Chapter 70. Thrombotic Thrombocytopenic Purpura, Hemolytic Uremia Syndromes, and the Approach to Thrombotic Microangiopathies

• The thrombotic microangiopathies (TMAs) include the spectrum of thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndromes (HUS) as well as related obstetric syndromes.
• The hallmarks of TMA are a microangiopathic hemolytic anemia (MAHA) and thrombocytopenia.
• TMA must be distinguished from other coagulopathies, such as disseminated intravascular coagulation (DIC) and collagen vascular disease with vasculitis, since therapeutic approaches differ.
• The clinical presentation of TTP/HUS is characterized by a pentad of findings: MAHA, thrombocytopenia, neurologic abnormalities, renal dysfunction, and fever.
• Plasma exchange is the therapy of choice for TTP/HUS, with adjunctive therapies including plasma infusion, corticosteroids, splenectomy, and/or immunosuppressive agents.
• TTP/HUS is a hematologic emergency, and patients are at risk of developing tissue anoxia, lactic acidosis, renal failure, or catastrophic central nervous system injury.
• Plasma exchange may be complicated by catheter accidents, air embolus, citrate toxicity, and pulmonary edema.

Moschcowitz's original description of TTP in 1925 was based on a triad of findings: anemia (of the microangiopathic hemolytic type), thrombocytopenia, and neurologic symptoms. In 1966, 271 cases of TTP were reviewed, and the features of fever and renal impairment were added to form a clinical pentad.1 Subsequent series have confirmed that renal involvement is common, with proteinuria, hematuria, or azotemia seen in 80% of patients with TTP.2,3 Hemolytic uremic syndromes (MAHA, thrombocytopenia, and renal failure) are regarded as part of a spectrum of TMA, which at one end consists of TTP with predominantly neurologic findings and minimal renal abnormality, and at the other end consists of profound renal dysfunction with little or no central nervous system (CNS) pathology. The latter syndromes are more common in childhood, in the postpartum period, and following use of chemotherapeutic (mitomycin C) or immunosuppressive (cyclosporine) agents. On occasion, the evolution of renal manifestations in TTP can become indistinguishable from HUS, so that attempts at rigid distinction are generally unrewarding.4

The age of onset of TTP/HUS ranges from infancy to the eighth decade, with a peak incidence in the third decade. Females are more frequently affected than males by a ratio of 2:1. Childhood HUS often presents with antecedent illness, typically gastroenteritis related to enterotoxin-producing strains of Escherichiacoli or Shigella. TMA associated with pregnancy includes several syndromes with considerable overlap, making prospective differentiation difficult.5,6 Pregnancy-induced hypertension (PIH; eclampsia and pre-eclampsia) is often associated with subtle laboratory abnormalities consistent with a degree of underlying TMA; on occasion this becomes clinically significant. When hypertension, elevated liver enzyme levels, and a low platelet count occur together as a syndrome in the peripartum period, the term HELLP syndrome is applied (see Chap. 105). TTP may also be encountered in the second or third trimesters of pregnancy; unlike thrombocytopenias associated with PIH, it may not improve rapidly with termination of the pregnancy and may require further treatment. Finally, postpartum HUS is distinguished by its onset after delivery. Characterization of TMA in pregnancy is often made in the context of this clinical information.

TTP syndromes have also been described as drug-induced in patients receiving antiplatelet agents,7,8 chemotherapeutic agents9 (such as mitomycin C), or immunosuppressive agents (such as cyclosporine or FK 506)10 following organ transplantation. Transplantation patient populations are growing, and these patients are likely to be encountered in the critical care environment. Transplant patients are at risk for multiple complications that may be associated with coagulopathy and cytopenia, so making the correct diagnosis is challenging. TTP/HUS has also been associated with human immunodeficiency virus (HIV) infection,11 and more recently TTP/HUS has been identified as a complication related to antiplatelet therapy such as ticlopidine7 and clopidogrel.8

TTP/HUS has also been described as a complication in patients with collagen vascular disease such as systemic lupus erythematosus (SLE).12 Vasculitic syndromes and end-organ involvement in these patients may mimic the clinical pentad associated with the TTP syndrome, making clinical differentiation between these two syndromes problematic.

