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Home , Vasculitis

THROMBOTIC THROMBOCYTOPENIC AND HEMOLYTIC UREMIC SYNDROME

DANA BARTLETT, BSN, MSN, MA, CSPI

Dana Bartlett is a professional nurse and author. His clinical experience includes 16 years of ICU and ER experience and over 20 years of as a poison control center information specialist. Dana has published numerous CE and journal articles, written NCLEX material, written textbook chapters, and done editing and reviewing for publishers such as Elsevire, Lippincott, and Thieme. He has written widely on the subject of toxicology and was recently named a contributing editor, toxicology section, for Critical Care Nurse journal. He is currently employed at the Connecticut Poison Control Center and is actively involved in lecturing and mentoring nurses, emergency medical residents and pharmacy students.

ABSTRACT

Thrombotic is a rare blood disorder. Patients often experience thrombocytopenia, due to red blood cell destruction, and microvascular , and the disease is often connected with an acquired autoimmune deficiency. When the thrombotic affects the kidneys and is caused by bacteria, it is known as hemolytic uremic syndrome. Etiology, complications, monitoring and treatment of the patient with thrombocytopenic purpura and hemolytic uremic syndrome are discussed.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1 Policy Statement

This activity has been planned and implemented in accordance with the policies of NurseCe4Less.com and the continuing nursing education requirements of the American Nurses Credentialing Center's Commission on Accreditation for registered nurses. It is the policy of NurseCe4Less.com to ensure objectivity, transparency, and best practice in clinical education for all continuing nursing education (CNE) activities.

Continuing Education Credit Designation

This educational activity is credited for 2 hours. Nurses may only claim credit commensurate with the credit awarded for completion of this course activity.

Pharmacology content 0.5 hours (30 minutes).

Statement of Learning Need

Health clinicians are required to be knowledgeable about the etiology of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, including complications. This blood disorder can become fatal if not recognized and left untreated. Clinicians need to be knowledgeable to educate patients about the disease risks and management.

Course Purpose

To help health clinicians develop an understanding of the etiology, diagnosis, monitoring and treatment of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 2 Target Audience

Advanced Practice Registered Nurses and Registered Nurses

(Interdisciplinary Health Team Members, including Vocational Nurses and Medical Assistants may obtain a Certificate of Completion)

Course Author & Planning Team Conflict of Interest Disclosures

Dana Bartlett, BSN, MSN, MA, CSPI, William S. Cook, PhD, Douglas Lawrence, MA, Susan DePasquale, MSN, FPMHNP-BC – all have no disclosures.

Acknowledgement of Commercial Support There is no commercial support for this course.

Please take time to complete a self-assessment of knowledge, on page 4, sample questions before reading the article.

Opportunity to complete a self-assessment of knowledge learned will be provided at the end of the course.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 3 1. Thrombocytopenia is defined as a platelet count less than:

a. 300 b. 90 c. 150 d. none of the above

2. True or False: In hereditary TTP, the ADAMTS13 gene is not flawed; whereas in acquired TTP, the gene is flawed.

a. True b. False

3. Complications of TTP, , anemia, renal injury and neurological symptoms, can be serious and lead to a fatal outcome in about _____ percent of cases.

a. 90% b. 25% c. 50% d. 30%

4. Acquired thrombotic thrombocytopenic purpura (TTP) is more common than hereditary TTP and it is seen mostly in

a. individuals over age 50. b. Caucasians as opposed to African-Americans. c. men. d. in females, particularly during and after pregnancy.

5. Acute renal failure is characteristic of

a. rheumatoid . b. thrombotic thrombocytopenic purpura. c. activity of von Willebrand factor. d. hemolytic uremic syndrome.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 4 Introduction

Thrombotic thrombocytopenic purpura is a rare blood disorder. Patients often experience thrombocytopenic anemia due to red blood cell destruction, and microvascular thrombosis. This disorder is often connected with an acquired autoimmune deficiency. When the thrombotic microangiopathy affects the kidneys and is caused by bacteria, it is known as hemolytic uremic syndrome. The causes and complications of thrombotic thrombocytopenic purpura, which include bleeding are important for health clinicians to understand, specifically the monitoring and treatment required to support safe and appropriate care of affected individuals to avoid complications that may lead to death. A case study is included, which may be seen in the hospitalized patient who present with thrombocytopenia, to illustrate how some patients with thrombotic thrombocytopenic purpura may manifest symptoms, including appropriate diagnostic testing and treatment options, such as pharmacological treatment and supportive care.

Thrombocytopenia: Epidemiology And Pathogenesis

Platelets play an important role in hemostasis, which is the process of a blood clot being formed from the fluid part of blood. When there is injury to the vessel wall, platelets create a hemostatic plug to stop the bleeding. If there is a problem with platelet production or function, or if platelet destruction is occurring, thrombocytopenia can ensue and lead to significant bleeding complications. Normal platelet count is between 150 and 350 x 9 10 /L, and thrombocytopenia is defined as a platelet count less than 150.

Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) is a rare blood disorder characterized by severe thrombocytopenia and microangiopathic hemolytic nursece4less.com nursece4less.com nursece4less.com nursece4less.com 5 anemia, both of which can cause microthrombi and organ ischemia.1-4 The disease can be acquired or hereditary and the acquired form is more common. Acquired TTP affects approximately 4.5 people per million per year and hereditary (also called congenital or idiopathic, and known formally as Upshaw Schulman syndrome) affects approximately 2.9 people per million per year.5

Acquired TTP is more common in females, particularly during and after pregnancy; the most common age of those affected is between 30 and 50 years of age, and the disease is more common in African-Americans.6 Hereditary TPP is more common in children7 but adults can develop hereditary TTP. Thrombotic thrombocytopenic purpura is a potentially dangerous disease, and, if left untreated, the mortality rate has been reported to be as high as 90%.8 Hereditary TTP is caused by an inherited deficiency of ADAMTS13, an enzyme that helps to regulate normal functioning of von Willebrand factor.4,7 Von Willebrand factor is a glycoprotein that is involved in platelet adhesion (and thus blood clotting) and when ADAMTS13 is lacking the activity of von Willebrand factor is increased, resulting in widespread platelet adhesion and blood clotting.9,10 A deficiency in ADAMTS13 is the underpinning of hereditary TTP but these gene mutations do not completely explain the disease.

