Purpura, thrombotic thrombocytopenic

Thrombotic thrombocytopenic purpura (TTP) is an uncommon syndrome resulting from diffuse occlusion of small arterioles and capillaries by hyaline microthrombi. It is characterized by fever, thrombocytopenic purpura, microangiopathic hemolytic anemia, and neurologic and renal dysfunction. While cardiac pathology in TTP is commonly seen at autopsy, clinical cardiac dysfunction is rare and typically results from conduction system involvement. While 3% to 8% of patients with TTP report chest pain on admission, reports of fatal ventricular pump failure are extremely rare. We now report a case of TTP resulting in death from widespread myocardial necrosis. This patient presented with elevated cardiac enzymes and electrocardiographic disturbances that mimicked viral myocarditis, as well as a profound thrombocytopenia. Such a case may represent the extreme of a distribution of cardiac involvement in TTP or the consequence of an unidentified autoimmune process capable of precipitating severe myocardial TTP.

(Arch Pathol Lab Med. 1999;123:937-940)

Thrombotic thrombocytopenic purpura (TTP) is a rare syndrome of unknown etiology, classically characterized by the clinical pentad of fevers, microangiopathic hemolytic anemia, thrombocytopenia, and neurologic and renal dysfunction. Only 40% of patients exhibit all the features, rendering this a difficult diagnosis that may be missed by clinicians unfamiliar with the syndrome. The pathology of TTP is well described, consisting of widespread ischemic damage caused by hyaline thrombi present in the terminal arterioles and capillaries of many organs. These thrombi consist predominantly of aggregated platelets with little fibrin, leading to the hypothesis that TTP is the result of an abnormal interaction between endothelia, platelets, and von Willebrand factor.1,2

The etiology of TTP remains obscure, although recent reports have implicated abnormal high-molecular-weight von Willebrand factor multimers.3,4 Under high shear stress, these multimers may cause spontaneous platelet aggregation and thrombi formation. The closely related hemolytic-uremic syndrome (HUS) is strongly correlated with gastroenteritis caused by cytotoxin-producing strains of Escherichia coli or Shigella organisms. These Shiga toxins are directly cytotoxic to endothelia, an effect that may lead to platelet activation and thrombi formation in vivo. In contrast, TTP is most commonly sporadic. Predisposing factors include prior viral infections, cyclosporine therapy, chemotherapy, or various autoimmune diseases that have been implicated but are uncommonly identified.

A diffuse disease, TTP affects multiple organ systems. The brunt of the disease is manifest in neuropathy (including headache, confusion, paresis, and dysphasia) and renal dysfunction (including hematuria, proteinuria, and azotemia); however, involvement of the heart, pancreas, spleen, adrenals, and other organs is well described. Cardiac involvement, in particular, may lead to conduction defects or signs and symptoms of coronary artery occlusion.5-7 While 3% to 8% of patients may present with chest pain on admission8,9 and cardiac involvement is commonly seen at autopsy, reports of cardiac pump failure due to TTP are rare.10,11 Here we describe a fatal case of TTP in a patient whose initial presentation was of profound thrombocytopenia with signs and symptoms of diffuse myocarditis.

REPORT OF A CASE

A 47-year-old postmenopausal Dominican woman presented to the emergency department with 2 days of gross hematuria and back pain. Three months prior, she had been admitted for chest pain, but a myocardial infarction was ruled out. Six weeks later, during an emergency department visit for anxiety, microscopic hematuria, a hematocrit of 0.37, and platelet count of 380 x 10^sup 9^/L were noted. Eight days prior to admission, the patient developed fatigue and subjective fevers. Minor dental bleeding was also noted 2 days prior to admission. At this time she reported no headache, motor deficits, difficulty speaking, nausea, vomiting, abdominal pain, or chest pain. Medical history was notable for hypertension and echocardiographically determined left ventricular hypertrophy.

In the emergency department, the patient was noted to be obese, afebrile, and of clear mental status. Her pulse rate was 110/min and regular, with a blood pressure of 160/90 mm Hg. Petechiae were noted on her upper back. Her examination findings were otherwise notable only for a previously described II /VI systolic murmur across the precordium. Renal computed tomographic scan revealed no evidence of hydroureter, hydronephrosis, or renal mass. When her laboratory results revealed a hematocrit of 0.36 without schistocytes and a platelet count of 3 x 10^sup 9^ / L, she was admitted for possible idiopathic thrombocytopenic purpura. Prednisone (60 mg/d) was started.

