CHAPTER 119 HEREDITARY QUALITATIVE PLATELET DISORDERS
CHAPTER 119 HEREDITARY QUALITATIVE PLATELET DISORDERS
BARRY S. COLLER
DEBORAH L. FRENCH
Glycoprotein IIb/IIIa (aIIbb3; CD41/CD61) – Glanzmann Thrombasthenia
Glycoprotein Ib (CD42b,c), IX (CD42a), and V—Bernard-Soulier Syndrome
GPIb (CD42b,c)—Platelet-Type (Pseudo–) von Willebrand Disease
Glycoprotein Ia/IIa (a2b1; VLA-2; CD49b/CD29)
Abnormal Membrane-Cytoskeletal Interactions
d-Storage Pool Deficiency
Gray Platelet Syndrome (a-Granule Deficiency)
a,d-Storage Pool Deficiency
Quebec Platelet Disorder
Abnormalities of Platelet Coagulant Activity
Definition and History
Etiology and Pathogenesis
Therapy, Course, and Prognosis
Abnormalities of Platelet Agonist Receptors, Signal Transduction, and Secretion
Defects in Platelet Agonist Receptors or Agonist-Specific Signal Transduction
Defects in Signal Transduction
Defects in Phospholipase C, Ga q, Calcium Mobilization, and Calcium Responsiveness
Abnormalities of platelet function manifest themselves primarily as excessive hemorrhage at mucocutaneous sites, with ecchymoses, petechiae, epistaxis, gingival hemorrhage, and menorrhagia most common. Both quantitative and qualitative platelet abnormalities can produce these symptoms, so it is necessary to exclude thrombocytopenia by performing a platelet count (see Chap. 117). A prolonged bleeding time in a patient with a normal platelet count is indicative of a qualitative platelet abnormality, von Willebrand disease (see Chap. 135), or afibrinogenemia (see Chap. 124). Acquired qualitative platelet abnormalities are discussed in Chap. 120, and the hereditary qualitative platelet abnormalities are the subject of this chapter.
The hereditary qualitative platelet disorders can be classified according to the major locus of the defect (Table 119-1; Fig. 119-1). Thus, abnormalities of platelet glycoproteins, platelet granules, and signal transduction and secretion can all result in hemorrhagic diatheses and prolonged bleeding times. Glanzmann thrombasthenia results from abnormalities in either GPIIb or GPIIIa, resulting in loss of GPIIb/IIIa receptor function. This results in a profound defect in platelet aggregation and secondary defects in platelet adhesion and platelet coagulant activity. Loss of the platelet GPIb/IX/V complex due to abnormalities in GPIba, GPIbb, or GPIX results in the Bernard-Soulier syndrome, which is characterized by giant platelets and thrombocytopenia. The major defect is in platelet adhesion due to a decrease in platelet interactions with von Willebrand factor, but abnormalities in thrombin-induced aggregation are also present. Other defects in platelet GPIa/IIa (a2b1) and GPVI, as well as isolated defects in agonist receptors or proteins involved in signal transduction may also produce hemorrhagic symptoms, but these disorders are less well characterized. Abnormalities of platelet coagulant activity, that is, the ability of platelets to facilitate thrombin generation (see Chap. 111 and Chap. 112), can also lead to a hemorrhagic diathesis, but this platelet defect is unique in not usually producing mucocutaneous hemorrhage or a prolonged bleeding time.
The following abbreviations and acronyms are used in this chapter: CMV, cytomegalovirus; ICAM-1, intercellular adhesion molecule 1; PCR, polymerase chain reaction; WASP, Wiskott-Aldrich syndrome protein.
TABLE 119-1 INHERITED DISORDERS OF PLATELET FUNCTION
FIGURE 119-1 Evaluation of patients for abnormalities in platelet number or function and related disorders.
A reduced platelet count occurs in patients with purely quantitative platelet disorders (inherited or acquired) as well as in patients who have inherited qualitative platelet disorders associated with thrombocytopenia. Platelet size (determined from the blood film and/or the mean platelet volume) helps to separate the inherited quantitative platelet syndromes from the acquired thrombocytopenias and the inherited combined quantitative and qualitative thrombocytopenias (see Chap. 117). Very small platelets are characteristic of the Wiskott-Aldrich syndrome. Large platelets that lack purple granules are observed in the gray platelet syndrome (a-storage pool deficiency), but one needs to be certain that the stain is working properly and that there is no plasma factor producing platelet degranulation such as an abnormal immunoglobulin. Confirmation of the diagnosis of gray platelet syndrome is obtained with biochemical analysis of a-granule contents. Patients with platelet-type (pseudo–) von Willebrand disease (vWd) and type 2B vWd have moderate thrombocytopenia and large platelets. Studies of GPIb function and biochemistry are required to establish the diagnosis. The platelets in Bernard-Soulier syndrome are truly giant, with many larger than erythrocytes; the diagnosis is confirmed with biochemical and functional analyses of the GPIb/IX/V complex.
The bleeding time is prolonged in virtually all patients with qualitative platelet disorders (although to various extents) except in platelet coagulant activity disorders, in which the serum prothrombin time is the preferred screening assay. Other tests of platelet coagulant activity are used to establish the diagnosis. Platelet aggregation can separate patients into those with defects in the primary wave of platelet aggregation (dependent on fibrinogen, von Willebrand factor, or their respective receptors) and those with defects in the secondary wave of aggregation. Enhanced ristocetin-induced platelet aggregation at low concentrations of ristocetin has been identified in patients with platelet-type vWd (who have a defect in the GPIb receptor that facilitates von Willebrand factor binding) and in patients with type 2B von Willebrand disease (who have an intrinsic defect in von Willebrand factor) (see Chap. 135). These two diseases can be distinguished by analyzing the binding of the patient’s von Willebrand factor to normal platelets, or the ability of cryoprecipitate or asialo–von Willebrand factor to aggregate patient platelets; confirmation of the diagnosis of platelet-type von Willebrand disease requires analysis of GPIb.
Neither ristocetin nor the snake venom botrocetin induces platelet aggregation if the plasma lacks functional von Willebrand factor, as in most cases of von Willebrand disease (see Chap. 135), or if the platelets lack functional GPIb/IX complexes, as in Bernard-Soulier syndrome. The defect in von Willebrand disease, but not in Bernard-Soulier syndrome, can be corrected by adding normal plasma. Direct analysis of von Willebrand factor and the platelet GPIb/IX complex will confirm the diagnosis.
Patients whose plasma lacks fibrinogen (afibrinogenemia) (see Chap. 124) or whose platelets cannot bind fibrinogen because of abnormal GPIIb/IIIa receptors (Glanzmann thrombasthenia) will have no primary wave of platelet aggregation in response to ADP or epinephrine. Analysis of plasma fibrinogen and platelet GPIIb/IIIa receptors can differentiate between these two groups. Isolated defects in the primary response to collagen have been observed in patients with abnormalities in platelet GPIa/IIa (a2b1) or GPVI. Platelet glycoprotein analysis can separate these from each other. Other isolated defects in one or more of the ADP receptors or the thromboxane A2 receptor will result in decreased ADP-induced platelet aggregation, whereas isolated defects in the receptors for epinephrine or platelet-activating factor lead to defects in primary aggregation in response to these agonists.
A heterogeneous group of platelet defects can result in an abnormal secondary wave of platelet aggregation in response to ADP and epinephrine, and diminished response to low concentrations of collagen and thrombin, but they can be broadly separated into granule defects and defects in the platelet release reaction. These two groups can be distinguished on the basis of their release of granule contents in response to high concentrations of thrombin: platelets from patients with release reaction abnormalities will release normal amounts of granule contents whereas patients with reduced granule contents will release abnormally small amounts of granule contents. a-granule contents and dense body contents can be measured immunologically and biochemically; electron microscopy can confirm the diagnosis of granule defects. Release reaction abnormalities can be subcategorized by analysis of the response to arachidonic acid or a thromboxane A2 analogue, as well as by measuring release of arachidonic acid, calcium fluxes, and phosphoinositide metabolism. (Adapted from Coller,493 reprinted with permission.)
GLYCOPROTEIN IIb/IIIa (aIIbb3; CD41/CD61) – GLANZMANN THROMBASTHENIA
DEFINITION AND HISTORY
Glanzmann thrombasthenia is an inherited hemorrhagic disorder characterized by a severe reduction in, or absence of, platelet aggregation in response to multiple physiologic agonists due to qualitative or quantitative abnormalities of platelet glycoprotein (GP) IIb (aIIb; CD 41) and/or GPIIIa (b3; CD61).
Glanzmann, a Swiss pediatrician, described a group of patients with hemorrhagic symptoms and “weak” platelets (i.e., thrombasthenia) in 1918.1 Subsequent studies demonstrated that platelets from thrombasthenic patients failed to aggregate in response to physiologic agonists such as ADP, epinephrine, collagen, and thrombin2,3,4 and 5; had markedly reduced2,4,5 and 6 levels of platelet fibrinogen; and had reduced or absent clot retraction.7 In the mid-1970s, Nurden and Caen8 and Phillips and colleagues9 discovered that thrombasthenic platelets were deficient in both GPIIb and GPIIIa. Later studies demonstrated that GPIIb and GPIIIa form a calcium-dependent complex in the platelet membrane that functions as a receptor for fibrinogen and other adhesive glycoproteins.10,11,12 and 13 Cloning and sequencing of the cDNAs for GPIIb14 and GPIIIa15 identified them as separate protein subunits that are members of the integrin receptor superfamily16 and permitted the molecular biological characterization of the disorder in affected patients. Identification of the DNA defects in selected patients has provided information on the structure-function relationships of the GPIIb/IIIa receptor and permitted DNA-based carrier detection and prenatal diagnosis.17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57 and 58
ETIOLOGY AND PATHOGENESIS
Glanzmann thrombasthenia is a rare disorder characterized by autosomal recessive inheritance with a worldwide distribution. In regions where consanguineous matings are common, groups of patients with the disorder have been identified, and in several populations founder mutations have been identified by analyzing polymorphisms in the DNA surrounding the affected mutation. These include 42 patients from South India; 39 patients from the Iraqi-Jewish population in Israel; 46 Arab patients from Israel, Jordan, and Saudi Arabia; and a smaller number of patients from three Gypsy families.6,24,41,59,60,61,62 and 63 An analysis of the gene frequency for the more common mutation causing Glanzmann thrombasthenia in the Iraqi-Jewish population revealed 6 of 700 individuals to be carriers.41
The platelet GPIIb/IIIa receptor is required for platelet aggregation induced by all of the agonists thought to operate in vivo (ADP, epinephrine, thrombin, collagen, thromboxane A2) (see Chap. 111).10,11 and 12 Consequently, abnormalities in the receptor result in a failure of platelet plug formation at sites of vascular injury, leading to excessive bleeding and bruising.