Sibling studies show that the clinical course of hereditary TTP can be quite different patient to patient despite the presence of the same ADAMTS13 mutations.11,12 The level of ADAMTS13 deficiency does not necessarily correlate with expression of the disease,13 and hereditary TTP typically requires an environmental stressor or trigger to manifest.4,14 These stressors or triggers are listed in Table 1.6,15-26 For detailed information about drug- induced TTP the reader is referred to Al-Nouri, 2015.20

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 6 Hereditary TTP Triggers

Acute , i.e., HIV,

Alcohol

Drugs, particularly cyclosporine, quinine, and tacrolimus

Malignancies

Pregnancy

Systemic erythematosus

Acquired TTP is caused by autoimmune antibodies that decrease the activity and level of the ADAMTS13 enzyme.5 In the great majority of cases of acquired TTP there is no obvious cause for the formation of these antibodies,6,27 and this is called primary or idiopathic acquired TTP. Acquired TTP may also be caused - or associated with – autoimmune disorders like systemic lupus erythematosus (SLE) or , drugs, human immunodeficiency virus (HIV) , liver disease, malignancies, pregnancy, and solid organ transplantation.5,27,28 This is called secondary acquired TTP. There is some evidence that acquired TTP, as with hereditary TTP, requires a stimulus to be expressed and the ADAMTS13 deficiency alone cannot explain the disease.29

Hemolytic Uremic Syndrome

Hemolytic uremic syndrome is characterized by hemolytic anemia, thrombocytopenia, and acute renal failure30 and there are two forms of the disease, typical and atypical. Both typical and atypical hemolytic uremic syndrome (HUS) cause direct injury to the kidneys (from the Shiga toxin

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 7 itself or by mechanical damage from microthrombi), thrombocytopenia, and a prothrombotic state that causes microthrombi and .

Typical HUS is caused by infection by Shiga toxin-producing E. coli bacteria, and 90% of all cases of HUS are typical HUS.31 The source of the bacteria can be contaminated food, contaminated water (including swimming pools), person-to-person contact, or contact with an infected animal.32 Typical HUS can also be (rarely) caused by invasive pneumococcal disease;33 and it usually affects children younger than 5 years of age and the elderly.33,34 It is much more common in children than in adults.35,36 The annual incidence of typical HUS has been estimated to be two cases per 100,000 population.33

Atypical HUS is a very rare disease that is primarily caused by a genetic defect in the complement system.32 Atypical HUS can also be precipitated (triggered) by drugs, infections, rare inborn metabolic deficiencies, and certain disease states.26,32,37-39 It is unclear if these cause the disease or cause the disease in people who have the genetic defect in the complement system.

Atypical HUS Triggers

Cancer

Drugs, i.e., antiplatelet drugs, cyclosporine, quinine, tacrolimus

Infections, i.e., HIV

Metabolic deficiencies

Organ transplantation

Pregnancy

Systemic lupus erythematosus

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 8 Case Study: John

John is a 50-year-old male with a medical history significant for . He is otherwise healthy and takes his antihypertensive medication faithfully. He develops symptoms including and dizziness. He presents to the local emergency room for further evaluation.

He undergoes a STAT CT scan of the brain, which reveals no evidence of . A CBC is drawn and notes a normal count (WBC) of 6.1. His hemoglobin is decreased at 10.2 and his platelet count is also decreased at 25. Upon further questioning, John states that as far as he knows, he has never had any abnormalities in his red blood cell or platelet counts. A peripheral blood smear, analyzed by the pathologist, reveals a significant amount of schistocytes.

The ER physician performs a physical exam and notes several bruises. John denies any recent trauma. He does not take blood thinners, including warfarin, clopidogrel, or aspirin. Lab work notes normal PT (prothrombin time) and PTT (activated partial thromboplastin time).

Diagnosis And Clinical Presentations Of TTP

Thrombotic thrombocytopenic purpura was often described as characterized by a pentad of microangiopathic hemolytic anemia, severe thrombocytopenia, neurologic , renal damage, and .6 This presentation was common when effective treatments were not available, but it is not the norm now.6,27 Unexplained microangiopathic hemolytic anemia and severe thrombocytopenia are usually considered to be highly suggestive for TTP6,40 and if the ADAMTS13 level is <10% of the average and/or an ADAMTS13 antibody is detected then a diagnosis of TTP can be made.6,27,41 Signs and symptoms are nonspecific and vary quite a bit nursece4less.com nursece4less.com nursece4less.com nursece4less.com 9 from patient to patient. Patients may present with mild, subjective complaints or they may be critically ill.

