Thrombotic Thrombocytopenic Purpura

TTP is a rare disorder characterized by the abrupt appearance of microangiopathic hemolytic anemia, severe thrombocytopenia, and a markedly elevated level of serum lactate dehydrogenase.2,6 Neurologic dysfunction, fever, and renal failure may also occur, but they are not consistently present.² TTP is more commonly found in adults and is rare in children, and there is a higher incidence in females than in males.^6,7 Typical laboratory findings at presentation include a hemoglobin concentration of less than 10 g/dL, a platelet count of less than 20 × 10⁹/L, and schistocytes observed on the peripheral blood film (Figure 24-3). After the bone marrow begins to respond to the anemia, polychromasia and nucleated RBCs may also be observed. The white blood cell (WBC) count is often increased, and immature granulocytes (left shift) may appear. The bone marrow shows erythroid hyperplasia and a normal number of megakaryocytes. Various amounts of protein, RBCs, and urinary casts may be present in the urine depending on the extent of the renal damage. Results of coagulation tests are usually within the reference range, which differentiates TTP from DIC.

The pathophysiology of TTP involves the release of long von Willebrand factor (VWF) multimers from vascular endothelial cells.⁸ The long VWF multimers adhere to endothelial cells and rapidly bind platelets through specific receptor-ligand interaction and subsequently trigger platelet aggregation. In the process platelets are removed from circulation, which causes severe thrombocytopenia, and the platelet-VWF (hyaline) microthrombi block small blood vessels, which leads to ischemia in the brain, kidney, and other organs.^2,8 In addition, RBCs are sheared as they pass through small vessels partially blocked by microthrombi, which results in RBC fragmentation and hemolytic anemia. The marked increase in lactate dehydrogenase is attributed more to the massive tissue ischemia than to the RBC lysis.

TTP may be acquired or familial. The acquired type is very heterogeneous, and the mechanisms that trigger the TTP pathophysiology are not completely clear. Approximately half of the patients present with secondary TTP associated with stem cell transplantation, pregnancy, disseminated cancer, autoimmune disorders, systemic infection, and use of certain drugs, including antiplatelet and chemotherapeutic agents.3,6,7 Of the remaining nonsecondary or idiopathic TTP cases, about 50% to 80% show a severe deficiency (less than 10% activity) of the VWF-cleaving protease known as a disintegrin-like and metalloprotease domain with thrombospondin type 1 motifs 13 (ADAMTS 13).^6,7,9 Under normal conditions, ADAMTS 13 cleaves the long multimers of VWF into shorter segments as they are released from the endothelial cells, thus preventing excessive platelet adhesion, aggregation, and microthrombi formation.^2,5 The ADAMTS 13 deficiency in acquired TTP has been attributed to inhibition by an immunoglobulin G (IgG) autoantibody, but inhibitory autoantibodies are not consistently found in all patients with the deficiency.^6,10,11 For the remaining cases of idiopathic TTP, the underlying cause is not known.⁹

Approximately 80% of patients with idiopathic TTP respond favorably to plasma exchange therapy, likely due to the removal of the offending ADAMTS 13 autoantibody and infusion of replacement ADAMTS 13 enzyme from donor plasma.5,7 Therefore it is important that this type of TTP be recognized and quickly treated with plasma exchange therapy to avoid a fatal outcome.⁵ Approximately one third of patients who respond to plasma exchange experience recurrent episodes of TTP.³ Except when the TTP is related to autoimmune disease, pregnancy, or ticlopidine use, patients with secondary TTP generally do not respond well to plasma exchange, and the prognosis in these cases is poor.^5,6,7,12

Familial TTPs are rare disorders due to mutations in the ADAMTS13 gene. Over 90 different mutations have been identified, and symptomatic individuals are either homozygous for one of the mutations or compound heterozygous for two different mutations.¹² The mutations result in reduced ADAMTS 13 activity, usually 5% to 10% of normal.³ Familial TTP usually presents in infancy with recurrent episodes; however, some patients may not be symptomatic until adulthood after their system is stressed by pregnancy or a severe infection. Infusion of fresh frozen plasma supplies the deficient ADAMTS 13 enzyme.³

Hemolytic Uremic Syndrome

HUS is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure from thrombi formed mainly in the glomerular microvasculature.⁵ There are two general types of HUS: D+ HUS, which is preceded by an episode of acute gastroenteritis, often with bloody diarrhea; and atypical HUS, which does not have antecedent diarrhea.⁵ Patients with HUS have the typical laboratory findings of microangiopathic hemolytic anemia discussed previously. In addition, there is usually a mild to moderate decrease in platelets and evidence of renal failure, including an elevated level of serum creatinine, proteinuria, hematuria, and the presence of hyaline, granular, and RBC casts in the urine (see Box 24-2).

