Thrombotic Thrombocytopenic Purpura (TTP)


Article Author:
Michael Stanley


Article Editor:
Joel Michalski


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
4/2/2019 12:48:57 AM

Introduction

Thrombotic Thrombocytopenic Purpura (TTP) is a type of microangiopathic hemolytic anemia that classically has been characterized by the pentad of fever, thrombocytopenia, hemolytic anemia, renal dysfunction, and neurologic dysfunction. TTP results from either a congenital or acquired decrease or absence of the enzyme "a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13"  (ADAMTS13). Low levels of ADAMTS13 results in microthrombi formation which leads to end-organ ischemia and damage. [1][2][3]The central nervous system (CNS) and kidneys are the two most common organ systems affected by TTP. Diagnosis is very important because TTP is a medical emergency which, without treatment, has a very high mortality. 

Etiology

TTP results from a decrease or absence of the enzyme ADAMTS13. TTP can be either congenital or acquired. Acquired TTP is more common than the congenital type and is caused by autoantibodies targeting ADAMTS13. Antiplatelet drugs, immunosuppressive agents, HIV, estrogen-containing birth control, and pregnancy are the most commonly listed triggers for ADAMTS13 autoantibody formation causing acquired TTP. The less common congenital form of TTP results from mutations to ADAMTS13. [4][5]

Epidemiology

TTP is a rare disease; the exact prevalence is not clear. Studies cite incidences between 1 and 13 cases per million people depending on geographic location. TTP most often occurs after 40 years of age, but congenital forms can occur in children. TTP is more common in women with a 2:1 female to male predominance. [6]The mortality in TTP without treatment is 90%, but this drops to a mortality of 10% to 20% with proper treatment. However, even with successful treatment relapse occurs in up to 36% of patients. 

Pathophysiology

A deficiency of ADAMTS13 that is caused by gene mutations or acquired autoantibodies is central to the pathophysiology of TTP. The ADAMTS13 enzyme is responsible for breaking down ultra-large VWF multimers. When ADAMTS13 is deficient, large Von Willebrand Factor (VWF) multimers accumulate leading to platelet aggregation, hemolysis, and microthrombi formation. [7][8]he microthrombi cause ischemia is leading to damage to end organs, with the most common being the central nervous system (CNS) and kidneys. Thrombocytopenia results from platelet consumption during thrombus formation. Anemia results from hemolytic destruction of red blood cells as they pass through small vessels that are partially occluded by thrombi.

History and Physical

Signs and symptoms of TTP that reflect the underlying end-organ damage include thrombocytopenia and hemolytic anemia. The CNS is the most commonly affected end organ, with manifestations that can include a headache, focal neurologic deficits, seizures, confusion, and vertigo. Signs and symptoms associated with volume overload and/or cardiac arrhythmias can occur due to TTP causing acute renal failure. Hemolytic anemia can cause fatigue, dyspnea, and jaundice. The thrombocytopenia can present as mucosal bleeding as well as petechial and/or purpuric skin findings. Many patients present with a fever. 

Frequently, the presentation of TTP is somewhat indolent. Most cases are discovered in the ambulatory setting after a period of days to weeks that the patient feels poorly. 

Although renal failure is part of the classic presentation, in practice, it is rare to have renal dysfunction. Some providers recommend looking for other causes of TMA that can present with renal failure (HUS); that is, the presence of renal failure suggests against TTP. In addition, if the patient presents with a coagulopathy, it is unlikely to be a patient with TTP.

Evaluation

The classic TTP pentad of fever, thrombocytopenia, hemolytic anemia, renal dysfunction, and neurologic dysfunction cannot be relied on for diagnosis because it only occurs in 50% of cases. Laboratory evaluation plays a critically important role in the diagnosis of TTP because signs and symptoms are variable and end-organ damage can be delayed. For diagnosis, the labs must show anemia and thrombocytopenia along with an indication of active hemolysis, such as the presence of schistocytes, increased unconjugated bilirubin, increased reticulocyte count, increased lactate dehydrogenase, and decreased haptoglobin.[9][10][11]

If renal dysfunction is present, labs often show increased serum creatine, proteinuria, and hematuria. PT and PTT will be normal which differentiates TTP from disseminated intravascular coagulation. ADAMTS13 activity assay should be ordered, but results will not be immediately available. The findings of thrombocytopenia, anemia, and schistocytes, in the absence of DIC, is all that is needed for the presumptive diagnosis of TTP. Once TTP is confirmed, serologic testing should be ordered for autoantibodies, viral hepatitis, and HIV. In females able to bear children, a pregnancy test should be obtained. 

