Underestimated complications in thrombotic thrombocytopenic purpura—haemolytic uraemic syndrome

Vincent M. Brandenburg1, Sören Gaertner1, Katharina Lindemann-Docter2, Jan R. Ortlepp3, Ralf Westerhuis1, Markus Ketteler1, Ralf Westenfeld1 and Jürgen Floege1

1 Department of Nephrology, 2 Department of Pathology and 3 Department of Cardiology, University Hospital Aachen, Aachen, Germany

Correspondence and offprint requests to: Dr med. Vincent M. Brandenburg, Medizinische Klinik II, Universitätsklinikum der RWTH Aachen, Pauwelsstrasse 30, 52057 Aachen, Germany. Email: vincent.brandenburg{at}post.rwth-aachen.de

Keywords: cardiogenic shock; haemolytic uraemic syndrome; hyaline thrombus; myocardial infarction; thrombotic thrombocytopenic purpura



   Introduction
 Top
 Introduction
 Case reports
 Discussion
 Teaching points
 References
 
Thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome (TTP-HUS) represent clinical entities with the common findings: consumptive thrombocytopenia, microangiopathic haemolytic anaemia, intravascular fibrin/platelet thrombus formation and consecutive organ dysfunction. Although overlaps exist, traditionally, the TTP (Moschcowitz syndrome with predominant central nervous system involvement) and the HUS (Gasser syndrome with predominant renal involvement) have been differentiated on clinical grounds.

The introduction of plasmapheresis has provided substantiated benefit in terms of survival rate and the mortality rate of TTP-HUS has been reduced from over 90% to ~15–20% [1–3]. However, despite the rapid initiation of up-to-date therapy, TTP-HUS remains a potentially life-threatening disorder. The causes of death depend on the variability of vital organ affection (e.g. the central nervous system or myocardial involvement). We describe two patients with fatal TTP-HUS, in whom autopsy confirmed widespread myocardial hyaline thromboses correlating well to the clinical picture of acute myocardial infarction and therapy-resistant cardiogenic shock.



   Case reports
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 Introduction
 Case reports
 Discussion
 Teaching points
 References
 
Clinical courses
Two Caucasian men (patients A and B) with sporadic, idiopathic TTP, died of cardiogenic shock during a fulminant episode of TTP. Signs of microvascular haemolytic anaemia (absent haptoglobin, anaemia with LDH and bilirubin elevation, schistocytes in peripheral blood smears) as well as central nervous system involvement were present in both, while creatinine levels were only elevated in patient B (maximal serum creatinine 1.7 mg/dl, normal range 0.7–1.2). Both were markedly hypertensive upon admission. After an initial phase of stabilization with daily plasmapheresis the clinical situation rapidly deteriorated. Hence, twice daily plasmapheresis as well as prednisolone therapy (1 mg/kg body weight) were initiated. Each plasmapheresis session was performed using fresh frozen plasma with an exchange volume of 40–50 ml/kg body weight.

Patient A
Patient A was a 50-year-old man, in whom TTP was diagnosed 8 years ago. At that time he suffered from a right-sided medial and posterior cerebral infarction with transient hemiparesis and hemianopsia. Neurological recovery afterwards was complete. Subsequently, eight relapses had been recorded, all characterized by thrombocytopaenia and haemolytic anaemia but no additional neurological complications or renal function disturbances. Each was treated with repetitive plasmapheresis. Three years ago the von Willebrand-Factor cleaving protease (ADAMTS13) activity was 13% of the normal value. Two years ago, elevated levels of troponine I (up to 5 µg/l, normal level <1.0) were measured during a relapse. No other signs of myocardial damage could be detected at that time and echocardiography did not show pathological results. Finally, remission time between relapses decreased to <1 month. Hence, prednisolone (20 mg/day) and vincristine (cumulative dosage 4 mg) therapy was started 2 months ago. Table 1 gives an overview of the laboratory and clinical findings during the current hospital stay.


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Table 1. Compendium of the disease course in patient A

 


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Fig. 1. Cranial computed tomography scan of patient A showing several areas of territorial infarctions of the middle and posterior cerebral artery.

 
Patient B
A 51-year-old previously healthy man was admitted to our hospital because of seizures. Based on the interpretation of the laboratory tests the presumed diagnosis was TTP. Plasmapheresis was initiated immediately. ADAMTS13 activity was not measured. Table 2 gives an overview of the laboratory findings as well as the clinical course of patient B.


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Table 2. Compendium of the course of patient B

 


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Fig. 2. Twelve-lead electrocardiogram (50 mm/s, 10 mm = 10 mV) of patient B revealing anterior ST-segment elevation myocardial infarction.