Differential Diagnosis of TTP

Autoimmune diseases, i.e, lupus nephritis Autoimmune hemolysis Disseminated intravascular coagulation Hemolytic uremic syndrome Infections Malignancy Malignant hypertension Pregnancy-related HELLP (hemolysis, elevated liver enzymes, low platelets) medications Vasculitis

Neurologic Signs and Symptoms

Neurologic signs and symptoms are common (approximately 50-90% of all patients),6 but some patients do not have any neurological signs and symptoms.27 The neurologic physical manifestations can be mild or severe and they may be transient and fluctuate. Aphasia, ataxia, blurred vision, cognitive deficits, coma, , dizziness, reversible encephalopathy, seizures, and stroke have been reported.6,42-44

Fever

Thrombotic thrombocytopenic purpura can cause fever, but it is not a common sign of the disease.6,27,45

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 10 Gastrointestinal

Abdominal pain, diarrhea, nausea, and vomiting are common signs and symptoms of TTP.27

Renal

Most patients who have TTP have normal or mildly elevated serum creatinine levels and acute injury caused by TTP is rare.46

Atypical and Rare Presentations

Adrenal, cardiac, cardiovascular, pancreatic, pulmonary, and visual damage can occur.6,27,47-51

Relapses

Approximately 20-50% of patients who have acquired TTP will have relapses52,53 and some patients have chronic, multiple relapses.52,53 Patients who have hereditary TTP are often treated with regular, prophylactic infusions of fresh frozen plasma but some patients only have relapses during periods of stress such as infection, pregnancy, or surgery and thus are treated as needed.14

Laboratory Findings of TTP

ADAMTS13 activity < 10% and presence of an ADMATS13 autoantibody Haptoglobin level is reduced Hemolytic anemia Indirect bilirubin is elevated Lactate dehydrogenase (LDH) is elevated Normal INR, aPTT, and PTT Thrombocytopenia

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 11 Diagnosis And Clinical Presentation Of HUS

Typical HUS is diagnosed by presence of Shiga toxin and E. Coli in a stool culture. Atypical HUS is a clinical diagnosis; DNA testing and testing of complement activity are of limited diagnostic value for this disease.10,54 Typical and atypical HUS are both characterized by hemolytic anemia, thrombocytopenia, and renal damage.

The clinical presentations of typical and atypical HUS are very similar and cardiac, gastrointestinal, neurologic, pulmonary, and renal signs and symptoms are possible.2,55 Some of these are minor, some are quite serious, eg, cardiac tamponade, coma, peripheral , and seizures54-57 but all of them are non-specific. The clinical issues that distinguish typical from atypical HUS and HUS from TTP are the gastrointestinal, cardiac, (specifically hypertension), renal damage, and course of the illness.

Gastrointestinal Symptoms

Patients who have typical HUS usually have and diarrhea, the latter often being bloody, for several days before anemia and renal damage occur.32 The onset of signs and symptoms from the time of exposure to the pathogen has been estimated to be from 2 to 12 days,58 and most patients develop other systemic signs and symptoms about 7 days after the gastrointestinal problems start.30

Hypertension

Hypertension is a well-known of atypical HUS. It can occur in children and adults. Hypertension appears to be more likely if a patient had a severe case of HUS complicated by neurological problems; and,

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 12 hypertension may develop many years after complete recovery from HUS and in the absence of signs of renal impairment.57-64

Renal Damage

Hemolytic uremic syndrome is the most common cause of acute renal failure in pediatric patients and irreversible renal damage may occur.65,66

Course of the Illness

Recovery from typical HUS is usually complete.30,32,58 However, if neurological complications develop, or a patient has low platelet count, a high count, or prolonged anuria, the prognosis is worse and a small percentage of patients suffer serious sequelae such as stroke or loss of renal function.32,67 The mortality rate from typical HUS has been estimated to be 2.9%.68 Atypical HUS is often chronic and reoccurring and permanent renal damage (approximately 50%) and death (approximately 25%) are much more likely than with typical HUS.30

Laboratory Findings of HUS

Anemia Thrombocytopenia Serum creatinine elevations Shiga toxin/E. Coli in stool

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 13 Treatment Of TTP

Aside from the specific therapies for acquired and hereditary TTP, basic or supportive care is important, such as hydration and monitoring for bleeding and infections, cardiac problems, and other complications.

Acquired TTP

The three standard treatments for acquired TTP are plasma exchange therapy, immunosuppressive drugs, and splenectomy. There are of course other therapies that have been used or are being investigated but inclusion and discussion of these is beyond the scope of the module.

Plasma Exchange Therapy

Plasma exchange therapy is the cornerstone of treatment for acquired TTP,8,10,69,70 and the mechanism of action is thought to be removal of and replacing ADAMTS13.45 The standard regimen is one plasma volume exchange a day, using fresh frozen plasma, for five to seven days69 but some patients may require up to four weeks of plasma exchange70, and need adjunctive therapies, as well.69 A response to therapy is measured by a sustained increase in platelet count of >150 × 109/L.69,70

The risks of plasma exchange therapy include allergic reactions, complications of central IV line placement, exacerbation of the disease state, , and sensitivity to citrate in the plasma.70 Approximately 50% of treated patients will have a disease exacerbation after plasma exchange therapy has been stopped, so patients should be observed in-hospital for several days after cessation of therapy.70 Between 10-42% of patients will be refractory to plasma exchange and need additional therapies.45

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 14 Immunosuppressive Drugs

Corticosteroids, i.e., methylprednisolone, , are frequently prescribed concomitantly with plasma exchange therapy, hopefully to suppress production of autoantibodies.45,69 Other drugs that have immunosuppressive actions such as cyclosporine and rituximab have been shown to be helpful for treating acquired TTP,53,71 but there are no consensus guidelines for their use.45,71

Splenectomy

Splenectomy (presumably) affects the production of autoantibodies in patients who have acquired TTP.45 It has been used for the treatment of refractory TTP,45,72 but it is not clear when and for whom it should be used and the clinical evidence has reported successes and failures.45,72

Hereditary TTP

The primary treatment for hereditary TTP is periodic infusions, i.e., every two to three weeks, of fresh frozen plasma;14,69,73 this approach has been shown to be very effective.14 Infusions of Factor VII or cryoprecipitate can be used, especially if volume overload is a potential problem.14,69 Immunosuppressive therapy is not recommended.14 In between therapy sessions platelet count should be monitored to determine if it is > 150 x 109/L, and the frequency of treatments depend on laboratory tests results and a patient’s clinical condition.

