Which assessment findings indicate that a patient may be experiencing TTP?

Etiology/Pathogenesis

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ADAMTS13 is severely deficient in TTP

Primary event in HUS is microthrombi formation and complement alternative pathway activation

Tissue factor or bacterial toxin activation of coagulation cascade is primary event in DIC

Pathogenesis of TA-TMA is most likely due to injury to endothelial cells

Clinical Issues

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RBC fragmentation is common finding in all MAHA

Daily plasmapheresis (plasma exchange) is standard treatment for TTP

Supportive care is mainstay treatment in HUS and TA-TMA

Eculizumab is standard of care in aHUS

Eculizumab has shown benefit in HUS, TTP, and TA-TMA

Treating primary cause is paramount in DIC

Diagnostic Checklist

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Combination of schistocytosis and thrombocytopenia raises possibility of MAHA

MAHA is diagnosis of clinicopathologic correlation

Definitions

Thrombotic microangiopathy (TMA) is a lesion of arteriolar and capillary vessel wall thickening with intraluminal platelet thrombosis and a partial or complete obstruction of the vessel lumina. Laboratory features of thrombocytopenia and microangiopathic hemolytic anemia are almost invariably present. Depending on whether renal or brain lesions prevail, two pathologically indistinguishable but somehow clinically different entities have been described: hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Because HUS can involve extrarenal manifestations and TTP may be associated with severe renal disease, the two can be difficult to distinguish on clinical grounds.1 In comparison to HUS, TTP is associated with more severe thrombocytopenia and less severe acute kidney injury (AKI),2 but changes in platelet count and kidney function largely overlap in HUS and TTP and there are no cut-off values that discriminate the two syndromes. However, newly identified pathophysiologic mechanisms have allowed for the differentiation of the two syndromes on a pathogenetic basis and have paved the way to specific diagnosis and treatment (Table 29.1 andFig. 29.1).

The term HUS was introduced in 1955 by Gasser and coworkers in their description of an acute fatal syndrome in children characterized by hemolytic anemia, thrombocytopenia, and severe AKI. HUS occurs most frequently in children under the age of 5 years (incidence 5 to 6 per 100,000 children per year compared with an overall incidence of 0.5 to 1 per 100,000 per year). Over 90% of cases are associated with infection by Shiga-like toxin (Stx) producingEscherichia coli (STEC). STEC-HUS occurs primarily in children, except in epidemics, when it may occur in patients with a wider range of ages. For example, from May 2011 until July 2011, several European Countries, particularly Northern Germany, experienced one of the largest STEC-HUS outbreaks ever reported with 3816 patients suffering fromE. coli O104:H4 infection, with 845 cases. Almost 90% of affected patients were adults and, compared with previous STEC epidemics, there was a higher prevalence of affected women.3Streptococcus pneumoniae causes a distinctive form of HUS accounting for 40% of childhood cases not associated with Stx-producing bacteria.4 Approximately 10% of HUS cases are classified as atypical, caused neither by Stx-producing bacteria (STEC orShigella dysenteriae) nor byStreptococcus.5 Atypical HUS is less common than STEC-HUS, with an annual incidence of 0.5 to 2 per million per year. It can occur at any age and is a very severe disease. Before the introduction of complement inhibition therapy, 50% of patients with atypical HUS progressed to end-stage renal disease (ESRD) and 25% died in the acute phase.4,5 Neurologic symptoms and fever can occur in 30% of patients. Pulmonary, cardiac, and gastrointestinal (GI) manifestations also can occur.

Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are thrombotic microangiopathies that are characterized by thrombocytopenia, hemolytic anemia, and multisystem organ failure. They are rare entities, but they may occur during pregnancy, are life threatening, and can be difficult to distinguish from HELLP syndrome (hemolysis,elevatedliver enzymes, andlowplatelets) (Table 53.3). The estimated incidence is 1 case per 25,000 births.288 Early diagnosis and treatment are critical because the mortality rate may be reduced by 90%.289

TTP is characterized by central nervous system (CNS) abnormalities, severe thrombocytopenia, and intravascular hemolytic anemia. The most common CNS abnormalities are headache, altered consciousness, seizures, and sensorimotor deficits. Renal dysfunction and fever also may occur. Individuals with HUS have renal involvement as the major finding, as well as thrombocytopenia and hemolytic anemia. The conditions are difficult to distinguish from each other. Up to 50% of patients with HUS have CNS abnormalities, and renal dysfunction may occur in up to 80% of those with TTP. For this reason, the two disorders are often considered as a single entity.290,291 Some experts advise that TTP be used to refer to adults with the condition, with or without neurologic or renal abnormalities, and that HUS should refer to children with renal failure, typically afterEscherichia coli infection.292 Recent consensus definitions and terminology have been published by an International Working Group that also distinguishes between the two conditions.293

The pathophysiology of TTP and HUS is abnormal, and profound intravascular platelet aggregation leads to multiorgan ischemia. In HUS this occurs predominantly in the kidney; the inciting event in TTP is uncertain. One possibility is an abnormal immune response, because the condition is associated with several autoimmune disorders. It is more common among women and non-Hispanic blacks, consistent with many other autoimmune conditions.294 Other possibilities are medications such as chemotherapy agents, viral infections, and perhaps pregnancy itself, although many individuals have no risk factors. Larger than average vWF multimers appear to contribute to the pathophysiology, promoting abnormal platelet aggregation.295 ADAMTS13, a plasma enzyme, cleaves these vWF multimers, preventing the formation of platelet clumps. ADAMTS13 activity may be absent in patients with TTP, making this a risk factor for the condition.296 ADAMTS13 deficiency may be congenital,297 or it may be acquired through the development of autoantibodies.298 HUS is most often seen in children after a diarrheal illness caused byE. coli. Hemolysin, often from verotoxin-producing strains ofE. coli, attaches to receptors in renal epithelium, leading to endothelial injury, platelet activation or aggregation, and ischemia.299,300 In adults, HUS is often precipitated by pregnancy, chemotherapy, or bone marrow transplantation. The recurrence risk is higher for adults and patients who do not have infectious diarrhea as an inciting event.

Abstract

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy that leads to microangiopathic hemolytic anemia and thrombocytopenia. Acquired TTP results from autoantibodies binding to ADAMTS13, an enzyme that cleaves high-molecular-weight von Willebrand factor (VWF) multimers. The accumulated high-molecular-weight VWF multimers bind platelets leading to thrombocytopenia and microvascular occlusion, causing red blood cell shearing and destruction. Acquired TTP affects 4 per 106 person years and is most common in middle-aged women of African descent. Prompt treatment with therapeutic plasma exchange (TPE) is essential, reducing mortality from 90% to <20%. Daily TPE is continued until platelet recovery. Typically corticosteroids are used in conjunction with TPE in patients with acquired TTP. Other options for immune modulation include rituximab and other immunosuppressive agents; however, currently these are reserved for patients with refractory or relapsed disease. TTP may also be congenital as a result of ADAMTS13 deficiency and respond best to regular plasma infusions.

Introduction

Thrombotic thrombocytopenic purpura (TTP) is the most extensive and dangerous intravascular platelet clumping disorder. For about 55 years after the disease was first recognized, almost everyone with TTP died quickly. Physicians were fascinated by the dramatic clinical presentations and were horrified by the near 100% mortality rate. Many hematologists, even those with limited experience in trying to manage this rarely encountered patient, believed intuitively that an understanding of the mechanism of systemic intravascular platelet aggregation in TTP would provide important insights into the pathophysiology of common, localized forms of arterial platelet thrombosis (e.g., heart attack, stroke).

