About the Condition

Description/definition:

Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially fatal blood disorder caused by deficiency of von Willebrand factor cleaving protease, called ADAMTS131, which results in a thrombotic microangiopathy characterized by thrombocytopenia, microangiopathic hemolytic anemia, and multiorgan ischemia due to systemic platelet-rich microthrombi.

There are two types of TTP:

  1. Congenital TTP (also called Upshaw-Schulman syndrome), caused by mutations in the ADAMTS13 gene. These account for about 5% of cases of TTP.
  2. Acquired TTP (also called immune TTP or immune-mediated TTP), caused by inhibitory autoantibodies directed towards ADAMT13. Acquired TTP accounts for the remaining 95% of cases:
    • Primary – no underlying precipitating causes.
    • Secondary – underlying precipitating cause, including connective tissue disease, HIV, pregnancy, and certain drugs.

Pathophysiology:

Von Willebrand factor (vWF) mediates the binding of platelets to the subendothelial surface of the blood vessel wall. vWF circulates as multimers of varying size. The largest of these multimers – termed ultra large multimers – are the most hemosatically active. In regions of high shear stress (especially microvessels), the vWF ultra large multimers unfold, exposing sites that bind ADMATS13, leading to cleavage of the multimer and reduction of platelet adhesion and aggregation. Deficiency in ADAMTS13 activity results in increased levels of ultra large vWF multimers, which, in turn, lead to uncontrolled platelet adhesion and aggregation. vWF-induced platelet aggregation causes widespread microthrombi, thrombocytopenia due to platelet consumption, and microangiopathic hemolytic anemia from mechanical fragmentation of red blood cells.

Clinical presentation:

Patients typically present with severe microangiopathic hemolytic anemia (MAHA; hemoglobin almost always <10 gm/dL) and thrombocytopenia (platelet count almost always <30 x 109/L) associated with symptoms/signs and lab tests consistent with end organ damage including:

  • Central nervous system – in two thirds of cases:
    • Major neurologic findings in about 40% of cases, including:
      • Coma
      • Stroke
      • Seizure
      • Transient focal abnormalities
    • Minor neurologic findings in about 25% of cases, including:
      • Headache
      • Confusion
  • Gastrointestinal symptoms in about 70% of cases, including:
    • Abdominal pain
    • Nausea
    • Vomiting
    • Diarrhea
  • Kidney:
    • Kidney involvement is often seen on biopsy.
    • Acute kidney injury is uncommon. Creatinine may be normal or slightly increased; creatinine >2 mg/dL is rare. 
  • Heart
    • Chest pain
    • Arrhythmias
    • Symptoms of heart failure
  • Lungs (rare)

Presentations in older adults may include less-severe thrombocytopenia and more severe organ involvement.

Diagnosis:

Diagnosis of TTP is suggested in patient with isolated microangiopathic hemolytic anemia, thrombocytopenia, and evidence of organ dysfunction, especially brain or heart.

Testing to support the diagnosis of TTP:

  • Suggested tests:
    • Complete blood count (CBC):
      • Anemia, sometimes microcytic from the schisoctyosis/fragmentation
      • Thrombocytopenia – mean platelet count on presentation about 10 x 109/L.
    • Peripheral smear:
      • Schistocytes – two or more schistocytes per high power field, though no threshold schistocyte number below which the possibility of TTP can be excluded.
      • Polychromatophilia
    • Hemolytic indices:
      • LDH
      • Haptoglobin
      • Bilirubin
      • AST
  • Additional tests:
    • Direct antiglobulin (Coombs) test (DAT)
    • Coagulation testing (PT, aPTT, fibrinogen, D-dimer)
    • Serological tests for HIV, hepatitis B virus, and hepatitis C virus
    • Pregnancy test when appropriate
    • Testing to assess presence and extent of specific organ damage:
      • Renal function (BUN, creatinine)
      • Cardiac troponin
      • EKG
      • Brain imaging if neurological findings

Testing in preparation for possible rituximab use:

  • Check hepatitis B virus (HBV) serologies prior to plasmapheresis (HBV reactivation rate during rituximab treatment has been reported to be 20%-55% overall).

