eMedicine Specialties > Emergency Medicine > Hematology & Oncology

Thrombocytopenic Purpura

Author: Deborrah Symonette, MD, MPH, Healthcare Consultant, DSKSD, Inc
Contributor Information and Disclosures

Updated: Jul 28, 2008

Introduction

Background

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening multisystem disorder that is considered a true medical 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 thrombi were prevalent. These thrombi remain the hallmark of the pathologic diagnosis. Since that time, advances in the pathophysiology, etiology, and medical management of TTP have been noteworthy.
 
 
This life-threatening condition may have a positive outcome if recognized early and medical intervention is initiated early. Thrombocytopenic purpura is a syndrome with diagnostic criteria developed 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. 

In 1977, a breakthrough in effective cure was reported. Bukowski et al used whole-blood exchange transfusion and fresh frozen plasma (FFP). Later, Byrnes and colleagues used plasma infusion. 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 treatment1 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%. 

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.

Mechanism

Von Willebrand factor (VWF) is an adhesive protein that mediates thrombus formation at sites of vascular injury. It is the largest soluble protein found in human plasma and considered the major pathogenic factor in TTP. It is synthesized in the endothelial cells and megakaryocytes. It is present in platelets, endothelial cells, and subendothelium. 
 
In 1982, Moake and his colleagues observed ultralarge von Willebrand factor (ULVWF) multimers in the plasma of 4 patients with relapsing TTP2,3 These multimers were the same size as those noted in the endothelial cells. The plasma of normal individuals has much smaller VWF. Moake suggested that there was a deficiency in an enzyme that reduces the large VWF to its normal size in plasma in patients with TTP. Also noted was that this large VWF has a greater ability to adhere with platelets mediating a thrombus formation. 

The agitated endothelial cells are the main source of ULVWF multimers in the bloodstream where they bind to specific surface platelet receptors. The ULVWF multimers entangled with platelets adhering to the subendothelium. The pathogenesis of TTP is due to the platelet clumping in the microvasculature. There is an increased adherence of the ULVWF and lack of a functioning proteolytic enzyme to normalize this multimer. The sheer stress of fluid and platelet thrombi in the microcirculation does not enhance proteolysis of ULVWF. How the adhesive bond opposes shear stress in the microangiopathic causing platelet initiating thrombus formation and contribute to platelet activity is yet to be solved.
 
The von Willebrand factor-cleaving protease was isolated by two independent laboratories in 1996. Furlan, Lammle, and colleagues⁴ in Switzerland and Tsai⁵ 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.
           
They were able to document that ADAMTS-13 was severely deficient in patients with congenital TTP or acquired TTP. Congenital ADAMTS-13 deficiency is caused by mutations of the ADAMTS 13 gene. Patients with the familial form have severe protease deficiency. ADAMTS-13 gene mutation in familial TTP causes inactivity or decreased activity of ADAMTS-13. Acquired deficiency occurs with the  production of autoantibodies inhibiting ADAMTS-13 activity. 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-13.⁴ Acquired TTP is idiopathic secondary complications of autoimmune disease, malignancy, stem cell transplantation, pregnancy (especially the third trimester), certain drugs (including ticlopidine, mitomycin, clopidogrel, and cyclosporine) or infection.
           
Plasma exchange has been the first-line therapy for TTP since 1991. Congenital deficiency can replace the deficiency and mutations in the ADAMTS-13 gene by plasma infusion. Acquired deficiency can remove the inhibitor of ADAMTS-13 by plasmapheresis. However, plasma exchange is more effective treatment than plasma infusion.
 
There are thrombotic microangiopathies that have similar clinical presentations. TTP and hemolytic uremic syndrome (HUS) were once thought to have shared the pathophysiological etiology. HUS is caused by Shiga-like toxin-producing E coli O157:H7. HUS is characterized by prominent renal involvement. TTP is associated with pregnancy, infections, cancer, drugs, transplants, and vasculitis. Symptoms are similar for TTP and HUS based solely on their clinical presentation. It is now known that TTP but not HUS has a severe deficiency in ADAMTS-13. A diagnosis is now possible distinguishing TTP from HUS.

