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Hamostaseologie 1996; 16(02): 144-150
DOI: 10.1055/s-0038-1656649
Übersichtsarbeiten/Review Articles
Schattauer GmbH

Megakaryocytes and Platelets in Diabetes Mellitus

D. Tschöpe
1   Diabetes Research Institute at the Heinrich Heine University, Düsseldorf
,
E. Lampeter
1   Diabetes Research Institute at the Heinrich Heine University, Düsseldorf
,
B. Schwippert
1   Diabetes Research Institute at the Heinrich Heine University, Düsseldorf
› Author Affiliations
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Publication History

Publication Date:
23 July 2018 (online)

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Summary

In patients with diabetes mellitus vascular diseases and related complications still represent the main cause of death. Neuropathy, nephropathy, retinopathy and disturbed nutritive tissue perfusion result from reduced capillary microcirculation. Macroangiopathic mechanisms lead to accelerated cerebral, coronary and peripheral artery disease precipitating life terminating thrombotic events superimposed to those vascular lesions. Thus morbidity and mortality depend mainly on vascular complications. The functional thromboresistance is reduced in the diabetic state with hyperactive platelets operating by three mechanisms: 1) microembol-isation of the capillaries; 2) local progression of preexisting vascular lesions by secretion of constrictive, mitogenic and oxidative substances; 3) trigger of the prognosis limiting arterial thrombotic event. The increased functional properties of di-abetic platelets result from the primary release of larger platelets with enhanced thromboxane formation capacity and increased numbers of functional glycoprotein receptors GPIb and GPIIb-llla which are synthesized in the megakaryocytes. It could be demonstrated with the Düsseldorf III method of flowcytometric activation marker testing (CD62, CD63, thrombospondin) that predominantly large platelets circulate in an activated state even in very early (pre)diabetic stages sug-gesting that the megakaryocyte-platelet system might be systemically affected. Based on these observation a "stem cell hypothesis" is developed which suggests that bone marrow derived platelets may be systemically involved in the pathogenesis of the vascular complications and eventually of type-l diabetes. The idea of antiplatelet agents as an useful early adjunct to metabolic therapy is promoted.

