history of Present Illness
The patient is a female in her 50s who presents with abdominal pain for one month prior to presentation. Her symptoms were initially intermittent but have been constant for the past week. Her pain starts in the epigastrium and radiates to the bilateral lower quadrants. It is sharp and severe with no modifying factors. Associated symptoms include decreased appetite and nausea without emesis. She endorses
intermittent chronic non-bloody diarrhea but her bowel movements for the past week are normal and formed. She has seen her primary physician for these symptoms who prescribed a proton pump inhibitor and ondansetron without relief. She has been referred to a gastroenterologist but has not yet had her appointment.
Past Medical History: Hypertension, CAD, AAA
Past Surgical History: Cholecystectomy
Medications: ASA, lisinopril, omeprazole, metoprolol tartrate, atorvastatin, ondansetron
Vitals: T 98.3°F BP 127/79 HR 84 RR 17 SaO2 98% on room air
Physical Exam: The patient is alert and overall non-toxic appearing despite looking mildly uncomfortable. Oropharynx is moist without any intraoral lesions or gingival abnormalities. Abdominal exam reveals a soft abdomen with normal bowel sounds. Palpation elicits epigastric and bilateral lower quadrant tenderness without guarding or rebound. Cardiac, pulmonary, and neurologic examinations are all within normal limits. Skin exam is without rash, bruising, or petechiae.
WBC: 10.5 Hgb: 13.7 Plt: 9 x 10^9/L
Total Bilirubin: 1.7 Indirect Bilirubin: 1.4 LDH: 888 INR: 1.1 PT: 13.9
CT Abdomen and Pelvis: No acute abnormality in the abdomen or pelvis. 3.1 x 3.6 cm infrarenal abdominal aortic aneurysm. Borderline splenomegaly.
The patient was admitted to medicine with abdominal pain, mild anemia with indirect hyperbilirubinemia, and severe thrombocytopenia concerning for an acute microangiopathic process. Hematology was consulted from the emergency department, evaluated the patient, and recommended a peripheral smear. The smear demonstrated one to two schistocytes per high-powered field, less than the diagnostic cut-off suggestive of thrombotic thrombocytopenic purpura (TTP). Given the concern for possible idiopathic thrombocytopenic purpura (ITP), omeprazole was discontinued due to its risk of drug-induced ITP. Hemolysis labs including complete blood count (CBC), lactate dehydrogenase (LDH), haptoglobin, and bilirubin levels were trended. On hospital day one, the patient’s repeat platelet count was 15 × 10^9/L and her hemoglobin had dropped by two grams. Based on the newly derived PLASMIC score (see below), the patient had a high positive predictive value for TTP associated with severe ADAMTS13 deficiency. Therefore, treatment for acute TTP was initiated with daily plasma exchange and high dose prednisone. The patient tolerated plasma exchange therapy well. After each round of therapy her platelet count and evidence of hemolysis gradually improved. After two sessions, her abdominal symptoms resolved. After three sessions, her laboratory studies normalized. The ADAMTS13 activity level returned at less than 2% confirming the suspected diagnosis of TTP. On the day of discharge her platelets had improved to 293 x10^9/L and she had no further evidence of hemolysis. The patient was discharged on prednisone 60mg daily with plans for outpatient plasma exchange and hematology follow-up.
TTP is a rare, life-threatening primary thrombotic microangiopathy caused by functional or intrinsic deficiency of the von Willebrand factor (vWF) cleaving protein ADAMTS13. This results in severe thrombocytopenia, microangiopathic hemolytic anemia, and multi-organ injury. ADAMTS13 deficiency comes in two forms. The first is an acquired mechanism via immune-mediated autoantibodies against ADAMTS13. The second is an inherited mechanism via mutations of the ADAMTS13 gene called Upshaw-Schulman syndrome. The estimated annual incidence of acquired TTP is 2.88 per million persons whereas the estimated annual incidence of inherited TTP is less than one per million persons. The subsequent discussion will focus on acquired TTP as it is more likely to present for the first time as an adult (90% of cases) and is associated with other more common conditions.
The only known risk factor for developing TTP is severe ADAMTS13 deficiency. ADAMTS13 is a protein that cleaves vWF, which is a glycoprotein secreted by endothelial cells to support platelet adhesion. It elongates within high shear stress environments and enables platelet aggregation. Intermittent shear stress events naturally elongate vWF in normal physiologic conditions. This opens ADAMTS13 cleavage sites and allows the ADAMTS13 protein to cleave and inactivate vWF. This helps regulate platelet aggregation. Decreased ADAMTS13 protein activity results in increased levels of abnormally large, sticky vWF multimers. Platelets then spontaneously aggregate leading to widespread formation of microvascular microthrombi. Platelets are consumed within these thrombi resulting in thrombocytopenia. Red blood cells are lysed by microthrombi causing a microangiopathic hemolytic anemia.
