THROMBOTIC THROMBOCYTOPENIC PURPURA
• In the past, the diagnosis of thrombotic thrombocytopenic purpura (TTP) was made based on a pentad that included microangiopathic hemolytic anemia (MAHA), thrombocytopenia, neurologic involvement, nonoliguric renal insufficiency, and fever. Clinically, waiting for development of the pentad may delay the diagnosis of TTP, delay treatment, and result in a fatal outcome. Currently, unexplained MAHA and thrombocytopenia in the absence of oliguric renal failure are sufficient to make a working diagnosis of TTP and initiate emergent plasma exchange (PLEX).
• These laboratory tests are recommended for patient evaluation:
• Complete blood count (shows anemia and moderately to severely decreased “platelet count”).
• Peripheral blood smear (shows “schistocytes/fragmented red cells”, a hallmark of thrombotic microangiopathy [TMA]).
• Reticulocyte count (is elevated).
• Haptoglobin (is usually undetectable in TTP).
• “Lactate dehydrogenase” (LDH) (usually more than twice the upper limit of normal in TTP).
• Blood urea nitrogen, serum creatinine (determines nonoliguric renal insufficiency).
• Liver function tests, including direct and indirect bilirubin.
• Plasma “ADAMTS13 activity” (< 10% is diagnostic of TTP) and inhibitor level (usually detected in 90% of cases of TTP).
• Prothrombin time, partial thromboplastin time, fibrinogen, and d- dimers (to rule out DIC).
• Direct antiglobulin test (to rule out autoimmune hemolytic anemia).
• Daily plasma exchange (PLEX) using plasma as a replacement fluid (1–1.5 total body plasma volume) until platelet count is normal for 2 days, then taper PLEX to three times a week, then twice a week, and then once a week. Discontinue when platelets remain greater than 150,000/mcL.
• Prednisone 1 mg/kg/day taper pari passu with PLEX.
• Plasma (10–15 cc/kg) or cryoprecipitate (one dose = 10 units of pooled cryoprecipitate) infusion if PLEX will be delayed > 6 hours.
• Exacerbation or relapsing TTP.
• Rituximab (Rituxan)1 (375 mg/m2) weekly for 2–4 weeks.
• Cyclosporine (Neoral)1 (2–3 mg/kg/day up to 6 months).
• Vincristine (Oncovin)1 (1.4 mg/m2 once a week for 4 weeks).
• Bortezomib (Velcade)1 (1.3 mg/m2 1–2 cycles).
• Splenectomy as a last resort.
1 Not FDA approved for this indication.
Thrombotic thrombocytopenic purpura (TTP) is a rare (1–2 cases/million) but life-threatening thrombotic microangiopathy (TMA) disorder characterized by the presence of microthrombi in microcirculation of various organs, including the brain, kidneys, heart, and abdominal viscera. Microthrombi consist of platelets and von Willebrand factor (VWF), resulting in microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. MAHA refers to the fragmentation of red blood cells (schistocytes) during their passage through partially occluded arterioles and capillaries by microthrombi. TTP diagnosis requires a high degree of suspicion, because a delay in initiating PLEX, the current standard of care, could result in a poor response or fatal outcome. In the past, diagnosis of TTP was made based on a pentad that included MAHA, thrombocytopenia, neurologic involvement, renal affection, and fever. This pentad was found in patients who had died of TTP indicating advanced disease; therefore, one should not wait for development of a pentad, which could delay TTP diagnosis with a potentially fatal outcome. Currently, unexplained MAHA and thrombocytopenia in the absence of oliguric renal failure are sufficient to make a working diagnosis of TTP and initiate emergent PLEX.
In congenital TTP (Upshaw Shulman syndrome), ultra large (UL) multimers of VWF were detected during remission and were absent during relapse. Later, a VWF cleaving protease (ADAMTS13, a disintegrin and metalloproteinase with thrombospondin 1 motif, 13th member of the family) was identified that was responsible for cleaving UL multimers secreted from endothelium into normal sized VWF multimers seen in normal plasma. This cleavage occurs under high shear rate flow conditions in smaller blood vessels where the UL-VWF undergoes unfolding, exposing the cleavage site for ADAMTS13.