Keywords

Platelets - megakaryocytes - flowcytometry - diabetes
 

  • REFERENCES

  • 1 Abrams CHS, Ellison N, Budzynski AZ, Shattil SJ. Direct detection of activated platelets and platelet-derived microparticles in humans. Blood 1990; 75: 128-38
    PubMedGoogle Scholar
  • 2 Antiplatelet Trialist Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988; 296: 310
    CrossrefPubMedGoogle Scholar
  • 3 Banga JD, Sixma JJ. Diabetes mellitus, vascular disease and thrombosis. Clin Haematol 1986; 15: 465-92
    PubMedGoogle Scholar
  • 4 Bath PM, Gladwin AM, Carden N, Martin JF. Megakaryocyte DNA content is increased in patients with coronary artery atherosclerosis. Cardiovasc Res 1994; 28: 1348-52
    CrossrefPubMedGoogle Scholar
  • 5 Bauer KA, Rosenberg RD. The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of hemostatic system activation. Blood 1987; 70: 343-50
    PubMedGoogle Scholar
  • 6 Baumgartner HR, Sakariassen KS. Factors controlling thrombus formation on arterial lesions. Ann NY Acad Sci 1987; 162-77
    PubMedGoogle Scholar
  • 7 Bennett PH. Epidemiology of Diabetes Mellitus. In: Diabetes mellitus. Rifkin H, Prts Jr. D. (eds.) New York: Amsterdam, London: Elsevier; 1990: 249-56
    Google Scholar
  • 8 Brand FN, Abbott RD, Kannel WB. Diabetes, intermittent claudication, and risk of cardiovascular events. The Framingham Study. Diabetes 1989; 38: 504-9
    CrossrefPubMedGoogle Scholar
  • 9 Bransome ED. Financing the Care of Diabetes Mellitus in the U.S. Diab Care 1992; 15 (Suppl. 01) 1-5
    PubMedGoogle Scholar
  • 10 Bray PF, Rosa JP, Johnston GI, Shiu DT, Cook RG, Lau C, Kan YW, McEver RP, Shuman MA. Platelet glycoprotein Ilb/IIIa chromosomal localization and tissue expression. J Clin Invest 1987; 80: 1812-7
    CrossrefPubMedGoogle Scholar
  • 11 Breddin HK, Kryzwanek HJ, Althoff P, Kirchmaier CM, Rosak C, Schepping M, Weichert W, Ziemen M, Schoeffling K, Überla K. Spontaneous platelet aggregation and coagulation parameters as risk factors for arterial occlusions in diabetics. Results of the PARD-study. Int Angiol 1986; 5: 181-95
    PubMedGoogle Scholar
  • 12 Broudy VC, Lin NL, Kaushansky K. Thrombopoietin (cmpl Ligand) acts synergistically with erythropoietin, stem cell factor, and interleukin-11 to enhance murine megakaryocyte colony growth and increase megakaryocyte ploidy in vitro. Blood 1995; 85: 1719-26
    PubMedGoogle Scholar
  • 13 Brown AS, Martin JF. The megakaryocyte platelet system and vascular disease. In: Megakaryocytes and Platelets in Vascular Disease. Schrör K, Rösen P, Tschöpe D. (eds). Eur J Clin Invest 1994; 24 (Suppl. 01) 9-15
    CrossrefPubMedGoogle Scholar
  • 14 Bruno E, Miller ME, Hoffmann R. Interacting cytokines regulate in vitro human megakaryocytopoiesis. Blood 1989; 73: 671-7
    PubMedGoogle Scholar
  • 15 Burstein SA. Effects of interleukin 6 on megakaryocytes and on canine platelet function. Stem Cells 1994; 12: 386-93
    CrossrefPubMedGoogle Scholar
  • 16 Caux C, Saeland S, Favre C, Duvert V, Mannoni P, Banchereau J. Tumor necrosis factor-alpha strongly potentiates interleukin-3 and granulocyte-macrophage colony-stimulating factor-induced proliferation of human CD34+ hematopoietic progenitor cells. Blood 1990; 75: 2292-8
    PubMedGoogle Scholar
  • 17 Ceriello A. Coagulation activation in Diabetes mellitus: the role of hyperglycemia and therapeutic prospects. Diabetologia 1993; 36: 1119-25
    CrossrefPubMedGoogle Scholar
  • 18 Colwell JA. et al. Consensus Statement. Role of cardiovascular risk factors in prevention and treatment of macrovascular disease in diabetes. Diab Care 1989; 12: 573-9
    CrossrefPubMedGoogle Scholar
  • 19 Colwell JA. Clinical Trials of Antiplatelet Agents in Diabetes Mellitus: Rationale and Results. Sem Thromb Hemostas 1991; 17: 439-44
