eMedicine Specialties > Emergency Medicine > Hematology & Oncology

Thrombotic Thrombocytopenic Purpura

Author: Deborrah Symonette, MD, MPH, Healthcare Consultant, DSKSD, Inc
Coauthor(s): Deepak Sharma, Touro College of Osteopathic Medicine, New York; Priya S Abraham, Touro College of Osteopathic Medicine, New York; Vanessa Yoo, Touro College of Osteopathic Medicine, New York; Wafa Qamar, Touro College of Osteopathic Medicine, New York
Contributor Information and Disclosures

Updated: Sep 16, 2009

Introduction

Background

Thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening multisystem disorder that is considered a true medical hematological emergency. Moschcowitz first described TTP in 1924 when he observed that a 16-year-old girl had anemia, petechiae, and microscopic hematuria. She died of multiorgan failure, and, at autopsy, disseminated microvascular hyaline platelet thrombi were prevalent in terminal arterioles and capillaries of the heart and kidneys. These platelet-rich thrombi remain the hallmark of the pathologic diagnosis. Microangiopathic hemolytic anemia along with the aggregation of platelet thrombi are present in a setting of microvascular injury and high fluid shear stress.

Varying degrees of organ ischemia due to the vascular occlusion occur. In this life-threatening disease, recognizing the clinical presentation and initiating medical intervention early are critical. This is difficult at times because there is a range of overlapping signs and symptoms with other microangiopathic diseases, such as hemolytic uremic syndrome (HUS). Both TTP and HUS have thrombocytopenia and microangiopathic hemolytic anemia but different medical management pathways. The patient may not present with all of the signs and symptoms of TTP, and there can be a gray zone as to which microangiopathy truly exists. TTP is a medical emergency with diagnostic criteria for treatment that is not always definitive but, if TTP is suspected, then the first-line treatment of plasma exchange should be initiated to save the patient's life.

Prior efforts to identify this disease clinically lead to the development of a diagnostic criteria classifying thrombotic thrombocytopenic purpura as a syndrome in 1966 by Amorosi and Ultmann. They reviewed 255 patients previously reported and 16 other patients. They outlined a pentad of clinical features including microangiopathic hemolytic anemia, thrombocytopenia, neurologic abnormalities, fever, and renal dysfunction.1 Later studies show this pentad is seen in 40% of cases. A triad of microangiopathic hemolytic anemia, thrombocytopenia, and neurologic abnormalities are seen in 74%.2 Clinically, if a patient presents with thrombocytopenia (without coagulopathy), red cell fragmentation, elevated lactate dehydrogenase (LDH) level, and muscle and organ ischemia, consider TTP urgently in the differential diagnosis.3

Thrombotic microangiopathic diseases

Thrombotic thrombocytopenic purpura (TTP) is categorized into acquired (idiopathic) TTP and congenital (familial) TTP. Acquired TTP is mainly idiopathic, but there are other conditions and comorbidities besides idiopathic. Congenital TTP is a rare autosomal recessive disease present in childhood. Acquired and congenital TTP are both part of the larger spectrum of thrombotic microangiopathic diseases. These diseases have microvascular thrombosis and hemolysis with fragmented red blood cells.

TTP and hemolytic uremic syndrome (HUS) were once thought to have shared the pathophysiological etiology. Hemolytic uremic syndrome is usually found in children, and renal involvement is significant. Hemolytic uremic syndrome is caused by Shiga-like toxin-producing E coli O157:H7 in 90% of the cases.4 Hemolytic uremic syndrome is characterized by a triad of hemolytic anemia, thrombocytopenia, and acute renal failure. TTP is usually found in adults and characterized by hemolytic anemia, thrombocytopenia, and, to a lesser extent, neurological manifestations. Symptoms are similar for TTP and HUS based solely on their clinical presentation. Microthrombi in TTP are mainly platelets, but microthrombi in HUS have more fibrin deposition.

