Valentina Bellino
Patrizia Marchisio
DEFINITION
Thrombotic Thrombocytopenic Purpura (TTP or Moschcowitz syndrome) is an acquired, congenital, or familial disorder caused by platelet aggregation with thrombosis in terminal arterioles and capillaries.
This haematologic disorder involving the formation of platelet aggregates in the microvasculature. The consumption of platelets in these aggregates results in severe thrombocytopenia. Occlusive platelet thrombi form in many organs including the brain, kidneys, heart, spleen, pancreas, adrenal glands, and gastrointestinal tract, causing tissue ischaemia and release of large amounts of lactate dehydrogenase (LDH). In addition, erythrocytes are fragmented as they transverse small vessels narrowed by platelet thrombi leading to haemolysis and the formation of schistocytes.
EPIDEMIOLOGY
Incidence: 5-10 cases per year per million people.
Age:
- Can occur at any age;
- More common between 10 and 40 years;
- Median age at diagnosis: 35 years.
Sex:
SYMPTOMS
The characteristic pentad of thrombocytopenia, haemolytic anemia, fever, fluctuating neurological symptoms, and renal dysfunction are the hallmarks of TTP. However, only 40% of patients present with the complete pentad. More recently the clinical criteria for diagnosis of TTP have been simplified to thrombocytopenia and haemolytic anemia without an otherwise identifiable cause.
Often, but not always, there are signs of haemorrhage such as petechiae, ecchymoses and purpura because of the very low platelet count in the acute phase (<20×10^9/L). The most frequently reported neurological symptoms are coma, convulsions and motor deficits, associated with headache, visual disorders and an altered mental state, although neurological symptoms are not always present and tend to occur particularly in the more advanced stages of the disease.
DIAGNOSIS
Histopathology
Presence of schistocytes on a peripheral blood smear (Fig.1) as a sign of haemolytic anaemia
Fig. 1
Peripheral smear from a patient with thrombotic thrombocytopenic purpura: red blood cells are fragmented and appear as schistocytes. Certain schistocytes have the appearance of helmet cells. Spheroidal cells often are present. Occasional nucleated erythroid precursors may be present
Laboratory tests
- Complete blood count: mild to very severe anemia and thrombocytopenia
- Elevated serum lactate dehydrogenase level because of hemolysis
- Elevated Indirected bilirubin
- Decreased haptoglobin
- Increased reticulocyte count
- Direct antiglobulin test: negative
- ADAMTS 13 activity: decreased
- Urinalysis: sediment relatively benign, proteinuria and microscopic hematuria
- Serum creatinine level: elevated
- PT, PTT, fibrinogen concentration: usually normal or only mildly abnormal
- Antinuclear antibody: positive in 20%
Imaging
imaging studies may be indicated depending on clinical presentation.
- Head CT:
may be necessary to assess neurological status (intracranial bleeding, infarcts)
- Renal ultrasonography:
may be necessary to assess reason for decreased kidney function
- Ultrasonography or CT of abdomen:
may be necessary to assess spleen
PATHOGENESIS
Fig.2
In conditions of high shear blood flow, the Ultra Large multimers of VWF are anchored in string-like formations by the P-selectin exposed on the surface of activated endothelium.
A lack of ADAMTS13 protease in plasma, either in absolute terms or relative to the increased need to cleave UL VWF, triggers massive intravascular aggregation of platelets caused by the UL VWF, which in turn leads to the development of microthrombi.
PATIENT RISK FACTORS
Vascular
Vasculitis
Genetic
mutations in the ADAMTS13 gene, which is located on chromosome 9q34 and codes for the metalloprotease ( Congenital TTP )
Acquired
autoantibodies against ADAMTS13, autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis), infections (particularly HIV), drugs (ticlopidine, clopidogrel, cyclosporine A, interferon α, statins, mitomycin C, cisplatin, gemcitabine)
Hormonal
Pregnancy and use of oral contraceptives
TISSUE SPECIFIC RISK FACTORS
Vascular
High shear blood flow
Physiopathological (due to tissue function and activity)
A) activation of endothelial cells: overexpression of P-selectin, decrease of prostacyclin and apoptosis of endothelial cells;
B) activation/aggregation of platelets: presence of aggregating agents other than UL VWF and presence of platelet-aggregating proteases such as calpain and cathepsins.
