BSS presents in infancy or childhood with ecchymoses, epistaxis, and gingival bleeding.¹⁶ Later manifestations include menorrhagia and postpartum, gastrointestinal, and posttraumatic
hemorrhage. Hemarthroses and expanding hematomas are unusual. Although the severity of bleeding is variable and may not always correlate with the extent of thrombocytopenia and the degree of GPIb-IX-V deficiency,³⁵ it can be severe enough to require transfusion and suppression of menses. In a review of 59 patients, for example, there were 10 deaths.³⁶ In some patients with BSS, the severity of hemorrhage inexplicably declines over the course of the disease.³⁶

The bleeding time in patients with BSS is markedly prolonged to >20 minutes.¹⁶ Most patients are thrombocytopenic to some degree, and platelet counts <20,000/µL have been reported.³⁷ Nonetheless, platelet counts vary within kindreds and even in individual patients. BSS platelets are large when observed on peripheral blood smears¹⁶; 30% to 80% have mean diameters >3.5 µm, and occasional platelets are as large as 20 to 30 µm in diameter.³⁸ There is contradictory evidence about the size of BSS platelets in the circulation. It has been reported that circulating BSS platelets are normal in size³⁹ but have increased membrane, perhaps located in the surface-connected open-canalicular system that is extruded when platelets spread during the preparation of a blood smear.⁴⁰ Others have reported that the volume of circulating BSS platelets is increased⁴¹ and that they have a more spherical shape⁴¹ with a more deformable membrane.⁴² The molecular basis for the macrothrombocytopenia of BSS is not known. However, amelioration of the macrothrombocytopenia when an IL4-GPIbα fusion protein was expressed in a murine BSS model suggests that absence of the GPIbα cytoplasmic domain contributes to this abnormality.⁴³

Erythrocytes and white blood cells are normal in BSS. Distinctive abnormalities have not been observed in marrow megakaryocytes by light microscopy,⁴⁴ although demarcation membrane system abnormalities have been observed by electron microscopy.⁴⁵ The laboratory tests that distinguish BSS from normal platelets are the failure of BSS platelets to agglutinate in the presence of ristocetin or botrocetin and the failure of vWF to restore agglutination (FIGURE 65.1).¹⁶ Aggregation of BSS platelets in response to ADP, collagen, and epinephrine is normal.¹⁶ However, the rate of thrombin-stimulated aggregation can be reduced.⁴⁶
Although the serum prothrombin time has been reported to be decreased in BSS⁴⁷ and both collagen-induced platelet procoagulant activity and factor XI binding to be absent,⁴⁸ prothrombin consumption has also been reported to be normal⁴⁹ and platelet procoagulant⁴⁹ and prothrombinase activity to be increased.⁵⁰ An unexplained decrease in thrombin-, trypsin-, and thromboxane-stimulated phospholipase C (PLC) activity has also been reported.⁵¹ GPIb-IX-V can be a target for drug-dependent anti-platelet antibodies⁵²; such antibodies fail to bind to BSS platelets.⁵³

BSS is an autosomal recessive disorder.¹⁶ In most instances, GPIb-IX-V is not present on the surface of BSS platelets, but in a few cases, 7% to 47% residual GPIb or GPIb-IX has been detected.⁵⁴ Many, but not all, obligate BSS heterozygotes have platelets that are larger than normal and a content of GPIb intermediate between normal and affected individuals.^38,55 Consistent with its rarity, consanguinity has often been present in affected families.

The gene for GPIbα is located on chromosome 17p12-ter, the GPIbβ gene on chromosome 22q11.2, the GPIX gene on chromosome 3q21, and the GPV gene on chromosome 3q29.¹⁶ Each gene has a compact “intron-depleted” structure; the genes for GPIbα, GPIbβ, and GPV each contain two exons and the gene for GPV contains three.⁵⁶ The open reading frame and 3′ untranslated region of each gene is encoded by a single exon except for GPIbβ where its single intron is inserted into the codon for the fourth residue of its signal peptide.⁵⁷ Like other genes expressed by megakaryocytes, the 5′ flanking region of each gene contains potential binding sites for the transcription factors GATA, Ets, and Sp-1.^58,59,60 In addition, polymorphic variation in the region surrounding the GPIbα translation initiation site appears to be a determinant of the level of GPIb-IX-V expression.⁶¹