The GPIIb/IIIa receptor is also responsible for the uptake of fibrinogen from plasma into platelet a granules,64,65,66 and 67 so patients with Glanzmann thrombasthenia have markedly reduced levels of platelet fibrinogen.2,4,5,68,69 Clot retraction requires platelets with intact GPIIb/IIIa receptors,70,71 and 72 presumably to make contact with fibrin, and so patients with Glanzmann thrombasthenia usually have abnormal clot retraction.2,7
Defects in either GPIIb or GPIIIa result in the same functional defect because both subunits are required for receptor function (see Chap. 111). Biosynthetic studies indicate that GPIIb and GPIIIa form a complex soon after protein synthesis in the rough endoplasmic reticulum73,74 and 75; subsequent posttranslational processing76 and transport to the platelet membrane require that the complex be intact (Fig. 119-2).77,78 Complex formation protects the glycoproteins from proteolytic digestion,73,74,75 and 76 so if either GPIIb or GPIIIa is absent or unable to form a normal complex, the other subunit will be rapidly degraded. Thus, a deficiency in either glycoprotein produces a deficiency in both. Since complex formation and vesicular transport are also required for proteolytic processing of pro-GPIIb into its constituent GPIIba and GPIIbb subunits,76 if complex formation and/or vesicular transport does not occur normally, the very small amount of residual GPIIb will be pro-GPIIb, not mature GPIIb.79
FIGURE 119-2 Biosynthesis of the GPIIb/IIIa complex. (Adapted from Coller493 with permission.)
GPIIIa (b3) can also combine with the aV-integrin (CD51) sub-unit to form the aVb3 “vitronectin” receptor15,80,81 (Fig. 119-3) (see Chap. 111). Despite its common name, this receptor can bind many of the same adhesive glycoproteins as GPIIb/IIIa, although there are some differences in ligand preference and binding sequences.81,82,83,84 and 85 A small number of aVb3 receptors are present on platelets (50 to 100 per platelet)84,86,87; osteoclasts, endothelial cells, and uterine cells, among others, also have aVb3 receptors.88,89 and 90 Glanzmann thrombasthenia patients with defects in GPIIIa also are deficient in aVb3, whereas patients with defects in GPIIb have either normal or increased numbers of platelet aVb3 receptors.19,20,35,84,87,89 At present, there is no evidence that patients who lack aVb3 receptors in addition to lacking GPIIb/IIIa receptors have a more severe hemorrhagic diathesis or suffer from any other abnormalities, perhaps because alternative receptors containing aV associated with other b-subunits can substitute for aVb3.87
FIGURE 119-3 The relationship between the GPIIb/IIIa (aIIbb3) and aVb3 receptors. Both receptors share the common b-integrin subunit GPIIIa (b3). GPIIb/IIIa is present at high density on platelets, is platelet-specific, and is abnormal in all patients with Glanzmann thrombasthenia. The aVb3 receptor is expressed at very low levels on platelets, is not platelet-specific, and is only decreased in Glanzmann thrombasthenia patients whose defects are in GPIIIa (b3).
The molecular biological abnormalities in more than 60 patients with Glanzmann thrombasthenia have been identified, and they are listed in an internet database that is updated continuously40 (http://med.mssm.edu/glanzmanndb) and can be reached through the Williams Hematology website (http://www.williamshematology.com). Table 119-2 and Fig. 119-4 and Fig. 119-5 contain information on mutations of particular interest. Of note, about 40% of the patients with identified mutations are compound heterozygotes rather than homozygotes, indicating that a sizable number of silent carriers are present in the population. Where consanguinity is common, the disorder is more likely to be due to a homozygous mutation arising in a founder, but even under these circumstances more than one mutation may be present. Thus, in the Iraqi Jewish population, in which consanguinity has been present from 586 BCE to the present, three separate mutations have been identified.41,91
TABLE 119-2 SELECTED MOLECULAR BIOLOGIC ABNORMALITIES IN GLANZMANN THROMBASTHENIA
FIGURE 119-4 Glanzmann thrombasthenia mutations located within the vicinity of the metal ion–dependent adhesion site (MIDAS) of GPIIIa (b3). A ribbon diagram of the MIDAS domain located within GPIIIa (b3) is shown and represents the minimal ligand-binding region of this integrin subunit. The cation-binding D119xS121xS123 motif and coordinating residues D217 and E220 are shown in the highlighted circle. The location of Glanzmann thrombasthenia mutations within and surrounding the MIDAS domain are shown. (Adapted from Tozer94 with permission.)
FIGURE 119-5 Glanzmann thrombasthenia mutations located within the b-propeller structure of GPIIb. A is the view from the top and B is the view from the side. This structure was deduced from the amino acid sequence of the aIIb integrin subunit. A ribbon diagram of a seven blade (W1-W7) b-propeller structure is shown. Each blade is comprised of anti-parallel b-strands (numbered 1-4 from the inside to the outside) that are connected by hairpin loops. The hairpin loops connecting b-strands 1-2 and 3-4 are located at the bottom of the structure and the loops connecting strands 3-4 and 4-1, which are hypothesized to support ligand binding, are located on the top of the structure. The calcium-binding domains are located within the 1-2 connecting loops in blades W4-7, and thus lie on the bottom of the structure; the location of three of the four calcium ions is shown as turquoise spheres. The location of selected Glanzmann thrombasthenia mutations within and surrounding the calcium-binding domains and within the third blade of the propeller are shown. (Adapted from Springer101 with permission.) A 3-dimensional version of this figure is available from the Williams Hematology website (http://www.williamshematology.com).
Mutations within the Metal Ion-dependent Adhesion Site of GPIIIa (b3) A metal ion-dependent adhesion site (MIDAS) or MIDAS domain,92 which is highly conserved in six integrin receptor a-subunits and required for ligand-binding,93 is also present in the GPIIIa (b3) subunit.94 Mutagenesis and molecular modeling experiments have suggested that a highly conserved DxSxS amino acid sequence95 motif plus additional coordinating residues are brought together in the three-dimensional structure of the GPIIIa subunit to form the putative cation-binding sphere of the MIDAS domain.92 Ten missense mutations in ten patients with Glanzmann thrombasthenia have been identified within the cation-binding sphere of the MIDAS domain (Table 119-2, Figure 119-4). Two mutations, D145Y in the unprocessed protein sequence (D119Y in the processed protein sequence) (Cam variant)18 and D145N (D119N) (patient NR),96 are located within the conserved DxSxS amino acid motif; three mutations, R240W (R214W) (Strasbourg I variant and patient CM),25,33 R240Q (R214Q) (patient ET),23 and R242Q (R216Q) (patient SH),97 are located within the putative metal ion coordinating sites23; four mutations, L143W (L117W) (patient MK),98 S188L (S162L) (patient BL),55 L288P (L262P) (patient LD)46 and H306P (H280P) (patients HJ, NT, TK)47 are located within the vicinity of the MIDAS domain. The mutations at residue D119 result in severe abnormalities of platelet GPIIb/IIIa function but do not affect GPIIb/IIIa surface expression, whereas the mutations at L117 results in the intracellular retention of misfolded receptor complexes. The mutations at residues R214 and R216, S162, and L262 result in GPIIb/IIIa receptors that are abnormally sensitive to dissociation by calcium chelation, and the mutations at residues S162, L262, and H280P result in reduced surface expression. Further support for the importance of the MIDAS domain comes from studies in which the mutations D119N, R214W, D217N, E220Q, and E220K were introduced into CHO cells in vitro99 and shown to result in functional abnormalities.
Mutations within the GPIIb (a-subunit) b-propeller Sequence Based on its homology to another integrin a-subunit, the amino-terminal 450 amino acids of GPIIb, which contains the minimal ligand-binding sequence,100 has been predicted to fold into a seven-repeat (blade) b-propeller, containing four cation-binding sites.101 Each repeat contains 4 b-strands,102 predicted to fold into one blade of the propeller.101 Loops connect the b strands, with those connecting strands 2-3 and 4-1 extending above the propeller and those connecting strands 1-2 and 3-4 extending below the propeller. The four calcium-binding sites that are homologous to E-F hand motifs are located on the loops below the propeller, and it has been proposed that the ligand binding domains lie on the loops above the propeller.101
A number of Glanzmann thrombasthenia mutations are located within the GPIIb b-propeller (Table 119-2; Fig. 119-5). One set of mutations is located within and surrounding the calcium-binding domains, and another set is located within and around the third blade (designated W3) of the b-propeller (Fig. 119-5). Five missense mutations, one nonsense mutation, and one in-frame deletion mutation have been reported within and surrounding the calcium-binding domains in a total of 10 patients. Many of these mutations affect transport of the GPIIb/IIIa complex to the cell surface. These mutations include a G273D (G242D) substitution (patient FLD)35 which precedes the first calcium-binding domain; a F320S (F289S) (Japanese-1)48 which precedes the second calcium-binding domain; a E355K (E324K) substitution (patients FL, Swiss, and Japanese-2)36,48,56 located between the second and third calcium-binding domains; a R358H (R327H) substitution (patients KJ and Mila-1)37,38 also located between the second and third calcium-binding domains; a G449D (G418D) substitution (patient LM)34 which precedes the fourth calcium-binding domain; a V425D426 deletion (patient LeM)39 at the beginning of the fourth calcium-binding domain; and a Y471X (Y440X) nonsense mutation just following the fourth calcium-binding domain.53
Another set of mutations are located within the vicinity of the third blade (W3) of the b-propeller, which contains a predicted b-turn structure that has been implicated in ligand binding to GPIIb/IIIa and other integrin receptors.103,104 Three missense mutations and one insertion found in five patients result in functionally defective receptors. P176A (P145A) (Mennonite and patient JF) and P176L (P145L) (Chinese-14)44 substitutions and an R192T193 (R161T162) (patient KO)51 insertion are located within the 4-1 connecting hairpin loop between the second (W2) and third (W3) blades of the propeller. A L214P (L183P) substitution (patient LW)54 is located at the end of the second b-strand near the 2-3 connecting hairpin loop. Independent support for the functional importance of this region comes from in vitro CHO cell expression system data99 indicating that a D255V (D224V) mutation,105 located within the 4-1 connecting hairpin loop between the third and fourth blades of the propeller, disrupts receptor ligand binding.
