Thrombotic Thrombocytopenic Purpura Behzad Poopak, DCLS PhD. Tehran medical Branch Islamic Azad university bpoopak@yahoo.com
Case Summary Ms. X, a 35-year year-old woman Complained of weakness, low grade fever, periods of forgetfulness, and memory loss for last week or so. Denied any viral/bacterial illness prior to onset of symptoms. +Oral contraceptives, but no other drugs. Large number of bruises on her extremities. As her condition worsen, she began to be afflicted with frequent seizures, headaches, and dizziness.
Key Information Pointing to Diagnosis Symptoms Low grade fever Periods of forgetfulness and memory loss Seizures, headaches, and dizziness Bruises on extremities Table 1: Laboratory Results Test Result Normal Range Hemoglobin 6.0 g/dl 12.3-15.3 15 3 g/dl Hematocrit 0.18 L/L 0.38-0.46 L/L White Blood Cells 8.9 x 10 9 /L 4.1-10.9x10 9 /L Platelet 31 x10 9 /L 150-450x10 9 /L Sinificant Laboratory Findings Peripheral Smear: Reticulocyte 2.5% Schistocytes and polychromasia Protein 2+ Table 2: Results of urinalysis Blood + * Renal insufficiencies
Significant lab results confirmed the presence of hematuria, decreased hemoglobin, and thrombocytopenia, but most importantly, the presence of Schistocytes. All of these findings are consistent with a hemolytic episode associated with: Micriangyophatic Hemolytic Anemia (MAHA). Diagnosis: MAHA
Epidemiology Suspected TTP-HUS HUS- 11cases/million/yr Idiopathic TTP-HUS- 4.5 cases/million/yr Severe ADAMTS13 deficiency- i 1.7 cases/million/yr Incidence rates were greater for women and African-Americans Americans Prior to plasma exchange, mortality rate was as high as 90%, now less than 20%
Classic Symptoms of TTP-HUS Microangiopathic hemolytic anemia (MAHA) Thrombocytopenia Acute renal insufficiency (more common in HUS) Neurologic abnormalities (more common in TTP) Fever * Only thrombocytopenia and MAHA without another apparent etiology are required to initiate plasma exchange for presumed TTP-HUS HUS.
Terminology TTP and HUS (hemolytic uremic syndrome) are both acute syndromes with abnormalities in multiple organ systems Although some studies appear to distinguish these two entities the presenting features are essentially the same in most adult patients. Furthermore, the pathologic changes are the same and so is the initial treatment.
Definitions and Diagnosis The Classic Pentad of TTP Microangiopathic hemolytic anemia Thrombocytopenia Renal insufficiency or abnormalities Neurologic abnormalities that can be fluctuating Fever Most common symptoms at presentation are nonspecific and include abdominal pain, nausea, vomiting and weakness.
TTP HUS NUMBER OF SUBJECTS 66 66 45 Hemolytic Anemia 100 100 Thrombocytopenia 94 60 Neurologic changes 90 15 Acute Renal Failure 2 98 Fever 50 21 Reminder: Both are clinical diagnoses! Adapted from Veyradier, A, et al. Blood 2001; 98:1765 1765.
Major Causes of TTP-HUS Idiopathic: 37% Infection: 9% Drug-Associated: 13% HIV Cyclosporine Tacrolimus Mitomycin C Bleomycin and cisplatin Gemcitabine Quinine i Ticlopidine and clopidogrel Autoimmune Disease: 13% Scleroderma SLE APLA Streptococcus pneumoniae Pregnancy/Postpartum: 7% Bloody Diarrhea Prodrome: 6% Shiga toxin production (ex: E. coli 0157:H7) Shigella dysenteriae type 1 Verocytotoxin production by Citrobacter freundii Hematopoietic cell transplantation: 4%
Differential Diagnosis Vasculitis Malignant Hypertension DIC Antiphosphospholipid Syndrome
TTP: Current Diagnostic Criteria Thrombocytopenia Microangiopathic hemolytic anemia No alternative explanation
Definitions Continued MAHA-nonimmune hemolysis (negative DAT) with prominent red cell fragmentation ti (schistocytes schistocytes) t on peripheral blood smear. Will exhibit increased LDH and indirect bili. Schistocytes-in t in the appropriate clinical i l setting schistocyte count>1% was strongly suggestive of TTP- HUS, ie 2 or more schistos in microscopic field at 100x magnification. Thromoboctyopenia- mean in a series was 25,300 prior to treatment. Renal disease- due to renal thrombotic microangiopathy, which is usually associated with a UA that is often near normal with only mild proteinuria (between 1-2 g/day) and few cells or casts
Definitions Continued Neurologic symptoms - most are subtle, such as transient confusion or severe headache. Focal, objective abnormalities are less common, but grand mall seizures and coma can occur. Fever- less frequent finding, but the presence of chills and high spiking fever should suggest dx of sepsis or DIC. Cardiac involvement- incidence is difficult to determine, but diffuse platelet thrombi and associated dh hemorrhage h in cardiac tissues can lead to arrythmias, MIs, sudden death, shock, or heart failure.