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Diabetes Epidemiology Research International Mortality Study Group. International evaluation of causespecific mortality and IDDM. Diabetes Care 1991; 14: 55-60
    CrossrefPubMedGoogle Scholar
  • 21 DiMinno G, Silver MJ, Cerbone AM, Riccardi G, Rivellese A, Mancini M. Platelet fibrinogen binding in diabetes mellitus. Differences between binding to platelets from nonretinopathic and retinopathic diabetic patients. Diabetes 1986; 35: 182-5
    CrossrefPubMedGoogle Scholar
  • 22 Driesch E, Tschoepe D, Lampeter E, Nieuwenhuis HK, Roesen P, Gries FA. Increased Pselectin expression indicates platelet activation in healthy ICA+ first degree relatives of IDDM pateients. Diabetologia 1993; 36 (Suppl. 01) A45 *
    PubMedGoogle Scholar
  • 23 Dupont H, Dupont MA, Larrue J, Boisseau MR, Bricaud H. Megakaryopoiesis disturbances in atherosclerotic rabbits. Atherosclerosis 1987; 63: 15-26
    CrossrefPubMedGoogle Scholar
  • 24 Early Treatment Diabetic Retinopathy Study Research Group. Effects of Aspirin Treatment on Diabetic Retinopathy. ETRDS Report Number 1991; 8 Ophtalmology 98, Supplement 757-65
    PubMedGoogle Scholar
  • 25 Edmonds M, Brown A, Martin J. Abnormal megakaryocyte-platelet axis in diabetics with peripheral vascular disease. Diabetologia 1994; 37: A91
    CrossrefPubMedGoogle Scholar
  • 26 Fitzgerald DJ, Roy L, Catella F, Fitzgerald GA. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315: 983-9
    CrossrefPubMedGoogle Scholar
  • 27 Gewirtz A. Megakaryocytopoiesis: The state of the art. Thromb Haemost 1995; 74: 204-9
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Giles H, Smith REA, Martin JF. Platelet glycoprotein IIb-IIIa and size are increased in acute myocardial infarction. Eur J Clin Invest 1994; 24: 69-72
    CrossrefPubMedGoogle Scholar
  • 29 Hancock V, Martin JF, Lelchuk R. The relationship between human megakaryocyte nuclear DNA content and gene expression. Br J Haematol 1993; 85: 692-7
    CrossrefPubMedGoogle Scholar
  • 30 Handagama P, Scarborough RM, Shuman MA, Bainton DF. Endocytosis of fibrinogen into megakaryocyte and platelet agranules is mediated by x2ß3 glycoprotein IIb/IIIa. Blood 1993; 82: 135-8
    PubMedGoogle Scholar
  • 31 Hendra TJ, Oswald GA, Yudkin JS. Increased mean platelet volume after acute myocardial infarction relates to diabetes and to cardiac failure. Diabetes Res Clin Pract 1988; 5: 63-9
    CrossrefPubMedGoogle Scholar
  • 32 Hussain MJ, Peakman M, Gallati H, Lo SS, S, Hawa M, Viberti GC, Watkins PJ, Leslie RDG, Vergani D. Elevated serum levels of macrophage-derived cytokines precede and accompany the onset of IDDM. Diabetologia 1996; 39: 60-9
    PubMedGoogle Scholar
  • 33 Ikehara S, Kawamura M, Takao F, Inaba M, Yasumizu R, Than S, Hisha H, Sugiura K, Koide Y, Yoshida TO, Ida T, Imura H, Good RA. Organ-specific and systemic autoimmune disease originate from defects in hematopoietic stem cells. Proc Natl Acad Sci 1990; 87: 8341-4
    CrossrefPubMedGoogle Scholar
  • 34 Jacobs J, Sena M, Fox N. The cost of hospitalization for the late complications of diabetes in the United States. Diab Med 1990; 8: 523-9
    PubMedGoogle Scholar
  • 35 Kanz L, Mielke R, Fauser AA. Aanalysis of human hemopoietic progenitor cells for the expression of glycoprotein IIIa. Exp Haematol 1988; 16: 741-7
    PubMedGoogle Scholar
  • 36 Kristensen S, Martin JF. Platelet heterogeneity and coronary artery thrombosis. Platelets 1991; 2: 11-7
    CrossrefPubMedGoogle Scholar
  • 37 Kojima H, Hamazakki Y, Nagata Y, Todokoro K, Nagasawa T, Abe T. Modulation of platelet activation in vitro by thrombopoietin. Thromb Haemost 1995; 74: 154-5
    PubMedGoogle Scholar