As shown in FIGURE 65.2, at least 56 different mutations responsible for BSS have been identified in the genes for GPIbα, GPIbβ, and GPIX.⁶² Most are missense mutations or nucleotide deletions and insertions resulting in frameshifts and premature stop codons. However, several unique mutations have been identified: deletion of the entire GPIbβ locus on chromosome 22q11.2, occasionally in the setting of the velocardiofacial syndrome^63,64; a more circumscribed homozygous deletion of the GPIBB locus that included SEPT5 gene resulting in the BSS, cortical dysplasia, developmental delay, and a platelet secretion defect⁶⁵; a C to G transversion in the GATA binding site of the GPIbβ promoter resulting in decreased GPIbβ gene transcription⁶⁶; and an Ala140Thr in the transmembrane domain of GPIX.^67,68 The latter is noteworthy because it is consistent with observations that transmembrane domain interactions
are involved in efficient GPIb-IX-V expression⁶⁹ and with the impairment of GPIb-IX expression observed when the GPIbβ transmembrane domain was mutated in vitro.⁷⁰ The monoallelic GPIbα mutation Ala156Val, known as the “Bolzano mutation,” has been reported to be the most common cause of inherited thrombocytopenia in Italy. It has been associated with a mild bleeding diathesis, a variable degree of thrombocytopenia, and a modest but consistent increase in platelet diameter and volume.⁷¹ It is also noteworthy that many BSS mutations have been reported multiple times, suggesting that there may be “hot spots” for mutation in the GPIbα, GPIbβ, and GPIX genes.

BSS must be differentiated from other conditions that are associated with large platelets and thrombocytopenia (macrothrombocytopenia). Inherited disorders associated with macrothrombocytopenia are listed in Table 65.1 and can be readily differentiated from BSS because BSS platelets fail to agglutinate in the presence of ristocetin (FIGURE 65.1).⁷² Many of these conditions are discussed in detail in Chapter 64.

Macrothrombocytopenia is a characteristic feature of mutations in the MYH9 gene located on chromosome 22q12.3-q13.2 encoding the nonmuscle myosin heavy chain IIA (NMMHC-IIA).^73,74 Previously, these MYH9 disorders were segregated into four separate autosomal dominant inherited syndromes—the May-Hegglin anomaly and the Sebastian, Fechtner, and Epstein syndromes—based on the presence or absence of Döhle body-like leukocyte inclusions, hereditary nephritis, cataracts, and sensorineural deafness.⁷⁵ However, because each results from mutations in the MYH9 gene, it now seems appropriate to consider them as a single entity whose variability results from the variable expression of MHY9 mutations and whose common feature is macrothrombocytopenia. In general, the function of platelets affected by MHY9 mutations is normal,^76,77,78 and if hemorrhage occurs, it is usually due to thrombocytopenia.⁷⁹

Macrothrombocytopenia also occurs in the gray platelet syndrome (GPS), a disorder resulting from platelet α-granule deficiency⁸⁰ and due, at least in some cases, to mutations in the gene NBEAL2 (see below).^81,82,83 In contrast to BSS platelets, GPS platelets are pale gray on Wright-stained blood smears and agglutinate normally in the presence of ristocetin.⁸⁴ In a reevaluation of the Montreal platelet syndrome, large platelets, thrombocytopenia, and spontaneous platelet aggregation were found to be due
to type 2B vWD caused by a heterozygous V1316M mutation in exon 28 of the vWF gene.^85,86 Mediterranean macrothrombocytopenia refers to putative differences in platelet count and size between Europeans of Northern and Mediterranean origin⁸⁷; in Italy, this may be due to heterozygosity for BSS, in particular heterozygosity for the “Bolzano mutation” Ala156Val.⁸⁸ Mediterranean stomatocytosis/macrothrombocytopenia, the rare combination of stomatocytic hemolysis and macrothrombocytopenia, results from excess plant sterols in the blood and is caused by mutations in the ABCG5 and ABCG8 genes linked to phytosterolemia.⁸⁹ Several reported patients had significant bleeding histories. Sex-linked macrothrombocytopenia occurs in patients with GATA-1 transcription factor mutations,^90,91,92 and macrothrombocytopenia with dystrophic megakaryocytes and neutrophils lacking sialyl-Lewis-S antigen was described in an infant who died at 37 months due to hemorrhage.⁹³ In the Paris-Trousseau syndrome,⁹⁴ a part of the Jacobsen syndrome,⁹⁵ a deletion of the long arm of chromosome 11 at q23.3 containing the gene for the transcription factor FLI1 results in mild thrombocytopenia, subpopulations of large platelets and platelets containing giant α-granules, and the expansion of immature megakaryocyte progenitors.⁹⁶ Mutations in the filamin A gene located on chromosome Xq28 are responsible for periventricular nodular heterotopia and the otopalatodigital syndrome; macrothrombocytopenia and bleeding, misinterpreted as ITP, has been present in some patients.⁹⁷ In platelet-type vWD, mutations within the vWF binding domain of GPIbα induce spontaneous vWF binding to GPIbα and the clinical picture of type IIB vWD which itself can be associated with macrothrombocytopenia.^{9,98,99,100,101,102} There are also anecdotal reports of thrombocytopenia and giant platelets, often associated with a mild bleeding diathesis but lacking the features of either BSS or the MHY9 disorders.^103,104 In two other reports, macrothrombocytopenia was associated with the presence of large platelet granules whose origin was uncertain.^105,106