ADAMTS13 is severely deficient (< 10%) in patients with both congenital and acquired TTP. Persistence of UL-VWF multimers in microcirculation results in the complete unfolding of the molecule, enabling it to bind to platelets at GPIb, producing platelet-VWF microthrombi in capillaries and arterioles causing end organ ischemic damage. Elevated lactate dehydrogenase (LDH) reflects not only MAHA but also tissue damage. Thus, the higher the LDH, the more severe the disease.
TTP can be divided into (1) a congenital form resulting from a genetic defect in the ADAMTS13 gene and (2) an acquired form secondary to the presence of an autoantibody against ADAMTS13 enzyme, reducing its activity < 10% (Figure 1). Congenital TTP can present in the neonatal period; early childhood; or later in life, when it is usually associated with an inciting trigger in the form of pregnancy, severe infection, surgery, or other stress. Acquired TTP is usually idiopathic without underlying disorder, whereas it is secondary when associated with an underlying autoimmune disorder such as SLE, HIV, and use of ticlopidine, etc. Other clinical conditions that present with MAHA and thrombocytopenia with nonsevere ADAMTS13 deficiency are grouped under a broader term called TMA.
FIGURE 1 Classification of TTP. Abbreviations: MAHA, microangiopathic hemolytic anemia; TTP, thrombotic thrombocytopenic purpura; ADAMTS13, a disintegrin and metalloproteinase with thrombospondin motif 1, 13th member of the family; TMA, thrombotic microangiopathy; HUS, hemolytic uremic syndrome; PLEX, plasma exchange; Ab, antibody.
Idiopathic TTP is a disease of young adults (20–50 years, F:M ratio 2:1) with the majority being African American. Most patients present in the emergency department with an acute onset of vague, anemia-like symptoms (malaise, fatigue, weakness) and thrombocytopenia (petechiae, gum bleed). Detailed evaluation reveals the onset of these symptoms several days before presentation. Up to 70% to 80% of patients have some neurologic features, including severe headaches, visual disturbances, focal neurologic deficits, transient ischemic attack, memory deficits, unusual behavior, confusion, seizures, paraparesis, stupor, and coma. Mild renal insufficiency is seen in < 50% and fever in < 15%. As a result of the generalized nature of the disease, any organ system could be affected.
Unexplained MAHA and thrombocytopenia constitute the diagnostic features and are associated with elevated LDH, reticulocytosis, undetectable haptoglobin, elevated bilirubin, and nonoliguric renal insufficiency in some patients. A severe deficiency of ADAMTS13 (< 10% activity with a detectable inhibitor in up to 90% of patients) confirms the diagnosis. Because this is usually a test that is sent to a reference laboratory, this measurement is unavailable in most places at the time of clinical diagnosis. Based on the initial clinical and laboratory features, PLEX should be initiated emergently, as a delay could increase not only morbidity but also mortality. A sample for ADAMTS13 must be drawn before initiating PLEX or plasma/cryoprecipitate infusion to avoid measuring enzyme from transfused products. ADAMTS13 is a stable enzyme; if a sample for ADAMTS13 could not be drawn before plasma therapy, a routine coagulation test sample may be used. In congenital TTP, there is persistent severe deficiency of ADAMTS13 (without an inhibitor) associated with ADAMTS13 gene defect. However, this diagnosis is at times made difficult because many patients, especially children and young adults, are often misdiagnosed as immune thrombocytopenia or anemia of unknown origin or Hemolysis Elevated Liver enzymes and Low Platelets (HELLP) syndrome in pregnancy.