Treatment Of HUS

Typical hemolytic uremic syndrome HUS is primarily treated with symptomatic, supportive care:67 1) volume replacement with IV fluids, 2) transfusion with red blood cells and/or platelets, 3) antiepileptics if seizures nursece4less.com nursece4less.com nursece4less.com nursece4less.com 15 occur, and 4) hemodialysis if develops. Antibiotics and antimotility drugs are contraindicated for patients who have typical HUS,67 and they may increase the risk that an infection with Shiga toxin producing E. coli will progress to HUS.67 Antithrombotic drugs are not recommended for these patients.67

Eculizumab is a monoclonal antibody that blocks complement activation, and it is often used for treating patients who have atypical HUS. There is some evidence (albeit limited) that it may be helpful for treating typical HUS 74,75 and Niaudet notes: “Although these data are limited and preliminary, we administer eculizumab to patients with STEC-HUS and severe CNS involvement (i.e., seizures, coma, neurologic defect) in our center because these patients are at significant risk for death and long-term morbidity. We also consider eculizumab in cases of other severe organ involvement, such as cardiac dysfunction.”67

Atypical HUS is treated in much the same way as typical HUS, with an emphasis on supportive care,76 but the primary difference is that eculizumab should be first-line therapy for treating patients who have atypical HUS.76,77 Case reports and case series have confirmed the drugs effectiveness77 and eculizumab is relatively safe.

Complement activity is necessary for protection against meningococcal infection. No meningococcal infections related to eculizumab therapy in patients with atypical HUS have been reported77 but the risk is very real and meningococcal infections associated with eculizumab have occurred in other patient populations. Every patient who has atypical HUS and will be treated with eculizumab must be pre-treated with meningococcal vaccine at least 2 weeks prior to treatment initiation; if the need for treatment is urgent,

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 16 vaccinate the patient as soon as possible.78,79 Eculizumab is given intravenously: 900 mg once a week for four doses; 1200 mg once a week at week five, and 1200 mg every two weeks. Liver enzymes and hepatic function should be monitored during therapy with the drug77 as a small case series of children treated with eculizumab had hepatotoxicity, i.e., elevated transaminases.80 Serious adverse reactions such as hypertension resolved after eculizumab was discontinued.77

Patient Information And Preventive Measures

It is very important that nurses educate thrombocytopenic patients about their risk of bleeding and interventions to minimize the risk. Patients should avoid activities that increase the risk of bleeding. For example, thrombocytopenic patients should use soft toothbrushes and be careful when flossing to decrease the risk of oral bleeding. Patients should be instructed to shave with electric razors instead of blades. Additionally, contact sports should be avoided. Patients should also be assessed for risk of falls. Clinicians should discuss tips to prevent falls, such as creating a safe environment in the home. Patients, especially elderly patients, may need assistive devices.

Patients with low platelet counts should avoid unnecessary invasive procedures. These patients should also be instructed on a bowel regimen to prevent constipation and straining. Thrombocytopenic patients should not use suppositories or enemas. Sexual activity can increase risk of bleeding. Patients should be advised to use lubricant when engaging in sexual activity; and, if the platelet count is severely decreased, they should abstain.

Patients should also be instructed to avoid certain medications that may affect platelet function, such as ibuprofen and aspirin. The use of antiplatelet nursece4less.com nursece4less.com nursece4less.com nursece4less.com 17 drugs and/or anticoagulant drugs for treating patients who have TTP is not uniform; some clinicians prescribe them and some do not8,81 and there is little in the literature for guidance for their use in this situation.

On Reflection: Case Study John

John’s neurological symptoms worsen and he has intermittent episodes of confusion. His metabolic panel reveals an elevated creatinine of 2.3 with a glomerular infiltration rate (GFR) less than 60. John is noted to have severe renal insufficiency.

The attending physician consults hematology and . The hematologist immediately orders ADAMTS13 assay. However, her level of suspicion for TTP is high and she immediately starts John on high-dose methylprednisolone.

The hematologist arranges for insertion of a central venous catheter and contacts blood bank to arrange for plasma exchange. She also orders rituximab. The nursing staff monitors John’s CBC closely and educates him on bleeding precautions. His nurses also perform neurological checks frequently and monitor for any signs of bleeding.

John starts plasma exchange and Rituximab the following day. After four days, his platelet count has increased to 157. The plasma exchanges are discontinued and the platelet count remains above 150. With the help of the nephrology team, John’s kidney function improves.

Once John is getting close to being discharged, he is switched to oral prednisone and given very specific instructions. He is scheduled for outpatient follow up with his hematologist later that week. Once he is eventually tapered off steroids, he continues to follow closely with his hematologist.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 18 Summary

While thrombotic thrombocytopenic purpura is usually associated with an acquired autoimmune condition and hemolytic uremic syndrome is usually associated with bacterial infection, they can have similar presentations and complications. TTP and HUS are rare but serious conditions that require prompt diagnosis and treatment. These patients are acutely ill and can suffer from a number of complications, including life-threatening bleeding, anemia, kidney failure, and brain damage. If left untreated, these conditions can be fatal.

Health clinicians play an integral role in caring for these patients and keeping them safe. Oftentimes, these patients are acutely ill. Teaching patients and their families about bleeding precautions often becomes the responsibility of the nurse. Following bleeding precautions and preventing falls can help prevent further harm. The health care team is in an excellent position to improve patient outcomes.

Please take time to help NurseCe4Less.com course planners evaluate the nursing knowledge needs met by completing the self-assessment of Knowledge Questions after reading the article, and providing feedback in the online course evaluation.