Various terms have been used for other thrombotic microangiopathies such as TTP-like diseases, secondary TTP, or nonidiopathic TTP. In addition, TTP may also be drug-induced.5 At times, distinguishing TTP from other thrombotic microangiopathies that have similar overlapping clinical presentations is very difficult. The complexity of categorizing these comorbidities or other conditions has not been resolved. Thrombotic microangiopathies have varying causes and pathology but present with clinical manifestations that are TTP-like. These include drugs such as quinine, ticlopidine, clopidogrel, and cyclosporine; cancers; vasculitis; hematopoietic stem cell transplantation; infections such as human immunodeficiency virus infection; and pregnancy, especially in the third trimester.5 Further investigation is needed to classify this group.6

In 1977, a breakthrough in treatment was reported by Bukowski et al using whole-blood exchange transfusion, also known as plasmapheresis and fresh frozen plasma (FFP). Shortly after, Byrnes and colleagues used plasma infusion. During the plasma exchange, the entire plasma volume is replaced with normal human plasma and the large molecular inhibitory antibodies are removed and the plasma is replenished with the deficient protease. Delay in starting the plasma exchange is correlated with treatment failure. If a delay is unavoidable, begin plasma infusion until the plasma exchange is available. Intravenous (IV) plasma exchange is the present standard of treatment for thrombotic thrombocytopenic purpura. Fresh frozen plasma has become the standard replacement fluid with its plasma protein levels closely paralleling physiological levels.3,7

Plasma infusion and plasma exchange have had a significant impact on the life expectancy of patients. With the introduction of plasma exchange, the survival rate has improved from approximately 3% prior to the 1960s to 82%. By 1991, a landmark clinical trial by Rock et al presented evidence of the efficacy of plasma exchange treatment.8 Early recognition of the clinical features and intervention with plasma exchange can reduce the mortality rate associated with TTP from 90% to approximately 10-20%. Early recognition and management are essential for patient survival. Plasma infusion is a temporary measure, and its use is limited by volume overload. Plasma exchange is the treatment of choice for patients with acquired TTP. Congenital TTP responds to plasma infusion.

Pathophysiology

The TTP syndrome is characterized by microangiopathic hemolysis and platelet aggregation/hyaline thrombi whose formation is unrelated to coagulation system activity. Platelet microthrombi predominate; they form in the microcirculation (ie, arterioles, capillaries) throughout the body causing partial occlusion of vessels. Organ ischemia, thrombocytopenia, and erythrocyte fragmentation (ie, schistocytes) occur. The thrombi partially occlude the vascular lumina with overlying proliferative endothelial cells. The endothelia of the kidneys, brain, heart, pancreas, spleen, and adrenal glands are particularly vulnerable to TTP. The liver, lungs, gastrointestinal tract, gallbladder, skeletal muscles, retina, pituitary gland, ovaries, uterus, and testes are also affected to a lesser extent. No inflammatory changes occur. The occlusion of the microthrombi affects many organs, and a myriad of symptoms are presented.

Mechanism

von Willebrand factor (vWF) was observed in 1982 by Moake and his colleagues. This is a large, adhesive glycoprotein that mediates thrombus formation at sites of vascular injury. vWF is synthesized in the endothelium and megakaryocytes, and it circulates in the plasma. Various sizes of multimers were noted, and the large form, ultralarge von Willebrand factor (ULVWF) multimers were secreted from the endothelium.9 These are the largest soluble protein found in human plasma and are considered the major pathogenic factor in TTP due to the platelet clumping in the microvasculature.

The ULVWF is the most active of the various-sized multimers and is found in platelets, endothelial cells, and subendothelium. They were seen in the plasma of 4 patients with relapsing TTP.10,11 The plasma of normal individuals has much smaller vWF. Moake suggested that there is a deficiency in an enzyme that reduces the large vWF to its normal size in plasma of patients with TTP. This large vWF appeared to have a greater ability to adhere with platelets mediating a thrombus formation. The large vWF combine with platelets consumed from the arterioles and capillaries of organs in a high-shearing stress environment and cause endothelial injury leading to ischemia. The red blood cells collide with the thrombi, and fragment leads to hemorrhage. As a result, the organ function is compromised.

The agitated endothelial cells are the main source of ULVWF multimer secretion into the bloodstream where they bind to specific surface platelet receptors. The ULVWF multimers adhere to the damaged endothelium or exposed subendothelium, with the platelet receptor binding to the ULVWF. The sheer stress of fluid and platelet thrombi in the microcirculation does not enhance proteolysis of ULVWF but rather thrombi formation. How the ULVWF multimers-platelets thrombus is able to adhere and oppose the high velocity blood flow is unclear, and research is ongoing.12

In 1996, the von Willebrand factor-cleaving protease was isolated by two independent laboratories. Furlan, Lammle, and colleagues13 in Switzerland and Tsai14 in New York isolated the von Willebrand factor-cleaving protease known as ADAMTS-13. ADAMTS-13 is a metalloprotease consisting of multiple structural and functional domains and is the major regulator of the size of vWF in plasma. These domains may participate in the recognition and binding of ADAMTS-13 to vWF. The ULVWF multimers are cleaved by ADAMTS-13 as they are secreted from endothelial cells.