 
Cardiac autopsy findings
The heart of patient A was enlarged and weighted 480 g, the left ventricular wall was thickened (17 mm). Macroscopically, the left posterior myocardium showed a 6 x 7 cm large yellowish pale discolouration; multiple smaller similar areas were found in the left anterior myocardium. These findings corresponded microscopically to multiple areas of necrosis (estimated to be 6–12 h old) and scarring of the myocardium of both ventricles, suggesting recurrent ischaemic events with a more acute myocardial infarction. No significant coronary sclerosis was detectable.

Patient B had a normal sized heart weighting 310 g. Both ventricle walls were thickened (left ventricle 17 mm, right ventricle 6 mm). Seventy millilitres of serous pericardial effusion was present. The left anterior myocardium displayed a 1.5 x 1.5 cm and the left posterior myocardium a 3 x 2.5 cm sized pale yellow area. The microscopic examination revealed recent necrosis (<6 h) of single myocytes as well as groups of myocytes, suggesting an acute infarction as the cause of death. The left anterior descending artery presented with atherosclerotic lesions but without significant stenosis. The other coronary arteries did not show coronary sclerosis.

The epicardium and endocardium of patients A and B revealed multiple disseminated petechial haemorrhages, that could also be detected in large areas of the left and right ventricular myocardium. The microscopical examination of both hearts showed multiple hyaline microthrombi in intramural arterioles and capillaries (patient A: Figure 3, colour image in online Supplementary Material). The microthrombi stained strongly in the PAS reaction and contained large amounts of von Willebrand factor.



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Fig. 3. Patient A: left ventricular myocardium showing hyaline microthrombi within small arterioles as well as adjacent areas of myocardial necrosis and scarring (haematoxylin–eosin, original magnification x50).

 
In addition, hyaline intravascular microthrombi could also be detected in the adrenal gland, kidneys, liver and pancreas of patient B.



   Discussion
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 Introduction
 Case reports
 Discussion
 Teaching points
 References
 
The knowledge about cardiac involvement in TTP-HUS is as old as Moschcowitz's first description of the entity 100 years ago [4]. On autopsy of a 16-year-old girl, he found widespread thrombotic occlusion of the arterioles and capillaries in the heart, the kidneys and other internal organs. The aim of the present review was to focus on myocardial involvement in TTP-HUS.

Premortem presentation
The exact incidence of cardiac involvement in TTP-HUS and its clinical impact are not known. Even detailed reviews about TTP-HUS infrequently provide conclusive data about cardiac involvement in this disorder. Typical clinical signs and complaints related to myocardial infarction are rarely reported in the TTP-HUS literature: In the largest cohort of TTP-HUS patients published so far (275 patients) [1] chest pain as a hint for cardiac involvement was described in only 6% of all patients. Some anecdotes of myocardial infarctions were reported previously as the clear cause of death in TTP-HUS [5,6]. Interestingly, none of these reports described premortem chest discomfort. On the other hand, in a small prospective evaluation among patients with TTP-HUS three out of 10 revealed clinical signs of myocardial infarction intravitam (i.e. angina pectoris, ECG changes, positive troponine I measurements) [7]. In summary, both the clinical signs and symptoms as well as the clinical findings vary substantially. Based on the available literature reports, it is currently impossible to distinguish the impact of either arrhythmia or pump-failure related mortality in TTP-HUS from other causes of death, e.g. central nervous system involvement.

Postmortem findings
While clinical judgement may underestimate cardiac involvement, the true dimension is finally elucidated by autopsy: Ridolfi et al. [8] summarized 17 autopsies in cases of TTP-HUS. All patients had tachycardia, 53% had signs of left- of right-sided congestive heart failure, 35% had suspicious ECG changes and 18% had hypotension during the course of the disease. However, the authors stated that ‘problems related to cardiac function were not a major feature of the clinical course of most patients’. Remarkably, histology revealed in all patients myocardial thrombotic involvement graded mild (24%), moderate (29%) and severe (47%) based on the number of affected small vessels. Moreover, only the pancreas and the adrenal glands were more constantly affected by microvascular thromboses. Cuttner [9] reported upon 19 cases of TTP-HUS, of whom seven died. Among three autopsies performed all had ‘extensive intravascular thrombi in the heart’ and two had myocardial infarctions as a significant contributing factor to death. Bell et al. [10] found that widespread myocardial hyaline thrombi were the likely cause of sudden unexpected death in eight patients with TTP-HUS. Interestingly, compared with the wide dissemination of these microscopic lesions, evidence of macroscopic myocardial damage (i.e. haemorrhage or frank necrosis) was only rarely detected [1,8]. The heart conduction system was involved in 70% of TTP-HUS cardiac autopsies in previous reports [8]. However, relevant conduction system abnormalities only occurred in 20% of these patients during their life-time (bradycardia, AV-dissociation).