Completing the study questions is optional and is NOT a course requirement.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 19 1. Thrombocytopenia is defined as a platelet count less than:

a. 300 b. 90 c. 150 d. None of the above

2. True or False: In hereditary TTP, the ADAMTS13 gene is not flawed; whereas in acquired TTP, the gene is flawed.

a. True b. False

3. Complications of TTP, bleeding, anemia, renal injury and neurological symptoms, can be serious and lead to a fatal outcome in about _____ percent of cases.

a. 90% b. 25% c. 50% d. 30%

4. Acquired thrombotic thrombocytopenic purpura (TTP) is more common than hereditary TTP and it is seen mostly in

a. individuals over age 50. b. Caucasians as opposed to African-Americans. c. men. d. in females, particularly during and after pregnancy.

5. Acute renal failure is characteristic of

a. rheumatoid arthritis. b. thrombotic thrombocytopenic purpura. c. activity of von Willebrand factor. d. hemolytic uremic syndrome.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 20 6. In the case study mentioned above, John was getting close to being discharged and the doctor switched him from rituximab to oral ______with scheduled outpatient follow up.

a. prednisone b. toradol c. zofran d. protonix

7. True or False: Fever is a common sign of thrombotic thrombocytopenic purpura.

a. True b. False

8. The primary treatment for hereditary thrombotic thrombocytopenic purpura (TTP) is

a. immunosuppressive drugs. b. splenectomy. c. administration of rituximab. d. periodic infusions of fresh frozen plasma.

9. Atypical hemolytic uremic syndrome (HUS) is primarily treated with

a. antibiotics. b. antithrombotic drugs. c. antimotility drugs. d. eculizumab.

10. Patients should also be instructed to avoid certain medications that may affect platelet function, such as

a. rituximab and prednisone. b. eculizumab and prednisone. c. ibuprofen and aspirin. d. antiplatelet drugs.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 21 CORRECT ANSWERS:

1. Thrombocytopenia is defined as a platelet count less than:

c. 150

p. 5: “Normal platelet count is between 150 and 350 x 109/L, and thrombocytopenia is defined as a platelet count less than 150.”

2. True or False: In hereditary TTP, the ADAMTS13 gene is not flawed; whereas in acquired TTP, the gene is flawed.

b. False

p. 6: “Hereditary TTP is caused by an inherited deficiency of ADAMTS13, an enzyme that helps to regulate normal functioning of von Willebrand factor.”

p. 7: “Acquired TTP is caused by autoimmune antibodies that decrease the activity and level of the ADAMTS13 enzyme.”

3. Complications of TTP, bleeding, anemia, renal injury and neurological symptoms, can be serious and lead to a fatal outcome in about _____ percent of cases.

a. 90%

p. 6: “Thrombotic thrombocytopenic purpura is a potentially dangerous disease; if left untreated, the mortality rate has been reported to be as high as 90%.”

4. Acquired thrombotic thrombocytopenic purpura (TTP) is more common than hereditary TTP and it is seen mostly in

d. in females, particularly during and after pregnancy.

pp. 5-6: The disease can be acquired or hereditary and the acquired form is more common…. Acquired TTP is more common in females, particularly during and after pregnancy; the most common age of those affected is between 30 and 50 years of age, and the disease is more common in African-Americans. Hereditary TPP is more common in children7 but adults can develop hereditary TTP.”

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 22 5. Acute renal failure is characteristic of

d. hemolytic uremic syndrome.

p. 13: “Hemolytic uremic syndrome is the most common cause of acute renal failure in pediatric patients and irreversible renal damage may occur.”

6. In the case study mentioned above, John was getting close to being discharged and the doctor switched him from rituximab to oral ______with scheduled outpatient follow up.

a. prednisone

p. 18: “Once John is getting close to being discharged, he is switched to oral prednisone and given very specific instructions. He is scheduled for outpatient follow up with his hematologist later that week. Once he is eventually tapered off steroids, he continues to follow closely with his hematologist.”

7. True or False: Fever is a common sign of thrombotic thrombocytopenic purpura.

b. False

p. 10: “Thrombotic thrombocytopenic purpura can cause fever, but it is not a common sign of the disease.”

8. The primary treatment for hereditary thrombotic thrombocytopenic purpura (TTP) is

d. periodic infusions of fresh frozen plasma.

p. 15: “The primary treatment for hereditary TTP is periodic infusions, i.e., every two to three weeks, of fresh frozen plasma this approach has been shown to be very effective.”

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 23 9. Atypical hemolytic uremic syndrome (HUS) is primarily treated with

d. eculizumab.

p. 16: “Atypical HUS is treated in much the same way as typical HUS, with an emphasis on supportive care, but the primary difference is that eculizumab should be first-line therapy for treating patients who have atypical HUS. Case reports and case series have confirmed the drugs effectiveness and eculizumab is relatively safe.”

10. Patients should also be instructed to avoid certain medications that may affect platelet function, such as

c. ibuprofen and aspirin.

pp. 17-18: “Patients should also be instructed to avoid certain medications that may affect platelet function, such as ibuprofen and aspirin. The use of antiplatelet drugs and/or anticoagulant drugs for treating patients who have TTP is not uniform; some clinicians prescribe them and some do not and there is little in the literature for guidance for their use in this situation.”

References Section

The References below include published works and in-text citations of published works that are intended as helpful material for your further reading.