Mutations That Affect Receptor Activation The cytoplasmic domain of GPIIIa plays a functional role in integrin activation and the regulation of ligand binding.22,106,107 Two Glanzmann thrombasthenia mutations have been identified in this region (Table 119-2). One is a R750X (R724X) nonsense mutation (patient RM)45 that results in the deletion of the carboxy-terminal 39 residues of GPIIIa, and the other is a S778P (S752P) missense mutation (patient P or Paris I).22,107,108 This latter patient is unusual in that he had no history of excessive hemorrhage, but he did have a prolonged bleeding time and his platelets did not aggregate in response to ADP. These mutations do not severely affect surface expression of platelet GPIIb/IIIa complexes, but both mutant receptors are unresponsive to agonist stimulation. Mammalian cell expression studies show normal adhesion to immobilized fibrinogen but abnormal cell spreading. Cells expressing the S778P (S752P) mutant receptors have reduced focal adhesion plaque formation and cells expressing the R750X (R724X) mutant receptors have undetectable tyrosine phosphorylation of focal adhesion kinase, pp125FAK. These mutations provide evidence for the role of the GPIIIa cytoplasmic tail in inside-out signaling (i.e., platelet signals that lead to GPIIb/IIIa adopting a high-affinity ligand binding conformation) and outside-in signaling (i.e., signaling to the interior of the platelet as a result of GPIIb/IIIa binding ligand).
The clinical manifestations of a total of 232 patients with Glanzmann thrombasthenia have been the subject of two reviews, and Table 119-3 summarizes data from 177 of these patients.6,24 Menorrhagia occurs in nearly all patients, especially at the time of menarche. Purpura can be present immediately after birth but often is not dramatic. Petechiae of the face and subconjunctival hemorrhage associated with crying may be the first symptoms in neonates and babies. Epistaxis is a common symptom and can be life-threatening.6,24,109 It usually abates in adulthood. Gingival bleeding can be a chronic source of blood (and iron) loss, especially if the teeth are not kept in good repair. Gastrointestinal bleeding was only present in 12 percent of patients in one review6 but was present in 49 percent of patients in another.24 Gastrointestinal bleeding is usually intermittent, and it is often difficult to identify the bleeding site.
TABLE 119-3 BLEEDING IN PATIENTS WITH GLANZMANN THROMBASTHENIA
Hemarthroses are very rare, and spontaneous ones even rarer, distinguishing Glanzmann thrombasthenia from the hemophilias and related illnesses. The platelet abnormality in Glanzmann thrombasthenia undoubtedly increases the risk of excessive bleeding when there is trauma to the central nervous system, but it is remarkable that spontaneous central nervous system bleeding is so rare.6,24
Patients with Glanzmann thrombasthenia do not appear to bleed excessively during pregnancy, but immediate postpartum hemorrhage is very common unless platelet transfusions are administered.6 Delayed postpartum hemorrhage can also be severe; it may be less likely to occur in patients delivered by cesarean section.6 Surgical procedures, including oral surgery, are usually complicated by excessive bleeding unless prophylactic platelet transfusions are administered.6,24,110
The hemorrhagic diathesis in Glanzmann thrombasthenia is notable for its variability and the lack of correlation between the biochemical platelet abnormalities and clinical severity.6 Even within groups of patients such as the Iraqi Jews, most of whom share the same genetic abnormality and have very similar platelet function and biochemical profiles, there is a wide spectrum of clinical severity.24,41 Moreover, the severity of bleeding symptoms can vary significantly during the lifetime of individual patients. Thus, factors other than the platelet defect itself play important roles in determining the risk of bleeding.
Carriers of Glanzmann thrombasthenia appear to be asymptomatic and generally have normal results in platelet function tests,6,24 but a prolonged bleeding time has been reported in at least one heterozygote.57
Characteristic laboratory data in patients with Glanzmann thrombasthenia are given in Table 119-4. Patients have normal platelet counts and morphology, prolonged bleeding times, decreased or absent clot retraction, and abnormal platelet aggregation responses to physiologic stimuli (Fig. 119-6). Platelets of patients with Glanzmann thrombasthenia have a normal (or near-normal) initial slope of ristocetin-induced aggregation, reflecting the normal levels of plasma von Willebrand factor and the normal platelet GPIb/IX content; the reduced second wave of aggregation at low doses of ristocetin reflects the impaired GPIIb/IIIa function,111 and the interesting cyclical aggregation at higher doses of ristocetin112 probably reflects a complex interaction between ristocetin-induced binding of von Willebrand factor to GPIb/IX and inhibition of this interaction by released ADP.113 In each case, the abnormalities reflect the inability of the platelets to bind fibrinogen and/or other adhesive glycoproteins. Platelets undergo normal shape change in response to ADP and thrombin, demonstrating their ability to undergo metabolic and cytoskeletal changes in response to these agents. Similarly, high doses of thrombin and collagen produce normal release of dense body and a-granule contents2,4,114; the release reaction abnormalities observed with lower doses of these agents reflect the lack of augmentation of the release reaction normally produced by platelet aggregation.2,111,115,116 and 117
TABLE 119-4 LABORATORY FEATURES OF GLANZMANN THROMBASTHENIA
FIGURE 119-6 Patterns of platelet aggregation in response to several agonists in different disease states, including von Willebrand disease (vWD); Bernard-Soulier syndrome (BSS); platelet release defects (PRD), including aspirin ingestion; storage pool disease (SPD); and Glanzmann thrombasthenia (GT). Note that patients with platelet release defects have abnormal arachidonic acid–induced aggregation whereas those with storage pool deficiency have nearly normal responses to arachidonate. (Courtesy of Dr. Robert Handin, with permission.)
Platelets in whole blood or platelet-rich plasma adhere to glass because fibrinogen first becomes deposited on the glass and the platelets then adhere to the immobilized fibrinogen.118,119 Platelets from patients with Glanzmann thrombasthenia fail to adhere to glass,2,4,118 and this forms the basis of their abnormality in the glass bead retention assay.120 Platelet coagulant activity has been variably reported as normal or abnormal,2,3,4 and 5,121,122 and 123 probably as a result of variations in the assays used to assess this activity or individual patient differences. A defect in platelet microparticle formation and support of thrombin generation has been identified in some patients,122,123,124 and 125 but not all patients appear to share this abnormality.126 GPIIb/IIIa and aVb3 have been shown to bind prothrombin, probably accounting for some of the abnormalities identified.127,128
In flow chamber studies, thrombasthenic platelets adhere normally to deendothelialized blood vessels at low and intermediate shear rates but do not spread normally or form platelet thrombi.129,130 and 131 A defect in adhesion occurs at higher shear rates. A paradoxical increase in fibrin formation on these surfaces has been observed with thrombasthenic platelets, but the explanation for this phenomenon remains unknown.132
Platelet GPIIb/IIIa and aVb3 can be quantitated by any one of several techniques, including, monoclonal antibody binding (using flow cytometry or radiolabeled binding), immunoblotting, and surface labeling followed by sodium dodecyl-sulfate polacrylamide gel electrophoresis (SDS-PAGE) (Fig. 119-7). Based on the results of such studies, patients with Glanzmann thrombasthenia have been subcategorized by GPIIb/IIIa content into those with less than 5 percent of normal GPIIb/IIIa (type I), 5 to 20 percent (type II), or 50 percent or more (variants).6,133 In one review of 64 patients, 78 percent were type I, 14 percent were type II, and 8 percent were variants.6 The subtyping of Glanzmann thrombasthenia into type I, type II, and variants predated the identification of GPIIb/IIIa abnormalities as the cause of Glanzmann thrombasthenia and was based on functional data. With current methods of more precise laboratory analysis and the recognition of the diverse clinical and functional abnormalities present in Glanzmann thrombasthenia, this categorization provides only limited information.
FIGURE 119-7 Analysis of platelet proteins and antiplatelet antibodies by sodium dodecyl sulfate-polyacrylamide-gel electrophoresis. The figure is a drawing made from original material to allow a clearer, more consistent presentation of typical analyses. Solubilized platelet proteins were separated by electrophoresis through a slab gel containing a 7 to 12 percent exponential gradient of acrylamide. Lane 1 represents a Coomassie blue protein stain of normal whole platelets. Among the major membrane glycoproteins (GPs), only GPIIb is seen as a distinct band. Lanes 2 through 4 represent autoradiographs of platelets labeled by lactoperoxidase-catalyzed radioiodination (to react with cell-surface proteins), and lanes 5 through 8 represent fluorographs of platelets labeled by sequential treatment with neuraminidase, galactose oxidase, and 3H-labeled sodium borohydride (to react with cell-surface carbohydrate). Lanes 2 and 5 represent normal platelets. Lanes 3 and 6 represent platelets from a patient with the Bernard-Soulier syndrome. The absence of GPIb can be seen with both techniques, and the absence of GPV, GPIX, and a high-molecular-weight band that may contain complexes of GPIb can be seen in lane 6. Lanes 4 and 7 represent platelets from a patient with Glanzmann thrombasthenia, demonstrating the absence of GPIIb and IIIa. Lane 8 is an immunoblot. Normal platelet proteins were transferred from the gel section to nitrocellulose paper that was first incubated with anti-P1A1 (a human alloantibody that reacts with GPIIIa) and then 125I-labeled staphylococcal protein A; the radiolabeled protein was finally developed by autoradiography. (From George JN, Nurden AT, Phillips DR: Molecular defects in interactions of platelets with the vessel wall. N Eng J Med 311: 1084, 1984 with permission).
Although there are very few aVb3 receptors per platelet, they can be reliably measured by radiolabeled antibody binding and by flow cytometry87; they can also be measured on patient lymphocytes after transformation with Epstein-Barr virus.134 The aVb3 level is very useful in making a preliminary assessment of whether the patient has a defect in GPIIb or GPIIIa, since patients who lack GPIIIa also lack aVb3 receptors.135
Fibrinogen-binding studies assess the function of the GPIIb/IIIa complex.10,11 The most common method is to add radiolabeled fibrinogen to platelets suspended in buffer (prepared either by washing or gel filtration) and then measure the binding of radioactivity when the platelets are stimulated with ADP10,11 or a similar agonist. Fibrinogen can also be labeled with a fluorescent molecule, and then flow cytometry can be used to measure fibrinogen binding. These techniques are most useful in detecting qualitative abnormalities of GPIIb/IIIa in patients with variant Glanzmann thrombasthenia. The binding of a monoclonal antibody (PAC1) to platelets gives similar information because the antibody only binds to the activated form of GPIIb/IIIa.136
Carriers of Glanzmann thrombasthenia have essentially normal platelet function.59 Their platelets, however, only contain about 60 percent of the normal number of GPIIb/IIIa receptors.137 Carrier detection is most accurately performed by DNA analysis when the defect is known, and advances in PCR technology allows this to be performed even with DNA obtained from cells in random urine samples.21
Platelet fibrinogen is reduced to about 10 percent of normal in patients with marked reductions in GPIIb/IIIa2,5,68,69 but is variably reduced in patients with significant amounts of GPIIb/IIIa.133,138,139 Its presence may provide insights into the nature of the functional defect.