PLASMIC score:

  • Used to estimate the pretest probability of HIT in adults with features of thrombotic microangiopathy (TMA). The PLASMIC score assigns points for a number of positive and negative clinical features. Clinical parameters include:
    • Platelet count <30 x 109/L
    • Hemolysis (defined by reticulocyte count >2.5 percent, undetectable haptoglobin, or indirect bilirubin >2 mg/dL)
    • No active cancer
    • No solid organ or stem cell transplant
    • MCV <90 fL
    • INR <1.5
    • Creatinine <2.0 mg/dL
  • Schistocytes are not included in the score because they are considered a precondition for applying the score.
  • The score gives one point for each parameter:
    • 6 to 7 points – high probability of TTP
    • 5 points – intermediate probability of TTP
    • 0 to 4 points – low probability of TTP

Diagnosis is confirmed by ADAMTS13 testing:

  • Blood samples should be drawn before commencement of plasma exchange.
  • Measures ADAMTS13 activity by testing the ability of patient plasma to cleave vWF multimers or synthetic vWF peptides.
  • Plasma ADAMTS13 activity (< 5%-10%) confirms diagnosis of TTP.
  • Presence of a functional inhibitor of ADAMTS13 in mixing studies or anti-ADAMTS13 immunoglobulin G (IgG) antibodies are found in immune TTP.
  • Absence of anti-ADAMTS13 antibodies suggests congenital TTP (which may be further defined by ADAMTS13 mutations in genetic screening).

Treatment:

TTP should be treated as a medical emergency.

Treatment goals are to reduce anti-ADAMTS13 antibodies (in immune ITP) and replenish ADAMTS13 (in congenital TTP).

Newly diagnosed immune TTP

The cornerstone of management is plasma exchange (removes autoantibodies and replenishes ADAMTS13 levels) and corticosteroids. The value of this treatment regimen was shown in a 1991 study that reported a 90% survival in patients with TTP-HUS treated with plasma exchange and corticosteroids, compared to an historical survival rate of < 10%. Plasma exchange is continued daily until the platelet count reaches normal levels and symptoms have resolved. ADAMTS13 levels during initial plasma exchange may lag behind clinical response and is not useful in determining the duration of plasma exchange.

A number of additional treatments may be considered. These include immunosuppressive agents such as rituximab, a monoclonal antibody that targets CD20 antigen present on B lymphocytes, and a new drug called caplacizumab, which is humanized anti-von Willebrand factor (vWF) single-variable-domain immunoglobulin (nanobody) that targets the AI domain of vWF, preventing its interaction with platelet glycoprotein 1b-IX-V.

Red cell transfusions should be administered as needed, but platelet transfusions are contraindicated unless there is life-threatening bleeding.

Antiplatelet agents have not been shown to be beneficial and may increase bleeding.

Refractory or relapsed immune TTP

Options include:

  • Increase frequency and/or volume of plasma exchange.
  • Addition of rituximab if not already in use.
  • Stronger immunosuppressives such as cyclosporine, vincristine, or cyclophosphamide.
  • Caplacizumab
  • Splenectomy

Prognosis:

TTP is associated with a mortality of approximately 85% if left untreated and <10% in those treated with plasma exchange. Without treatment, TTP typically follows a progressive course in which neurologic deterioration, cardiac ischemia, irreversible renal failure, and death.

Outcomes of immune TTP:

  • Clinical response – sustained normalization of the platelet count and LDH <1.5 times the upper limit of normal with first line therapy, with no new or progressive manifestations of ischemic organ injury.
  • Clinical remission – either a sustained clinical response for ≥30 days after first line therapy or attainment of a partial or complete ADAMTS13 remission (whichever occurs first).
  • ADAMTS13 remission – ADAMTS13 activity recovery to ≥20% is a partial ADAMTS13 remission; ADAMTS13 activity recovery to the lower limit of normal for the assay or greater is a complete ADAMTS13 remission.
  • Refractory disease – lack of a clinical response.
  • Disease exacerbation – Recurrence of thrombocytopenia without another cause following a response but ≤30 days after stopping TPE or anti-VWF therapy.
  • Clinical relapse – Recurrence of thrombocytopenia following a remission without another cause (subsequently must be confirmed by documenting ADAMTS13 activity <10%).
  • ADAMTS13 relapse – ADAMTS13 activity <20% following an ADAMTS13 remission.