1. Abbott DW, Friedman KD, Karafin MS. Differentiation of pernicious anemia from thrombotic thrombocytopenic purpura: The clinical value of subtle pathologic findings. Transfus Apher Sci. 2016 Sep 28. pii: S1473-0502(16)30122-7. doi: 10.1016/j.transci.2016.08.005. [Epub ahead of print] 2. Bansal R, Baer MR, Zimrin AB, Law JY. Isolated thrombocytopenia and liver function abnormalities characterizing an atypical presentation of thrombotic thrombocytopenic purpura. Ann Hematol. 2016;95(12):2079-2080. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 24 3. George, JN. How I treat patients with thrombotic thrombocytopenic purpura. Blood. 2010;116(20):4060-4069. 4. Shenkman B. Einav Y. Thrombotic thrombocytopenic purpura and other thrombotic microangiopathic hemolytic : Diagnosis and classification. Autoimmun Rev. 2014;13(4-5):584-586. 5. Rinott N, Mashiach T, Horowitz NA, et al. A 14-Year Experience in the management of patients with acquired immune thrombotic thrombocytopenic purpura in northern Israel. Acta Haematol. 2015;134(3):170-176. 6. Rogers HJ, Allen C, Lichtin AE. Thrombotic thrombocytopenic purpura: The role of ADAMTS13. Cleve Clin J Med. 2016;83(8):597-603. 7. Hanby HA, Zheng XL. Current status in diagnosis and treatment of hereditary thrombotic thrombocytopenic purpura. Hereditary Genet. 2014;3(1). pii: e108. 8. Patriquin CJ, Clark WF, Pavenski K, et al. How we treat thrombotic thrombocytopenic purpura: Results of a Canadian TTP practice survey. J Clin Apher. 2016 Jul 31. doi: 10.1002/jca.21489. [Epub ahead of print] 9. Zheng XL. ADAMTS13 and von Willebrand factor in thrombotic thrombocytopenic purpura. Annu Rev Med. 2015;66:211-225. 10. Mannucci PM, Cugno M. The complex differential diagnosis between thrombotic thrombocytopenic purpura and the atypical hemolytic uremic syndrome: Laboratory weapons and their impact on treatment choice and monitoring. Thromb Res. 2015;136(5):851-854. 11. Veyradier A, Lavergne JM, Ribba AS, et al. Ten candidate ADAMTS13 mutations in six French families with congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome). J Thromb Haemost. 2004;2(3):424-429. 12. Furlan M, Lämmle B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Best Pract Res Clin Haematol. 2001;14(2):437-454. 13. Page EE, Kremer Hovinga JA, Terrell DR, Vesely SK, George JN. Clinical importance of ADAMTS13 activity during remission in patients with acquired thrombotic thrombocytopenic purpura. Blood. 2016;128(17):2175-2178. 14. Pérez-Rodríguez A, Lourés E, Rodríguez-Trillo Á, et al. Inherited ADAMTS13 deficiency (Upshaw-Schulman syndrome): a short review. Thromb Res. 2014;134(6):1171-1175. 15. Park YA, Hay SN, King KE, et al. Is it quinine TTP/HUS or quinine TMA? ADAMTS13 levels and implications for therapy. J Clin Apher. 2009;24(3):115-119. 16. Ferrari B, Cairo A, Pontiggia S, Mancini I, Masini L, Peyvandi F. Congenital and acquired ADAMTS13 deficiency: Two mechanisms, one patient. J Clin Apher. 2015;30(4):252-256. nursece4less.com nursece4less.com nursece4less.com nursece4less.com 25 17. Khodor S, Castro M, McNamara C, Chaulagain CP. Clopidogrel-induced refractory thrombotic thrombocytopenic purpura successfully treated with rituximab. Hematol Oncol Stem Cell Ther. 2016;9(2):76-79. 18. Rivaud E, Massiani MA, Vincent F, Azoulay E, Coudrec LJ. Valacyclovir hydrochloride therapy and thrombotic thrombocytopenic purpura in an HIV-infected patient. Arch Intern Med. 2000;160(11):1705-1706. 19. Kotbi N, Han B, Cheng D, Odom AE. Opana(®) ER induced thrombotic thrombocytopenic purpura. Int Med Case Rep J. 2015;8: 97-98. 20. Al-Nouri ZL, Reese JA, Terrell DR, Vesely SK, George JN. Drug-induced thrombotic microangiopathy: a systematic review of published reports. Blood. 2015;125(4):616-618. 21. Scully M. Thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome microangiopathy in pregnancy. Semin Thromb Hemost. 2016;42(7):774-779. 22. Abu-Hishmeh M, Sattar A, Zarlasht F. Systemic lupus erythematosus presenting as refractory thrombotic thrombocytopenic purpura: A diagnostic and management challenge. A case report and concise review of the literature. Am J Case Rep. 2016;17: 782-787. 23. Blum D, Blake G. Lupus-associated thrombotic thrombocytopenic purpura-like microangiopathy. World J Nephrol. 2015;4(5):528-531. 24. Fujino Y, Inoue Y, Onodera M, et al. Acute pancreatitis-induced thrombotic thrombocytopenic purpura with recurrent acute pancreatitis. Clin J Gastroenterol. 2016;9(2):104-108. 25. Warner NC, Vaughan LB, Wenzel RP. Human immunodeficiency virus associated thrombotic thrombocytopenic purpura, a clinical conundrum. J Clin Apher. 2016 Oct 6. doi: 10.1002/jca.21514. [Epub ahead of print] 26. Govind Babu K, Bhat GR. -associated thrombotic microangiopathy. Ecancermedicalscience. 2016 Jun 28;10:649. doi: 10.3332/ecancer.2016.649. eCollection 2016. 27. George JN, Cuker G. Pathophysiology of acquired TTP and other primary thrombotic microangiopathies (TMAs). UpToDate. November 9, 2016. http://www.uptodate.com/contents/pathophysiology-of-acquired-ttp- and-other-primary-thrombotic-microangiopathies-tmas. Accessed November 16, 2016. 28. Blombery P, Scully M. Management of thrombotic thrombocytopenic purpura: current perspectives. J Blood Med. 2014; 5:15-23. 