INTRODUCTION	Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

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 noted that his 16 year-old patient had anemia; petechiae; microscopic hematuria; and at autopsy, disseminated microvascular thrombi. Since that time, the pathophysiology, etiology, and medical management of TTP have expanded. This life-threatening condition may have positive outcomes if recognized early and if medical intervention is initiated early.

Thrombocytopenic purpura is a syndrome characterized by microangiopathic hemolytic anemia, thrombocytopenia, neurologic abnormalities, fever, and renal dysfunction. With the introduction of plasma exchange, the survival rate has improved from approximately 3% prior to the 1960s to 82%. Early plasma exchange initiation has beneficial outcomes. With early recognition of the clinical features, this life-threatening illness can be treated, with effective patient clinical responses in many cases.

Thrombotic microangiopathies TTP and hemolytic uremic syndrome (HUS) were once thought to have shared the same pathophysiological etiology; however, more recent findings suggest that TTP is a different entity than HUS. They are closely related disorders and are characterized by microvascular lesions with platelet aggregation. HUS is more common in children and is caused by strains of enterohemorrhagic Escherichia coli, especially E coli O157:H7 carrying the Shigalike toxin. HUS is characterized by prominent renal involvement. TTP is associated with pregnancy; diseases such as HIV, cancer, bacterial infection, and vasculitis; bone marrow transplantation; stem cell transplantation; and drugs.

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

In most cases of familial TTP and acquired idiopathic TTP, the endothelial cells secrete and release the ultralarge (UL) von Willebrand factor (ULVWF) multimers. The sheer stress of fluid and platelet thrombi in the microcirculation should enhance proteolysis of ULVWF. The agitated endothelial cells are the main source of ULVWF multimers in the bloodstream where they bind to specific surface platelet receptors. In 1982, Moake et al showed that the ULVWF multimers were unusually large in patients with chronic relapsing TTP. ULVWF multimers entangle with platelets adhering to the subendothelium. Two independent research groups reported a lack of ULVWF-cleaving protease activity in the blood of patients with TTP. The lack of ULVWF-cleaving protease activity was suggested to be due to the presence of antibodies or a severe deficiency of ULVWF-cleaving protease.

The ULVWF multimers are cleaved by ADAMTS-13 as they are secreted from endothelial cells. Failure to degrade the ULVWF multimers is believed to cause the familial and acquired idiopathic types of TTP. The ULVWF-cleaving protease, ADAMTS-13, is inhibited by the production of autoantibodies in acquired idiopathic TTP and ADAMTS-13 gene mutations in familial TTP causing inactivity or decreased activity of ADAMTS-13. 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 the ULVWF-cleaving protease, whereas patients with the familial form have complete protease deficiency. In TTP, insufficiency of ADAMTS-13 may be the key component in the pathogenesis of ULVWF multimer–induced platelet thrombosis.

TTP differs from HUS by having a deficiency in ULVWF-cleaving protease ADAMTS-13 activity not found in HUS, and HUS has sufficient uninhibited protease. The intervention of plasma exchange is ineffective because its role is to remove antibodies and replace VWF-cleaving protease. Differentiating TTP from HUS benefits the patient because plasma exchange is not a benign intervention. This differentiation also saves costs and time. Research is ongoing, but, presently, TTP is suggested to be a different entity than HUS.

ULVWF multimers are abundant and fibrinogen/fibrin is minimal in TTP, whereas fibrinogen/fibrin is abundant in disseminated intravascular coagulation (DIC). The ULVWF multimer is a marker found in the plasma of patients most likely to have a recurrence of TTP.

Other interactions, both transcellular and intercellular, are suggested in TTP, including various combinations of platelets, leukocytes, erythrocytes, and endothelium. These interactions may be the key stimuli in the initiation of cell activity and morphological changes that occur in TTP.

Frequency:

• In the US: 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	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

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

• Prodrome resembling a viral, flu-like 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 lactate dehydrogenase (LDH) is extremely elevated (ie, >1000 U/L); LDH 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 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