Thrombotic Thrombocytopenic Purpura and Related Thrombotic Microangiopathies

Introduction

Thrombotic thrombocytopenic purpura (TTP) is one of the most devastating thrombotic disorders of humans and carries a mortality rate of about 90% if untreated. Even with current state-of-the art therapy, mortality has not improved significantly over the past 3 decades, remaining at about 20% per episode. Recent breakthroughs in understanding the mechanisms of this remarkable and heterogeneous disorder lend confidence that we will be able to further reduce this stubborn and persistent mortality rate, both through treatment of the acute disease and the reduction in relapses. New insights are very likely to shed light into many other diseases that share elements of TTP pathophysiology, diseases that span the gamut from acute systemic infections, sickle cell disease, and malaria, to thrombotic diseases of the large arteries, including myocardial infarction (MI), stroke and atherosclerosis.

TTP is a rare disorder, although its incidence appears to have increased dramatically in the past 3 decades, partially because of enhanced awareness of the disease, reduced stringency in the criteria for diagnosis, and a real increase, which is coincident with the emergence of new infectious diseases such as acquired immunodeficiency syndrome (AIDS) and new drugs.

Historical Review

The first known description of TTP was by Eli Moschcowitz, a Hungarian-born American physician who, in 1924, published in the Proceedings of the New York Pathological Society the course of the disease in a 16-year-old girl he treated for the disorder at Beth Israel Hospital in New York City the preceding year. The girl had a rapidly deteriorating clinical course, highlighted by petechiae, thrombocytopenia, hemiparesis, pulmonary edema, and finally death. On postmortem examination, Moschcowitz found terminal arterioles and capillaries occluded by hyaline thrombi, without perivascular inflammation or endothelial desquamation. The thrombi were later determined to be composed primarily of platelets. Moschcowitz posited that a “powerful poison which had both agglutinative and hemolytic properties” was the cause of this frightening new disease, now known as thrombotic thrombocytopenic purpura and sometimes called Moschcowitz disease in honor of its discoverer.

Without any specific therapies, TTP was almost uniformly fatal. In retrospect, many therapies used were reasonable, given what we now know about the autoimmune etiology of the most common acquired form. Such therapies included corticosteroids, immune suppressants, and often splenectomy. Successful treatment of TTP with high-dose corticosteroids was first reported in 1959. The same year saw another breakthrough with a report of remission induced with transfusion of fresh whole blood. In 1977, it became apparent that the beneficial component in the blood was plasma, when Byrnes and Khurana reported that relapses in chronic TTP could be prevented or reversed by infusion of only a few units of fresh frozen plasma (FFP) or its cryoprecipitate-poor fraction (cryosupernatant). Later it was proposed that plasma exchange was superior to simple plasma infusion, and this was demonstrated in a randomized clinical trial. In 1979, Lian and coworkers proposed that TTP plasma contained a platelet-aggregating substance that could aggregate normal platelets and was not dialyzable. These investigators also showed that the ability of this substance to aggregate platelets was diminished as a function of time when the TTP plasma was incubated with normal plasma. In 1982, Moake and colleagues provided considerable insight into the pathogenesis of the disorder when they demonstrated that patients with the chronic relapsing form of the disease contained “unusually large” von Willebrand factor (VWF) multimers in their plasma during disease remission. These unusually large multimers (now also called ultra-large (UL)VWF) were much larger than those present in normal plasma and of a size comparable to those found in endothelial cell supernatants. These investigators proposed that ULVWF was the agglutinative substance in TTP plasma and also posited (presciently) that TTP was caused by deficiency in a plasma “VWF depolymerase.” Both of these proposals have now been shown to be correct.

In the late 1990s, Furlan and associates and Tsai and Lian reported that the “VWF processing activity” postulated by Moake et al. is a VWF-cleaving metalloprotease absent in patients with familial TTP, which is transiently inhibited in many patients with acquired idiopathic TTP. Finally in 2001, three groups identified this metalloprotease, two by traditional biochemical approaches and one by the relatively new genetic technique of positional cloning in the study of a family with genetic deficiency of the metalloprotease. This protease was thus identified as the 13th member of the ADAMTS ( a d isintegrin a nd m etalloproteinase with t hrombo s pondin-1 repeats) family, which is unique from the other members in that it contains two CUB domains (see later for more details). Hence this important VWF-specific enzyme is referred to as ADAMTS13 . In the decade since this discovery, a considerable amount has been learned about how ULVWF promotes microvascular thrombosis, the functions of the metalloprotease, and the exciting new potential therapies that will be discussed later.