Despite the well-described association of TTP/HUS syndromes with pre-existing comorbidities or inciting agents, most cases of TTP currently present as idiopathic, community-acquired syndromes, perhaps in association with an antecedent viral syndrome. Much progress has been made in recent years regarding the pathophysiology of TTP in this setting, which is discussed below.

The clinical presentation of TTP varies with the extent and severity of the thrombotic lesions. Neurologic findings can be nonspecific and include headache alone or with changes in mental status. Often these seemingly minor manifestations of disease are discovered by careful history-taking to have preceded more fulminant findings associated with anemia, thrombocytopenia, or renal failure. Neurologic findings may be more obvious, including seizures, obtundation, focal neurologic deficits, or coma. Altered mental status in TTP has also been described as secondary to nonconvulsive status epilepticus.13 Fever is present in approximately two thirds of cases.

Although the presence or absence of renal failure may affect prognosis, the heterogeneity of patients with TMA is greater than this single clinical parameter.4 Survival rates without (78%)14 or with (83%)15 acute renal failure have been reported not to be different. Thus while patients can be characterized according to their extent of neurologic or renal abnormalities, at present a clinical distinction for adult patients with TMA between TTP and HUS does not seem useful.

Laboratory findings in TTP/HUS are often striking. Thrombocytopenia may be profound, with platelet counts of <50,000/μL frequently observed. Anemia is of a microangiopathic type, and the peripheral smear is remarkable for fragmented red blood cells (RBCs), polychromatophilia, nucleated RBCs, and a markedly diminished platelet count (Fig. 70-1). Intravascular hemolysis frequently causes elevation of total bilirubin (predominantly the direct fraction) and lactate dehydrogenase (LDH). Urinalysis usually reveals proteinuria or hematuria; varying degrees of diminished glomerular filtration rate may be seen. Diagnosis of TTP/HUS by tissue biopsy has been advocated by some, but findings are often consistent with, but not specific for, TTP/HUS. Gingival biopsy, a previously popular test, lacks sensitivity and specificity.16

The earliest pathologic descriptions of TTP/HUS emphasized the presence of hyaline thrombi in the terminal arterioles and capillaries of the heart, liver, and kidneys. These hyaline deposits have subsequently been shown to consist largely of agglutinated platelets. A degree of associated fibrin deposition is regarded as a secondary phenomenon, since its presence is variable and patients with TTP do not routinely exhibit the coagulation abnormalities of DIC.

The pathogenesis of this diffuse microvascular thrombosis, while unclear,17 is becoming better understood. The initial event is inappropriate platelet adhesion, aggregation, and mediator release on endothelial surfaces that results in vascular occlusion, with the characteristic hyaline thrombi of platelets and fibrin. Systemic endothelial cell damage appears to be a central component of the pathogenesis of TTP/HUS,18 particularly in patients with virutoxin-mediated HUS associated with pathogenic E. coli or Shigella.19 Endothelial damage stimulates the release of unusually large von Willebrand factor (vWF) multimers20 that may cause platelet agglutination and microvascular occlusions.21 Deficiency of a vWF cleaving protease (vWFCP, or ADAMTS13) was initially reported in patients with familial or idiopathic TTP, but not in patients with HUS.22 However, other reports found reduced vWFCP levels in HUS,23 and in other conditions with thrombocytopenia, including DIC and idiopathic thrombocytopenic purpura (ITP),24 and in patients with liver cirrhosis, chronic renal insufficiency, and acute inflammatory states.25 In one report, reduced vWFCP levels were observed in other thrombocytopenic disorders, and had only moderate sensitivity (0.45) and low specificity (0.30) in patients with a clinical diagnosis of TTP/HUS.24 In a second report using a vWVFCP cutoff level of 30%,26 the collagen-binding assay performed with a sensitivity of 94%, specificity of 93%, and a positive predictive value of 79%. Although vWFCP activity is decreased (<30%) in a substantial proportion of patients with thrombocytopenia of various causes, a severe (<5%) deficiency is more specific for TMA commonly labeled TTP.27