Patients with TTP clinically present on a spectrum ranging from nearly asymptomatic to critically ill. The historical pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, neurological symptoms, and renal failure has been shown through several cohort studies to exist in less than 10 percent of acute TTP cases.[1,3] Typical presenting signs and symptoms include a combination of microangiopathic hemolytic anemia (jaundice and fatigue with median hemoglobin 8-10 g/dL), thrombocytopenia (petechiae and mucosal bleeding with platelets <30 × 10^9/L), and multi-system organ dysfunction. The central nervous system is primarily affected in TTP, but all organs can be involved. This makes differentiating between TTP and other thrombotic microangiopathies (e.g., hemolytic uremic syndrome) quite difficult. About 60% of patients have neurologic symptoms at presentation ranging from headache to seizures. Patients often present with GI symptoms like abdominal pain and diarrhea, due to the mesenteric ischemia which occurs in approximately 35 percent of cases. The cardiovascular system is affected in about 25 percent of cases, ranging from isolated ECG abnormalities to myocardial infarction. Acute renal failure is seen in approximately 27 percent of cases.
About 50 percent of patients with TTP may have another concomitant or preexisting clinical condition. The most frequently associated conditions are bacterial infections, autoimmune diseases (e.g., systemic lupus erythematous [SLE]), pregnancy, drugs (notably cyclosporine and clopidogrel), HIV infection, malignancy, and organ transplantation. It is thought that these concomitant conditions may be the triggering mechanism for a TTP episode. Early detection and diagnosis of TTP is vital to initiate appropriate treatment and limit morbidity and mortality. In the emergency department, providers should suspect acquired TTP in adults with severe thrombocytopenia and microangiopathic hemolytic anemia. This is suggested by indirect hyperbilirubinemia and elevated LDH. TTP should also be suspected in the setting of more commonly associated conditions such as SLE, pregnancy, HIV, malignancy, and organ transplantation. TTP should also be considered in patients with new neurological symptoms or acute myocardial infarction with unexplained thrombocytopenia and hemolytic anemia.
In cases of suspected TTP, additional testing to assess for the presence and extent of endorgan damage is indicated. Because patients are at risk for microvascular thrombotic events, providers should obtain laboratory testing to evaluate for coagulopathy, renal dysfunction, cardiac ischemia, and neurologic sequelae. In uncomplicated cases of TTP, standard coagulation parameters are typically unaffected. Renal assessment is usually normal but can demonstrate elevated serum urea and creatinine levels. Urinalysis may show proteinuria and/or hematuria. A troponin level greater than 0.1 µg/L is present in up to 60 percent of cases, although the majority of patients have no clinical cardiac involvement. Repolarization changes on electrocardiogram are present in 10 percent of cases.
Emergency department management includes urgent hematology-oncology consultation and obtaining a peripheral blood smear. In 2012, the International Council for Standardization in Hematology (ICSH) systematized the identification and diagnostic merit of schistocytes. According to the ICSH published guidelines, greater than 1 percent schistocytes or roughly four per high powered field in the absence of other significant red blood cell changes suggests thrombotic microangiopathy. Measurement of ADAMTS13 activity is the only specific confirmatory diagnostic test, but will not result during an ED visit and should be ordered in consultation with a specialist. Treatment should not be delayed while waiting for ADAMTS13 activity to result because of the high morbidity and mortality rates associated with delayed diagnosis of TTP. Because early diagnosis and treatment is so important, a new pointbased TTP scoring system has recently been developed and validated to predict an acquired ADAMTS13 deficiency.