The differential diagnosis of TTP includes clinical conditions that present with MAHA and thrombocytopenia but without severe ADAMTS13 deficiency, that is, TMA. These conditions include hematopoietic stem cell transplantation, drug toxicities (mitomycin, clopidogrel [Plavix], cyclosporine A [Neoral], etc.), malignant hypertension, HELLP syndrome with severe preeclampsia, mechanical cardiac devices, for example, (left venricular assist devices, intra-aortic balloon pump and mechanical heart valves), diseminated intravascular coagulation (DIC), vasculitis, and both diarrhea-associated and atypical hemolytic uremic syndrome (HUS).
PLEX is the standard of care therapy. Its use has reduced mortality from > 90% to < 20%. Ideally, it should be initiated within 4 to 6 hours of suspected diagnosis. The patient’s plasma (which contains autoantibody) is selectively removed during PLEX (1.0–1.5 plasma volume processed) and replaced with donor plasma containing ADAMTS13. Neurologic symptoms usually disappear within 24 to 48 hours. The platelet count is the most useful laboratory parameter to follow because LDH and hemoglobin lag behind. Complete clinical response, defined as normalization of platelet count for at least 2 days with near normal LDH, generally is achieved with seven to nine daily PLEX in most patients. Thereafter, a gradual taper, that is, PLEX every other day in the first week, twice in the next week, and once in the third week, may be performed. Given the autoimmune nature of the disease, glucocorticoid therapy is often given from the beginning.
Approximately 30% to 50% of patients will have exacerbation of the disease (worsening of clinical or laboratory features after initial response) or relapses (recurrence of the disease 30 days after discontinuation of PLEX). Such patients require additional PLEX and other immunomodulatory therapies, e.g., rituximab (Rituxan),1 cyclosporine (Neoral),1 vincristine (Oncovin),1 bortezomib (Velcade),1 or splenectomy as a last resort. A dialysis-type catheter is required for PLEX and can be placed with ultrasound guidance in patients with platelet counts as low as 10,000/mcL. With the exception of a life- threatening bleed, platelet transfusion is contraindicated in TTP because it is a thrombotic disorder of platelet consumption, and transfused platelets may worsen the condition (appearance of new neurological symptoms, myocardial infarction, etc.). If initiation of PLEX is likely to be delayed, either plasma or cryoprecipitate can be infused temporarily to supplement ADAMTS13. Congenital TPP is treated with plasma infusions (10–15 ml/kg); however, cryoprecipitate and intermediate purity factor FVIII concentrate that contain adequate ADAMTS13 have been used successfully to avoid volume overload in susceptible patients.
Considering the relatively high frequency of cardiac involvement, cardiac monitoring should be performed initially. While PLEX is an otherwise safe procedure, complications related to catheter infection and line thrombosis are not uncommon and should be identified as soon as possible to avoid exacerbation of the disease. If the ADAMTS13 is > 10%, then TTP diagnosis is generally ruled out and PLEX may be discontinued depending upon underlying conditions.
Although PLEX has reduced the mortality in last two decades, most deaths occur within 24 to 48 hours of presentation and are due to delay in administration of PLEX for a variety of reasons, including a delay in diagnosis or the line placement or nonavailability of PLEX at the institution. After one PLEX, survival rates can increase to > 90%.
Importantly, no clinical and laboratory parameter exists to predict outcome. At this stage, ADAMTS13 has a diagnostic but not prognostic value.
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2. Rock G.A., Shumak K.H., Buskard N.A., et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med. 1991;325:393–397.
3. Sarode R., Bandarenko N., Brecher M.E., et al. Thrombotic thrombocytopenic purpura: 2012 American Society for Apheresis (ASFA) consensus conference on classification, diagnosis, management, and future research. J Clin Apher. 2013;doi:10.1002/jca.21302.
4. Shah N., Rutherford C., Matevosyan K., et al. Role of ADAMTS13 in the management of thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP). Br J Haematol. 2013;163:514–519.
5. Tsai H.M. Thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome—An update. Hematol Oncol Clin North Am. 2013;27:565–584.