On further interview, she reported diffuse and disabling myalgias. Creatine kinase (CK) levels were 547 U /L, with MB fraction of 33.4 U/L (6.1%) and cardiac troponin I of 22.8 (mu)g/L (normal

Echocardiography indicated left ventricular hypertrophy with an estimated ejection fraction of 75% and 2 small left ventricular wall motion abnormalities. An electrocardiogram was unchanged from 5 months prior. On day 2, the patient developed 2 bouts of chest pain, with an electrocardiogram revealing nonspecific T-- wave changes. On day 3, she developed increasing lethargy. Her hematocrit had declined to 0.24 and a peripheral blood smear indicated 5% to 10% schistocytes. The diagnosis of TTP was made, with the elevation of cardiac enzymes left unexplained. Daily single-volume plasmapheresis with replacement with cryopoor fresh-frozen plasma was started.

Serologic analysis at this time showed the following: antinuclear antibodies of 1:80 (mouse liver) and 1:160 (hep-2), positive anti-RNP negative anti-DNA, negative anti-DNA, negative anti-Sm, negative antiplatelet antibodies, negative rheumatoid factor, and negative anticardiolipin antibodies. By day 4, she was disoriented, her hematocrit remained unchanged despite blood transfusions, and she became febrile to 38.6 deg C. The CK and CK-MB levels had risen to 963 U/L and 55.9 U/L, respectively. On the morning of day 5, the patient's oxygen saturation abruptly declined to 80% on 40% face mask, and she was intubated. Despite oxygen saturation of more than 90%, her systolic blood pressure declined to 70 mm Hg shortly thereafter. Cardiac monitor tracings showed QRS prolongation that responded to calcium chloride, insulin, and sodium bicarbonate. Two-dimensional echocardiography now revealed global right ventricular and left ventricular dysfunction with an estimated left ventricular ejection fraction of 35% to 40% and a small pericardial effusion. Other laboratory findings included hematocrit of 0.27, platelet count of 3 x 10^sup 9^/L, CK/CK-MB of 2484/42.8 U/L, urea nitrogen of 16.1 mmol/L (45 mg/dL), creatinine of 221 (mu)mol/L (2.5 mg/dL), and potassium of 5.2 mmol/L. Despite fluids and pressors, the patient was unable to maintain adequate blood pressure, developed electromechanical dissociation, and died 2 hours after intubation.

AUTOPSY FINDINGS

At autopsy, scattered mucocutaneous petechiae were present. Multiple macroscopic and microscopic areas of hemorrhagic necrosis were present in the myocardium of both ventricles (Figure 1) but particularly common in the right ventricle. These showed early polymorphonuclear cell infiltrates, suggesting their presence of 1 to 2 days. Further findings were an area in the posterior inferior left ventricle (0.5 cm) that showed myocardial necrosis with hemosiderin-laden macrophages present, suggesting a duration of approximately 5 days, and an area of diffuse scarring (1.0 cm) in the posterior papillary muscle, consistent with an old infarct. Adjacent to and within the areas of necrosis were hyalinized arteriolar microthrombi (Figure 2) that stained poorly for fibrin and contained large amounts of von Willebrand factor by immunoperoxidase staining (data not shown). Additional cardiac pathology included cardiomegaly (1010 g) with 4-chamber hypertrophy and dilatation with asymmetric septal hypertrophy (4 cm in maximal thickness) and postinflammatory scarring of the mitral and aortic valve leaflets with superimposed nonbacterial thrombotic endocarditis. Annular calcifications of the mitral valve were present. Focal thickening and fusion of 1 commissure of the aortic valve caused deformation of the left ventricular outflow tract. Also present were focal chronic pericarditis, a right atrial venous malformation, and a congenital 4-cusped pulmonary valve. There was no evidence of myocarditis and only mild coronary atherosclerosis. The absence of myocyte disarray in the subaortic region of the interventricular septum ruled out idiopathic hypertrophic subaortic stenosis as the etiology of the documented asymmetric septal hypertrophy. Multifocal acute cerebral infarcts associated with hyaline microthrombi were present. Hyaline microthrombi and areas of hemorrhagic necrosis were also present in the pancreas and kidneys, and there was massive acute hepatic necrosis.