Inhibitors (characterized as IgG antibodies) against the vWFCP have been detected in one report in two thirds of plasma samples in the acute phase from patients with TTP-HUS.28 Another report29 found that 79% of patients with idiopathic, community-acquired TTP/HUS have low (<5%) levels of vWFCP; of these, vWFCP inhibitor was detected in 73%. vWFCP has recently been identified as a new member of the metalloproteinase family,30 and was subsequently cloned.31 Levy and colleagues32 found that vWFCP is mutated in congenital TTP, thereby proving that the protease is directly involved in protection from microangiopathy. Finally, autoantibodies to vWFCP have also been found in patients who developed ticlopidine-associated TTP.33

A recent report suggested that in patients with TTP and normal vWFCP activity, factor V Leiden may be an important pathophysiologic risk factor.34 While the vWFCP deficiency may not be specific for TTP,23 its deficiency along with the presence of vWFCP inhibitor appears to correlate with a prolonged course and multiple relapses.29,35 It is clear that disorders of diverse causes converge on a clinical phenotype that includes TMA,36 and laboratory evaluations based on vWFCP levels and inhibitor assays will facilitate dissection of these potentially distinct entities.

The differential diagnosis of the thrombotic microangiopathies includes disease processes presenting with thrombocytopenia and MAHA (Table 70-1). Most commonly, the clinician must distinguish between TTP/HUS and the DIC syndromes or distinguish TTP/HUS from a collagen vascular disease (CVD) such as systemic lupus erythematosus (SLE) with vasculitis (Table 70-2). DIC may be associated with many diseases (see Table 70-1) and results in widespread generation and deposition of intravascular fibrin in small blood vessels, accompanied by a consumptive coagulopathy with clotting factor activation as a primary process. This condition is to be distinguished from TTP/HUS, in which the primary process is platelet aggregation at the vascular endothelial surface.

Distinguishing Thrombotic Thrombocytopenic Purpura from Disseminated Intravascular Coagulation

DIC may be initiated by either endothelial injury (the intrinsic coagulation pathway) or release of tissue thromboplastin (the extrinsic coagulation pathway). Either process can cause platelets to undergo intravascular aggregation when exposed to collagen and thrombin. The clinical manifestations of DIC arise from injury related to intravascular thrombosis or from bleeding that results from consumption and depletion of clotting factors and platelets. Acute DIC syndromes usually present with bleeding and demonstrable hypo- or afibrinogenemia. In more chronic forms of DIC in which reticuloendothelial system clearance mechanisms, clotting factor production, and marrow cell production compensate for consumption, patients can present with thrombosis rather than hemorrhage. Typical thrombotic problems include deep vein or superficial thrombophlebitis, pulmonary embolus, cerebrovascular accidents, or nonbacterial (marantic) endocarditis.

DIC shares with TTP the features of MAHA and thrombocytopenia (see Table 70-2). In one series, the frequency of MAHA as judged by peripheral smear was 68% in patients with DIC. In the same series, thrombocytopenia (platelet count <150,000/μL) was seen in 96% of cases of DIC; however, significant thrombocytopenia (platelet count <50,000/μL) was much less common (57%).

A number of laboratory findings will help to distinguish TTP from DIC (see Table 70-2). As noted above, hypofibrinogenemia is typical of fulminant, consumptive DIC. In addition, as clotting factors are consumed, prolongation of the prothrombin time (PT) and partial thromboplastin time (PTT) is seen. Also, the systemic generation of fibrin can lead to activation of the fibrinolytic system, either by activation of plasminogen by tissue activators released from vascular endothelium or by Hageman factor–dependent activation. Fibrinolysis results in the appearance of fibrin degradation products (FDPs) in the serum that can be measured. While none one of these laboratory tests alone can distinguish TTP from DIC, in the aggregate they are sufficient to permit a specific diagnosis (see Table 70-2 and Chap. 69).