Classification of thrombotic microangiopathies in the future will have a simplistic method of measuring the ADAMTS-13 activity rather than the present day cumbersome method of measuring. Differentiating TTP from HUS benefits the patient since plasma exchange is not a benign intervention. This differentiation also saves costs and time.
 
ADAMS-13 multimers are abundant and fibrinogen/fibrin is minimal in TTP, whereas fibrinogen is abundant in disseminated intravascular coagulation (DIC). The ULVWF, that is, ADAMS-13 multimer, is a marker found in the plasma of patients most likely to have a recurrence of TTP.

It appears that VWF plays a role in occlusive arterial thrombosis. Development of a simpler method of measuring the ADAMTS-13 proteolytic multimers, detecting autoantibodies and advancing in our understanding of how ADAMTS-13 is regulated are forthcoming. ADAMTS-13 may be a therapeutic instrument in the management of thrombotic thrombocytopenic purpura and of more common illnesses such as myocardial infarction and ischemic stroke.

Frequency

United States

More than 75 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 3.7 cases per 1 million patients. The incidence today is higher, with greater awareness of this disorder and increasing reports of TTP secondary to other illnesses and drugs.

Mortality/Morbidity

The mortality rate associated with 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.
• One third of patients who survive the initial episode experience a relapse within the following 10 years.

Race

No significant racial difference exists.

Sex

This condition is more common in women than in men, with a female-to-male ratio of 3:2.

Age

TTP 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 TTP is rarely found, and the current clinical factors leading to the diagnosis include the following:

1. Thrombocytopenia
2. Schistocytosis
3. Elevated serum lactate dehydrogenase (LDH) levels (often markedly elevated)
4. Absence of other disease entities that could explain the thrombocytopenia and microcytic hemolytic anemia

Patients with thrombotic thrombocytopenic purpura (TTP) present with nonspecific complaints.

• Prodrome resembling a viral, flulike illness
  • Fever (60%)
  • Fatigue/generalized malaise
  • Arthralgias
• Hematologic changes
  • Thrombocytopenia, with petechial hemorrhages in the lower extremities and a lack of bleeding
  • Anemia - Hemoglobin levels less than 10 g/dL
• 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%)
• Cardiac changes
  • Heart failure
  • Arrhythmias
• Abdominal pain (24%) - May be related to gastrointestinal ischemia
• A patient can present with some or all of the characteristics of the classic pentad, which includes the following:
  • Thrombocytopenia
  • Fever
  • Renal changes (88%) with gross hematuria (15%)
  • Neurologic deficit
  • Hematologic changes
• Microangiopathic hemolytic anemia (MAHA)

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)
  • Jaundice (ie, hemolysis)
  • Severe hypertension (ie, renal failure)
  • Neurologic deficits (eg, altered mental status, seizure)
  • Splenomegaly

Causes

• Pregnancy and the postpartum state account for 10-25% of cases of TTP.
  • 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.
• Thrombotic microangiopathic disorder is uncommon but occurs in greater frequency in patients with HIV-1 infection; it may be the initial presenting syndrome.
  • 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.
  • Management consists of plasma exchange, antiplatelet agents (eg, dipyridamole, sulfinpyrazone, aspirin, dextran), and splenectomy for refractory cases. Survival rate and prognosis are poor.
• TTP often is associated with cancer.
  • Anemia and thrombocytopenia occurring with TTP may be out of proportion to that expected from cancer and chemotherapy reactions.
  • LDH level is elevated, and 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.
  • Cancer chemotherapeutic agents associated with TTP include mitomycin C, tamoxifen, bleomycin, cytosine arabinoside, and daunomycin.
• Noncancer chemotherapeutic and other drugs suspected of causing TTP include immunosuppressive agents (eg, cyclosporine A), crack cocaine, ticlopidine, oral contraceptives, penicillin, and rifampin.
• Toxins associated with TTP include the following:
  • Escherichia coli
    • E coli O157:H7 is a toxin-producing bacteria.
    • E coli toxin is found in undercooked foods.
    • E coli toxin is associated with diarrhea and outbreaks of HUS in children and to a lesser degree associated with TTP.
    • E coli toxin is concentrated in the renal and brain endothelium.
  • Spider and bee venoms

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