COMMENT

The first description and illustration of hyaline microthrombi in TTP were of cardiac pathology.1 Cardiac involvement in TTP is commonly seen at autopsy,5,6 typically consisting of scattered, focal intramyocardial hemorrhages and hyaline arteriolar occlusions but only minimal myocardial necrosis.6 Serum cardiac enzyme elevations have only been reported sporadically.10,11 While congestive heart failure can occur,6,10,12 cardiac deaths are generally attributed to arrhythmias.6,7,13 We have, however, identified 2 well-documented cases of TTP where death was attributed to pump failure.10,11 As in the present case, both showed extensive myocardial hemorrhages at autopsy, and one had antemortem elevations in creatine kinase.11 It is possible that these cases merely represent the extreme of a distribution and that clinically detectable myocardial disease, secondary to randomly located foci of hemorrhagic necrosis, occurs in TTP more commonly than is generally recognized.6,10

Alternatively, clinically important cardiac dysfunction is unusual and may require the presence of a coexisting process. While left ventricular hypertrophy has been previously offered as a possible predisposing factor in the onset of widespread myocardial necrosis in TTP,11 only the current case had this manifestation. A second possibility would be that of an autoimmune process involving the heart. Although nonbacterial thrombotic endocarditis occurs in TTP,8 the valvular lesions are reminiscent of those that can occur with systemic lupus erythematosus (SLE) and, occasionally, other rheumatologic disorders. Chronic pericarditis and elevated levels of antinuclear and anti-- RNP antibodies are additional findings suggesting a chronic autoimmune process in this patient. Association of TTP with autoimmune disorders has been reported.14,15 The patient's serologic findings-particularly the positive anti-RNP, negative anti-DNA, and negative anti-Sm findings-are most consistent with a mixed connective tissue disease (MCTD).16 Cardiac involvement is common in this syndrome, most often manifesting as pericarditis and mitral valve prolapse.17,18 In SLE, while attention has focused more on the association between myocardial damage and anticardiolipin antibodies (which were negative in the present case),19 a loose association between myocarditis and anti-RNP antibodies has also been suggested.20 However, neither valvular pathology nor myocardial damage is a typical finding in MCTD, and neither of 2 previous cases of TTP arising in the context of MCTD entailed such cardiac pathology.21,22 Moreover, neither of the 2 prior cases of cardiac pump failure in TTP entailed structural cardiac evidence of an autoimmune disorder, although 1 patient did exhibit a weak antinuclear antibody titer and positive rheumatoid factor.11 Thus, while our patient's positive anti-RNP titers are suggestive, they do not appear sufficient to explain her fulminant cardiac demise.

Recent reports suggest3,4 that nonfamilial TTP may be caused by an IgG antibody directed against a plasma von Willebrand factor cleaving enzyme, while familial forms are due to a congenital lack of the protease enzyme. Deficiency of the enzyme leads to accumulation of high-molecular-weight multimers that cause spontaneous platelet aggregation under high shear stress conditions. If so, then nonfamilial TTP may be considered an autoimmune process, as either a distinct entity or part of other autoimmune syndromes.

Recovery from TTP-related heart failure has been reported.10 These patients underwent plasmapheresis and showed evidence of recovery of left ventricular function over 1 to 4 weeks. Our patient did not develop sufficient clinical criteria to diagnose TTP until late in her clinical course; daily plasmapheresis did not influence her progressive decline. The difficulty of diagnosing TTP is widely recognized, as only 40% of patients will eventually display the classic clinical pentad.9 Whether unexplained cardiac enzyme elevations with profound thrombocytopenia should be considered an indication for plasmapheresis-- both in the context of a known autoimmune disorder and otherwise-is currently unknown. However, as this case illustrates, the coexistence of these 2 abnormalities should raise the possibility of TTP as a unifying diagnosis.

We thank W. Hallowell Churchill, MD, David Golan, MD, David Tuveson, MD, Alfonso Brown, MD, Esteban Burchard, MD, Jon Baker, MD, Jean Cabral RN, and the staff of the medical intensive care unit for their help in the preparation of this article.

References

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Accepted for publication March 19, 1999.

From Harvard Medical School (Mr Podolsky), and the Department of Pathology (Drs Zembowicz, Schoen, and Benjamin) and the Division of Pulmonary and Critical Care Medicine (Dr Sonna), Brigham and Women's Hospital, Boston, Mass.

Reprints: Richard J. Benjamin, MB ChB, PhD, Department of Pathology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.

Copyright College of American Pathologists Oct 1999
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