A history of mucocutaneous hemorrhage, as opposed to hemarthroses and muscle hemorrhage, helps to differentiate disorders of platelet function (including von Willebrand disease) from the hemophilias and related disorders. The symptoms of qualitative platelet function disorders and thrombocytopenia are essentially identical, so their differentiation depends on laboratory studies, most importantly the platelet count. Similarly, the symptoms of von Willebrand disease and the different qualitative platelet disorders are often indistinguishable, and so assays of factor VIII, von Willebrand factor, and platelet function are required to make the definitive diagnosis. Although patients with afibrinogenemia have platelet aggregation studies similar to those of patients with Glanzmann thrombasthenia, they are more likely to have histories of umbilical stump bleeding, fetal wastage, muscle hemorrhage, and intraabdominal hemorrhage in addition to the mucocutaneous hemorrhage typical of Glanzmann thrombasthenia. A plasma fibrinogen assay establishes the diagnosis. Hereditary disorders, such as Glanzmann thrombasthenia, are usually present at birth or have their onset in early childhood. Thus, the history can be helpful in distinguishing inherited from acquired abnormalities. Figure 119-1 is a flow diagram that depicts a logical series of steps one may take in evaluating patients with mucocutaneous hemorrhage. In situations where it is important to rapidly ascertain whether a patient has Glanzmann thrombasthenia, a tentative diagnosis can be established based on a normal platelet count, reduced or absent clot retraction, a prolonged bleeding time, and the lack of platelet clumps when a specimen of unanticoagulated blood is used to make a blood smear.
Autoantibodies to GPIIb/IIIa may produce the phenotype of Glanzmann disease and many of the characteristic laboratory abnormalities.140,141,142,143 and 144 Mixing studies using patient plasma and normal platelets should identify these acquired autoimmune disorders. A preliminary report suggested that some patients with acute promyelocytic leukemia may have deficiencies of platelet GPIIb/IIIa,145 perhaps due to disruption of the GPIIb and GPIIIa genes, both at 17q21.32, as a result of the common translocations affecting chromosome 17 in this disorder146 (see Chap. 93).
THERAPY, COURSE, AND PROGNOSIS
Therapy involves both preventive measures and treatment of specific bleeding episodes. Dental hygiene is especially important in minimizing gingival hemorrhage. Antiplatelet agents should be avoided. Iron and folate may be needed in patients with sufficient ongoing hemorrhage to cause anemia and iron depletion. Hepatitis B vaccine should be administered early in life, using a small-gauge needle and with prolonged direct pressure to the injection site to prevent excessive bleeding. Hormonal therapy can control menorrhagia in virtually all patients. Since menorrhagia is often most severe at the time of menarche, and can result in the need for emergency hysterectomy,147 it may be justified to initiate hormonal therapy before menarche,6 but the possibility of premature cessation of bone growth needs to be considered as well.
Antifibrinolytic agents may be useful in patients with gingival bleeding or who are undergoing tooth extractions. Either epsilon aminocaproic acid (40 mg/kg PO given four times daily)6 or tranexamic acid (0.5 to 1.0 g PO given three or four times daily)148,149 have been recommended based on studies in patients with hemophilia A or B; tranexamic acid usually produces fewer gastrointestinal side effects than epsilon aminocaproic acid. These agents are contraindicated if disseminated intravascular coagulation is present. A tranexamic acid mouthwash (10 ml of a 5 percent solution used four times daily) is effective in controlling gum bleeding in patients treated with oral anticoagulants and in patients with hemophilia,150 and the author has found this helpful in Glanzmann thrombasthenia. Desmopressin (DDAVP) (see Chap. 135) usually does not normalize the bleeding time in patients with Glanzmann thrombasthenia,6,151 but exceptions have been reported.152 Anecdotal reports suggest that it may improve hemostasis, even without normalizing the bleeding time.152,153
Topical agents can also help arrest bleeding in Glanzmann thrombasthenia patients. Gelfoam (a form of resolvable, oxidized, regenerated cellulose) soaked in either tranexamic acid or topical thrombin, or any one of several fibrin sealants prepared from a source of fibrinogen and a source of thrombin, with or without antifibrinolytic agents or other components,155,156 have been used in patients with coagulopathies, with the latter being particularly effective. Bovine thrombin, however, has induced antibody formation to itself and contaminating factors V and XI; at least some antibodies to factor V have cross-reacted with human factor V and caused serious hemorrhage.157,158 IgE-mediated anaphylaxis has also been reported with bovine topical thrombin.159 A microfibrillar collagen hemostatic agent of bovine origin has been used to secure hemostasis in bleeding normal individuals. However, antibodies to bovine (and rabbit) tissue factor have been identified in some patients treated with this hemostatic agent, but these did not cross-react with human tissue factor nor did they induce a hemorrhagic diathesis.160 For dental procedures, custom splints of soft acrylic help prevent excessive hemorrhage.161
Control of epistaxis can be particularly difficult. A step-wise approach has been described that involves the following: elevation of the head and local pressure; topical vasoconstriction with cottonoid pledgets and oxymetazoline; cauterization with silver nitrate or trichloroacetic acid; anterior packing; posterior packing; and, finally, arterial ligation or embolic occlusion of the internal maxillary artery.109 When the simple topical measures fail to control bleeding, platelet transfusions are administered.
Postpartum hemorrhage may benefit from administration of low concentrations of prostaglandin E2 or F2a via continuous intrauterine irrigation162,162a; this experimental technique has been effective in normal patients with severe postpartum hemorrhage, but additional data are required about its effectiveness in patients with platelet disorders.
Erythropoietin was reported to improve the bleeding time and platelet retention in one patient with Glanzmann thrombasthenia, even without producing a significant increase in hemoglobin concentration.152 A positive effect of erythropoietin on platelet function, independent of an effect on hemoglobin, has also been reported in uremia.163,164
Transfusion of platelets (see Chap. 142) is the mainstay of therapy for serious bleeding in Glanzmann thrombasthenia and as prophylaxis prior to surgery or other major hemostatic stresses. Since patients are likely to need transfusions throughout their lifetimes, hepatitis B vaccine should be administered at an early age, and all transfusions of both platelets and packed red blood cells should be given with leukocyte depletion filters to decrease the risk of alloimmunization165 and cytomegalovirus (CMV) transmission.166 Febrile transfusion reactions can be diminished by leukodepletion at the time of blood collection.167 Even in patients who are refractory to platelets, leukocyte depletion filters may improve the recovery of transfused platelets in the circulation.168 Females of childbearing potential who are Rh negative should not be given Rh-positive platelets. It may also be justified to use only HLA-matched platelets, even early in the patient’s course, to minimize the risk of alloimmunization.169 The use of family members’ platelets may be convenient, but if consideration is given to marrow transplantation from a family member, it may be advisable to avoid donations from family members. Similarly, if bone marrow transplantation is considered, and the patient has not already developed CMV infection, it may be desirable to select blood from donors who do not have evidence of CMV infection.
Platelet alloimmunization poses several different problems in patients with Glanzmann thrombasthenia, depending upon the antigen involved. In addition to antibodies directed at platelet proteins other than GPIIb/IIIa, such as HLA determinants, patients can make several different types of antibodies to GPIIb and/or GPIIIa. These include antibodies to: (1) the well-recognized polymorphic alloantigens on GPIIb and IIIa170 (see Chap. 138); (2) other regions of GPIIb/IIIa that are not involved in ligand binding; and (3) the ligand-binding regions of GPIIb/IIIa. Since the platelets from most patients with Glanzmann thrombasthenia lack GPIIb/IIIa alloantigens, antibodies against these determinants, as well as against other nonligand-binding domains of GPIIb/IIIa, could theoretically be produced either as a result of transfusions or pregnancy. Such antibodies could result in refractoriness to platelet transfusions, a predisposition to developing posttransfusion purpura, or a predisposition to having children with neonatal isoimmune thrombocytopenia (see Chap. 117).170 One possible case of neonatal thrombocytopenia based on such a mechanism has been reported, but an autoantibody could not be excluded.171
The development of antibodies that inhibit GPIIb/IIIa function has the potential to make further transfusions ineffectual, even if the platelets circulate. Several such cases have been reported.6,171,172,173 and 174 The antibodies produced by the patients induce a thrombasthenic defect in normal platelets. If patients with antibodies to GPIIb/IIIa that block ligand binding have severe hemorrhage, it is reasonable to try plasmapheresis to remove the offending antibodies, but the efficacy of such treatment is not defined, and at best it provides only short-term benefit.175 It is notable that at least one patient has been reported to have had an inhibitory antibody for more than 15 years without significant hemorrhage.6,176
Allogeneic marrow transplantation has been reported in two patients with Glanzmann thrombasthenia. The first was a 5-year-old male who had several severe gastrointestinal hemorrhages.177 His bleeding diathesis was cured, and 9 years after the transplant he was alive and well, but with mild graft-versus-host disease.6 The second patient, who required multiple hospital admissions to control bleeding but had only received a platelet transfusion once, was transplanted at age 2.5 years from an HLA-identical sibling who was heterozygous for Glanzmann thrombasthenia.178 She was well 19 months after the transplant.
Recombinant factor VIIa has been used to treat at least seven patients with Glanzmann thrombasthenia, two of whom had antibodies to HLA antigens or GPIIb/IIIa.179,180,181 and 182 Although the preliminary reports have indicated favorable results in securing hemostasis, in one case thromboembolism occurred 6 days after the termination of a 15-day continuous infusion. Thus, at the time of writing, this treatment is experimental.
Progress has been made in gene therapy approaches to correcting the genetic defect in Glanzmann thrombasthenia,183 and a GPIIIa-deficient mouse model of Glanzmann thrombasthenia provides a useful animal system for assessing the potential of gene therapy for human treatment.184 Since methods of marrow transplantation and gene transfer therapy are likely to improve, it will be important to reassess the risk:benefit ratios of these therapies for individual patients with Glanzmann thrombasthenia.