Thrombotic thrombocytopenic purpura. Image courte...

Thrombotic thrombocytopenic purpura. Image courtesy of Deepak Sharma.

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Thrombotic thrombocytopenic purpura. Image courte...

Thrombotic thrombocytopenic purpura. Image courtesy of Deepak Sharma.


Acquired TTP is associated with production of anti-ADAMTS13 antibodies inhibiting ADAMTS-13 activity. Congenital (familial) thrombotic thrombocytopenic purpura is associated with mutations of the vWF-cleaving protease ADAMTS-13 gene encoding, and ADAMTS-13 is inactivated or decreased. ADAMTS-13 is severely deficient in patients with both congenital TTP or acquired TTP. Furlan et al found in their investigation, including retrospective analysis of plasma samples, that an autoimmune mechanism may be responsible in patients with acquired deficiency of ADAMTS-13.13  

Plasma exchange has been the first-line therapy for acquired TTP since 1991. Plasma infusion is used for congenital deficiency and can replace the deficiency and mutations in the ADAMTS-13 gene. Congenital TTP is a relapsing condition. For acquired TTP, more than 50% of patients with severe ADAMTS-13 deficiency relapse usually within the year.15 For acquired TTP, the inhibitor of ADAMTS-13 is removed by plasma exchange and is more effective than plasma infusion. Nevertheless, relapsing cases do occur in those with severe ADAMTS-13 deficiency.11 The ULVWF is a marker found in the plasma of patients most likely to have a recurrence of TTP in acquired TTP, and this is also observed in congenital TTP.

ADAMST-13 multimers are abundant and fibrinogen/fibrin is minimal in TTP, whereas fibrinogen is abundant in disseminated intravascular coagulation (DIC). The life span of ADAMTS-13 is 2-4 days, and, if a relapse occurs after plasma exchange, then repeat treatment with plasma exchange is recommended. Certain immunosuppressive drugs and splenectomy are treatments for refractory cases of acquired TTP. Reasons for relapsing after plasma exchange in patients with severe ADAMTS-13 deficiency are unclear. An immune regulation defect may play a role in patients with recurrent ADAMTS-13 deficiency, but investigation is ongoing.

Future development in research

A greater focus on thrombotic thrombocytopenic purpura has emerged in recent years with advances in pathophysiology and diagnostic testing. Understanding the pathophysiology of thrombotic thrombocytopenic purpura is continuous and too early to have clearly defined evidence-based standards applicable to patient management and treatment.

Classification of thrombotic microangiopathies through better methods of assays measuring the ADAMTS-13 activity rather than the present-day cumbersome method of measuring the ADAMTS-13 proteolytic multimers, in addition to ways of detecting autoantibodies, and advances in our understanding of how ADAMTS-13 is regulated are forthcoming.8

Further research into replacement therapy with recombinant ADAMTS-13 instead of plasma16 and reliable standardized assays with rapid results to measure ADAMTS-13 levels of activity will assist in diagnosis, leading to appropriate treatment plans. For example, differentiating TTP from HUS benefits the patient since plasma exchange is the treatment of choice for TTP not HUS, and plasma exchange is not a benign intervention. It is known that TTP has a severe deficiency in ADAMTS-13 not seen in HUS. Clinical trials using immunosuppressive treatments or alternative replacement fluids along with better prognostic measures for treatment are for the future.

vWF plays a role in occlusive arterial thrombosis and the possibility of ADAMTS-13 as a therapeutic instrument to discover ways of treating and managing more common platelet-mediated illnesses such as myocardial infarction and ischemic stroke is a beneficial research challenge.

Frequency

United States

More than 80 years ago, the occurrence rate of this uncommon disorder was 1 case per 1 million patients; however, the incidence rate is increasing, with the incidence rate a decade ago being 4-11 cases per 1 million patients. The incidence today is higher, with greater awareness of this disorder and increasing reports of thrombotic thrombocytopenic purpura (TTP) in patients with comorbidities, conditions, and drug therapy.17  

Incidence today is 6.5 cases per million per year, with a predominance in women. Less than 5% of cases are congenital.

