Chapter 90: Antibody-Mediated Thrombotic Disorders: Thrombotic Thrombocytopenic Purpura and Heparin-Induced Thrombocytopenia

INTRODUCTION

• Thrombotic microangiopathies are characterized by thrombocytopenia, microangiopathic hemolytic anemia, and microvascular thrombosis, leading to variable injury of the central nervous system, kidney, and other organs.

• The classic form of thrombotic microangiopathy (ie, thrombotic thrombocytopenic purpura [TTP]) is usually associated with an acquired (autoimmune) deficiency of ADAMTS13, a metalloprotease that cleaves the ultralarge multimers of von Willebrand factor normally produced by endothelial cells but that are hypercoagulable.

• Hemolytic uremic syndrome (HUS) refers to the thrombotic microangiopathy that mainly affects the kidney and may be diarrhea-associated (caused by enteric infection with Shiga-toxin producing gram-negative microorganisms) or atypical, often due to abnormalities in the regulation of the complement cascade.

• Secondary thrombotic microangiopathies occur in association with infections, certain drugs, metastatic cancer, malignant hypertension, or after stem cell transplantation.

• Heparin-induced thrombocytopenia (HIT) is a significant complication of heparin treatment, associated with mild to moderate thrombocytopenia and a high frequency of both arterial and venous thrombosis. HIT is caused by the formation of anti–heparin/platelet factor-4 antibodies that activate platelets, leukocytes, and endothelial cells.

THROMBOTIC THROMBOCYTOPENIC PURPURA

Etiology and Pathogenesis

• Most cases of TTP are caused by autoantibodies that inhibit ADAMTS13. Congenital deficiency of ADAMTS13 (Upshaw-Schulman syndrome) is rare but well established (see Chap. 88).

• The underlying mechanism causing TTP is unregulated von Willebrand factor–dependent platelet thrombosis.

• Ultra-large von Willebrand factor multimers are released from endothelial cells of the vessel wall and mediate platelet adhesion by binding connective tissue at sites of vascular injury and to platelet glycoprotein Ib on the platelet surface. ADAMTS13 cleaves the von Willebrand factor multimers, thereby preventing platelet-vessel wall interactions in the absence of vascular injury.

• Deficiency of ADAMTS13 leads to spontaneous microvascular platelet thrombosis, causing microvascular obstruction and microangiopathic hemolytic anemia.

Epidemiology and Clinical Features

• The incidence of TTP in the United States has been estimated at approximately 4.5 per million per year.

• The peak incidence is between ages 30 and 50 years, and the disease is rare before age 20 years. The female-to-male ratio averages approximately 2:1, but female preponderance is even more pronounced at relatively younger ages.

• Other risk factors for TTP include African ancestry and obesity and genetic risk factors, such as a low frequency of HLA-DR53.

• The onset of TTP can be dramatically acute or insidious, developing over weeks.

• Approximately one-third of patients have symptoms of hemolytic anemia. Thrombocytopenia typically causes petechiae or purpura; oral, gastrointestinal or genitourinary bleeding is less common but can be severe.

• Systemic microvascular thrombosis can affect any organ, and the consequences are variable. Renal involvement is common, but acute renal failure occurs in fewer than 10% of cases. Neurologic findings can be transient or persistent and may include headache, visual disturbances, vertigo, personality change, confusion, lethargy, syncope, coma, seizures, aphasia, hemiparesis, and other focal sensory or motor deficits.

• Many patients have fever. The symptoms of TTP sometimes can be quite atypical, either at first ...