Although Glanzmann thrombasthenia is a severe disease, the prognosis for survival is generally good. In one series, 2 of 64 patients died of hemorrhage and in another, 3 of 43 patients died of hemorrhage.6,24 A nationwide survey in Japan identified 98 Glanzmann thrombasthenia patients in 1976 and 192 in 1991.185 The mortality rate in 1976 was 6.8 percent, which was slightly higher than for hemophilia. By 1991, the mortality rate decreased to 4.9 percent. The age-adjusted standardized mortality ratio decreased from 1.76 to 0.83 over the same time, and the percentage of patients over 30 years old increased from 4.5 percent to 24.5 percent. These data indicate that the prognosis improved significantly during the study period.
GLYCOPROTEIN Ib (CD42b,c), IX (CD42a), AND V—BERNARD-SOULIER SYNDROME
DEFINITION AND HISTORY
Bernard-Soulier syndrome is an inherited disorder characterized by thrombocytopenia, giant platelets, and a failure of the platelets to undergo selective von Willebrand factor–dependent platelet interactions as a result of abnormalities in the platelet GPIb/IX complex (CD42). Defective interactions between platelets and thrombin may also be present.
In 1948 Bernard and Soulier described two children from a consanguineous family who had a severe bleeding disorder characterized by mucocutaneous hemorrhage.186,187 Evaluation of the patients’ blood revealed variable thrombocytopenia and giant platelets. Beginning in the early 1970s, Bernard-Soulier syndrome platelets were shown to have a functional defect in von Willebrand factor-dependent platelet adhesion and agglutination.188,189 and 190 In 1975 Nurden and Caen identified an abnormality in platelet GPIb as the cause of the functional defect.191 Later studies confirmed the defect in von Willebrand factor-GPIb interactions192,193 and 194 and identified additional defects in platelet GPV and GPIX.195,196 A mouse model of Bernard-Soulier syndrome has been produced by gene targeting of GPIba.197
ETIOLOGY AND PATHOGENESIS
Epidemiology This rare disease, with a prevalence estimated as less than 1 in 1 million has been reported from countries around the world.187,195,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,235,236,237,238,239,240,241,242,243,244,245,246,247 and 248 Consanguinity is common in the families with affected children187 because the disorder is usually inherited as an autosomal recessive trait and because spontaneous mutations appear infrequently. However, an autosomal dominant form of the disease has been reported.221
Causes of Hemorrhage Four different features of Bernard-Soulier syndrome may contribute to the hemorrhagic diathesis: thrombocytopenia, abnormal platelet interactions with von Willebrand factor, abnormal platelet interactions with thrombin, and abnormal platelet coagulant activity.
The pathophysiology of the thrombocytopenia is uncertain. Early studies suggested a marked shortening of platelet survival, presumably due to the decrease in platelet surface charge resulting from the GPIb defect.249,250 Later studies using 111In-oxine to label platelets reported more modest or no shortening of platelet survival, indicating that ineffective thrombopoiesis and/or decreased thrombopoiesis may contribute to the thrombocytopenia.251,252 Irregularities in the demarcation membrane system have been identified in Bernard-Soulier syndrome megakaryocytes and may contribute to abnormal platelet production.253 Based on observations in other giant platelet syndromes (see Chap. 117), the large size of Bernard-Soulier platelets would tend to diminish the adverse hemostatic effects of the thrombocytopenia because the platelet mass is better preserved. However, in fact, the bleeding diathesis with Bernard-Soulier syndrome is more severe than expected from the thrombocytopenia, reinforcing the conclusion that the qualitative platelet defect is clinically significant.176,187
The platelet GPIb/IX complex functions as a receptor for von Willebrand factor (see Chap. 111 and Chap. 135).241,254,255 This interaction is crucial in the adhesion of platelets to subendothelial surfaces, especially under high shear conditions, where von Willebrand factor acts as a bridge between the subendothelial matrix and the platelet.130,131 The relative roles of subendothelial von Willebrand factor, plasma von Willebrand factor, and platelet von Willebrand factor have not been completely defined, but they probably all contribute.255
GPIb/IX–von Willebrand factor interactions can also occur in platelet suspensions at high shear rates; this can lead to platelet activation, with subsequent aggregation mediated by GPIIb/IIIa.255,256,257 and 258 Whether the shear rates in vivo ever reach the levels required to initiate von Willebrand factor binding, however, is not established.
The platelets of patients with Bernard-Soulier syndrome have a decreased response to platelet activation by thrombin, especially at limiting concentrations of thrombin.259,260,261 and 262 Bernard-Soulier platelets are deficient in two different proteins that interact with thrombin, namely GPIba, which binds thrombin,254,263,264 and 265 and GPV, which is a thrombin substrate (see Chap. 111). Paradoxically, mice deficient in GPV actually have increased sensitivity to thrombin activation.266 Thus, the GPIba defect in thrombin binding seems to override the enhanced sensitivity to thrombin expected from the GPV defect. Since thrombin is one of the major physiologic activators of platelets, this abnormality may also contribute to the hemorrhagic diathesis.
Bernard-Soulier platelets appear defective in supporting thrombin generation as judged by the serum prothrombin time,267 a test performed with whole blood, but in other tests of platelet coagulant activity, Bernard-Soulier platelets support coagulation as well as or better than normal platelets.121,268 Defects in collagen-induced coagulant activity and the association of factors V, VIII, and XI with Bernard-Soulier platelets have been described,268 but their significance is unclear. Abnormal membrane lipids have also been reported.269 Binding of von Willebrand factor to GPIb/IX has been implicated in fibrin-dependent, but not fibrin-independent, augmentation of platelet coagulant activity, and thus fibrin-dependent coagulant activity is likely to be abnormal in Bernard-Soulier syndrome.123 This finding might be able to partially reconcile the above observations, since the serum prothrombin time is one of the few assays used to assess platelet coagulant activity in which fibrin forms.
The mechanisms producing the giant platelets in Bernard-Soulier syndrome have not been identified, but since giant platelets are found in Bernard-Soulier syndrome variants in which GPIb/IX is present, but unable to bind ligand, it has been proposed that the abnormality is due to the inability of GPIb/IX to bind a postulated novel bone marrow ligand.241 It cannot be due to an inability to bind von Willebrand factor, since patients lacking von Willebrand factor do not have large platelets. A defect in GPIb/IX-mediated signaling due to a deficiency of phospholipase C has been described, and it has been proposed that this abnormality may be the cause of the large platelets.241,270 A mechanical alteration in the plasma membrane of Bernard-Soulier platelets has been identified by micropipette experiments, showing the plasma membranes to be more deformable than normal.271 The increased deformability may reflect the loss of the normal interaction of GPIb/IX with the cytoskeleton via actin-binding protein (filamin-1) (see Chap. 111).
Bernard-Soulier platelets are deficient not only in GPIba, GPIbb, and GPIX, but also in GPV, and all of these proteins are thought to exist in a complex (see Chap. 111).196,241,272 It is of considerable interest that all of these proteins share highly conserved leucine-rich regions.241,254,255 One possible explanation for the loss of surface expression of all the proteins is that they need to form a complex during biosynthesis in order to be transported to the surface255; evidence supports the need for GPIba, GPIbb, and GPIX to all be present for optimal surface expression,273 but data from mice deficient in GPV indicate that this glycoprotein is not required for surface expression of the GPIb/IX complex.266
At the molecular level, the platelets from different patients with Bernard-Soulier syndrome are heterogeneous, with many having no detectable GPIb and others having variable amounts, up to 50 percent of normal.208,210,215,217,241,270,274,275 There also is variability in the degree of concordance in the reduction of GPIb and the other deficient proteins.223,276
Molecular Biological Defects The molecular biological basis of Bernard-Soulier syndrome has been determined in a number of patients, and data on some of these patients are given in Table 119-5. Defects have been identified in GPIba, GPIbb, and GPIX, but not in GPV. Nearly one-half of the defects affect the leucine-rich repeats or the conserved flanking sequences, supporting the importance of these structural elements in the biogenesis and surface expression of the GPIb/IX/V complex. Three patients have been described who are homozygous for a deletion in the last 2 bases of codon 492 of GPIba (nucleotides 1523 and 1524) resulting in a frame shift that alters the membrane-spanning region and results in premature termination, and another patient has been described who is heterozygous for this deletion and a missense mutation of GPIba.236,238,239,247 The defect in the transmembrane domain appears to result in a poorly anchored GPIba, as indicated by the presence of GPIba antigen in plasma. Haplotype analysis indicated that the mutations in these 4 apparently unrelated patients may, in fact, have derived from a common founder. Two reported defects in GPIbb are of particular interest because in both cases one of the GPIbb genes, and several nearby genes on chromosome 22, were deleted, resulting in the patients having the DiGeorge/Velo-cardio-facial syndrome.231,232,245 In other studies of patients with the Velo-cardio-facial syndrome due to heterozygous deletions of 22q11, giant platelets and relative thrombocytopenia, but no bleeding disorder or abnormal platelet function were observed, consistent with the patients being heterozygous for GPIb/IX deficiency.243
TABLE 119-5 MOLECULAR BIOLOGIC ABNORMALITIES IN BERNARD-SOULIER SYNDROME
Several variants of Bernard-Soulier syndrome have been described. An autosomal dominant form has been ascribed to a heterozygous mutation in the second leucine-rich repeat of GPIba (Leu57Phe).221 Presumably, the abnormal GPIba interferes with the function of the normal ones. The affected patients have moderate bleeding symptoms, moderate thrombocytopenia, and giant platelets. The GPIb is unusually susceptible to proteolysis and functions ineffectively with regard to its interactions with von Willebrand factor. The “Bolzano” defect, which has been described in two patients, involves the sixth leucine-rich repeat of GPIba (Ala156Val). This mutation results in a GPIba molecule that cannot bind von Willebrand factor but can bind thrombin. In one patient, the Bolzano defect was homozygous, and the patient had nearly normal levels of GPIb/IX/V complex.216 In the other, it coexisted with a 12 amino acid deletion and an amino acid substitution (Glu181Lys); GPIba platelet expression was markedly reduced in this patient.248 A Japanese patient heterozygous for 2 mutations in GPIbb, one of which produced an additional Cys at amino acid 88, had a mild bleeding disorder, significant amounts of functional platelet GPIb/IX/V complex, and very large platelets; of note, the patient did not have thrombocytopenia. A defect in GPIbb cross-linking to GPIba was proposed as the cause of the abnormality.239
Epistaxis is the most common symptom of Bernard-Soulier syndrome (70 percent), with ecchymoses (58 percent), menometrorrhagia (44 percent), gingival hemorrhage (42 percent), and gastrointestinal bleeding (22 percent) also common.187 Hemorrhagic symptoms that occur with lower frequency include posttraumatic bleeding (13 percent), hematuria (7 percent), cerebral hemorrhage (4 percent), and retinal hemorrhage (2 percent). There is considerable variability in symptoms among patients,176 even among patients within a single family.241,277 A review that includes brief descriptions of the clinical features of 55 patients, reported through 1998, has been published.241
Platelet Number and Morphology Thrombocytopenia is present in nearly all patients but is variable in its severity, ranging from about 20,000 platelets/µl to near normal levels. Platelets are large on smear, with more than one-third usually having diameters greater than 3.5 µm and some being as large or larger than lymphocytes. The platelets display only minor variations in vesicular structures and the open canalicular system by electron microscopy.187 The membrane of Bernard-Soulier platelets appears to be more deformable than normal,271 perhaps because GPIb ordinarily interacts with the platelet cytoskeleton (see Chap. 111).278
Bleeding Time The bleeding time is almost always prolonged, but the degree of prolongation is variable.