Mortality/Morbidity

The mortality rate associated with thrombotic thrombocytopenic purpura (TTP) approached 100% until the 1980s; the drop in mortality rate since that time is attributed to earlier diagnosis and improvement in therapy with plasma exchange. 

Presently, the mortality rate is approximately 95% for untreated cases. The survival rate is 80-90% with early diagnosis and treatment with plasma infusion and plasma exchange. 

Thirty percent of patients who survive the initial episode experience one or more relapses within 2 years.

Race

No significant racial difference exists.  

Sex

Thrombotic thrombocytopenic purpura is more common in women than in men, with a female-to-male ratio of 2:1 to 3:1.18

Age

Thrombotic thrombocytopenic purpura is most common in adults, although it can occur in neonates to persons as old as 90 years. The peak occurs in the fourth decade of life, with a median age at diagnosis of 35 years.

Clinical

History

  • The pentad of findings associated with thrombotic thrombocytopenic purpura (TTP) is rarely found. Patients with TTP present with nonspecific complaints, and the current clinical factors leading to the diagnosis include the following:
    • Thrombocytopenia with petechial hemorrhages in the lower extremities and a lack of bleeding
    • Schistocytosis
    • Anemia - Hemoglobin levels less than 10 g/dL
    • Serum lactate dehydrogenase (LDH) levels often markedly elevated
    • Absence of other disease entities that could explain the thrombocytopenia and microcytic hemolytic anemia
  • Neurologic changes
    • Altered mental status (36%) - Patients can present with confusion, generalized headaches, altered mental status, focal deficits, seizures, visual disturbances, and coma. Symptoms may wax and wane secondary to the microhemorrhagic and microocclusive vascular changes in the brain. CNS bleeding is an ominous sign.
    • Seizures (16%)
    • Hemiplegia (12%)
    • Paresthesias (4%)
  • Renal changes (88%) with gross hematuria (15%)
  • Fever (60%)
  • Abdominal pain (24%) - May be related to gastrointestinal ischemia or pancreatitis2
  • Cardiac changes
    • Heart failure
    • Arrhythmias
  • Fatigue/generalized malaise
  • Viral, flulike illness
  • Arthralgias

Physical

Physical examination findings may be normal. Typical signs include the following: 

  • Fever  
  • Purpura - Nonpalpable small purpuric spots or petechiae occur with thrombocytopenia (ie, platelet count <50 X 109/L)  
  • Petechial hemorrhages in the lower extremities  
  • Retinal hemorrhages  
  • Jaundice (ie, hemolysis)  
  • Severe hypertension (ie, renal failure)  
  • Neurologic deficits (eg, altered mental status, seizure)
  • Splenomegaly

Causes

  • Pregnancy can trigger congenital and acquired thrombotic thrombocytopenic purpura (TTP), especially second trimester and postpartum after delivery, and accounts for 10-25% of cases of TTP.19
    • TTP usually presents before 24 weeks' gestation and can be distinguished from other thrombotic microangiopathic disorders in that thrombocytopenia occurs without DIC.
    • Central nervous system (CNS) findings occur early and are disproportionate to alterations in blood pressure, renal dysfunction, or hepatic compromise.
    • The course of the syndrome is not altered by termination of pregnancy.
    • Improvement in survival rate is due to aggressive treatment with plasmapheresis or plasma transfusion. 
  • Cancers are associated with TTP, especially adenocarcinoma of the breast, gastrointestinal tract, and prostate cancer.2
    • Anemia and thrombocytopenia occurring with TTP may be out of proportion to that expected from cancer and chemotherapy reactions.
    • LDH level is elevated, and the Coombs test result is negative.
    • In the cancer patient, coagulation factor consumption is often low.
    • Both TTP and DIC can be present in the same patient and may be difficult to distinguish.
    • TTP is associated with various infections.
  • HIV-related TTP
    • Thrombotic microangiopathic disorder is uncommon but occurs in greater frequency in patients with HIV-1 infection; it may be the initial presentation.
    • The usual presentation is thrombocytopenia, MAHA, renal abnormalities, and neurologic dysfunction.
    • Serum LDH level is extremely elevated (ie, >1000 U/L); LDH level also is elevated with Pneumocystis carinii infection, high-grade B-cell lymphoma, and sulfa drug reactions.
  • Autoimmune diseases such as systemic lupus erythematosus and other autoimmune diseases can present as idiopathic TTP with severe ADAMTS-13 deficiency and thrombotic microangiopathy.20
  • Medication-induced TTP
    • Heparin is the most common medication associated with thrombocytopenia (3-7% of patients with IV heparin use).22
    • Ticlopidine and clopidogrel are closely related antiplatelet agents. TTP develops after 1-2 weeks of therapy. The mechanism causing TTP is not clear. ADAMTS-13 is identified in some but not all of the patients. Plasma exchange should be initiated early to reduce mortality from 60% to 14-20%.20,21
    • Quinine2 an ingredient in some "tonic" water and an agent used for "night cramps of the legs" causes thrombocytopenia.22
    • Cancer chemotherapeutic agents associated with TTP include mitomycin C, tamoxifen, bleomycin, cytosine arabinoside, and daunomycin.
    • Noncancer chemotherapeutic and other drugs related to TTP include immunosuppressive agents (eg, cyclosporine A), crack cocaine, oral contraceptives, penicillin, and rifampin.
  • Toxins (eg, bee venoms23 ) are associated with TTP.
  • Autoimmune disorders
  • Infectious process and sepsis
  • Splenic sequestration
  • Transplant-associated TTP
  • Vasculitis
  • Vascular surgery postoperative 5-9 days2
  • Infections -Streptococcus pneumonia, cytomegalovirus2