Clinical Manifestations

Initially TTP was defined by a clinical pentad of laboratory and physical signs: thrombocytopenia, microangiopathic hemolytic anemia, neurologic signs, renal signs, and fever. More recently, these criteria have been narrowed to thrombocytopenia and microangiopathic hemolytic anemia in the absence of any other obvious cause for these findings, in part because these were the criteria used to define the disorder in the randomized clinical trial that established the superiority of plasma exchange over plasma infusion. The thrombocytopenia can be severe, especially in those with a drastic reduction (<10%) in ADAMTS13 activity. Schistocytes (mechanically fragmented erythrocytes) are seen on examination of the blood smear, which also typically shows increased reticulocytes and often nucleated red blood cells (RBCs) as the marrow responds to intense hemolysis. Neurologic signs and symptoms are common at presentation and range in severity from headaches, confusion, and transient bizarre mentation to sensorimotor deficits, aphasia, seizures, and coma. The heart and spleen are also frequently affected. Heart involvement may be asymptomatic or heralded by symptoms such as chest pain, syncope, dyspnea, or palpitations. In one retrospective study of 41 patients, chest pain typical of MI or angina pectoris was only present in three patients; others described the pain as burning, sharp, or pleuritic. Of the 41 patients, 27 had elevated plasma troponin T levels; those with the higher levels tended to have overt cardiac symptoms. Of the 22 patients with troponin T levels above 0.05 µg/L, 13 showed electrocardiographic (ECG) abnormalities that ranged from nonspecific T-wave changes, rhythm abnormalities, and bundle branch block to overt signs of infarction (Q waves). Rhythm abnormalities could result in sudden death and could be caused by infarction of the myocardium or microvascular occlusions producing ischemia of the sinoatrial or atrioventricular node or the bundle of His or the Purkinje conduction system. Abdominal pain is sometimes present and may be due to ischemic pancreatitis or colitis. Alternatively, pancreatitis has been reported to precipitate episodes of TTP. Approximately 5% to 10% of TTP episodes begin with abdominal symptoms. Fever and/or renal dysfunction occur in a minority of patients. Renal abnormalities may include proteinuria and hematuria, as well as azotemia. Early, evolving, and overt manifestations of an acute acquired idiopathic TTP episode and the therapeutic actions triggered are summarized in Table 24.1 . A patient may appear in the emergency department or the physician's office at any stage of the disorder.

Laboratory Findings

The degree of thrombocytopenia in TTP reflects the extent of intravascular platelet clumping and consumption. Platelet counts are often less than 20,000/µL during acute episodes of TTP. Erythrocytes fragment as they attempt to navigate the small blood vessels through webs of ULVWF with adherent platelets and as they experience the markedly elevated shear stresses that accompany luminal narrowing of the microvessels. This process produces the characteristic schistocytes seen on blood films ( Fig. 24.1 ). Occasionally, schistocytes do not appear until one or several days after the initial clinical presentation. Hemolysis is predominantly intravascular and, along with tissue damage, contributes to the often markedly elevated serum levels of lactate dehydrogenase (LDH).

Coagulation studies are characteristically normal during the early stages of a TTP episode. In the setting of extensive tissue necrosis, however (as during an especially severe or protracted episode of TTP), secondary disseminated intravascular coagulation (DIC) may occur as a result of activation of the coagulation pathway initiated by the binding of factor VIIa to exposed tissue factor (TF) on the necrotic tissue. Secondary DIC can be detected by the appearance of elevated levels of D-dimers or fibrin degradation products (FDPs) in the blood, the prolongation of prothrombin time (PT) or partial thromboplastin time (PTT), and the decreased fibrinogen levels.

Types of Thrombotic Thrombocytopenic Purpura

TTP can be classified as either congenital, in which the affected individual contains mutations to the two alleles of the ADAMTS13 gene that prevent expression or proper function of the protein product; or acquired, almost always the result of inhibition or clearance of the enzyme by autoantibodies. The acquired disorder is more common and, as with most autoimmune disorders, occurs more often in women than in men. It can be precipitated by a number of conditions including infections (especially viral; e.g., human immunodeficiency virus [HIV-1]), drugs, pregnancy, cancer, and bone marrow transplantation. Nevertheless, one study found that over three-fourths of cases had no obvious precipitating cause. About two-thirds of successfully treated adult patients with acquired idiopathic TTP never experience recurrence. Those with several recurrences experience them at irregular intervals, often commencing within the first year after the initial episode. Recurrence is more common in those who present with ADAMTS13 levels below 5% and high-titer inhibitory antibodies.

Congenital TTP may manifest in infancy or childhood or may be undetected for decades. Pregnancy is often a precipitating factor. In some patients, episodes occur at regular (3- to 4-week) intervals correlating with the disappearance of ADAMTS13 from the plasma after a prior treatment.

Drugs can also cause a syndrome clinically indistinguishable from idiopathic TTP. In some cases, use of the drugs is associated with production of inhibitory ADAMTS13 antibodies; in others, ADAMTS13 activity is normal. Quinine is most often associated with a syndrome with features of both TTP and hemolytic uremic syndrome (HUS). Although initially assumed to be caused by drug-dependent antibodies because they were found in patient plasma, ADAMTS13 activity levels are not usually found to be depressed, although the fact that most assays involve small peptide substrates may miss instances in which cleavage of multimeric VWF is inhibited. The structurally similar platelet function inhibitors ticlopidine and clopidogrel have both been implicated in the development of TTP. These two drugs, which differ from each other by a single carboxymethyl group, inhibit the platelet adenosine diphosphate (ADP) receptor P2Y12 and are used to prevent arterial thrombosis.

Mitomycin C, cyclosporine, tacrolimus, chemotherapeutic agents in combination, gemcitabine, and total body irradiation have been associated with subsequent development of thrombotic microangiopathy (TMA). This syndrome often resembles HUS more closely than TTP and usually develops weeks to months after exposure to the drug. Patients who have been treated for various illnesses with bone marrow/stem cell transplantation make up a relatively large subgroup. TMA has also been reported after solid organ transplantation (i.e., kidney, liver, heart, lung).