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Thrombospondin as an early marker of acute coronary syndromes

Three Part Question

In [patients with suspected cardiac chest pain presenting to the Emergency Department] does [measurement of plasma thrombospondin] enable [exclusion of acute coronary syndrome]?

Clinical Scenario

A forty-five year-old businessman presents to the Emergency Department with vague central chest pain for the past 2 hours. ECG is normal and you refer for troponin testing. He is very dissatisfied at having to be admitted and considers taking his own discharge.
You wonder if there is a better way to exclude an acute coronary syndrome without having to admit for over 12 hours. Knowing that platelet activation is key to the pathogenesis of acute coronary syndromes and, having heard that thrombospondin may be a marker of this, you wonder if measurement of thrombospondin would allow earlier exclusion of acute coronary syndrome.

Search Strategy

OVID Medline 1966 - 2005 August Week 3
OVID Embase 1980 - 2005 Week 32
CINAHL 1982 - 2005 August Week 4
[exp Myocardial Infarction/ OR exp Angina, Unstable/ OR exp Coronary Thrombosis/ OR (myocard$ adj (infarct$ OR ischem$ OR ischaem$)).mp. OR (acute coronary syndrome OR ACS OR AMI OR MI).mp.] AND [exp Thrombospondin/ OR (thrombospondin$ OR TSP$).mp.] limit to human and English language

Search Outcome

28 papers were identified in Medline, of which 1 was relevant.
43 papers were identified in Embase, of which 1 was relevant.
No papers were identified in CINAHL.
In total, one relevant paper was identified.

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses
Ffrench et al
51 healthy controls and 28 patients with myocardial infarction, within 24 hours of onset of thoracic pain.Prospective diagnostic cohortThrombospondin level in controls (to establish an upper limit of normal)Mean 54 +/- 15.7ng/ml (apparently 95% CI). Upper limit of normal taken as 79.7ng/ml (no explanation, see below)Small numbers Baseline characteristics, other than gender, not reported. Unmatched controls and cases (controls 71% female; cases 11% female). No robust diagnostic criteria for diagnosis of MI ("conventional" ECG and enzymatic criteria used). CPK and transaminases gold standard biochemical markers for MI - now outdated. Incongruous reporting of data. Thrombospondin in controls 54+/-15.7ng/ml. If this is the range, the scatter graph is plotted inaccurately. If it is the 95% CI, the normal range (79.7ng/ml) was calculated incorrectly, which could significantly change the conclusions drawn. Use of antiplatelet therapy not reported. 14 patients (50%) received heparin for >2 hours before blood sampling.
Thrombospondin levels in cases v. controlsSignificantly higher in cases v. controls (P<0.001). However, 54% of cases had results within the established normal range.


Thrombospondin (TSP) is a large matricellular protein with diverse functions. It is a major constituent of platelet alpha granules and is released upon platelet activation. Plasma levels have been shown to increase 170-fold following in vitro platelet activation (Dawes et al, 1983). In addition, TSP is secreted by endothelial cells (Mosher et al, 1982) and fibroblasts (Jaffe et al, 1983). TSP has several atherogenic actions, arresting growth of endothelial cells and inhibiting angiogenesis (Bagavandoss et al, 1990; Taraboletti et al, 1990; Good DJ et al, 1990), while promoting vascular smooth muscle cell growth and migration (Majack et al, 1986) and stimulating platelet activation and aggregation (Tuszynski et al, 1988). Its expression is rapidly upregulated at the sites of arterial injury and thrombus formation (Chen et al, 1999; Perlman et al, 1987). It is therefore plausible that plasma TSP levels may be increased in patients with ACS. However, only one small study with several significant weaknesses has investigated this possibility. The study demonstrated significantly higher TSP levels in patients with AMI than in controls. Although 54% of patients were reported as having levels within the normal range, it is not entirely clear how the 'normal range' was established and there are significant limitations to the now-outdated gold-standard diagnosis for AMI using CPK as the cardiac enzyme of choice. In addition to the published evidence, the author is aware of one as-yet unpublished study, which has investigated 34 patients with ACS and 24 patients with non-cardiac chest pain (McDowell et al, 2005). Results are awaited in the near future. There is a sound pathophysiological basis for use of TSP as a marker of ACS. In order to develop an early-rule out strategy for ACS for use in the Emergency Department, it is highly probable that a multimarker strategy is necessary to optimise sensitivity and negative predictive value. TSP may be a useful marker to incorporate into such a strategy. Combination with markers released in relation to other elements of the pathophysiological evolution of ACS may be useful.