  • 38 Lampeter E, Homberg M, Quabeck K, Schaefer UW, Wernet P, Bertrams J, Grosse-Wilde H, Gries FA, Kolb H. Transfer of insulin-dependent diabetes between HLA-identical siblings by bone marrow transplantation. Lancet 1993; 341: 1243-4
    CrossrefPubMedGoogle Scholar
  • 39 Landgraf-Leurs MMC, Ladik T, Smolka B, Bock T, Schramm W, Spannagl M, Landgraf R. Increased thromboplastic potential in diabetes: A multifactorial phenomenon. Klin Wochenschr 1987; 65: 600-6
    CrossrefPubMedGoogle Scholar
  • 40 Lok S, Foster DC. The structure, biology and potential therapeutic application of recombinant thrombopoietin. Stem Cells 1994; 12: 586-98
    CrossrefPubMedGoogle Scholar
  • 41 Lorenzi M, Cagliero E. Pathobiology of endothelial and other vascular cells in diabetes mellitus. Diabetes 1991; 40: 653-9
    CrossrefPubMedGoogle Scholar
  • 42 Martin JF, Trowbridge EA, Salmon G, Plumb J. The biological significance of platelet volume: its relationship to bleeding time, platelet thromboxane B2 production and megakaryocyte nulcear DNA concentration. Thromb Res 1983; 32: 443-60
    CrossrefPubMedGoogle Scholar
  • 43 Martin JF, Bath PM, Burr ML. Influence of platelet size on outcome after myocardial infarction. Lancet 1991; 338: 1409-11
    CrossrefPubMedGoogle Scholar
  • 44 McEver RP. (1992) Leukocyte Interactions Mediated by GMP140. In: Cellular and Molecular Mechanisms of Inflammation. Cochrane CG, Gimbrone MA. (eds). San Diego, New York, Boston, Sydney, Tokyo, Toronto: Academic Press Inc; 15-29
    Google Scholar
  • 45 Ostermann H, van de Loo J. Factors of the hemostatic system in diabetic patients-A survey of controlled studies. Haemostasis 1986; 16: 386-416
    PubMedGoogle Scholar
  • 46 Rösen P, Schwippert B, Tschöpe D. Adhesive proteins in platelet-endothelium interactions. In: Megakaryocytes and Platelets in Vascular Disease. Schrör K, Rösen P, Tschöpe D. (eds). Eur J Clin Invest 1994; 24 (Suppl. 01) 21-4
    CrossrefPubMedGoogle Scholar
  • 47 Rothe H, Fehsel K., Kolb H. Tumour necrosis factor alpha production is upregulated in diabetes prone BB rat. Diabetologia 1990; 33: 573-5
    CrossrefPubMedGoogle Scholar
  • 48 Ryffel B, Car BD, Woerly G, Weber M, Di Padova F, Kammüller M, Klug S, Neubert R, Neubert D. Longterm interleukin-6 administration stimulates sustained thrombopoiesis and acute-phase protein synthesis in a small primatethe marmoset. Blood 1994; 83: 2093-102
    PubMedGoogle Scholar
  • 49 Schafer AI. The hypercoagulable States. Ann Int Med 1985; 102: 814-28
    CrossrefPubMedGoogle Scholar
  • 50 Schick PK, William Gartner K, He XL. Lipid composition and metabolism in megakaryocytes at different stages of maturation. J Lipid Res 1990; 31: 27-35
    PubMedGoogle Scholar
  • 51 Schneider W, Gatterman N. Megakaryocytes: origin of bleeding and thrombotic disorders. In: Megakaryocytes and Platelets in Vascular Disease. Schrör K, Rösen P, Tschöpe D. (eds). Eur J Clin Invest 1994; 24: 16-20
    CrossrefPubMedGoogle Scholar
  • 52 Schultheiß HP, Tschoepe D, Esser J, Schwippert B, Roesen P, Nieuwenhuis HK, Schmidt-Soltau C, Strauer B. Large platelets continue to circulate in anactivated state after myocardial infarction. Eur J Clin Invest 1994; 24: 243-7
    CrossrefPubMedGoogle Scholar
  • 53 Sprafka JM, Burke GL, Folsom RA, McGovern PG, Hahn PL. Trends in prevalence of diabetes mellitus in patients with myocardial infarction and effect of diabetes on survival. Diabetes Care 1991; 14: 537-43
    CrossrefPubMedGoogle Scholar
  • 54 Steering Committee of the Physicians Health Study Research Group: Final report on the aspirin component of the ongoing physicians health study. N Engl J Med 1990; 321: 129-35
    PubMedGoogle Scholar
  • 55 The Damad Study Group. Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy. Diabetes 1989; 38 (491) 498
    PubMedGoogle Scholar