Treatment / Management

The mainstay of treatment in TTP is plasma exchange with high dose steroids (1 mg/kg of prednisone, advised by James George of Oklahoma University). This should be initiated as soon as possible on all patients who have unexplained hemolytic anemia and thrombocytopenia with a normal PT/INR and PTT. Both the ultra-large VWF multimers and the ADAMTS13 autoantibodies are effectively removed from circulation by plasma exchange therapy. Fresh frozen plasma (FFP) is the blood product of choice for plasma exchange. Other treatments used are corticosteroids, vincristine, and rituximab. [12][13][14]Corticosteroids should be considered as an adjunct to plasma exchange. The chemotherapeutic agent vincristine and the monoclonal antibody rituximab are often reserved for TTP cases refractory to plasma exchange. A packed red blood cell (PRBC) transfusion can be given if there is a clinical indication. Platelet transfusion is controversial but is considered to be contraindicated unless major bleeding is present. A hematologist should be consulted as soon as the diagnosis is considered.  [15]

Monitoring for response is essential to determine the duration of plasma exchange. Typically, hemolysis markers are checked daily. Plasma exchange usually is stopped once the platelet levels stabilize at above 150 for more than 48 hours.[16]

Pearls and Other Issues

Remember that all thrombotic microangiopathies (TMAs) cause microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, but not all findings of MAHA with thrombocytopenia are a result of a TMA syndrome. Other causes of MAHA with thrombocytopenia include:

  • HELLP syndrome (breakdown of red blood cells, hemolysis, elevated liver enzymes, and low platelet count occurring in pregnancy) and severe preeclampsia
  • Severe hypertension (hypertensive emergency)
  • Severe sepsis and disseminated intravascular coagulation (will have abnormal coagulation studies, while TTP will have normal coagulation studies)
  • Cancer
  • Autoimmune processes (lupus, scleroderma, heparin-induced thrombocytopenia, hemophagocytic lymphohistiocytosis
  • Mechanical causes (transjugular intrahepatic portosystemic shunt, cardiac valvular pathology)
  • Paroxysmal nocturnal hemoglobinuria
  • Transplant patients

Other primary TMA syndromes include the following:

  • Shiga toxin-mediated hemolytic uremic syndrome (HUS, usually with bloody diarrhea and associated with Escherichia coli 0157: H7)
  • Complement-mediated HUS (previously referred to as atypical HUS)
  • Drug-induced TMA: Chemotherapy (mitomycin and gemcitabine), cyclosporine, tacrolimus, bevacizumab, illegal narcotics.

Enhancing Healthcare Team Outcomes

TTP is a serious life-threatening disorder that is best managed by an interprofessional team that includes a nurse, hematologist, emergency department physician, nephrologist, neurologist and an internist. Besides steroids, many of these patients may benefit from plasmapheresis. Hence, the role of the nurse cannot be understated. Monitoring for response is essential to determine the duration of plasma exchange. Typically, hemolysis markers are checked daily. Plasma exchange usually is stopped once the platelet levels stabilize at above 150 for more than 48 hours. The outcomes of patients with TTP depend on age, presence of neurological deficits, renal dysfunction, response to treatment and other co-morbidity. Most patients require a prolonged stay in hospital as recovery is gradual.[17][18] (Level V)


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Thrombotic Thrombocytopenic Purpura (TTP) - Questions

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Which of the following drugs is most likely to cause thrombotic thrombocytopenic purpura?



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Which of the following is not an appropriate initial treatment for thrombotic thrombocytopenic purpura?



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A 17-year-old female college student presents to the emergency department complaining of severe bloody diarrhea, abdominal discomfort, lethargy, and headache. She states that she had a barbecue at a friend's house a day ago where he also drank some beer. While In the ED, the patient appears more lethargic and less responsive. Physical exam reveals petechiae on her chest and arms, and she also has a fever of 102.4 F. CBC reveals a Hgb of 7.9 mg/dL, WBC 18,000/microliter, and platelets of 85,000/microliter. BMP shows [Na] 135 mEq/dL , [K] 5.5 mEq/dL , [Cl] 89 mEq/dL , [BUN] 45 mg/dL, [Cr] 2.9 mg/dL as well as an elevated lactate dehydrogenase level. What would be expected on this patient's blood smear?



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A 16-year-old patient presents with fever, abdominal pain, and fatigue. The fever and fatigue started this morning which was shortly followed by a vague mid-abdominal pain that comes and goes. He had a seizure 30 minutes ago while sitting down in his living room. He lost consciousness during the seizure attack, but he did not urinate himself and did not bite his tongue. This is the first time this has happened to him. He denies nausea, vomiting, weakness, numbness, trauma to his head, or diarrhea. Complete blood count reveals hemoglobin: 10 g/dL, mean corpuscular volume: 85 fL, mean corpuscular hemoglobin concentration: 35 g/dl, lactate dehydrogenase: 450 U/L, white blood cells: 6000/mL, platelets: 70,000/uL. Liver enzyme tests reveal ALT: 60 IU/L, AST: 65 IU/L. Creatinine: 2.6 mg/dL. Which of the following treatments will benefit this patient?



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Which of the following clinical scenarios is thrombotic thrombocytopenic purpura most likely to have developed?



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A 65-year-old man with presents with complaints of fever and abdominal pain with bloody stools for the past two days. He has no significant past medical history and is not on any medications. On physical examination: temperature is 38.5 C, blood pressure is 150/90 mmHg, pulse is 103 bpm, and respiratory rate is 19/min. Cardiovascular and pulmonary exams were within normal limits. Neurological exam found the patient to be oriented to place and person but not time. Abdominal exam was positive for generalized tenderness to palpation with no guarding or rigidity and normal bowel sounds. Laboratory studies found a hematocrit of 30%, WBC count of 13,000/microL and platelet count of 40,000/microL. The unconjugated bilirubin was 3 mg/dL, creatinine was 3.7 mg/dL, and Lactate dehydrogenase was 1600 U/L. Peripheral smear showed the presence of schistocytes. What would the first line of management for this patient be?



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Thrombotic Thrombocytopenic Purpura (TTP) - References

References

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