Finally, the clinical context will often help to determine if DIC is a viable explanation for the observed abnormalities. Most often, the disease or disorder that is the precipitant of DIC is apparent. Amniotic fluid embolus, retained products of conception, and abruptio placentae are obstetric complications often associated with DIC. Septicemia is the substrate for DIC in many patients encountered in the ICU. The presentation of these patients may be fulminant, as in the Waterhouse-Friderichsen syndrome (shock, bleeding diathesis, and adrenal insufficiency in association with meningococcemia), or more indolent, as in the complex postoperative patient with a “smoldering” intra-abdominal source of infection. Trauma is a well-recognized cause of DIC and fibrinolysis resulting from the exposure of tissue thromboplastins and plasminogen activators to plasma.37 In trauma patients, unexplained bleeding during or after a surgical procedure may be the first manifestation of DIC. In the setting of head injury, as many as 70% of patients have clinical evidence of DIC.38

In summary, TTP/HUS can usually be distinguished readily from DIC by the clinical context and laboratory parameters. It is important to apply this principle, as all of the defining features of TTP/HUS—thrombocytopenia, MAHA, fever, neurologic dysfunction, and renal abnormality—are so common in the critically ill that a clear approach to this possible diagnosis is warranted.

Approach to the Pregnant Patient

Hematologic aberrations associated with PIH (pre-eclampsia/eclampsia; see Chap. 105) include MAHA, thrombocytopenia, and alterations of the coagulation mechanism. Evidence of MAHA can be found in 2% to 15% of women with PIH, and thrombocytopenia has been reported in as many as 18% of patients. Thus a subset of patients with PIH will have two of the cardinal hematologic abnormalities of TTP/HUS.5 It has been suggested that PIH and TTP/HUS share pathophysiologic features, specifically aberration in prostaglandin metabolism at the platelet-endothelial cell interface. In this regard it is interesting that plasma exchange has been reported to be a successful therapy in PIH. A subset of patients with PIH and thrombocytopenia may have marked elevation of liver function tests (HELLP syndrome). Right upper quadrant pain is often present and may mimic cholecystitis or peritonitis.

Postpartum HUS is characterized by predominant renal involvement; neurologic signs and fever are usually absent. It has been suggested that this syndrome is a clinical counterpart of the generalized Schwarzman reaction. It is hypothesized that bacterial endotoxins or vasoactive amines are discharged into the maternal circulation and either stimulate the coagulation cascade or initiate thrombosis by damage to the vascular endothelium.

As mentioned above, DIC syndromes accompany major complications of pregnancy. Usually these processes are associated with a catastrophic process such as amniotic fluid embolus or abruptio placentae. Less apparent and more indolent DIC may be encountered with retained products of conception.

Finally, TTP/HUS itself is encountered in pregnancy but is rare, with approximately 70 cases reported. It is likely that most pregnant patients with thrombocytopenia and MAHA are best classified as having PIH with hematologic abnormalities.10 The key features distinguishing these patients from the group with HELLP syndrome are the emergence of disease in late pregnancy, relatively mild hematologic irregularities, and prompt resolution of thrombocytopenia, MAHA, neurologic symptoms, and liver function abnormalities following delivery. HUS begins postpartum, with a predominance of renal dysfunction. DIC differs from TTP as described above (see Table 70-2). The small remaining group of patients whose clinical presentation is best described as TTP/HUS are best managed in pregnancy with the usual treatments (see below), with expeditious delivery or termination of pregnancy.39,40

Distinguishing Thrombotic Thrombocytopenic Purpura from Collagen Vascular Disease

An association between TTP/HUS and SLE has been reported. In one review, evidence of SLE was found in 7 of 64 cases initially diagnosed as TTP/HUS.1 TTP/HUS has also been reported in association with other CVDs, including rheumatoid arthritis, ankylosing spondylitis, and polyarteritis nodosa. On the other hand, vasculitis in association with SLE or another CVD may mimic TTP/HUS with findings of renal failure, fever, neurologic disturbance, thrombocytopenia, and MAHA. Serum complement levels are usually low in patients with vasculitis and normal in those with TTP/HUS (see Table 70-2). Antinuclear antibodies are positive in the great majority of patients with SLE. These CVD screening tests are indicated in all patients with a tentative diagnosis of TTP/HUS. If a diagnosis of a specific CVD can be made, therapy should be directed at that disorder, rather than at the associated hematologic problems.