  • 56 The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment and progression of longterm complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977-86
    CrossrefPubMedGoogle Scholar
  • 57 The TIMAD Study Group. Results of the TIMAD study. Arch Ophthalmol 1990; 108: 1577-83
    CrossrefPubMedGoogle Scholar
  • 58 Tschoepe D, Langer E, Schauseil S, Roesen P, Kaufmann L, Gries FA. Increased platelet volumesign of impaired thrombopoiesis in diabetes mellitus. Klin Wochenschr 1989; 67: 253-9
    CrossrefPubMedGoogle Scholar
  • 59 Tschoepe D, Ostermann H, Hübinger A, Ziegler D, Wiefels K, Gries FA. Elevated platelet activation in type I diabetics with chronic complications under long term near normoglycemic control. Haemostasis 1990; 20: 93-8
    PubMedGoogle Scholar
  • 60 Tschoepe D, Roesen P, Kaufmann L, Schauseil S, Kehrel B, Ostermann H, Gries FA. Evidence for abnormal platelet glycoprotein expression in diabetes mellitus. Eur J Clin Invest 1990; 20: 166-70
    CrossrefPubMedGoogle Scholar
  • 61 Tschoepe D, Spangenberg P, Esser J, Schwippert B, Kehrel B, Roesen P, Gries FA. Flowcytometric detection of surface membrane alterations and concomitant changes in the cytoskeletal actin status of activated platelets. Cytometry 1990; 11: 652-6
    CrossrefPubMedGoogle Scholar
  • 62 Tschoepe D, Esser J, Schwippert B, Roesen P, Kehrel B, Niewuenhuis HK, Gries FA. Large platelets circulate in an activated state in diabetes mellitus. Sem Thromb Haemostas 1991; 17: 433-9
    PubMedGoogle Scholar
  • 63 Tschoepe D, Schwippert B, Schettler B, Kiesel U, Rothe H, Roesen P. Gries FA Increased GPIIb/IIIa expression and altered DNA-ploidy pattern in megakaryocytes of diabetic BB-rats. Eur J Clin Invest 1992; 22: 591-8
    CrossrefPubMedGoogle Scholar
  • 64 Tschoepe D, Rösen P, Schwippert B, Gries FA. Platelets in Diabetes: the role in the hemostatic regulation in atherosclerosis. Sem Thromb Hemostas 1993; 19: 122-8
    Article in Thieme ConnectPubMedGoogle Scholar
  • 65 Tschoepe D, Schwippert B, Raic I, Schmidt-Soltau C, Roesen P. Wirkung von Acetyl-Salicyl-Säure auf die intravasale Thrombozytenaktivierung bei Typ-I-Diabetikern. Diab Stoffw 1994; 3: 391-6
    PubMedGoogle Scholar
  • 66 Tschoepe D, Driesch E, Schwippert B, Niewenhuis HK, Gries FA. Exposure of adhesion molecules on activated platelets in patients with newly diagnosed IDDM is not normalized by nearnormoglycemia. Diabetes 1995; 44: 890-5
    CrossrefPubMedGoogle Scholar
  • 67 Tschoepe D, Schwippert B.. Platelet Flow Cytometry-Adhesion Molecules. In: Hand-book of Experimental Pharmacology: Platelets and their Factors. Bruchhausen F, Walter U. (eds). Heidelberg: Springer (book in press); 1996
    Google Scholar
  • 68 Tschoepe D. Adhesion Molecules Influencing Atherosclerosis. Diab Res Clin Pract 1996; 30: 1-6
    CrossrefPubMedGoogle Scholar
  • 69 Valet G, Tschoepe D, Gabriel H, Valet M. Standardized, Self Learning Flow Cytometric List Mode Data Classifier: Classif 1 for Thrombocyte and Lymphocyte Immune Phenotyping. Ann NY Acad Sci 1993; 677: 233-51
    CrossrefPubMedGoogle Scholar
  • 70 Watanabe Y, Kawada M, Kobayashi B. Effect of insulin on murine megakaryocytopoiesis in a liquid culture system. Cell Structure and Function 1987; 12: 311-6
    CrossrefPubMedGoogle Scholar
  • 71 Winkelmann M, Pfitzer P, Schneider W. Significance of polypoidy in megakaryocytes and other cells in health and tumor disease. Klin Wochenschr 1987; 65: 1115-31
    CrossrefPubMedGoogle Scholar
  • 72 Winocour PD, Kinlough-Rathbone RL, Mustard JF. Pathways responsible for platelet hypersensitivity in rats with diabetes. II. Spontaneous diabetes in BB Wistar rats. J Lab Clin Med 1986; 107: 154-8
    PubMedGoogle Scholar
  • 73 Winocour PD. Platelet abnormalities in diabetes mellitus. Diabetes 1992; 41: 26-31
    PubMedGoogle Scholar