Platelet Factor 4: Production, Structure, and Physiologic and Immunologic Action

Platelet factor 4 (PF4) is a protein found in megakaryocytes and platelet α-granules (1, 2). Immunocytochemical studies show that it is present as well in mast cell granules (3) and on the endothelium of human umbilical veins, but not arteries (4). Early work on PF4 has been reviewed elsewhere (5–7). Human platelets contain about 18 ± 4 μg of PF4/109 (8). Thrombospondin, platelet-derived growth factor, and compounds derived from platelet basic protein such as β-thromboglobulin (β-TG) are found in platelet α-granules in addition to PF4. All are secreted when platelets are appropriately stimulated; for example, since thrombin is a strong stimulus, these compounds are present in much higher concentrations in serum than in plasma (e.g., 5334 vs 1.8 ng/ml for PF4 [9]). They are also secreted after contact of platelets with collagen in damaged blood vessels, for example. Production and Structure PF4 is synthesized by megakaryocytes (10), an ability that correlates with cytoplasmic maturity (2, 11). The PF4 is first packaged into vesicles and from there it is transferred to α-granules (2). Megakaryocytes express mRNA transcripts for PF4, but not for fibrinogen or albumin, which are taken up by megakaryocytes from plasma (12). Even blood platelets, which contain little mRNA, contain mRNA for PF4, whereas none is evident in human lymphocytes, cultured fibroblasts, and four types of malignant cells (13). Human PF4 is a 7.8-kDa protein that contains 70 amino acids, with two disulfide bonds, no tryptophan or methionine, two histidines, and a single tyrosine (Fig. 1). The position of its two disulfide bridges has been inferred by homology with the related compound β-TG (14). Its isoelectric point is 7.6 (15) and its extinction coefficient (1%, 280 μm) is reported to be 2.9 (3) or 5.4 (9).