TTP/HUS is a hematologic emergency. Patients will often need ICU admission because of profound anemia, shock, lactic acidosis, respiratory failure, or deteriorating neurologic function. Intubation and mechanical ventilation may be required because of ventilatory failure complicating CNS involvement or because of direct lung injury associated with pulmonary vascular involvement by TTP.41

Plasma Exchange

Once a diagnosis of TTP is made, plasma exchange is the therapy of choice. Since 1961, mortality for this disease has declined from >90% to <50%, likely owing to the institution of plasma exchange therapy. Some studies, however, have suggested that the overall mortality from TTP has actually increased in the United States in recent years.3 The prognosis of TTP is improved by prompt recognition and treatment, so that emergency apheresis should be conducted in any patient diagnosed with TTP/HUS. Plasma exchange of 150% of the plasma volume is instituted (3 to 4 L for normal-sized individuals) with plasma replacement. Two intravenous sites are required for the procedure, which uses 17 gauge (draw line) and 18 gauge (return line) catheters. Ideally, plasma exchange is conducted through a double-lumen dialysis catheter. Special precautions should be taken when placing large-bore central catheters in these thrombocytopenic patients, such as ultrasound guidance or placement in a compressible vessel (jugular or femoral vein).

Potential complications of plasma exchange include those related to line placement, air embolus, citrate toxicity, pulmonary edema, and risks associated with plasma transfusion (hives, urticaria, rash, anaphylactoid reactions). In one series over a 6-year period, 54 major complications, including 3 deaths, were identified to be related to plasma exchange in 42 (28%) of 142 consecutive patients with TTP/HUS.42 The risk of air embolus is reduced when the procedure is performed by experienced personnel. Machine safety devices include bubble traps and a bubble alarm that stops the machine when air is detected in the lines. Citrate toxicity can occur from the plasma citrate anticoagulant infused into the patient and is compounded by associated renal dysfunction. Citrate toxicity causes hypocalcemia and metabolic alkalosis and presents as oral paresthesias, numbness or tingling in the extremities, or a prolonged QT interval on the electrocardiogram. Hypocalcemia can be prevented by routinely administering 1 ampule of calcium gluconate by constant infusion per liter of plasma exchanged. An additional one half ampule may be administered if symptoms are experienced during the procedure. Periodic monitoring of ionized calcium levels is useful as well. In all cases, the relative benefits and risks of the procedure should be discussed with the patient or guardians, and informed consent obtained.

Plasma exchange should be performed daily until evidence indicates that the disease is in remission. The patient should have normal end-organ function, including normal mental status and renal function. The most sensitive indicator of response is a rising platelet count, which should be normal (>150,000/μL) for a number of days (3 to 5) before plasma exchange is discontinued. The LDH level is also a sensitive indicator of tissue hypoxia43 and can be used to monitor the response to therapy. RBC morphology on peripheral smear (see Fig. 70-1) should be examined sequentially, although improvement in cell fragmentation can lag behind clinical responses (such as improving mental status) by several days. Bone marrow reticulocyte response may not occur for 3 to 5 days, depending on the pace of presentation of the disease. The patient should be given folate (1 mg or more daily) in this setting of poor dietary intake, plasma exchange, and increased marrow requirement.

The usual course of plasma exchange lasts 5 to 14 days. Patients can be moved from the ICU when mental status has normalized and hematocrit and platelet count are increasing. The shortest treatment requirement we have observed is 3 days. Late responses in occasional patients have occurred after 14 days of therapy. Continued plasma exchange may be required for up to 4 weeks as long as the patient remains stable or is improving. Studies have suggested that under conditions of massive plasma replacement, plasma depleted of the largest multimers of von Willebrand factor (cryoprecipitate-poor plasma) might be preferable for the treatment of patients with recurrent or refractory TTP.44 Patients have been reported to respond to this cryosupernatant fraction as replacement fluid, despite having been refractory previously to plasma replacement therapy;45 the current standard for initial therapy, however, remains apheresis with plasma replacement.46

Salvage Therapies for Patients Who Recur or Fail to Gain Remission

Early relapse rates of up to 37% have been reported in patients with TTP/HUS, and 40% of centers routinely use a tapering schedule of apheresis.47 Occult infections have been described in association with refractory or recurrent TTP/HUS.48