The D+ HUS type comprises 90% of cases of HUS.¹³ The most common cause is infection with enterohemorrhagic serotypes of Escherichia coli (such as O157:H7).³ D+ HUS occurs most often in young children, but can be found in patients of all ages. Patients initially have acute gastroenteritis, often with bloody diarrhea, and after 1 to 3 days develop oliguria and other symptoms of renal impairment. About one fourth of patients develop neurologic manifestations.¹³

E. coli serotypes implicated in HUS release Shiga toxins (Stx-1 and Stx-2) that are absorbed from the intestines into the plasma, and have an affinity for the Gb3 glycolipid receptors on endothelial cells, particularly those in the kidney, brain, and intestines.3,14 The toxin is transported into the endothelial cells, where it inhibits protein synthesis and causes major endothelial cell injury. Although the mechanisms are not known, the Shiga toxin, together with many cytokines secreted as a result of the infection, may also induce changes in endothelial cells that are prothrombotic, including expression of adhesion molecules and secretion of increased amounts of long VWF multimers.^3,14 The end result is endothelial cell disruption, formation of platelet-fibrin thrombi that block the microvasculature in the glomeruli, and acute renal failure.^3,14 Microthrombi can also form in other organs in addition to the kidney. There is no specific treatment for D+ HUS, but patients are provided supportive care as needed, including hydration, dialysis, and transfusions.^13,14 The symptoms usually resolve spontaneously in 1 to 3 weeks, and the prognosis is favorable for most patients.¹³

Atypical HUS comprises about 10% of cases of HUS, is more commonly found in adults, and has a poor prognosis.12,15 Approximately half of the cases are familial and the other half are sporadic. The familial type is caused by mutations in genes that code for proteins involved in the alternative complement pathway or its regulation, such as the genes for factor H, factor I, factor B, membrane cofactor protein, and thrombomodulin.^12,15 The mutations result in uncontrolled activation of the complement pathway, which causes endothelial injury, activation of platelets and coagulation factors, and formation of platelet-fibrin thrombi that obstruct the glomerular microvasculature.^3,16 The sporadic form occurs secondary to some drugs, cancer, organ transplantation, pregnancy, and human immunodeficiency virus (HIV) infection.¹⁶

HELLP Syndrome

HELLP syndrome is a serious complication in pregnancy and is named for its characteristic presentation of hemolysis, elevated liver enzymes, and low platelet count. It occurs in fewer than 1% of all pregnancies, but develops in approximately 10% to 20% of patients with preeclampsia, most often in the third trimester.¹⁷ The exact pathogenesis is not known. In preeclampsia, abnormalities in the development of placental vasculature results in poor perfusion and hypoxia. As a result, antiangiogenic proteins are released from the placenta that block the action of placental growth factors, including vascular endothelial growth factor.^3,18 The continued vascular insufficiency of the placenta results in maternal endothelial cell dysfunction, which leads to platelet activation and fibrin deposition in the microvasculature, particularly in the liver.¹⁸

Anemia, biochemical evidence of hemolysis, and schistocytes on the peripheral blood film are found as in the other thrombotic microangiopathies. The platelet count is less than 100 × 10⁹/L; counts falling below 50 × 10⁹/L indicate a worse prognosis.18,19 The level of lactate dehydrogenase is elevated, which reflects the hepatic necrosis as well as the hemolysis. The level of aspartate aminotransferase can be markedly elevated due to the severe hepatocyte injury. The low platelet count and increased levels of lactate dehydrogenase and aspartate aminotransferase are major diagnostic criteria for the HELLP syndrome and are used to assess the severity of the disease.^17,18 The prothrombin time and the partial thromboplastin time are within the reference range, which distinguishes the HELLP syndrome from DIC. Therapy includes delivery of the fetus and placenta as soon as possible along with supportive care to control seizures, hypertension, and fluid balance. The mortality rate is 3% to 5% for the mother and 9% to 24% for the fetus.¹⁸