Labs to Look For Schistocytes on peripheral smear Elevated LDH Decreased Haptoglobin Increased Creatinine Thrombocytopenia (more pronounced in TTP than HUS)
*Intravascular Hemolysis is also associated with the presence of Schistocytes Burr Cells Renal Disease Liver Disease Burns Morphology : Fragmented Cells Possible Pathology Schistocyte Helmet Cells Prosthetic Heart Valve Microangiopathic Hemolytic Anemia Clostridial Infections G6PD Deficiency Pulmonary Emboli Disseminated Intravascular Coagulation Thrombotic Thrombocytope nic Purpura Hemolytic Uremic Syndrome Microangiopathic Hemolytic Anemia (MAHA)
SCHISTOCYTES!
Schistocytes-TTP
HUS-Diagnosis Diarrhoea (often bloody) Haematological microangiopathic haemolytic anaemia thrombocytopenia Fragmented red cells Absence of platelets
ADAMTS13 (Another Lab to Order) A Disintegrin-like And Metalloprotease with ThromboSpondin type 1 repeats Mapped the gene for the metalloprotease to chromosome 9q34 with linkage analysis Protease that cleaves ULVWf (Unusually Large Von Willebrand factor) in the circulation Decreased activity or inhibitor present in TTP, but not HUS Identified 12 mutations in patients with hereditary TTP clinical picture
VWF Cleaving Protease (ADAMTS13) Metalloprotease Thrombospondin 1 S P M D 1 Cys Spacer 2 3 4 5 6 7 8 CUB CUB Disintegrin ADisintegrin-like And Metalloprotease with ThromboSpondin-1 repeats (#13 among 19 total)
ADAMTS13 30 pts psdag diagnosed d with TTP: 6 pts. with familial TTP lacked all ADAMTS13 activity 24 pts. with nonfamilial l TTP 20 had severe deficiency (<5% of normal activity) 4 had moderate deficiency y( (5-25% of nml activity) 23 pts diagnosed with HUS: 21 pts. with normal activity Furlan, M, et al. Von Willebrand factor-cleaving cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. NEJM 1998; 339:1578 1578.
Pathogenesis VWF is synthesized in endothelial cells and assembled in large multimers that are present in normal plasma. The large multimers, ie unusually large von willebrand factor (ULVWF) are rapidly degraded in the circulation into normal size range of VWF multimers by ADAMTS13 13. ADAMTS13 deficiency could lead to accumulation of ULVWF multimers, platelet aggregation, and platelet clumping. ULVWF multimers accumulate in patients with TTP being found in platelet thrombi and serum. The ULVWF can attach to activated platelets thereby promoting aggregation.
Figure 1. Pathogenesis of idiopathic thrombotic thrombocytopenic purpura (TTP) caused by ADAMTS13 deficiency Sadler, J. E. Hematology 2006;2006:415-420 420 Copyright 2006 American Society of Hematology. Copyright restrictions may apply.
Von Willebrand Factor Cleaving Protease, vwf, and Platelets Under Normal Conditions vwf-cleaving protease (ADAMTS13) Tyr-Met AA bond in vwf Receptor for GP Ib on the platelets Platelet
vwf and Platelets When Von Willebrand Factor Cleaving Protease is Absent or Deficient
vwf and Platelets When Von Willebrand Factor Cleaving Protease is Absent or Deficient, Cont.