With the emerging evidence that some fraction of patients with TTP-HUS may have an autoimmune disease, along with the recognition that sustained treatment with plasma exchange is not without risk,42 there has been a re-examination of the potential usefulness of salvage therapies for patients with refractory TTP-HUS. Cryosupernatant plasma has been suggested to have a theoretical benefit over fresh frozen plasma (FFP) because it is depleted of vWF, and a retrospective study suggested efficacy.45 Glucocorticoid therapy is commonly utilized in patients with TTP-HUS; despite one favorable review49 on its value, no randomized study assessing an impact on the prognosis of TTP-HUS has been performed.50

Splenectomy has been reported to be of value51–60 in patients who do not have a complete or lasting response to plasma exchange. The value of splenectomy may be due to the removal of a major site of synthesis of a pathogenic IgG.28 In one report51 in patients who failed exchange, 9 (70%) of 13 refractory patients treated with splenectomy survived.

Adjunctive Therapies

In patients with an incomplete clinical response, splenectomy should be considered. High-dose steroid therapy has been advocated by some,61 but without convincing evidence of benefit.50 Our current approach is to use steroids only in patients who do not respond to plasma exchange and in those with a concurrent diagnosis of collagen vascular disease. Vincristine, presumably acting as an immunosuppressant, has also been reported to produce sustained remissions in a small series.62

In view of the pathophysiology of TTP/HUS, antiplatelet agents seem to be a rational addition to treatment. However, clinical trials have not shown a convincing impact of these drugs, including intravenous prostacyclin. Aspirin is difficult to give to an obtunded or comatose patient, and we discourage nasogastric tube placement for this purpose because of the risk of bleeding. Dipyridamole can be given intravenously. While larger series have shown that plasma exchange therapy coupled with antiplatelet agents results in complete remission in approximately two thirds of patients,63 antiplatelet therapy is no longer routinely used.

Plasma infusion therapy is useful in many patients, particularly those with chronic relapsing TTP/HUS. While plasma infusion (12 U every 24 hours) can be used acutely in patients at facilities that lack apheresis capability, this therapy should not delay the institution of plasma exchange nor prevent the transfer of the patient to a fully equipped referral unit.

Platelet transfusion is relatively contraindicated in TTP, because of clinical evidence that it is associated with relapse.64 If a diagnosis of TTP has been made, we do not recommend routine use of platelet support, except during invasive procedures. Heparin has been advocated for patients with HUS, but a randomized trial in pediatric patients failed to show benefit.65 Supportive therapy for HUS often requires renal dialysis, and plasma exchange may be considered for patients with HUS and rapid disease progression.40

Therapy with rituximab, a chimeric anti-CD20 monoclonal antibody directed against B lymphocytes, along with cyclophosphamide therapy has been described to successfully treat a patient with TTP/HUS that was chronically refractory (more than 2 years) to previously administered therapies including apheresis, steroids, splenectomy, vincristine, and cyclosporine therapy.66 This patient had a severe deficiency of vWFCP (ADAMTS13) activity and an antibody to ADAMTS13. Even during periods of clinical hematologic remission, the anti-ADAMTS13 was detectable and the ADAMTS13 levels remained low. Two courses of cyclophosphamide followed by rituximab therapy subsequently resulted in sustained clinical remission, along with disappearance of the ADAMTS13 inhibitor and detectable levels of ADAMTS activity (>17%) after more than 18 months of follow-up (see Fig. 70-2).

Despite a recent single-institution report of a 91% survival rate in patients with TTP,61 a review of 52 patients treated over 10 years at our own institution revealed a 33% mortality from TTP/HUS.51 This is in the same range as a 22% mortality rate reported in a Canadian clinical trial of plasma exchange in patients with TTP.14 A recent review of mortality data in the United States indicated that, despite a reduction in mortality related to TTP from nearly 100% of cases before the era of plasma exchange to an approximately 70% survival rate currently, the incidence of TTP-related deaths in the United States has increased over time.3 African-Americans and African-American females in particular, are affected disproportionately. The increased incidence of HIV infection and related disease has contributed to some of the increase in TTP mortality in recent years, but it does not completely explain most of the increase, which began before the onset of the HIV epidemic.