The PLASMIC score (figure 3) is a laboratory-derived scoring system to predict TTP. The score was generated from a cohort study of 214 patients with TTP in which 29 laboratory variables were evaluated. Five independent markers were identified as highly predictive of TTP. These markers include a platelet count less than 30 × 10^9/L, serum creatinine level less than 2.0, INR less than 1.5, mean corpuscular volume (MCV) less than 90, and the presence of a hemolysis variable (reticulocyte count greater than 2.5 percent, undetectable haptoglobin, or indirect bilirubin greater than 2.0 mg/ dL). Absence of active cancer, solid-organ transplant, or stem-cell transplant have high negative predictability and were also included in the score. Each of the seven factors is given a score of one point if present. A score of zero to four predicts a risk of deficient ADAMTS13 activity to be 4.3 percent. A score of seven predicts 96.2 percent risk of TTP. An intermediate score of five to six has limited utility with a TTP risk prediction of 56.8 percent. Accordingly, a patient with a high PLASMIC score is likely to benefit from definitive treatment with plasma exchange based solely on this score, whereas a patient with a low score should not be empirically treated. Because of these characteristics, this score is used by hematologists to initiate treatment early in a patient’s course, even prior to diagnostic confirmation with ADAMTS13 level. Emergency providers should be familiar with this scoring system because it can easily be calculated from testing obtained in the ED and can expedite diagnosis and treatment. Nonetheless, this scoring system should be used in conjunction with an ADAMTS13 activity level. Diagnosis is ultimately confirmed by an ADAMTS13 activity of less than 10 percent.[1,3,7,9]
Standard treatment for acute TTP is daily plasma exchange, often in conjunction with steroids. Daily plasma exchange replaces deficient ADAMTS13 and filters ADAMTS13 autoantibodies. Steroid therapy suppresses ADAMTS13 autoantibodies. Plasma exchange should be continued until the platelet count is greater than 150 × 10^9/L and LDH is less than 1.5 times the upper limit of normal. Cessation of plasma exchange is determined by normalization of laboratory values in conjunction with clinical improvement.
It is important to note that platelet transfusion is not indicated unless there is life threatening hemorrhage or if an emergent invasive procedure must be performed. While the evidence is conflicting, recent studies have shown increased risk of arterial emboli and mortality in those with TTP who received platelet transfusion. Studies have not, however, proven the traditional theory that transfusions "fuel the fire" in TTP or that transfusion is causally related to increased mortality. It is possible that those patients receiving platelet transfusions represent the more severely ill and therefore higher risk of mortality from the start. Regardless, it is standard practice to avoid platelet transfusions if at all possible in those with TTP.
TTP has a mortality rate of 10 to 20 percent and estimated relapse rates of 40 to 50 percent despite standard therapy.[1,10] Factors portending worse outcomes and treatment failure include older age, LDH greater than 10 times the upper limit of normal (suggestive of worse organ damage), and troponin values greater than 0.25 ng/dL.1 Some studies have suggested that severe ADAMTS13 deficiency during periods of remission may predict relapse without concomitant microangiopathic hemolytic anemia and thrombocytopenia. Recent studies show that immune modulators like rituximab can be considered in these instances.
Rituximab is an anti-CD20 monoclonal antibody. It is typically reserved for refractory TTP after 30 days of treatment, relapsing TTP, or poor response to first-line therapy. Akin to steroid therapy, rituximab targets autoantibodies against ADAMTS13. Retrospective and prospective studies where rituximab was used after suboptimal response to standard therapy have yielded promising remission rates ranging from 89 to 98 percent.1 Given these promising results, a phase 2 clinical trial showed that frontline treatment with rituximab plus plasma exchange and steroids may result in shorter hospitalization, fewer relapses, and no significant infectious or clinical adverse outcomes. Two other recent analyses have shown similar results. As such, frontline therapy with rituximab is an emerging yet controversial treatment as it may unnecessarily expose a patient to a cytotoxic agent when that patient may respond to standard therapy alone.
Emergency providers should treat TTP as a medical emergency with a goal to initiate plasma exchange within four to eight hours of initial clinical diagnosis. Treatment should not be delayed for confirmatory ADAMTS13 measurement. Plasma exchange transfusion requires placement of trialysis line or other hemodialysis catheter. In consultation with a hematologist, high dose steroids (oral prednisone 1 mg/ kg/day or IV methylprednisolone 1 g/day) are often administered. If plasma exchange is not available, fresh frozen plasma may be considered as a temporizing measure to replace deficient ADAMTS13 until definitive treatment with plasma exchange becomes available. The patient should be considered for admission to an intensive care unit. After admission and standard treatment via plasma exchange with or without steroids is initiated, serial measurement of hemolysis markers and thrombocytopenia should be monitored. The primary inpatient team should consider evaluating the patient for commonly associated conditions including HIV, pregnancy, and SLE. After complete therapeutic response, the patient should be followed by a hematologist and monitored long-term with periodic measurement of ADAMTS13 activity, even during periods of remission.
In summary, TTP is a diagnosis that can be made using simple laboratory data obtained in the ED. With the advent of the PLASMIC score, emergency providers can expedite treatment in consultation with a specialist. Standard therapy with plasma exchange and steroids leads to clinical response in most patients. Platelet transfusion should be avoided if possible. For patients who do not fully respond or relapse, rituximab should be considered. Through early recognition and treatment, emergency providers can lessen the morbidity and mortality associated with this rare disease process.
Authored by Javier Baez, MD
Posted by Matthew Scanlon, MD
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- Adapted from J. Evan Sadler. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood, 2008, 112 (1) 11-18.
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