29. George JN. Measuring ADAMTS13 activity in patients with suspected thrombotic thrombocytopenic purpura: when, how, and why? Transfusion. 2015; 55(1):11-13. 30. Bajracharya P, Jain A, Baracco R, Mattoo TK, Kapur G. Atypical hemolytic uremic syndrome: a clinical conundrum. Pediatr Nephrol. 2016;31(10):1615-1624. 31. Westra D, Volokhina EB, van der Molen RG, et al. Serological and genetic complement alterations in infection-induced and complement- nursece4less.com nursece4less.com nursece4less.com nursece4less.com 26 mediated hemolytic uremic syndrome. Pediatr Nephrol. 2016 Oct 7. [Epub ahead of print] 32. Karpman D, Loos S, Tati R, Arvidsson I. Haemolytic uraemic syndrome. J Intern Med. 2016 Oct 10. doi: 10.1111/joim.12546. [Epub ahead of print] 33. Groves AP, Reich P, Sigdel B, Davis TK. Pneumococcal hemolytic uremic syndrome and steroid resistant . Clin Kidney J. 2016;9(4):572-575. 34. Shen Y-M. Clinical evaluation of thrombotic micronagiopathy: identification of patients with suspected atypical hemolytic uremic syndrome. Thromb J. 2016 Oct 4;14(Suppl 1):19. eCollection 2016. 35. Byrne L, Jenkins C, Launders N, Elson R, Adak GK. The epidemiology, microbiology, and clinical impact of Shiga toxin-producing Escherichia coli in England, 2009-2012. Epidemiol Infect. 2015;143(16):3475-3487. 36. Ko H, Maymani H, Rojas-Hernandez C. Hemolytic uremic syndrome associated with Escherichia coli O157:H7 infection in older adults: a case report and review of the literature. J Med Case Rep. 2016; 10:175. doi: 10.1186/s13256-016-0970-z. 37. Asif A, Nayer A, Haas CS. Atypical hemolytic uremic syndrome in the setting of complement-amplifying conditions: case reports and a review of the evidence for treatment with eculizumab. J Nephrol. 2016 Nov 15. [Epub ahead of print] 38. Kransdorf EP, Kittleson MM, Kobashigawa JA. Atypical hemolytic-uremic syndrome immediately after heart transplantation. J Heart Transplant. 2014;33(6):664-665. 39. Reese JA, Bougie DW, Curtis BR, et al. Drug-induced thrombotic microangiopathy: Experience of the Oklahoma Registry and the Blood Center of Wisconsin. Am J Hematol. 2015;90(5):406-410. 40. Blombery P, Kivivali L, Pepperell D, et al. Diagnosis and management of thrombotic thrombocytopenic (TTP) in Australia: Findings from the first 5 years of the Australian TTP/thrombotic microangiopathy registry. Intern Med J. 2016;46(1):71-79 41. Wada H, Matsumoto T, Yamashita, Y. Natural history of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Semin Thromb Hemost. 2014;40(8):866-873. 42. Lasek-Bal A, Kosarz-Lanczek K, Kazibutowska Z. Acute neurological symptoms of Moschcowitz disease - case report. Neurol Neurochir Pol. 2014;48(4):296-298. 43. Yu WL, Leung T, Soo Y, Lee J, Wong KS. Thrombotic thrombocytopenic purpura with concomitant small- and large-vessel thrombosis, atypical posterior reversible encephalopathy syndrome and cerebral microbleeds. Oxf Med Case Reports. 2015;2015(2):179-182.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 27 44. Griffin D, Al-Nouri ZL, Muthurajah D et al. First symptoms in patients with thrombotic thrombocytopenic purpura (TTP): what are they and when do they occur? Transfusion. 2013; 53(1): 235-237. 45. Sayani FA, Abrams CS. How I treat refractory thrombotic thrombocytopenic purpura. Blood. 2015;125(25):3860-3867. 46. George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med. 2014;371(7):654-666. 47. Sarode R. Atypical presentations of thrombotic thrombocytopenic purpura: a review. J Clin Apher. 2009;24(1):47-52. 48. Takimoto T, Nakao M, Nakajo T, Chinen Y, Kuroda J, Taniwaki M. Acute as the initial thrombotic event of thrombotic thrombocytopenic purpura. Blood Coagul Fibrinolysis. 2016;27(8):948- 951. 49. Imanirad I, Rajasekhar A, Zumberg M. A case series of atypical presentations of thrombotic thrombocytopenic purpura. J Clin Apher. 2012; 27:221–226. 50. Nokes T, George JN, Vesely SK, Awab A. Pulmonary involvement in patients with thrombotic thrombocytopenic purpura. Eur J Haematol. 2014;92(2):156-163. 51. Soltes L, Schmalfuss IM, Bhatti MT. Cortical blindness due to reversible posterior leukoencephalopathy syndrome in a patient with thrombotic thrombocytopenic purpura and preeclampsia. Arch Ophthalmol. 2004;122(12):1885-1887. 52. Mai Falk J, Scharrer I. Idiopathic thrombotic thrombocytopenic purpura: strongest risk factor for relapse from remission is having had a relapse. Transfusion. 2016 Aug 11. doi: 10.1111/trf.13751. [Epub ahead of print] 53. Coppo P, Froissart A; French Reference Center for Thrombotic Microangiopathies. Treatment of thrombotic thrombocytopenic purpura beyond therapeutic plasma exchange. Hematology Am Soc Hematol Educ Program. 2015;2015:637-643. 54. Rafiq A, Tariq H, Abbas N, Shenoy R. Atypical hemolytic-uremic syndrome: a case report and literature review. Am J Case Rep. 2015; 16:109-114. 55. Greenbaum LA, Fila M, Ardissino G, et al. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016;89(3):701-711. 56. Bauer A, Loos S, Wehrmann C, et al. Neurological involvement in children with E. coli O104:H4-induced hemolytic uremic syndrome. Pediatr Nephrol. 2014;29(9):1607-1615. 57. Rigamonti D, Simonetti GD. Direct cardiac involvement in childhood hemolytic-uremic syndrome: case report and review of the literature. Eur J Pediatr. 2016 Sep 23. [Epub ahead of print]