Acquired BSS-like disorders can be differentiated from the congenital BSS by history. GPIb antibodies occur in some patients with idiopathic thrombocytopenic purpura¹⁰⁷; whether the antibodies themselves are responsible for bleeding is not clear because of concomitant thrombocytopenia. Two patients with myelodysplasia and a BSS-like syndrome have been reported,^108,109 as has a patient with a lymphoproliferative disorder and a circulating IgG antibody that inhibited ristocetininduced platelet agglutination, but was directed against an unidentified 210,000 mol. wt. platelet protein.¹¹⁰

Treatment of hemorrhage in patients with the BSS usually requires platelet transfusion.¹¹¹ Hormonal control of menses has been effective in managing menorrhagia.¹¹² Splenectomy has been attempted to increase the platelet count¹¹³ but has resulted in only transient increases and has not ameliorated the platelet function defect. Corticosteroids are not beneficial in this disorder. Desmopressin acetate (DDAVP) has been reported to shorten the bleeding time in some, but not all, affected individuals in whom it has been administered,^{114,115,116,117} but its efficacy in patients with hemorrhage is unclear. Antifibrinolytics such as epsilon aminocaproic acid and tranexamic acid can be useful adjuncts to other therapy.¹¹⁸ A number of anecdotal reports suggest that recombinant VIIa may be effective in the treatment of hemorrhage in BSS patients, although the degree of effectiveness has varied.^{119,120,121,122,123} Lastly, bone marrow transplantation from HLA-identical donors has been performed successfully in patients with BSS.^124,125

The clinical manifestations of GT in a large cohort of patients have been described in detail.¹²⁷ GT typically presents with mucocutaneous bleeding during the neonatal period or infancy, occasionally with bleeding following circumcision. Spontaneous petechiae are uncommon and bleeding generally results from conditions that would also cause bleeding in an otherwise normal individual. Thus, epistaxis is a frequent type of bleeding, especially during childhood, as are gingival bleeding and menorrhagia. Bleeding at menarche may be severe and require transfusion. Similarly, parturition represents a severe hemorrhagic risk. Other hemorrhagic manifestations include gastrointestinal bleeding and hematuria, but hemarthroses and deep hematomas are unusual. Serious bleeding may follow trauma or surgery. However, the severity of hemorrhage in thrombasthenia is not predictable, even within single kindreds, and does not correlate with the degree of α_IIbβ₃ deficiency. The apparent decline in the clinical severity of GT with age is likely due to a decrease in the incidence of conditions such as epistaxis with aging.

Platelet counts and platelet morphology on peripheral blood smears are normal. The bleeding time of affected individuals is markedly prolonged.¹⁵³ A diagnosis of GT is usually suspected when platelet aggregometry reveals absent agonist-stimulated platelet aggregation (see FIGURE 65.1). Platelet secretion induced by strong agonists such as thrombin is normal, but secretion in response to weak agonists such ADP and epinephrine which requires platelet aggregation does not occur. Coagulation tests, such as the prothrombin time and the partial thromboplastin time, are normal in GT, whereas clot retraction in the presence of GT platelets is absent or reduced.