Disseminated Intravascular Coagulation

DIC is characterized by the widespread activation of the hemostatic system, resulting in fibrin thrombi formation throughout the microvasculature. The major clinical manifestations are organ damage due to obstruction of the microvasculature and bleeding due to the consumption of platelets and coagulation factors and secondary activation of fibrinolysis.²⁰ DIC is a complication of many disorders, such as disseminated cancers, acute leukemias, infections, obstetric complications, crush or brain injuries, acute hemolytic transfusion reactions, extensive burns, snake or spider envenomation, and chronic inflammation (see Table 42-14).

Thrombocytopenia of varying degree is a consistent finding. Only about half the patients have schistocytes on the peripheral blood film.⁴ The prothrombin time and partial thromboplastin time are prolonged, the fibrinogen level is decreased, and the level of D-dimer is increased in DIC, which distinguish it from the other thrombotic microangiopathies.

Hypertensive Crisis

Hypertensive crisis or hypertensive emergency (previously called malignant hypertension) is a severe and abrupt increase in blood pressure with acute organ damage, particularly in the heart, brain, and kidney.²¹ The sudden mechanical stress induced by the elevated blood pressure damages the endothelial cells and results in increased vascular permeability, activation of coagulation factors and platelets, and fibrin deposition in damaged vessel walls.²¹ The manifestations of hypertensive crisis include encephalopathy, acute myocardial infarction, aortic dissection, pulmonary edema, severe preeclampsia, acute renal failure, and microangiopathic hemolytic anemia.^21,22 In one study, 27% of patients with hypertensive crisis had microangiopathic hemolytic anemia when the criteria were a platelet count of less than 150 × 10⁹/L and either an elevated level of lactate dehydrogenase or the presence of schistocytes on the peripheral blood film.²² When the hypertension is brought under control, the RBC fragmentation disappears and the platelet count returns to normal within a few days.^22,23

Exercise-Induced Hemoglobinuria

RBC hemolysis, with an increase in free plasma hemoglobin and a decrease in serum haptoglobin level, has been demonstrated after long-distance running and to a lesser extent after intensive cycling and swimming,25–27 but frank hemoglobinuria after exercise is a rare occurrence.²⁸ Exercise-induced hemoglobinuria has been reported mainly in endurance runners, but has also been observed after strenuous hand drumming.^25,29 Various causes have been proposed, including mechanical trauma from the forceful, repeated impact of the feet or hands on hard surfaces,^25,26,29 increased RBC susceptibility to oxidative stress,^30,31 and exercise-induced alterations in membrane cytoskeletal proteins.^31,32

Exercise-induced hemoglobinuria does not usually cause anemia unless the hemoglobinuria is particularly severe and recurrent.²⁸ Laboratory findings include a decreased level of serum haptoglobin, an elevated level of free plasma hemoglobin, and hemoglobinuria observed after strenuous exercise. Patients also have a slight increase in mean cell volume (MCV) and reticulocyte count, and with rare exceptions schistocytes are not observed on the peripheral blood film.^28,29 Exercise-induced hemoglobinuria is a diagnosis of exclusion, and other possible causes of hemolysis and hemoglobinuria should be investigated and ruled out.²⁸ There is no treatment for the disorder other than minimizing the physical impact on the feet with padding in shoes, running on softer terrain, or, if hemolysis is severe, discontinuing the activity.

Incidence

Half the world’s population (approximately 3.3 billion people) live in areas in which malaria is endemic and are at risk for the disease.36,37 Worldwide in 2008, there were an estimated 243 million cases of malaria with 863,000 deaths, mostly in children younger than 5 years of age.³⁶ The majority of deaths were in Africa (85%), followed by Southeast Asia (10%) and the Eastern Mediterranean region (4%).³⁶

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Introduction to Leukocyte Neoplasms Bone Marrow Failure Coagulation Instrumentation Acute Leukemias Hematopoiesis Platelet Production, Structure, and Function

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