Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2008 Sep 18;359(12):1261-70.
doi: 10.1056/NEJMra0800887.

Platelets, petechiae, and preservation of the vascular wall

Ralph L Nachman  1 , Shahin Rafii
Affiliations
Review

Platelets, petechiae, and preservation of the vascular wall

Ralph L Nachman et al. N Engl J Med. .
No abstract available

PubMed Disclaimer

Conflict of interest statement

No potential conflict of interest relevant to this article was reported.

Figures

Figure 1
Figure 1. Megakaryocyte–Endothelial Cell Cross-Talk
The megakaryocyte, through platelet production and release of key endothelial trophogens, directly determines the integrity and viability of the microvascular bed of bone marrow. In a reciprocal manner, in the “vascular niche” microenvironment, the endothelium directly influences megakaryocyte integrity by releasing a number of megakaryocyte trophogens. ANG1 denotes angiopoietin 1, BDNF brain-derived neurotrophic factor, EGF epidermal growth factor, FGF fibroblast growth factor, FGF4 fibroblast growth factor 4, GM-CSF granulocyte–macrophage colony-stimulating factor, PAF platelet-activating factor, PDGF platelet-derived growth factor, SCF stemcell factor–c-kit ligand, SDF-1 stromal cell–derived factor 1, TPO thrombopoietin, and VEGF-A vascular endothelial growth factor A.
Figure 2
Figure 2. Vascular Homeostasis
Stages in the life cycle of the vasculature are shown, from developmental vasculogenesis to non–steady-state angiogenesis in adult tissues to physiologic regression. Angiostability in the physiologic steady state is dependent on constitutive endogenous production of vascular endothelial growth factor A (VEGF-A), stimulated by platelets. Multiple angiogenic trophogens also participate in these stages. The black arrows indicate the major influences on maintenance of vascular integrity.
Figure 3
Figure 3. Adherens Junction at the Postcapillary Venular Bed
In the steady state, transmembrane vascular-endothelium cadherin molecules form a calcium-dependent zipperlike structure across adjacent cell membranes, through homophilic interactions. The cytoplasmic tails of the cadherin are part of an intracellular macromolecular complex including β-catenin, P120, α-catenin, vascular endothelial growth factor (VEGF) receptor 2 (VEGF-R2), and CD148 phosphatase. The platelet in the steady state maintains the molecular integrity of the adherens junction by constitutively releasing a panoply of endothelial trophogens including brain-derived neurotrophic factor (BDNF), epidermal growth factor (EGF), platelet-activating factor (PAF), sphingosine-1-phosphate (S1P), angiopoietin (ANG), and VEGF A (VEGF-A), among others. These trophogens signal through their respective receptors (BDNF-R, which binds BDNF; EGF-R, which binds EGF; endothelial differentiation gene 1 [EDG1], which binds S1P; angiopoietin receptor specific to endothelial cells [TIE2], which binds ANG; and PAF-R, which binds PAF), induce endogenous VEGF-A production, and activate the autocrine VEGF-A loop, which in turn induces VEGF-R2 phosphorylation, which is required for maintenance of the stability of the zipper. Specific phosphorylation sites of the catenin and cadherin constituents in the complex control stability and integrity of the intercellular junction and facilitate cytoskeletal attachment through F-actin. The paracrine pathway of exogenous VEGF-A signaling promotes survival in the steady state but proliferation in the nonsteady state. Shear stress at the luminal surface of the vessel wall and the platelet membrane may participate in the constitutive triggering of these platelet responses. PAF denotes platelet activating factor, and VE vascular endothelial.
Figure 4
Figure 4. Paracrine and Autocrine Vascular Endothelial Growth Factor A (VEGF-A)–Induced Endothelial-Cell Interactions
Exogenous VEGF-A in the physiologic steady state initiates signaling by phosphorylation of VEGF receptor 2 (VEGF-R2) and promotes cell survival. In nonsteady states, permeability is increased and proliferation is supported. Paracrine signaling is obligatory for the vasculogenesis of embryonic development and the angiogenesis of inflammation, cancer, pregnancy, and the female reproductive cycle. Autocrine endogenous VEGF-A also signals through phosphorylation of VEGF-R2 and in the steady state decreases permeability by stabilizing the intercellular junction. Autocrine stimulation is supportive of vasculogenesis and is not required for angiogenesis. The phosphorylation sites on VEGF-R2 may involve different residues after paracrine exogenous stimulation and autocrine endogenous stimulation.
Figure 5
Figure 5. Bleeding in Patients with Thrombocytopenia through Disassembly of the Adherens Junction
Below a critical number of platelets, the steady-state trophic effects on the endothelium are impaired and the multimolecular vascularendothelium cadherin complex breaks down, with subsequent loss of the intercellular barrier, permitting extravasation of red cells into the surrounding tissues. The autocrine vascular endothelial growth factor A (VEGF-A) loop is interrupted, with resultant downstream alterations in the phosphorylated status of the constituents in the complex. VEGF receptor 2 (VEGF-R2) becomes internalized by the cell in endosomes. In most patients, disassembly of the vascular-endothelium cadherin complex manifests in the skin as petechiae and in mucosal surfaces as local hemorrhagic blisters. These trophogens signal through their respective receptors. BDNF-R denotes brain-derived neurotrophic factor receptor, EDG1 endothelial differentiation gene 1, EGF-R epidermal growth factor receptor, PAF-R plateletactivating factor receptor, TIE2 angiopoietin receptor specific to endothelial cells, and VE vascular endothelial.
See this image and copyright information in PMC

Comment in

  • Platelets and the vascular wall.
    Mirakaj V, Köhler D, Rosenberger P. Mirakaj V, et al. N Engl J Med. 2008 Dec 18;359(25):2727-8; author reply 2728. doi: 10.1056/NEJMc082157. N Engl J Med. 2008. PMID: 19092160 No abstract available.

References

    1. Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007;357:2482–94. - PubMed
    1. Joris I, Majno G, Corey EJ, Lewis RA. The mechanism of vascular leakage induced by leukotriene E4: endothelial contraction. Am J Pathol. 1987;126:19–24. - PMC - PubMed
    1. Kitchens CS. Amelioration of endothelial abnormalities by prednisone in experimental thrombocytopenia in the rabbit. J Clin Invest. 1977;60:1129–34. - PMC - PubMed
    1. Jaffe EA, Hoyer LW, Nachman RL. Synthesis of von Willebrand factor by cultured human endothelial cells. Proc Natl Acad Sci U S A. 1974;71:1906–9. - PMC - PubMed
    1. Nachman R, Levine R, Jaffe EA. Synthesis of factor VIII antigen by cultured guinea pig megakaryocytes. J Clin Invest. 1977;60:914–21. - PMC - PubMed

Publication types

MeSH terms

Substances