COMPLICATIONS
- Hemorrhage
- Renal failure
- Stroke
- Coma
- Heart failure
- Sudden death if involvement of myocardial blood vessels
THERAPY
Current treatment of Thrombotic Thrombocytopenic Purpura (TTP): utility of von-Willebrand Factor cleving protease (ADAMTS 13) and Rituximab
The therapeutic strategies used in the management of TTP involve the use of plasma infusions and/or plasma exchange. These treatments, introduced many decades ago in the absence of controlled trials, reduced mortality from about 80-90% to 20-25%.
The description of the key role of Ultra Large VWF in the pathogenesis of TTP and the subsequent identification of ADAMTS13 clarified the mechanisms leading to the therapeutic efficacy of plasma treatment: this procedure removes the anti-ADAMTS13 antibodies in the secondary, immune-mediated forms and replaces the lack of the protease in the congenital forms.
It is, therefore, important to make the diagnosis quickly and start treatment with plasma as soon as a clinical diagnosis of TTP is made because of the presence of haemolytic anaemia, consumtive thrombocytopenia without any other apparent cause and an increase in serum LDH levels.
The main steps in the treatment of TTP are:
- Clinical diagnosis (presence of thrombocytopenia, haemolytic anaemia with schistocytes, raised levels of serum LDH, possible fluctuating neurological symptoms)
- Plasma infusion (30mL/kg), until the start of plasma exchange
- Plasma exchange (3-5L/day), until the platelet count exceeds 150×109/L for at least 3 days in the presence of normal serum levels of LDH
- Additional treatments: prednisone 1.0-1.5mg/kg/day
- Red blood cell transfusions
In recent years there has been an increase in the use of an anti-CD20 monoclonal antibody (rituximab) in TTP, particularly in those cases not responding to treatment with plasma exchange and characterised by multiple recurrences. The aim of treatment with rituximab in TTP is to block the production of anti-ADAMTS13 antibodies by depleting B lymphocytes. (Fig.3)
In patients with a first episode of acute plasma-refractory TTP this drug may produce clinical remission in a significant proportion of patients, result in a lowered plasma requirement and avoid the complications of salvage immunosuppressive therapy. The use of rituximab in acute refractory TTP appears to be safe, with no excess infectious complications. Rituximab, therefore ,should be considered in TTP patients with acquired ADAMTS-13 deficiency who fail to respond clinically after 7-14 days of standard treatment with daily PE and glucocorticoids.,
Fig.3
CD20 has an associated intracellular signal transduction mechanism following external receptor stimulation. It has been found that binding of Rituximab to CD20 induces the B lymphocyte to enter the apoptotic pathway
References
Theodore Wun, Wadie F Bahou, et al. Thrombotic Thrombocytopenic Purpura. Medscape Reference
Pier Mannuccio Mannucci, Silvia Lavoretano, Flora Peyvandi, Centro Emofilia e Trombosi A. Bianchi Bonomi, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena e Università degli Studi di Milano, Italia. The thrombotic microangiopathies. Blood Transfusion 2005; 3: 120-35
Hande H Tuncer, Charles A Mayfield, Marisa B Marques, Department of Pathology, University of Alabama, Birmingham, AL, USA. Current diagnosis and management of Thrombotic Thrombocytopenic Purpura: utility of von-Willebrand Factor cleaving protease (ADAMTS 13). Blood Transfusion 2005; 3: 32-41
Scully M, University College London Hospitals, London, UK. Rituximab in the treatment of TTP. Hematology. 2012 Apr;17 Suppl 1:S22-4
Rüfer A, Brodmann D, Gregor M, Kremer Hovinga JA, Lämmle B, Wuillemin WA.
Division of Haematology, Kantonsspital Luzern, Luzern, and University of Bern, Switzerland. Rituximab for acute plasma-refractory thrombotic thrombocytopenic purpura. A case report and concise review of the literature. Swiss Med Wkly. 2007 Sep 22;137(37-38):518-24
