
thrombocytopenia) to help estimate the pretest probability and support
the diagnosis of TTP.
• It was developed using a cohort of 214 adults with suspected TMA, and
validation was performed in two additional cohorts.
• Schistocytes are not included in the score because they are considered a
precondition for applying the score.
• The higher the score, the greater the likelihood of TTP:
a) 0 to 4 points – low probability of TTP.
b) 5 points – intermediate probability of TTP.
c) 6 to 7 points – high probability of TTP.
• While this score cannot substitute for clinical judgment and cannot be
used to definitively confirm or exclude the diagnosis of TTP, it may be
helpful for guiding the decision of whether to initiate TTP therapy while
awaiting the results of ADAMTS13 testing.

10. Management:
• PEX should be used for all patients with a presumptive or confirmed diagnosis of TTP.
• Glucocorticoids:
a) Standard Risk: Prednisone 1 mg/kg per day orally.
b) High Risk: IV methylprednisolone 1g daily for 3 days or 125 mg 2-4 times daily.
Followed by a dose of prednisone 1 mg/kg per day orally.
• Rituximab: UpToDate recommends using it as initial therapy in all patients with a
presumptive diagnosis of TTP unless there is a contraindication. Dosing: 375 mg/m2 IV
once a week for 4 consecutive weeks.

11. • Caplacizumab is a humanized monoclonal antibody fragment that binds to VWF and blocks its interaction with
platelet GPlb-IX-V.
• It halts the formation of microthrombi, but it does not reduce production of the autoantibody against ADAMTS13.
• FDA approved in 2019 for initial treatment of TTP together with PEX and immunosuppressive agents.
• Recommended for patients with a presentation that includes severe features such as critical illness, neurologic
findings, or high troponin levels.
• The dose and schedule of caplacizumab from clinical trials was 10 mg IV on day 1 followed by 10 mg SQ on day 1
after PEX and continued once daily SQ for 30 days after PEX has been stopped. Discontinuation was based on an
increase in ADAMTS13 activity to above 20 to 30%.

12. • Phase 3 study (HERCULES) trial randomly assigned 145 patients with acquired TTP to receive caplacizumab or placebo daily until
30 days beyond the last PEX procedure.
• All patients received daily PEX and glucocorticoids. Slightly less than half received rituximab.
• Caplacizumab was associated with the following outcomes:
a) Fewer deaths (1 with caplacizumab vs 3 with placebo).
b) Faster normalization of the platelet count (2.69 vs 2.88 days), which correlated with fewer days of PEX (mean, 5.8 vs 9.4).
c) Fewer exacerbations in the 30 days after stopping PEX (12 vs 38 percent).
d) Shorter hospitalization (mean, 9.9 vs 14.4 days) and fewer days in the intensive care unit (mean, 3.4 vs 9.7).
• Caplacizumab was generally well tolerated but was associated with more bleeding (65 vs 48 percent), likely due to interference
with VWF function. The bleeding was typically mild to moderate (epistaxis and gingival bleeding that resolved spontaneously). One
caplacizumab-treated patient with severe epistaxis was treated with VWF concentrate.

13. Response and Subsequent
Therapy:
• Platelet count response, defined as a
platelet count ≥150,000/mL for 2 days or a platelet
count plateau (normal or supranormal) for 3 days.
• PEX: discontinue PEX abruptly rather than tapering
because tapering has not been shown to increase
the likelihood of a durable response.
• Glucocorticoids: initiate a taper once the
ADAMTS13 activity is above 20-30%. The taper is
completed over the ensuing 2-3 weeks.
• Rituximab: finish a full 4-week course.
• Caplacizumab: continue after PEX and until
recovery of ADAMST13 function to 20-30%
regardless of the recommended 30-day period.

14. Definitions:
• TTP in remission: a normal platelet count and absence of TTP symptoms for 30 days after PEX is stopped, regardless of
ADAMTS13 activity level.
• Refractory TTP in the following cases:
a) TTP for which treatment with PEX and immunosuppression fails to produce a satisfactory response within 4 days of
starting therapy.
b) TTP characterized by development of new neurologic abnormalities during PEX that are not attributable to another
cause such as bleeding or infection.
c) TTP for which an exacerbation of symptoms or laboratory findings occurs during PEX or within the first 30 days of
stopping PEX.
• Relapse TTP: recurrence of an acute episode, manifested by thrombocytopenia and microangiopathic hemolytic anemia, in
a patient who had a disease remission following an episode of TTP

15. Management:
• Refractory Disease:
a) Evaluate for other causes.
b) Resume daily PEX if it was discontinued.
c) Intensify the steroid regimen (methylprednisolone IV 1g daily for 4 days).
d) Start Rituximab if not started already.
e) Start Caplacizumab if not started already. If it was started and stopped then restart it.
• Relapsed TTP:
a) PEX, Glucocorticoids, Rituximab.
b) Use Caplacizumab when indicated.
• Poor response to therapy: immunosuppressive agents can be used such as Cyclophosphamide, Bortezomib, Cyclosporine,
Mycophenolate Mofetil, NAC; and Splenectomy.