In addition to their inability to aggregate, GT platelets do not spread normally on the subendothelial matrix because of an impaired ability to interact with fibronectin and vWF in the matrix.¹⁵⁴ The amount of fibrinogen in the α-granules of GT platelets is decreased to absent.¹²⁷ Human megakaryocytes do not synthesize fibrinogen, but rather, it is derived from plasma by an α_IIbβ₃-mediated endocytic process.^{155,156,157,158,159} A number of biochemical reactions in platelets that require the presence of α_IIbβ₃ are impaired in GT platelets. For example, the tyrosine phosphorylation of multiple intracellular signaling proteins depends on ligand binding to α_IIbβ₃ and does not occur in GT platelets.¹⁶⁰ Calpain, a calcium-dependent thiol protease, is activated when stirred normal platelets are stimulated by thrombin, but not when GT platelets are treated in a similar manner.¹⁶¹ The kinetics of calcium exchange in unstimulated GT platelets is inexplicably decreased¹⁶² since it is not clear what role, if any, α_IIbβ₃ plays in calcium transport.^163,164 Clot retraction in blood containing GT platelets is either absent or reduced.^127,135

Aspects of platelet function that do not depend on α_IIbβ₃ are normal in GT. GT platelets interact normally with collagen¹⁵³ and undergo secretion when stimulated by “strong agonists” such as thrombin.¹⁶⁵ Incubation of GT platelets with ristocetin induces vWF binding to GPIb-IX-V¹⁰ and GT platelets adhere to vWF in the subendothelium.¹⁵⁴ GT platelets also express normal amounts of procoagulant activity following lysis.⁵⁰ However, agonist-stimulated prothrombinase activity varies and is influenced by the nature of platelet agonist.^50,166

The genes for α_IIb and β₃ are located on the long arm of chromosome 17 at q21→23¹⁶⁷ with the α_IIb gene at minimum distance of 365 kb downstream from the β₃ gene.¹⁶⁸ The α_IIb gene (ITGA2B) spans ≈18 kb and consists of 30 exons ranging in size from 46 to 220 bp.¹⁶⁹ Like the genes for other proteins expressed in megakaryocytes, its 5′ flanking region lacks TATA or CAAT boxes. Instead, it contains a linear array of regulatory elements that includes two motifs recognized by the GATA-1 transcription factor and its cofactor FOG^170,171; sequences flanking each GATA-1 binding site are recognized by Fli-1 and perhaps other members of the Ets family of transcription factors^{172,173,174,175}; and an Sp1-binding silencer element is located between the GATA-1 sites.¹⁷⁶ The gene for β₃ (ITGB3) spans 63 kb and contains 15 exons.^151,177 Like the α_IIb gene, the 5′ flanking region of the β₃ gene lacks TATA or CAAT boxes.¹⁷⁸

GT is an autosomal recessive disorder with disease clusters in populations where consanguinity is common. It has been subclassified into three types based on the amount of α_IIbβ₃ present per platelet and the presence or absence of α-granule fibrinogen and clot retraction.¹²⁷ In type I, platelets contain <5% of the normal amount of α_IIbβ₃ and clot retraction and α-granule fibrinogen are absent. In type II, platelets contain 10% to 20% of the normal amount of α_IIbβ₃, clot retraction is decreased, and α-granule fibrinogen is present. In “variant” thrombasthenia, the platelet content of α_IIbβ₃ is ≥50% of normal, indicating that the α_IIbβ₃ abnormality is qualitative, rather than quantitative.

Because the expression of α_IIbβ₃ on the platelet surface requires the formation of correctly folded heterodimers,¹⁷⁹ mutations in the genes for either α_IIb or β₃ can produce GT. Approximately 200 different mutations responsible for GT have been identified¹⁸⁰ (FIGURE 65.3). The vast majority of these mutations consist of a mix of missense and nonsense mutations, nucleotide deletions and insertions, and alternative splicing, resulting in type I and type II GT. However, the most informative mutations have been qualitative α_IIbβ₃ abnormalities (variant GT) that primarily perturb α_IIbβ₃ function rather than the level of α_IIbβ₃ expression.

