Case Study MICR 410 - Hematology Spring, 2011 Jazmin Graff Barbara Huang Marian Navarrete

Case Summary Ms. Chang, a 35-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 Table 1: Laboratory Results Test Result Normal Range Hemoglobin 6.0 g/dL 12.3-15.3 g/dL Hematocrit 0.18 L/L 0.38-0.46 L/L White Blood Cells 8.9 x 109/L 4.1-10.9x109/L Platelet 31 x109/L 150-450x109/L Reticulocyte 2.5% Symptoms Low grade fever Periods of forgetfulness and memory loss Seizures, headaches, and dizziness Bruises on extremities Sinificant Laboratory Findings Peripheral Smear: Schistocytes and polychromasia Table 2: Results of urinalysis Protein 2+ Blood + * Renal insufficiencies

Diagnosis: MAHA 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). Cause of MAHA: thrombotic thrombocytopenic purpura (TTP)

Pathophysiology of MAHA MAHA is a microangiphatic subgroup of hemolytic anemia and is caused by a mechanical disruption of the red blood cell membrane in circulation, leading to intravascular hemolysis. 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.

Pathogenesis of idiopathic TTP caused by ADAMTS13 deficiency Multimeric von Willebrand factor (VWF) adheres to endothelial cells or to connective tissue in the vessel wall. Platelets adhere to the VWF. In flowing blood, VWF in the platelet-rich thrombus is stretched and cleaved by the protease ADAMTS13, limiting thrombus growth. If ADAMTS13 is absent, VWF-dependent platelet accumulation continues, eventually causing microvascular thrombosis and TTP.

Microangiopathic Hemolytic Anemia (MAHA) Morphology : Fragmented Cells Possible Pathology Burr Cells Renal Disease Liver Disease Burns Schistocyte Prosthetic Heart Valve Microangiopathic Hemolytic Anemia Disseminated Intravascular Coagulation Thrombotic Thrombocytopenic Purpura Hemolytic Uremic Syndrome Clostridial Infections Helmet Cells G6PD Deficiency Pulmonary Emboli *Intravascular Hemolysis is also associated with the presence of Schistocytes Microangiopathic Hemolytic Anemia (MAHA)

Diagnostic Tests Tests that can identify MAHA should be performed when a hemolytic episode is suspected or has been determined. Repeat complete CBC and calculate all parameters Lactate dehydrogenase (LDH), haptoglobin, total bilirubin Direct Coombs (DAT) Repeat urinalysis tests (Dipstick Test) including differential values Color, clarity Leukocyte, WBC, RBC Nitrite, urobilinogen, glucose, and bilirubin Tests to identify TTP include: Patient history and type of bleeding There is currently no specific routine test to confirm the diagnnosis of TTP, instead the diagnosis is made on the basis of syptoms and blood tests such as blood count, blood film, renal functions and markers of hemolysis. Repeat complete coagulation studies including reaction times Prothrombin time (PT), activated partial thromboplastin time (APTT) Fibrin degradation products (FDP) – D-dimer Coagulation tests to rule of ITP and DIC!!!!

ITP: Idiopathic thrombocytopenic purpura TTP: thrombotic thrombocytopenic purpura DIC: Disseminated Intravascular Coagulation Slightly decreased fibrinogen and slightly prolonged coagulation results.

TTP vs HUS Often difficult to differentiate HUS: – Microangiopathic hemolytic anemia – Thrombocytopenia – Acute renal failure – Variable CNS symptoms NO FEVER!!!!!!!

Cause of MAHA: TTP 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. √

Therapy and Prognosis Therapy of MAHA should be initiated immediately due that severe blood loss can be deadly. Transfusion therapy should only be administer to patients with angina or severely compromised cardiopulmonary status. Discontinuing medications and other agents that can cause hemolysis. Administer folic acid to avoid pancytopenia. Treatment and Management of TTP Plasma exchange, plasma infusion Splenectomy if plasma exchange fails. Corticosteroids NO PLATELET TRANSFUSION!!! Prognosis: Untreated, TTP has a mortality rate of as high as 90% With plasma exchange, the mortality rate is reduced to 10-20%. Long-term survival is largely dependent on the presence or absence of serious underlying comorbidities such as cancer, HIV infection, or solid organ transplantation MI and stroke if give platelets!!!

Prevention of MAHA Prevention of MAHA will be to get prompt treatment for the underlying conditions causing TTP. Inherited and acquired TTP occur suddenly with no clear cause. You can’t prevent either type. http://www.health-writings.com/img/oj/thrombocytopenia-side-effects/blood_clot.jpg

(anemia caused by intravascular destruction of cells) Diagnosis: MAHA (anemia caused by intravascular destruction of cells) Complete hematologic diagnostic tests should be performed to link MAHA to TTP Mortality reduced to 10-20% with proper tx

References NEJM 2006; 354:1927-35 George, James MD-Thrombotic Thrombocytopenic Purpura. Uptodate. Diagnosis, Causes, and Treatment of TTP-HUS Hematology 2004:407-423.Recent Advances in Thrombotic Thrombocyotopenic Purpura, Sadler Et al Hematology 2007. TTP and ADAMTS13: When is testing appropriate? Mannucci et al Hematology 2006.Thrombocytopenic Purpura:A moving Target. Sadler Hoffman:Hematology: Basic Principles and Practice fourth edition. Chapters 42 and 132 Swiss Med Wkly 2007;137:518-524. Rituximab for acute plasma refractory thrombotic thrombocyotopenic purpura. Eur J Haematology 2005;75:436-440. Acquired TTP as presenting symptom of SLE. Successful treatment with plasma exchange and immunosuppression-report of 2 cases Abumuhor, I., & Kearns, H. H. (n.d.). Thrombotic Thrombocytopenic Purpura. In Thrombotic Thrombocytopenic Purpura (differential diagnosis) [Clinical Cases]. Retrieved August 29, 2006, from School of Health Professions: University of Missouri-Columbia website: http://www.vhct.org/ case2300/diagnosis.htm Becker, J. U., MD., & Brenner, B. E., MD., PHD. (2011, April 21). Background. In Thrombotic Thrombocytopenic Purpur in Emergency Medicine (drugs, conditions, and procedures) [Reference]. Retrieved May 22, 2011, from WebMD website: http://emedicine.medscape.com/article/206598-treatment. Klatt, E. C. (n.d.). Fragmentd Red Blood Cels [Photograph]. Retrieved from http://library.med.utah.edu/WebPath/HEMEHTML/HEME010.html

Point Spread Case summary 5 Key Information pointing to Diagnosis 15 Pathophysiology of the disease 25 Diagnostic tests 10 Therapy Prognosis Prevention Take home message Are all questions addressed? Appearance Presentation skills (individual) Total 100