Editor Comment

Abbreviations: MI: myocardial infarction; ACS: acute coronary syndrome; AMI: acute myocardial infarction; CPK: creatine phosphokinase

Clinical Bottom Line

There is a sound pathophysiological basis for the use of TSP as an early cardiac marker, but little research has been conducted in this area. Further research is required.

Level of Evidence

Level 3 - Small numbers of small studies or great heterogeneity or very different population.


  1. Ffrench P; McGregor JL; Berruyer M; Belleville J; Touboul P; Dawes J; Dechavanne M. Comparative evaluation of plasma thrombospondin, beta-thromboglobulin and platelet factor 4 in acute myocardial infarction Thrombosis Research 1985; 39: 619-624
  2. Dawes J; Clemetson KJ; Gogstad GO; McGregor J; Clezardin P; Prowse CV; Pepper DS. A radioimmunoassay for thrombospondin, used in a comparative study of thrombospondin, beta-thromboglobulin and platelet factor 4 in healthy volunteers Thrombosis Research 1983; 29: 569-581
  3. Mosher DF; Doyle MJ; Jaffe EA. Synthesis and secretion of thrombospondin by cultured human endothelial cells Journal of Cell Biology 1982; 93: 343-348
  4. Jaffe EA; Ruggiero JT; Leung LLK; Doyle MJ; McKeown-Longo PJ; Mosher DF. Cultured human fibroblasts synthesise and secrete thrombospondin and incorporate it into extracellular matrix Proc Natl Acad Sci USA 1983; 80: 998-1002
  5. Bagavondoss P; Wilks JW. Specific inhibition of endothelial cell proliferation by thrombospondin Biochemical and Biophysical Research Communications 1990; 170(2): 867-872
  6. Taraboletti G; Roberts D; Liotta LA; Giavazzi R Platelet thrombospondin modulates endothelial cell adhesion, motility and growth: a potential angiogenesis regulatory factor Journal of Cell Biology 1990; 111: 765-772
  7. Good DJ; Polverini PJ; Rastinejad F; Le Beau MM; Lemons RS; Frazier WA; Bouck NP. A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin Proc Natl Acad Sci USA 1990; 87: 6624-6628
  8. Majack RA; Cook SC; Bornstein P. Control of smooth muscle cell growth by components of the extracellular matrix: Autocrine role for thrombospondin Proc Natl Acad Sci USA 1986; 83: 9050-9054
  9. Tuszynski GP; Rothman VL; Murphy A; Siegler K; Knudsen KA. Thrombospondin promotes platelet aggregation Blood 1988; 72(1): 109-115
  10. Chen D; Asahara T; Krasinski K; Witzenbichler B; Yang J; Magner M; Kearney M; Frazier WA; Isner JM; Andres V. Antibody blockade of thrombospondin accelerates reendothelialization and reduces neointima formation in balloon-injured rat carotid artery Circulation 1999; 100: 849-854
  11. Perlman SB; Folts JD; Hammes RJ; Besozzi MC; Mosher DF. The accumulation of a platelet protein, thrombospondin, at the site of arterial thrombus formation: preliminary report European Journal of Nuclear Medicine 1987; 12: 492-495
  12. McDowell G; Gupta S; Densem C; Saha A; Levy RD; Keevil BG. The clinical utility of circulating plasma levels of thrombospondin and cellular adhesion molecules in the diagnosis of the acute coronary syndromes Unpublished 2005