Platelet Aggregation The hallmark findings in the Bernard-Soulier syndrome are the failure of platelets to aggregate in response to ristocetin189 or botrocetin,192,279 agents that require von Willebrand factor–GPIb interactions (Fig. 119-6). In von Willebrand disease, but not Bernard-Soulier syndrome, this defect can be corrected by adding normal plasma (or von Willebrand factor).
Although, the large size of the platelets in Bernard-Soulier syndrome and the thrombocytopenia make it technically difficult to perform platelet aggregation studies, in general, aggregation induced by ADP, epinephrine, or collagen is either normal or enhanced.190,219,280 The response to thrombin is usually dose-dependent, with essentially a normal response at high doses of thrombin260 but with a prolonged lag phase and a diminished response at low doses of thrombin.259,281
Platelet Coagulant Activity The coagulant activity of Bernard-Soulier platelets has been variably reported as reduced, normal, or increased.121,267,268 The variable presence of fibrin in the different assays used to assess platelet coagulant activity may account for these inconsistent results, since GPIb-von Willebrand factor interactions enhance platelet coagulant activity when fibrin is present but not when it is absent.123
Platelet GPIb/IX/V Content Platelet surface GPIb, GPIX, and GPV are usually decreased or absent in Bernard-Soulier syndrome. This can be established by monoclonal antibody binding or by biochemical and immunologic assessment of solubilized platelet proteins (Fig. 119-7).
Platelet-Thrombin Interactions GPIb may be responsible for the high-affinity binding of thrombin to platelets, but since there are only 50 high-affinity thrombin-binding sites per platelet and 25,000 GPIb molecules per platelet, perhaps only a subpopulation of GPIb molecules are involved.254 The relationship, if any, between GPIb and the seven-transmembrane domain thrombin receptors (PAR-1 and PAR-4) present on platelets remains to be defined (see Chap. 111), but it appears that both GPIb and the seven-transmembrane domain receptors are required for maximal response to thrombin.281 GPV, which is missing from the platelet surface in Bernard-Soulier syndrome, is cleaved by thrombin, but the cleavage does not appear to be necessary or sufficient for thrombin-induced platelet activation.266,282,283 As noted above, platelets of mice lacking GPV have increased responsiveness to thrombin.266
Ex Vivo Interaction with Subendothelial Surfaces Bernard-Soulier platelets demonstrate defective adhesion to subendothelial surfaces, especially at shear rates greater than 650 s–1.130,131,188,284 The results are similar to those in patients with von Willebrand disease.
Shear-Induced Platelet Aggregation Unlike normal platelets, Bernard-Soulier platelets are not aggregated by high shear rates.256,257 The initial interaction in this process appears to be binding of von Willebrand factor to GPIb,255 with subsequent activation of GPIIb/IIIa, perhaps through signaling via the protein 14-3-3z associated with the cytoplasmic domain of GPIba258,285 or either Fcg receptor IIA or the Fc receptor g chain, both of which have been identified as linked to the GPIb/IX complex and both of which are capable of initiating signal transduction (see Chap. 111).286,287
This is discussed in the section on the differential diagnosis of Glanzmann thrombasthenia above. Acquired Bernard-Soulier syndrome has been reported due to autoantibodies,288,289,290,291 and 292 as part of a juvenile myelodysplastic syndrome,293,294 and in association with acute myelogenous leukemia.294
THERAPY, COURSE, AND PROGNOSIS
The therapy of Bernard-Soulier syndrome is essentially identical to that for Glanzmann thrombasthenia (see above). Splenectomy has been performed when the diagnosis of immune thrombocytopenia was mistakenly made, but this usually does not normalize the platelet count or improve the bleeding diathesis.248 Oral contraceptives can control menorrhagia.295 Desmopressin (DDAVP) has been variably effective in decreasing the bleeding time.153,207,209,219,234,242,296,297 and 298 Platelet transfusions are effective when needed but carry a risk of alloimmunization, including the production of antibodies to the functional region of GPIb.299,300 A preliminary report indicates that factor VIIa infusion may be beneficial, but such therapy is experimental.301 Patients have had successful pregnancies and deliveries, but serious delayed bleeding can occur, and emergency hysterectomy has been required to control the hemorrhage.199,202,212,222,244,300 Neonatal thrombocytopenia presumed to be due to maternal alloimmunization has been reported.300
As with Glanzmann thrombasthenia, the prognosis of patients with Bernard-Soulier syndrome has improved as platelet transfusion support has become more readily available and other supportive measures have become more effective.
GPIb (CD42b,c)—PLATELET-TYPE (PSEUDO–) VON WILLEBRAND DISEASE
DEFINITION AND HISTORY
A heterogeneous group of patients has been described with mild to moderate bleeding symptoms, variably enlarged platelets, variable thrombocytopenia, and diminished plasma high-molecular-weight von Willebrand factor multimers. The fundamental defect in these patients is thought to be an enhanced interaction between an abnormal platelet GPIb/IX receptor and normal plasma von Willebrand factor.302,303,304,305,306 and 307 Since these patients have some of the hallmarks of von Willebrand disease, but the defect is in platelet GPIb/IX, it has been termed both pseudo-von Willebrand disease and platelet-type von Willebrand disease.
ETIOLOGY AND PATHOGENESIS
A qualitative abnormality in GPIb is thought to be responsible for this disorder, with ongoing in vivo binding of high-molecular-weight von Willebrand multimers to platelets causing depletion of the plasma high-molecular-weight multimers. In addition, the binding of von Willebrand factor to platelets may lead to shortened platelet survival, perhaps accounting for the variable thrombocytopenia. Inheritance appears to be autosomal dominant.
Abnormalities in the Mr of GPIb were identified in two families,307 but these may have resulted from a now-recognized polymorphism in GPIb (see Chap. 111) rather than being related to the functional disorder. Heterozygous point mutations in the GPIba DNA (Gly233 ® Val and Met239 ® Val) have been found in several different families.308,309,310 and 311 Both of these mutations are in the carboxy terminal flanking sequence of the leucine-rich repeats, a region implicated in ligand binding,241,254,255 (see Fig. 111-11) and molecular modeling suggests that the M239V substitution produces a significant conformational change in the molecule.312
Patients have mild to moderate mucocutaneous hemorrhage.
LABORATORY FEATURES AND DIFFERENTIAL DIAGNOSIS
The bleeding time is often, but not invariably, prolonged. Mild thrombocytopenia and somewhat enlarged platelets are present in some, but not all, patients. Plasma von Willebrand factor levels are mildly reduced, with a disproportionate reduction in the high-molecular-weight multimers.
The most characteristic laboratory finding in platelet-type von Willebrand disease is enhanced platelet aggregation in response to low concentrations of ristocetin302,303,304,305 and 306 or botrocetin.313 This same abnormality is present in patients with type IIb von Willebrand disease, as is selective depletion of plasma high-molecular-weight von Willebrand factor multimers (see Chap. 135). In platelet-type von Willebrand disease, however, the defect is in platelet GPIba, whereas in type IIb von Willebrand disease, the defect is in the von Willebrand factor molecule. Several assays can help differentiate between these abnormalities304,314,315 and 316: (1) normal von Willebrand factor (in cryoprecipitate or purified) will aggregate platelets from patients with platelet-type von Willebrand disease, but not platelets from patients with type IIb von Willebrand disease; (2) isolated platelets from patients with platelet-type von Willebrand disease will bind normal von Willebrand factor at lower concentrations of ristocetin than will normal platelets or platelets from patients with type IIb von Willebrand disease; (3) plasma von Willebrand factor from patients with type IIb von Willebrand disease will bind to normal platelets at lower-than-normal concentrations of ristocetin, whereas higher-than-normal concentrations of ristocetin are required to get the plasma von Willebrand factor from patients with platelet-type von Willebrand factor to bind to normal platelets315; and (4) von Willebrand factor lacking sialic acid residues (asialo–von Willebrand factor) will agglutinate platelets from patients with platelet-type von Willebrand disease in the presence of EDTA.317
THERAPY, COURSE, AND PROGNOSIS
Since normal von Willebrand factor (especially the high-molecular-weight forms) can bind excessively to the platelets of patients with platelet-type von Willebrand disease and potentially lead to rapid platelet clearance from the circulation, increasing the von Willebrand factor level by any means (desmopressin infusion or von Willebrand replacement with cryoprecipitate or von Willebrand factor concentrates) poses a potential risk of inducing thrombocytopenia.314,318 It may be possible to estimate this risk by assessing whether the patient’s platelets aggregate ex vivo in response to von Willebrand factor (as in cryoprecipitate).303 Low-dose cryoprecipitate has successfully supported hemostasis, without inducing thrombocytopenia in patients at risk of having thrombocytopenia.305,318,319 Consideration should also be given to platelet transfusion if thrombocytopenia is severe. A preliminary report indicates that factor VIIa infusion may be beneficial, but this therapy is experimental.321
GLYCOPROTEIN Ia/IIa (a2b1; VLA-2; CD49b/CD29)
GPIa/IIa (a2b1) can mediate platelet adhesion to collagen and platelet activation under certain conditions (see Chap. 111). Nieuwenhuis and coworkers321,322 reported a female patient with excessive posttraumatic bruising and menorrhagia, but no epistaxis, gum bleeding, or excessive bleeding after tonsillectomy or appendectomy, whose platelets selectively failed to aggregate or undergo shape change in response to collagen. The bleeding time was markedly prolonged, and the patient’s platelets failed to adhere and spread normally on subendothelial surfaces. The patient’s platelets only contained about 15 to 25 percent of the normal amount of GPIa,321,323 and a reduction in GPIIa was also apparent.321 It is difficult to draw conclusions about the physiologic role of GPIa/IIa in platelet function from this patient, since her GPIa/IIa deficiency was incomplete, her bleeding symptoms were mild, and some of the platelet function abnormalities (e.g., abnormal platelet-collagen interactions in the presence of the divalent chelating agent EDTA) are difficult to ascribe to the deficiency in GPIa/IIa.321,324
Another patient with GPIa deficiency has been described.325 She had a history of mucocutaneous and postoperative bleeding. Her bleeding time was prolonged, and platelet aggregation in response to collagen was selectively reduced but not absent. In addition to her GPIa defect, she also had little or no intact thrombospondin, and exogenous thrombospondin corrected the defect in platelet aggregation. The patient’s hemorrhagic symptoms and platelet defects disappeared when she reached menopause. Of note, the above patient reported by Nienwenhuis and coworkers also was reported to improve at the time of menopause.326
Approximately 3 percent of the Japanese population, about 2.4 percent of the African-American population, and 0.3 percent of the Caucasian population of the United States have platelets that lack GPIV.327,328 Although GPIV has been implicated in platelet interactions with collagen and thrombospondin,329,330 as well as in platelet-monocyte interactions,331 individuals lacking GPIV do not have a hemorrhagic diathesis. Platelets from these patients can bind thrombospondin via alternative receptors332 and there is controversy as to whether they have even a mild defect in adhesion to collagen.333,334 Two forms of GPIV (CD36) deficiency have been described: type I in which both platelets and monocytes are deficient, and type II in which only platelets are deficient.335 A C478T substitution leading to a Pro90Ser substitution and abnormal posttranslational modification is a common abnormality contributing to both type I and type II deficiencies in the Japanese population. In the type I form, patients are homozygous for the abnormality, whereas in type II deficiency, patients are doubly heterozygous for the Pro90Ser abnormality and an unidentified platelet-specific expression defect.335,336 Other abnormalities that have been associated with type I deficiency include a dinucleotide deletion (539-540) in exon 5, a 161 bp deletion (331–491) corresponding to loss of exon 4, and a nucleotide insertion at position 1159 in codon 317, leading to a frameshift and premature stop.337,338
GPIV (CD36) deficiency can result in refractoriness to platelet transfusions due to isoimmunization (see Chap. 138) and has been implicated in post-tranfusion purpura (see Chap. 117).339 GPIV (CD36) has also been implicated in monocyte binding of oxidized LDL and myocardial uptake of long-chain fatty acids.340 Individuals with type I GPIV (CD36) deficiency have profound abnormalities in myocardial long-chain fatty acid uptake as judged by nuclear medicine studies, and there may be an association with hypertrophic cardiomyopathy.340,341
GPVI can mediate platelet adhesion to collagen and is important in collagen-induced signal transduction (see Chap. 111). Two patients with mild bleeding disorders and deficiencies of platelet GPVI have been described.342,343 Both patients had selective abnormalities in platelet-collagen interactions. An acquired defect in GPVI due to an autoantibody has also been described344; platelets from this patient also had abnormal collagen-induced platelet aggregation.