Mutations located in the extracellular portion of α_IIbβ₃ cause GT by either impairing fibrinogen or vWF binding to the active α_IIbβ₃ conformation or by paradoxically inducing constitutive α_IIbβ₃ activation but causing GT by concurrently decreasing the amount of α_IIbβ₃ expressed on the platelet surface. Six missense mutations (the αIIb mutation Tyr143His¹⁸¹ and the β₃ mutations Asp119Tyr,¹⁸² Val193Met,¹⁸³ Arg214Trp,^184,185 Arg214Gln,¹⁸⁶ and Aspr217Val¹⁸⁷) are located in regions implicated in ligand binding to α_IIbβ₃ and cause GT by preventing ligand binding.^188,189
Similarly, an insertion of two amino acids (Arg-Thr) into the Cys146-Cys167 loop of α_IIb produced an inactive α_IIbβ₃ heterodimer.¹⁹⁰ An eighth mutation, β₃ Ser123Pro, did not impair α_IIbβ₃ expression or agonist-induced ligand binding but was associated with absent ADP- and collagen-induced platelet aggregation.¹⁹¹ The β₃ mutation, Leu196Pro, was identified independently in two French patients and severely restricted α_IIbβ₃ expression.^192,193 However, the residual α_IIbβ₃ that made it to the platelet surface was unable to bind ligands, presumably because the mutation prevents α_IIbβ₃ from assuming its active conformation. By contract, the β₃ mutation Cys560Arg locked α_IIbβ₃ in a high-affinity conformation, but like Leu196Pro, it likely produced a GT-phenotype because the small amount of constitutively active α_IIbβ₃ on the platelet surface was insufficient to support platelet aggregation.¹⁹⁴

The extracellular stalks of α_IIbβ₃ consist of the thigh, calf-1, and calf-2 domains of α_IIb and the epidermal growth factor (EGF)-like domains 1 to 4 and the β TD domain of β₃.¹⁹⁵ The distal portions of the stalks form an interface containing interacting energetic “hot spots” that are critical for maintaining α_IIbβ₃ in a stable, inactive conformation.^196,197 Thus, it is not surprising that four mutations involving cysteine residues located at the third and fourth EGF domains of β₃ (Cys49Arg,¹⁹⁸ Cys560Phe,¹⁹⁹ Cys560Arg,¹⁹⁴ and Cys598Tyr^199,199a) as well as a Gly579Ser mutation, not only resulted in type II thrombasthenia but also induced constitutive ligand-binding activity in the residual α_IIbβ₃. Similarly, a Ser527Phe mutation detected in the third β₃ EGF domain of a patient who presented with a mild bleeding diathesis was found to cause constitutive activation of recombinant α_IIbβ₃ expressed in Chinese hamster ovary cells.²⁰⁰

Naturally occurring mutations involving the β₃ cytoplasmic domain have confirmed the singular importance of this structure in regulating α_IIbβ₃ function. The first mutation identified, a missense mutation that results in the substitution of Pro for Ser at residue 752, prevents α_IIbβ₃ activation by cellular agonists,^201,202,203 likely because it abrogates binding of the cytoplasmic protein kindlin-3 to β₃ (see below).²⁰⁴ A second missense mutation, identified separately in two unrelated patients,^205,206 converts the Arg724 codon into a stop codon, resulting in the synthesis of a truncated β₃ molecule lacking 39 C-terminal amino acids. As a consequence, α_IIbβ₃ is unable to transduce both “inside-out” and “outside-in signals,” likely because β₃ is now unable to interact with both kindlin-3 and talin.²⁰⁴ A third mutation, identified in an Palestinian Arab with GT, produces aberrant mRNA splicing at the intron 14/exon 15 junction and replacement of the β₃ sequence distal to residue 741 with 40 unrelated amino acids.²⁰⁷ This results in the absence of the distal talin binding site in the β₃ cytoplasmic domain, as well the binding site for kindlin-3, and an α_IIbβ₃ extracellular domain that appears to be “locked” in its inactive conformation.²⁰⁸

Lastly, several heterozygous mutations located in the highly conserved membrane-proximal regions of the α_IIb and β₃ cytoplasmic domains have been associated with GT-like phenotypes and macrothrombocytopenia.²⁰⁹ Thus, replacement of α_IIb Arg995 with either Gln^209,210 or Trp²¹¹ and β₃ Asp723 with His^212,213 results in decreased, but not absent, platelet aggregation, an approximate 50% decrease in the total amount of platelet α_IIbβ₃ predominantly affecting the surface—rather than the granule—membrane pool, a moderate degree of macrothrombocytopenia and platelet “anisocytosis,” and partial α_IIbβ₃ activation when α_IIbβ₃ is expressed in tissue culture cells. A β₃ Leu718Pro mutation produced a similar phenotype,²¹⁴ as did a two residue deletion in the β TD domain of β₃.²¹⁵ How these mutations in α_IIbβ₃ produce this spectrum of abnormalities is not clear since “classic” GT is not associated with alterations in platelet number or size, but the association of macrothrombocytopenia with BSS and the MYH9 disorders suggests that perturbed α_IIbβ₃-cytoskeleton interactions could be involved.