VWF, ADAMTS13 and Platelet Adhesion With ADAMTS13 Without ADAMTS13 Normal VWF Multimers Normal Hemostasis Ultralarge VWF Multimers Microvascular Thrombosis (TTP)
TTP TTP can be categorized into 2 major forms: Hereditary: Often seen in children, and caused by mutations of ADAMTS13 gene Acquired: Mainly seen in adults, may be idiopathic or nonidiopathic. Idiopathic: results from autoantibodies that inhibit ADAMTS13 function Nonidopathic: TTP is secondary to other conditions such as hematopoeitic stem cell transplantation, certain drugs, infections, other autoimmune diseases, cancers, and so on.
ADAMTS13 Clinical Correlations ADAMTS13 deficiency y( (<5%)predicts: Idiopathic TTP Complete response to plasma exchange Survival ADAMTS13 inhibitor predicts: Prolonged time to complete response Death Relapse Reviewed in Coppo et al, Br J Haematol 2005; 132: 66-74
The Oklahoma TTP-HUS Registry ADAMTS13 measured di immediately before beginning the first plasma exchange, November 13, 1995 December 31, 2008 282 patients with 1 st episode of TTP ADAMTS13 measured in 261 (93%) Measurements (immunoblot immunoblot, FRETS)
The Oklahoma TTP-HUS Registry ADAMTS13 Activity <10 10% Stem cell transplant 1/1010 (10%) Pregnant/postpartum 3/15 (21%) Drug-associated 0/35 (0%) Bloody diarrhea 2/22 22 (10 10%) Additional/alternative diagnosis autoimmune diseases 3/3131 (10%) sepsis 4/22 (18 18%) malignancy 1/1010 (10%) other disorders 0/18 (0%) Idiopathic 46/98 (47%)
The Oklahoma TTP-HUS Registry 60 Consecutive Patients with Severe ADAMTS13 Deficiency (<10 10% activity) Age 41 years (9-71 71) Sex 49 (82 82%) female Race 21 (35%) black
The Oklahoma TTP-HUS Registry ADAMTS13 Deficiency (<10 10% activity) Neurologic abnormalities severe 30 (50%) mild 13 (22%) none 17 (28 28%) Renal function acute renal failure 6 (10 10%) renal insufficiency 27 (45%) normal 27 (55%) Fever 13 (22%) Complete Pentad 5 (8%)
ADAMTS13 An inhibitory autoantibody t to ADAMTS13 has been found at varying titers among high percentage of patients with idiopathic TTP who have severe ADAMTS13 deficiency, and the inhibitory IgG is directed at various elements of the protease. It has been suggested that levels of ADAMTS13 less than 5% with or without an inhibitor antibody may be part of a larger autoimmune response. Non-inhibitory antibodies to ADAMTS13 have also been demonstrated.
ADAMTS13 and prognosis So usually, in acute idiopathic TTP, there is a severe deficiency in ADAMTS13 activity (undetectable or <5%), although senstivity/specificity remains controversial. Severe deficiency is less common in secondary TTP. For most patients, a complete response to plasma exchange is accompanied by normalization of ADAMTS13 activity and disappearance of inhibitors, if present. Persistently undetectable ADAMTS13 in plasma during remission was found to be highly predictive of recurrence, and also the higher the antibody titers, clinical manifestations were more severe and responses to plasma exchange were delayed
Plasma Exchange Corticosteroids RITUXIMAB Treatment Humanized monoclonal l antibody against CD20 20, which is expressed on B cells, and it rapidly clears B cells from circulation, preventing replenishment of pathological plasma cells. Remission associated with disappearance of ADAMTS13 inhibitors and normalization of activity levels Should be considered in TTP patients who fail to respond to daily PE and corticosteroids after 7-14 days
Conclusions: Evaluation Forget the Classic Pentad of clinical features of TTP ADAMTS13 measurements: Limited diagnostic value Important p prognostic value
Conclusions: Management Plasma exchange remains essential treatment, but it has risks of death and major complications Appropriate use of platelet l t transfusions is appropriate
Conclusions: Long-Term Outcomes Relapse occurs in almost half of patients with ADAMTS13 <10% Risk of future pregnancies is small Risk of additional autoimmune disorders may be increased Neurocognitive abnormalities are common
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