ABNORMAL MEMBRANE-CYTOSKELETAL INTERACTIONS
DEFINITION AND HISTORY
The Wiskott-Aldrich syndrome, which affects four of every million males worldwide, is an X-chromosome-linked inherited disorder characterized by small platelets, thrombocytopenia, recurrent infections, and eczema, although only a minority of patients have all of the classic manifestations (see Chap. 88).345,346 and 347 In addition, a variety of immunologic abnormalities affecting T-lymphocyte function, immunoglobulin levels, cellular immunity, and responsiveness to polysaccharide antigens are commonly present.345,347 The immune deficiency is probably responsible for an increase in lymphoreticular malignancies associated with the disorder. Death from infection, hemorrhage, or malignancy is common before adulthood.
ETIOLOGY AND PATHOGENESIS
The Wiskott-Aldrich syndrome protein (WASP) has been identified and its amino acid sequence deduced from the cDNA. The protein contains a unique Wiskott homology domain, which is also present in a number of other genes that convey signals from the surface of cells to the actin cytoskeleton. The other domains, and their interactions with other proteins, are schematically depicted in Fig. 119-8.345 WASP is found in all hematopoietic stem-cell-derived lineages. It is likely that signals from G-protein-coupled receptors can initiate actin bundling via WASP. Not all patients with Wiskott-Aldrich syndrome have mutations in the WASP gene,345 and so other genes may be involved. An international database of WASP mutations348 is available and can be accessed via the Williams Hematology webpage.
FIGURE 119-8 Domain structure of the Wiskott-Aldrich syndrome protein and identification of molecules that interact with the protein. There is a second Wiskott homology domain just before the actin regulatory domain (ARD), which is not included in the figure. PSTPIP is a cytoskeletal-associated protein.345 PH, pleckstrin homology domain; WH1, Wiskott homology 1; PPPP, polyproline regions; GBD, GTPase binding domain; WIP, WASP-interacting protein; ARD, actin regulatory domain. Reproduced with permission from Sullivan.345
A defect in the surface glycoprotein sialophorin (CD43, gp115, leukosialin) has also been described in Wiskott-Aldrich syndrome.349 CD43 is a carbohydrate-rich protein found in one form on T lymphocytes, B cells, and monocytes, and in another form on neutrophils and platelets. The CD43 abnormalities are most likely a reflection of aberrant O-linked oligosaccharide biosynthesis,350 but the connection between the WASP defect and aberrant O-linked glycosidation is unknown. CD43 can bind intercellular adhesion molecule 1 (ICAM-1), a protein implicated in immune function,351 and so the CD43 abnormality may contribute to the immunodeficiency. Moreover, transgenic animals with overexpression of O-glycan Core 2 GlcNAc transferase (an enzyme that modifies CD43 and is increased in Wiskott-Aldrich platelets and resting T lymphocytes) have defects in T-cell function.352 Deficiencies in platelet GPIb, perhaps also due to aberrant O-linked oligosaccharide synthesis, have been described in some patients with the Wiskott-Aldrich syndrome,349,350 but this is not an invariant finding.352,353 Deficiencies in GPIa have also been recorded in some, but not all, patients.349 Similarly, decreases in platelet GPIIb/IIIa and GPIV have been reported based on flow cytometry studies, even after adjustment of the data for platelet size.352
The thrombocytopenia in Wiskott-Aldrich syndrome was initially ascribed to shortened platelet survival due to an intrinsic platelet defect, since autologous platelet survival was found to be short and transfused normal platelets were reported to have normal survival.354,355 and 356 A later study, however, found normal autologous platelet recovery and only a modest decrease in platelet survival.357 Since bone marrow megakaryocytes were not decreased, this indicated that ineffective thrombopoiesis was also contributing to the thrombocytopenia.347 The normal level of reticulated platelets found in Wiskott-Aldrich syndrome despite the thrombocytopenia, also indicates that ineffective thrombopoiesis may be contributing to the thrombocytopenia.352 The alterations in platelet glycoproteins may contribute to these phenomena, but so might the elevated platelet-associated IgG levels founds on the platelets of patients with Wiskott-Aldrich syndrome.352 Splenectomy consistently improves the platelet count,358,359 which supports shortened survival as a major mechanism of thrombocytopenia. Postsplenectomy, immune thrombocytopenia has been reported to be a common cause of recurrent severe thrombocytopenia and hemorrhage.345,347,360
The cause of the small size of the platelets is unknown, but it is reasonable to presume that it is related to an abnormality in the connection between the membrane and the cytoskeleton caused by the defect in the WASP. The spleen appears to play a complex role in the platelet size defect, since platelet size increases soon after splenectomy to near normal values but then decreases to below normal again over a period of months.355,358,361 Thrombocytopenia and small platelet size have been used to determine whether a fetus is affected with the syndrome, but a false-negative result has been reported, raising the possibility that the platelet abnormalities develop late in gestation.362
Variant forms of Wiskott-Aldrich syndrome characterized by thrombocytopenia and X-chromosome-linked inheritance have been reported.363
Platelets from most patients with Wiskott-Aldrich syndrome have qualitative as well as quantitative abnormalities. Most common is a deficiency in the storage pool of adenine nucleotides, producing a reduced positive feedback mechanism during platelet activation and aggregation.354,356,363 Abnormalities in platelet energy metabolism have also been described.356,364
Hemorrhage, recurrent infections, eczema, and lymphoreticular malignancies dominate the clinical picture. Autoimmune diseases, including arthritis, vasculitis, autoimmune hemolytic anemia, and immune thrombocytopenia, may complicate the disorder.360 There is enormous variability in disease severity, and this even extends to variability within individual kindreds.345 Correlations between WASP gene mutations and clinical manifestations are inexact, but patients whose cells express full-length protein may have better immunologic function.345,348
The platelet count is variably reduced, with 44 percent of patients in a large study having platelet counts less than or equal to 20,000/µl at the time of diagnosis, and the platelet volume is significantly reduced in nearly all patients.346,347 Lymphopenia and eosinophilia are present in a minority of patients. The bleeding time is usually prolonged to a greater extent than would be expected from the platelet count, but when the reduced platelet mass is considered, the bleeding time prolongation may not be inappropriate. Platelet aggregation and release of dense body contents are variably abnormal. Platelet ultrastructural abnormalities have been reported, but on balance it appears that platelet morphology is essentially normal.365
Results of immunologic evaluations vary significantly, but some patients have decreased numbers of CD8 T cells.346 Serum levels of IgG are usually normal, whereas serum levels of IgM are usually depressed and serum levels of IgA and IgE are usually elevated.347 Variable deficiencies in immune response to antigenic challenge, especially polysaccharide antigens, are common.347
THERAPY, COURSE, AND PROGNOSIS
Splenectomy usually, but not invariably, improves the thrombocytopenia and usually partially corrects the defect in platelet size, at least temporarily.346,358,359 It may also improve platelet function. Thus, splenectomy should be considered in patients with excessive hemorrhage. Opportunistic infections present serious problems.345,347,358 There is an increased risk of overwhelming bacterial sepsis after splenectomy, but this can be reduced by the use of pneumococcal, meningococcal, and Haemophilius influenza vaccines, as well as prophylactic antibiotics and intravenous immunoglobulin. Patients with Wiskott-Aldrich syndrome tend to have hypercatabolism of IgG and thus may require a higher dose and more frequent dosing of IgG.347 If platelet transfusion is required to stop hemorrhage, the platelets should be irradiated to prevent transfusion-related graft-versus-host disease. It is preferable to obtain platelets from donors who are free of cytomegalovirus.3
Bone marrow transplantation can cure the disorder.345,359 Since the prognosis is otherwise very poor, transplantation before the onset of significant immunodeficiency has been recommended when a histocompatible donor is available.345,359 Transplantation from matched unrelated donors can be successful in young patients, but the success rate declines after 5 to 6 years of age.347 Cord blood cells may be a useful alternative source of stem cells for transplantation.