Until the 1970s and 1980s, most physicians had never seen a case of TTP. Hematologists, even after years in practice, could recall one or two patients, at most, who had been given this diagnosis. Then, for unknown reasons, the disease increased in prevalence. Probably about 2000 new cases of acute acquired idiopathic TTP now occur annually in North America. At the Texas Medical Center in Houston, about 30 to 50 patients newly diagnosed with TTP are admitted each year (compared with 0 to 2 per year in the 1970s). This is likely to represent a true increase in acute acquired idiopathic TTP, and not simply improvement in recognition of a disorder with long‐established clinical and laboratory characteristics. Furthermore, several drugs in common use during the 1990s (e.g., ticlopidine) were found to induce, in a fraction of the many exposed patients, a type of TTP that is clinically indistinguishable from the acute acquired idiopathic type. Therefore, the remark several years ago in reference to paroxysmal nocturnal hemoglobinuria made by Dr. Wendell Rosse of the Duke University Medical Center that “more people study the disease than have it” no longer applies to TTP.

Publisher Summary

This chapter discusses thrombotic thrombocytopenic purpura (TTP), a thrombotic microangiopathy (TMA), a syndrome consisting of microangiopathic hemolytic anemia, thrombocytopenia, and end-organ damage secondary to microvascular thrombi. The pathophysiology of TTP involves an acute deficiency of von Willebrand factor (VWF)-cleaving metalloprotease (ADAMTS13). In idiopathic TTP, autoantibodies directed against ADAMTS13 cause enzyme dysfunction by increased clearance or impaired enzyme attachment. Mutations of the ADAMTS13 gene are associated with congenital TTP. The classic manifestations of TTP include pentad of anemia, thrombocytopenia, fever, neurological signs and renal failure. The use of therapeutic plasma exchange (TPE) is the primary therapy for TTP and if left untreated, the mortality associated with TTP is more than 90%. TPE can be initiated by using plasma products or cryoprecipitated reduced plasma. The refractory conditions in TTP include, lack of improvement in platelet count after seven daily TPE procedures, lack of normalization of platelet count after 3 weeks of treatment and worsening of disease despite treatment.

PATHOLOGY

Figure 28-1 demonstrates the characteristic features of the thrombotic microangiopathies. The histopathologic changes are characterized by fibrin accumulation in the lumina and walls of arteries, arterioles, and glomerular capillaries. By light microscopy, fibrin and platelet thrombi are present in many or few capillaries of variable numbers of glomeruli. As the disease progresses, glomeruli may have a lobular appearance with capillary wall double contours, or they may be ischemic, characterized by wrinkled and partially collapsed capillaries (see Fig. 28-1A and B). Arterioles and, to a lesser extent, arteries are thrombosed and contain fibrin in the walls, which also show muscular hypertrophy and mucoid intimal thickening, resulting in luminal narrowing (see Fig. 28-1C and D). Areas of infarcted renal parenchyma are found in patients with cortical necrosis. Immunofluorescence reveals fibrin in glomerular capillaries and in vascular walls and lumina. Ultrastructurally, glomerular capillary walls have wide subendothelial zones containing flocculent electron-lucent and -dense material representing altered fibrin, which may contain trapped erythrocytes (see Fig. 28-1E and F). There may be a new layer of basement membrane material beneath the widened subendothelial zone, accounting for the double-contour appearance of capillaries. Endothelial cells are swollen, capillary lumina are narrowed, and occasionally capillaries contain tactoids of fibrin. In ischemic glomeruli, capillary basement membranes are wrinkled. There are no electron-dense (immune complex) deposits.

All thrombotic microangiopathic renal lesions are morphologically similar, although subtle differences have been described. Some have suggested that biopsy specimens from patients with HUS may show more fibrin and erythrocytes within the thrombi. In contrast, TTP thrombi are composed of more platelets with little fibrin, and immunohistochemistry has demonstrated von Willebrand's factor (vWF), probably the large multimer form. Patients with HUS also may be more likely to have cortical necrosis than those with TTP. However, the pathologic findings are not sufficiently different to allow a specific diagnosis based on histology for most processes causing thrombotic microangiopathy, apart from scleroderma (see later discussion). The distinction among the thrombotic microangiopathies requires clinical assessment.

What are the signs and symptoms of TTP?

Which patient is most likely to experience TTP?

Is PT and PTT elevated in TTP?

Which finding is most likely when assessing a patient with thrombic thrombocytopenia purpura?