PBL Sessions: Hematology Organ System - 1
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Page 10
Final Discussion of Case:
Tasks
Discuss the logic of the plasmapheresis procedure for this patient.
Review the causes for thrombocytopenia and how to distinguish them.
Discuss how the underlying disease process in this patient led to the various findings.
Discuss the disease process and findings in the patient's deceased husband.
Prepare your group representative for the case wrap up session.
Key Issues
The patient is a 47-year-old woman who has been bothered by headaches for the past three days. She has been getting over an episode of "flu" in which she had a mild non-productive cough with fever and myalgia for about a week and a half.
Pathologic / Radiologic Learning Issues
Clinical Learning Issues
Discussion
Thrombotic thrombocytopenic purpura (TTP) / Thrombotic microangiopathy (TMA)
TTP has an incidence of 3.7 per 100,000 per year. It is slightly more common in women, with a peak incidence in the third decade. Some patients have an upper respiratory tract infection or flu-like syndrome in the 2 weeks preceding the onset of TTP. Occasional patients present with malaise, fatigue, fever, or other nonspecific symptoms that persist for days to weeks, and the diagnosis may not be made until neurologic dysfunction develops or renal failure develops.
The classic pentad of symptoms with TMA-TTP include microangiopathic hemolytic anemia (MAHA), thrombocytopenia, neurologic symptoms, fever, and renal dysfunction. However, only 40% of patients develop the complete pentad, whereas 75% present with a triad of MAHA, neurologic symptoms, and thrombocytopenic purpura. In data collected from patients during the last decade, the incidence of symptoms such as fever appears to have diminished, perhaps due to earlier diagnosis.
Neurologic symptoms can include headache and confusion, somnolence, seizures, aphasia, or coma. The neurologic findings may fluctuate in severity because of the apperance and disappearance of microthrombi in the cerebral microvasculature. Thrombocytopenia may be severe, with 25% of patients presenting with platelet counts below 20,000/microliter. Approximately 90% of patients experience bleeding complications out of proportion to the severity of thrombocytopenia, probably because of associated vascular injury.
Despite bleeding, the prothrombin time, partial thromboplastin time, and fibrinogen levels are often normal or only slightly abnormal. Small increased in fibrinogen degradation products occur in 50% of patients, and the fibrin D dimer assay is often increased.
Renal involvement is marked by hematuria, proteinuria, or mild elevations in serum creatinine. Renal disease usually worsens as the course of TTP progresses. A microangiopathic hemolytic anemia (MAHA) is caused by fragmentation of red blood cells traversing fibrin strands in the microvasculature or oxidant damage to the red blood cell membrane. The schistocytes or "helmet cells" seen on the peripheral blood smear are characteristic of TTP/TMA. Nucleated red blood cells are often seen on the peripheral blood smear. The direct antiglobulin (Coombs) test is usually negative.
TTP is a fulminant, often lethal disorder that may be initiated by endothelial injury and subsequent release of vWF and other procoagulant materials from the endothelial cell. Causes include pregnancy, metastatic cancer, mitomycin C, high-dose chemotherapy, HIV infection, and certain drugs, such as the antiplatelet angent ticlopidine. Characteristic findings include the microvascular deposition of hyaline fibrin thrombi, thrombocytopenia, microangiopathic hemolytic anemia, fever, renal failure, fluctuating levels of consciousness, and evanescent focal neurologic deficits. The presence of hyaline thrombi in arterioles, capillaries, and venules without any inflammatory changes in the vessel wall is diagnostic. Microvascular thrombi occur in most organs in patients with TTP and consist of platelet aggregates with little or no fibrin; there is no perivascular inflammation or overt endothelial-cell damage. The platelet thrombi contain abundant von Willebrand factor antigen but no fibrinogen (or fibrin), whereas the platelet thrombi in disseminated intravascular coagulation contain fibrin but not von Willebrand factor. The presence of a severe Coombs-negative hemolytic anemia with schistocytes or fragmented red blood cells in the peripheral blood smear, coupled with thrombocytopenia, and minimal activation of the coagulation system help to confirm the clinical suspicion of TTP. This disorder should be distinguished from vasculitis and SLE, which can predispose patients to TTP. Platelet-associated IgG and complement levels are usually normal in TTP.
The pathogenesis of TTP is related to release of vWF. Monomers of vWF are linked by disulfide bonds to form large multimers. A vWF-cleaving metalloprotease in plasma normally prevents the entrance into the circulation (or persistence) of unusually large multimers of vWF. This metalloprotease is called ADAMTS 13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains). In most patients with TTP, plasma ADAMTS 13 activity is less than 5 percent of normal. During an episode of acquired idiopathic thrombotic thrombocytopenic purpura or any recurrence, patients usually have undetectable or barely detectable plasma levels of ADAMTS 13.
The diagnosis of TMA must be made in a timely manner because delay carries with it the attendant risk of sudden death. The disorder should be considered when prodromal symptoms such as malaise, fatigue, gastrointestinal distress, or low-grade fever persist or progress in the face of symptomatic therapy. A complete blood count and an analysis of the peripheral blood smear are indicated in any patient with a protracted course. A provisional diagnosis of TMA should be made, and plasma-based therapy instituted, in any patient with the above-mentioned prodromal symptoms in whom MAHA and thrombocytopenia are discovered, unless an alternative diagnosis is evident.
The mortality rate of TTP-TMA approaches 100% without therapy. The treatment of acute TTP is based on the use of plasmapheresis along with infusion of fresh frozen plasma. Patients with TTP become transiently deficient in a plasma enzyme that depolymerizes ultra-high molecular-weight vWF released from endothelial cells. Therapy may lead to removal of the abnormal forms of vWF and increase the deficient enzyme. Overall mortality is markedly reduced with plasmapheresis, and the majority of patients recover with no residual renal or neurologic disease.
More than 80% of patients presenting for the first time with TMA-TTP can be treated successfully with plasmapheresis, but at least 30% of successfully treated adult patients will have one or more relapses. Approximately half of relapses occur within the first 2 months after therapy has been discontinued. Occasional patients with a chronic, relapsing form of TTP require maintenance plasmapheresis and plasma infusion, and a few patients are controlled only with corticosteroid therapy. Prior to the general availability of plasmapheresis, splenectomy was used to treat TMA-TTP, inducing remission in up to 50% of patients. Splenectomy is now used to treat patients not responding to plasmapheresis.
Hemolytic-uremic syndrome (HUS) has features similar to TTP, and it may be difficult to distinguish the two. In children, this variant occurs most commonly after an episode of E. coli 0157:H7 induced gastroenteritis.
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