Prevention and treatment
It appears obvious that severe cardiac involvement reduces the prognosis in TTP-HUS. However, resolution of cardiac dysfunction and even survival of frank cardiogenic shock with intensive ICU therapy and plasmapheresis has been reported [7]. In the future, the ability to monitor serum levels of highly specific cardiac tissue markers (e.g. troponins) may simplify the diagnosis of cardiac involvement in TTP-HUS. Therefore, we speculate that the systematic application of the up-to-date definitions of acute coronary syndromes might increase the incidence of premortem diagnosis of cardiac involvement in TTP-HUS.

What are the therapeutic options for TTP-HUS related cardiac damage? In the absence of prospective and controlled trials on cardiac TTP-HUS involvement we suggest close monitoring of cardiac involvement by daily ECG recordings and measurements of serum markers of myocardial cell damage in all patients. This close monitoring should continue for the duration of plasmapheresis therapy, i.e. as long as thrombocytopenia and haemolysis are present. If cardiac cell damage has been detected, telemetric surveillance is advisable for early detection of arrhythmias.

It warrants mentioning that modern therapeutic strategies for atherosclerotic acute coronary syndromes, e.g. the application of antiplatelet agents and heparins have not proven to be effective in TTP-HUS patients. Moreover, since ticlopidine and clopidogrel have been identified as a potential cause of TTP-HUS, their application cannot be recommended during an acute attack. Since prospective data are missing, plasmapheresis is still regarded as the mainstay of therapy in TTP-HUS independent of the organ involved.



   Teaching points
 Top
 Introduction
 Case reports
 Discussion
 Teaching points
 References
 

  1. Histological examination reveals cardiac involvement (hyaline thrombi) in virtually all deceased patients with TTP-HUS.
  2. Data on the clinical presentation of cardiac involvement in TTP-HUS are scarce. Judge-ment on clinical grounds appears to be insuffi-cient due to the danger of ‘silent’ myocardial damage.
  3. Cardiac involvement contributes significantly to mortality and morbidity in TTP-HUS.
  4. Therefore, daily monitoring for myocardial cell damage and arrhythmias is warranted during the acute phase of TTP-HUS.
  5. Currently, plasmapheresis remains the mainstay of therapy in cardiac involvement in analogy to other organ involvement in TTP-HUS.

Conflict of interest statement. The authors declare that there is no conflict of interest whatsoever with this manuscript. None of the authors have had involvements that might raise the question of bias in the work reported or in the conclusions, implications or questions stated.



   References
 Top
 Introduction
 Case reports
 Discussion
 Teaching points
 References
 

  1. Ridolfi RL, Bell WR. Thrombotic thrombocytopenic purpura. Report of 25 cases and review of the literature. Medicine (Baltimore) 1981; 60: 413–428[ISI][Medline]
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  3. Bell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med 1991; 325: 398–403[Abstract]
  4. Moschcowitz E. An acute febrile pleiochromic anemia with hyaline thrombosis of the terminal arterioles and capillaries. Arch Intern Med 1924; 36: 89–93
  5. Podolsky SH, Zembowicz A, Schoen FJ, Benjamin RJ, Sonna LA. Massive myocardial necrosis in thrombotic thrombocytopenic purpura: a case report and review of the literature. Arch Pathol Lab Med 1999; 123: 937–940[ISI][Medline]
  6. Eagle KA, Fallon JT. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 33-1994. A 41-year-old woman with thrombocytopenia, anemia and sudden death. N Engl J Med 1994; 331: 661–667[Free Full Text]
  7. McCarthy LJ, Danielson CF, Skipworth EM, Peters SL, Miraglia CC, Antony AC. Myocardial infarction/injury is relatively common at presentation of acute thrombotic thrombocytopenic purpura: the Indiana University experience. Ther Apher 2002; 6: 2–4[CrossRef][ISI][Medline]
  8. Ridolfi RL, Hutchins GM, Bell WR. The heart and cardiac conduction system in thrombotic thrombocytopenic purpura. A clinicopathologic study of 17 autopsied patients. Ann Intern Med 1979; 91: 357–363[ISI][Medline]
  9. Cuttner J. Thrombotic thrombocytopenic purpura: a ten-year experience. Blood 1980; 56: 302–306[Abstract]
  10. Bell MD, Barnhart JS Jr, Martin JM. Thrombotic thrombocytopenic purpura causing sudden, unexpected death—a series of eight patients. J Forensic Sci 1990; 35: 601–613[ISI][Medline]




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