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Follow-up: Thrombotic Thrombocytopenic Purpura
Multimedia: Thrombotic Thrombocytopenic Purpura
References
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Further Reading

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Keywords

thrombocytopenic purpura, Moschcowitz disease, thrombotic thrombocytopenic purpura, TTP, multisystem disorder, plasma exchange, fresh-frozen plasma, FFP, microangiopathic hemolytic anemia, hemolytic uremic syndrome, HUS, familial thrombotic thrombocytopenic purpura, familial TTP, acquired idiopathic thrombotic thrombocytopenic purpura, acquired idiopathic TTP, von Willebrand factor multimers, vWF, vWF multimers, vWF-cleaving protease, anemia, petechiae, microscopic hematuria, disseminated microvascular thrombi, thrombocytopenia, renal dysfunction, Escherichia coli, E coli O157:H7, Shigalike toxin, microangiopathic hemolysis, platelet microthrombi, ultralarge von Willebrand factor multimers, ULVWF multimers, ADAMTS-13 gene mutations, ULVWF multimer–induced platelet thrombosis, ULVWF-cleaving protease, petechial hemorrhages, seizures, CNS bleeding, heart failure, arrhythmias, gross hematuria, purpuric spots, plasmapheresis, plasma transfusion, thrombotic microangiopathic

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Contributor Information and Disclosures

Author

Deborrah Symonette, MD, MPH, Healthcare Consultant, DSKSD, Inc
Deborrah Symonette, MD, MPH is a member of the following medical societies: American College of Emergency Physicians
Disclosure: Nothing to disclose.

Coauthor(s)

Deepak Sharma, Touro College of Osteopathic Medicine, New York
Disclosure: Nothing to disclose.

Priya S Abraham, Touro College of Osteopathic Medicine, New York
Priya S Abraham is a member of the following medical societies: Student Osteopathic Medical Association (SOMA)
Disclosure: Nothing to disclose.

Vanessa Yoo, Touro College of Osteopathic Medicine, New York
Disclosure: Nothing to disclose.

Wafa Qamar, Touro College of Osteopathic Medicine, New York
Wafa Qamar is a member of the following medical societies: Microscopy Society of America
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Medical Editor

Miguel C Fernández, MD, FAAEM, FACEP, FACMT, FACCT, Associate Clinical Professor; Medical and Managing Director, South Texas Poison Center, Department of Surgery/Emergency Medicine and Toxicology, University of Texas Health Science Center at San Antonio
Miguel C Fernández, MD, FAAEM, FACEP, FACMT, FACCT is a member of the following medical societies: American Academy of Emergency Medicine, American College of Clinical Toxicologists, American College of Emergency Physicians, American College of Medical Toxicology, American College of Occupational and Environmental Medicine, Society for Academic Emergency Medicine, and Texas Medical Association
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Jeffrey L Arnold, MD, FACEP, Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center
Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physicians
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CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
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Chief Editor

Barry E Brenner, MD, PhD, FACEP, Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, University Hospitals, Case Medical Center
Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas Medical Society, New York Academy of Medicine, New York Academy of Sciences, and Society for Academic Emergency Medicine
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