Thrombocytopenic purpura in details for doctor

Thrombocytopenic Purpura



Deborrah Symonette, MD, MPH, Healthcare Consultant, DSKSD, Inc

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 treatment.¹ 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 TTP.^{2, 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.
Future development in research

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.

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:

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

Disseminated Intravascular Coagulation
Hemolytic Uremic Syndrome
Idiopathic Thrombocytopenic Purpura
Pregnancy, Eclampsia
Stroke, Hemorrhagic
Stroke, Ischemic


Other Problems to Be Considered

Autoimmune disorders
Cancer-associated TTP
Drug-induced TTP
HIV-related TTP
Infectious process and sepsis
Splenic sequestration
Transplant-associated TTP
Vasculitis

Workup


Laboratory Studies


Thrombotic thrombocytopenic purpura (TTP) is a clinical diagnosis with no pathognomonic laboratory test findings. In the past, a pentad of signs and symptoms was associated with TTP: thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, renal failure, and fever.
Currentclinical practice diagnostic criteria include thrombocytopenia, schistocytosis, and significant elevations in serum LDH levels to suggest the diagnosis of TTP. Measuring protease activity as a single test to distinguish TTP from HUS is not practical at this time. The absence of in vitro tests capable of detecting abnormalities in all the molecular interactions required for the cleavage of ULVWF multimers by ADAMTS-13 in vivo is a limitation.
Laboratory tests helpful in making the diagnosis include the following:

The classic pentad is rarely complete at presentation. Current clinical criteria for initiating therapy are as follows:

Early recognition and management are essential for patient survival.

Understanding the pathophysiology of thrombotic thrombocytopenic purpura (TTP) is ongoing and too early to have clearly defined evidence-based standard procedures that may be applicable for all patients. Intravenous (IV) plasma exchange, also called plasmapheresis, is the present standard of treatment for TTP. During the plasma exchange, the 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.

The goal of therapy is to reduce destruction of platelets.

Glucocorticoids


These agents have immunosuppressant activity.



Prednisone (Deltasone)


Glucocorticoids inhibit phagocytosis of antibody-covered platelets. Treatment of hemolytic anemia during pregnancy is conservative unless disease is severe (use lowest dose of glucocorticoids). In neonates, if platelet count drops below 50-75 X 10⁹/L, consider prednisone and exchange transfusions of immune globulin.

Dosing


Adult


0.05-2 mg/kg/d PO divided bid/qid; taper over 1-2 wk as symptoms resolve

Pediatric


4-5 mg/m²/d PO; alternatively, 1-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve

Interactions


Estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications


Documented hypersensitivity; viral, fungal, connective tissue, or tubercular skin infections; peptic ulcer disease; hepatic dysfunction; GI disease

Precautions


Pregnancy


B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions


Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur

Follow-up


Further Inpatient Care

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Eric J Hoffman, DO, and of previous editor, Charles V Pollack, Jr, MD, to the development and writing of this article.

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