A history of lifelong bleeding, a prolonged bleeding time, and absent platelet aggregation are diagnostic of GT and differentiate it from other disorders of platelet adhesion and secretion. Rare instances of acquired GT have been reported and can be differentiated from congenital GT by history. Although autoantibodies against α_IIbβ₃ are frequently detected in patients with idiopathic thrombocytopenic purpura,^216,217 they rarely induce a GT-like state.^{218,219,220,221} There are anecdotal reports of autoantibodies producing acquired GT in patients with Hodgkin and non-Hodgkin lymphoma, hairy cell leukemia, and after an allergic reaction to diclophenac.^222,223,224 A patient with multiple myeloma has also been reported whose IgG₁κ paraprotein was directed against β₃ and inhibited α_IIbβ₃ function.²²⁵ Congenital afibrinogenemia may be associated with a prolonged bleeding time and decreased in vitro platelet aggregation due to the absence of sufficient fibrinogen to support normal platelet aggregation.²²⁶

In the LAD-III/LAD-1/variant syndrome, patients manifest mucocutaneous bleeding and absent platelet aggregation, despite normal or nearly normal α_IIbβ₃ expression.^227,228,229 Concurrently, they suffer from recurrent and severe bacterial infections due to defective leukocyte integrin function, implying that the syndrome results from a general defect in integrin activation. Although initially attributed to defective expression of the Rap-1 activator CalDAG-GEFI,^229,230,231 in several kindreds,^232,233 mutations have been identified in the KINDLIN3 gene encoding the protein kindlin-3 that binds to β₁, β₂, and β₃ integrin cytoplasmic tails and is required for agonist-stimulated integrin activation.^204,234,235

The mainstay of treatment of bleeding in GT remains the transfusion of normal platelets.¹¹¹ Because bleeding is a lifelong problem, use of HLA-matched platelets should be considered to lessen the chance of refractoriness to transfusion due to platelet alloimmunization. Patients with GT, especially patients with null mutations, not infrequently develop alloantibodies against normal α_IIbβ₃ after transfusion, potentially limiting the effectiveness of transfused platelets.^{236,237,238,239} Protein A-Sepharose immunoadsorption has been reported to restore the efficacy of transfused platelets in this situation.²⁴⁰ Oral contraceptives have been useful in controlling menorrhagia. Regular dental care is essential in minimizing gingival bleeding, and fibrinolytic inhibitors, in addition to platelet transfusions, may be useful in controlling bleeding after dental extractions. Corticosteroids are not efficacious in managing bleeding in thrombasthenic patients,¹⁵³ and there is little evidence that desmopressin (DDAVP) is useful.^114,241 Recombinant factor VIIa has been found to be efficacious for the treatment of bleeding episodes and for obtaining surgical hemostasis in patients with GT, particularly in patients who have developed alloantibodies from prior platelet transfusions.^111,242,243 The GT phenotype of several severely affected individuals has been corrected by bone marrow,^{244,245,246,247} stem cell,^248,249 and unrelated donor cord blood bone marrow transplantation.²⁵⁰ Lastly, platelet gene therapy has improved hemostatic function in α_IIbβ₃-deficient dogs,²⁵¹ suggesting that at some point in the future, gene therapy could be used in humans.

Normal platelets contain ≈50 spherical or elongated structures termed α-granules that contain a variety of proteins, some of which are specific or relatively specific for platelets and others that are also found in plasma.²⁵³ The former include platelet factor 4 (PF4), β-thromboglobulin (βTG), platelet-derived growth factor, and thrombospondin (TSP), and the latter include fibrinogen, vWF, albumin, coagulation factor V (FV), IgG, fibronectin, and a number of protease inhibitors.²⁵⁴ The platelet-specific proteins and several of the plasma proteins such as vWF²⁵⁵ are synthesized by megakaryocytes, whereas others, such as albumin and IgG, reach the α-granules via endocytosis of circulating protein.²⁵⁶ The α-granule membrane contains many of the same proteins present in the platelet plasma membrane (α_IIbβ₃²⁵⁷ and GPIb-IX-V²⁵⁸) and others specific for α-granules (P-selectin^259,260 and osteonectin²⁶¹). Each can be translocated to the platelet surface following platelet activation.