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 28 58. Talarico V, Aloe M, Monzani A, Miniero R, Bona G. Hemolytic uremic syndrome in children. Minerva Pediatr. 2016;68(6):441-455. 59. Totina A, Iorember F, El-Dahr SS, Yosypiv IV. Atypical hemolytic-uremic syndrome in a child presenting with malignant hypertension. Clin Pediatr (Phila). 2013;52(2):183-186. 60. Tsai HM, Kuo E. From gestational hypertension and preeclampsia to atypical hemolytic uremic syndrome. Obstet Gynecol. 2016;127(5):907- 910 61. Hoenecke J, Hartmann H, Melk A. Arterial hypertension in children with hemolytic uremic syndrome after kidney transplantation. Pediatr Transplant. 2015;19(5):504-509. 62. Sajan T, Vinay S, Sonu N, Alan P. How atypical can atypical hemolytic uremic syndrome be? Clin Case Rep. 2014;2(2):57-59. 63. De Petris L, Gianviti A, Giordano U, Calzolari A, Tozzi AE, Rizzoni G. in the long-term follow-up of children with hemolytic uremic syndrome. Pediatr Nephrol. 2004;19(11):1241-1244. 64. Derad I, Obermann B, Katalinic A, et al. Hypertension and mild persist following severe haemolytic uraemic syndrome caused by Shiga toxin-producing Escherichia coli O104:H4 in adults. Nephrol Dial Transplant. 2016;31(1):95-103. 65. Hoenecke J, Hartmann H, Melk A. Arterial hypertension in children with hemolytic uremic syndrome after kidney transplantation. Pediatr Transplant. 2015;19(5):504-509. 66. Okuda Y, Ishikura K, Terano C, et al. Irreversible severe kidney injury and anuria in a 3-month-old girl with atypical haemolytic uraemic syndrome under administration of eculizumab. Nephrology (Carlton). 2016;21(3):261-265. 67. Niaudet P. Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children. UpToDate. January 6, 2016. https://www.uptodate.com/contents/treatment-and-prognosis-of-shiga- toxin-producing-escherichia-coli-stec-hemolytic-uremic-syndrome-hus- in-children. Accessed November 19, 2016. 68. Mody RK, Gu W, Griffin PM, et al. Postdiarrheal hemolytic uremic syndrome in United States children: clinical spectrum and predictors of in-hospital death. J Pediatr. 2015;166(4):1022-1029. 69. Sarode R, Bandarenko N, Brecher ME, et al. Thrombotic thrombocytopenic purpura: 2012 American Society for Apheresis (ASFA) consensus conference on classification, diagnosis, management, and future research. J Clin Apher. 2014; 29:148-167. 70. Raval JS, Mazepa MA, Brecher ME, Park YA. How we approach an acquired thrombotic thrombocytopenic purpura patient. Transfusion. 2014;54(10):2375-2382.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 29 71. Lim W, Vesely SK, George JN. The role of rituximab in the management of patients with acquired thrombotic thrombocytopenic purpura. Blood. 2015;125(10):1526-1531. 72. Umemura A, Sasaki A, Nitta H, Obuchi T, Baba S, Wakabayashi G. Laparoscopic splenectomy for the treatment of refractory thrombotic thrombocytopenic purpura. Clin J Gastroenterol. 2013;6(6):420-423. 73. Sharma D, Shastri S, Pandita A, Sharma P. Congenital thrombotic thrombocytopenic purpura: Upshaw-Schulman syndrome: a cause of neonatal death and review of literature. J Matern Fetal Neonatal Med. 2016;29(12):1977-1979. 74. Delmas Y, Vendrely B, Clouzeau B, Outbreak of Escherichia coli O104:H4 haemolytic uraemic syndrome in France: outcome with eculizumab. Nephrol Dial Transplant. 2014;29(3):565-572. 75. Pape L, Hartmann H, Bange FC, Suerbaum S, Bueltmann E, Ahlenstiel- Grunow T. Eculizumab in typical hemolytic uremic syndrome (HUS) with neurological involvement. Medicine (Baltimore). 2015 Jun;94(24):e1000. doi: 10.1097/MD.0000000000001000. 76. Niaudet P. Complement-mediated hemolytic uremic syndrome. UpToDate. September 27, 2016. https://www.uptodate.com/contents/complement-mediated-hemolytic- uremic-syndrome. Accessed November 20, 2016. 77. Palma LM, Langman CB. Critical appraisal of eculizumab for atypical hemolytic uremic syndrome. J Blood Med. 2016; 7:39-72. 78. Lexicomp. ® Eculizumab (Lexi-Drugs). 11/17/2016. Accessed November 20, 2016 from www.UCHC.edu. 79. Soliris [package inset]. New Haven, CT: Alexion Pharmaceuticals, Inc; 2015. 80. Hayes W, Tschumi S, Ling SC, Feber J, Kirschfink M, Licht C. Eculizumab hepatotoxicity in pediatric aHUS. Pediatr Nephrol. 2015;30(5):775–781 81. Mariotte E, Veyradier A. Thrombotic thrombocytopenic purpura: from diagnosis to therapy. Curr Opin Crit Care. 2015;21(6):593-601.

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