A heterogeneous group of disorders involving platelet granules has been described. They are broadly categorized into defects affecting dense granules (d-storage pool deficiency), a granules (a-storage pool deficiency, or gray platelet syndrome), or both dense bodies and a-granules (ad-storage pool deficiency).
d-STORAGE POOL DEFICIENCY
DEFINITION AND HISTORY
Based on the original description of Weiss and coworkers in 1969366 and subsequent studies by other investigators,367,368 d-storage pool deficiency is a heterogeneous disorder characterized by a mild bleeding tendency, abnormalities in the second wave of platelet aggregation, and variable deficiencies of the contents of platelet dense granules.
ETIOLOGY AND PATHOGENESIS
d-storage pool deficiency can be a primary, inherited platelet disorder or a component of a multisystem disorder, such as the Hermansky-Pudlak syndrome369,370 (variable oculocutaneous albinism, excessive accumulation of ceroid-like material in lysosomes in monocyte-macrophage cells in bone marrow and other tissues, variable pulmonary fibrosis, inflammatory bowel disease, and a hemorrhagic diathesis), the Chediak-Higashi syndrome371,372,373 and 374 (partial oculocutaneous albinism, giant lysosomal granules, and frequent pyogenic infections), and the Wiskott-Aldrich syndrome (see above and Chap. 88). Other diseases have been associated with d-storage pool deficiency (Ehlers-Danlos syndrome, osteogenesis imperfecta, thrombocytopenia with absent radii), but the relationship is less well established.368 The mode of inheritance in the primary form is not well defined,368 but an autosomal dominant pattern has been identified in some patients. The inheritence of the forms associated with multisystem disorders follows the autosomal recessive and X-linked patterns characteristic of those disorders.
An association between platelet granule defects and other inherited platelet abnormalities, and a predisposition to hematologic malignancies has been reported in several different families.375 Defects in platelet function and platelet granules in leukemia and myeloproliferative disorders have been reported376 but were originally presumed to be secondary to abnormalities of the leukemic clone or in vivo activation of platelets. However, since families have been reported whose members have a platelet abnormality prior to developing the hematologic malignancy, it is possible that the platelet abnormality and the leukemia may both be related to an underlying abnormality. Since several oncogenes appear to act via changes in signal transduction, this may be a link between the two phenomena.377 Monosomy 7 has been reported in more than one family.377
The etiology of primary human d-storage pool deficiency is unknown, but based on data from animal models it is most likely due to a defect intrinsic to hematopoietic precursors. In d-storage pool deficiency associated with Hermansky-Pudlak syndrome, there may be a total failure of d-granule formation as judged by electron microscopy of platelets and megakaryocytes365 and the absence of CD63 (ME491; limp-1; lamp-3; granulophysin), a lysosomal and dense granule membrane protein of Mr 40,000 that is also found in melanosomes (see Chap. 111).370,378 The disorder is unusually common in patients from northwest Puerto Rico, and linkage analysis of patients from this area led to the identification of the HPS gene, which is abnormal in these patients. The gene codes for a 700 amino acid protein of unknown function that is not homologous to other proteins.370 The mutation in the Puerto Rican kindreds is a 16-bp duplication in exon 15; other mutations of the same gene have been identified in patients from other ethnic groups.370 Mutations in the beta 3A subunit of the heterotetrameric AP3-complex, a protein involved in protein sorting to lysosomes, have also been identified in patients with Hermansky-Pudlack syndrome.379
In other forms of d-storage pool disease, data obtained with uranaffin, a dye that specifically stains amine-containing granules, indicate that dense granule membranes are formed but are not properly filled.368,380,381 The defects in the different substances contained in dense granules are also heterogeneous, with some patients able to secrete significant amounts of calcium and pyrophosphate even when adenine nucleotide secretion is nearly completely absent.368
The heterogeneity of human d-storage pool deficiency is matched by a similar heterogeneity among animals with disorders associated with abnormal platelet dense granules. Thus, 14 separate inherited mouse defects have been reported to include dense granule deficiencies382,383 and 384; one of these (pale ear or ep) has been linked to the mouse equivalent of the HPS gene,383 whereas another (pearl or pe) has been linked to the mouse equivalent of the beta 3A subunit of AP-3 complex.385 Another mouse mutation (the pallid mutation) has been genetically linked to protein 4.2.382 The beige mouse and rat serve as models for Chediak-Higashi syndrome, and the beige gene and a gene associated with Chediak-Higashi syndrome have been identified386 (see Chap. 111). Thus, cytoskeletal and membranoskeletal proteins may be important in d-granule formation and function. Several of these animal disorders are also characterized by abnormalities in lysosomes, pigment, and inner ear function.382,383
Patients with d-storage pool deficiency as part of the Hermansky-Pudlak syndrome may have severe, or even lethal, hemorrhage.370,387 For all other forms of the disorder, the bleeding tendency is only mild to moderate.368
Mucocutaneous hemorrhage is most common, with excessive bruising and epistaxis as well as increased bleeding after delivery, tooth extractions, and surgical procedures. The bleeding symptoms can be considerably more severe, however, if patients are taking aspirin or other antiplatelet agents.367,368
The results of platelet function tests are variable from patient to patient, and even in the same patient over time, making it difficult to provide precise criteria.365,366,367 and 368,388,389,390 and 391 The bleeding time is usually prolonged, and there may be some correlation between the severity of dense granule deficiency and the bleeding time prolongation392; however, patients with d-storage pool deficiency may have normal bleeding times.
Platelet aggregation abnormalities are characteristic (Fig. 119-6). ADP and epinephrine induce normal primary waves of aggregation, but the secondary waves are variably abnormal, with the defects ranging from minor to major. The concentration of collagen used affects the results obtained in patients with d-storage pool deficiency; low concentrations accentuate the abnormality and high concentrations obscure it. It is important, therefore, to use the lowest concentration that gives a strong response with normal platelets.368 If aspirin treatment of normal platelets results in a diminished aggregation response, the concentration of collagen is probably low enough to detect the abnormality in d storage pool–deficient platelets. Thrombin at high concentrations causes maximal release of platelet dense body contents, even when platelets have been treated with aspirin or have an intrinsic release reaction abnormality. Therefore, this reagent can distinguish between d-storage pool deficiency (diminished release) and abnormalities of the platelet release reaction (normal release). Release of ATP from platelets can be measured by luminescence simultaneously with platelet aggregation using specially designed aggregometers.115
More sophisticated tests can define further the extent of the platelet abnormality. The total platelet content of adenine nucleotides is reduced, and the ratio of total platelet ATP to ADP is increased because it more closely reflects the ratio in the cytoplasmic, “metabolic” pool of adenine nucleotides (about 8:1) than in the “storage” pool in dense granules (about 2:3) (see Chap. 111).368,388,392 Platelet serotonin is variably reduced, with the lowest levels found in patients with Hermansky-Pudlak syndrome.393 Serotonin can be taken up by platelets of patients with d-storage pool deficiency, but since it cannot be stored in dense granules it is rapidly catabolized.393 Abnormalities in platelet secretion and arachidonic acid metabolism have been identified but are quite variable, and it is not clear whether they result from the aggregation abnormalities.368,394,395 and 396 Reduced levels of plasma and platelet von Willebrand factor activity in association with a decrease in plasma high-molecular-weight multimers and an increase in low-molecular-weight multimers has been reported in Hermansky-Pudlak syndrome.397,398 Combined d-storage pool disease in Hermansky-Pudlak syndrome and reduced von Willebrand factor activity may result in more severe bleeding,397 but in one study no association between bleeding and von Willebrand factor levels could be identified.398
The decrease or absence of platelet dense bodies can be confirmed by electron microscopy, using either whole mounts399,400 or thin sections of platelets fixed in the presence of calcium.365 Some patients have abnormal granules.381,390,401 Uranaffin and osium may help to identify dense granules.380,402 The fluorescent amine mepacrine can be used to quantify dense bodies by fluorescent microscopy.403
Platelet thrombus formation on subendothelial surfaces is decreased in d-storage pool deficiency, and a hematocrit-related defect in platelet adhesion has also been noted.131
See “Differential Diagnosis” for Glanzmann thrombasthenia.
THERAPY, COURSE, AND PROGNOSIS
The general principles of patient management are similar to those described for Glanzmann thrombasthenia. Patients should be specifically instructed to avoid aspirin or other antiplatelet agents. Short courses of glucocorticoids before surgery may reduce the operative risk,368,404 but the effectiveness of this therapy is not clear. Desmopressin normalizes the bleeding time in only some patients, but it is possible that it improves hemostasis without complete bleeding time normalization.151,405,406,407,408 and 409 Cryoprecipitate can correct the bleeding time in patients with d-storage pool deficiency410; although this correction may be due to an increase in plasma von Willebrand factor, it is also possible that it is due to the infusion of platelet fragments and microparticles found in cryoprecipitate.411,412 Platelet transfusions should be effective in treating hemorrhage in patients with d-storage pool deficiency, but the mildness of the disorder rarely makes this necessary.
GRAY PLATELET SYNDROME (a-GRANULE DEFICIENCY)
DEFINITION AND HISTORY
Raccuglia413 reported the first patient with gray platelet syndrome, an 11-year-old female with a lifelong bleeding tendency, in 1971. Since then a number of additional patients with isolated abnormalities in platelet a-granules have been reported,414,415,416,417,418,419,420,421,422,423,424,425,426 and 427 including one patient with Goldenhar syndrome,414 and one patient with Marfan syndrome.426 A Japanese family with 24 affected members has also been reported,428 but these patients were atypical in having only about 50 percent reduction in platelet factor 4 and only a partial loss of platelet granularity; they also had apparently coincidental reductions in von Willebrand factor.
ETIOLOGY AND PATHOGENESIS
Studies utilizing antibodies to the a-granule membrane protein P-selectin (CD62P) and other a-granule membrane proteins indicate that gray platelets contain a-granule membranes, but the membranes form abnormal vesicular structures rather than a granules.429,430 The P-selectin (CD62P) molecules join the plasma membrane when platelets are stimulated with thrombin, indicating that the membranes are able to fuse with the plasma membrane. Antibodies specific for proteins contained in a granules, such as fibrinogen and von Willebrand factor, identify small and misshapen a granules in gray platelets, further supporting a defect in packaging.431 Plasma levels of the a-granule proteins b-thromboglobulin and platelet factor 4 are normal or increased, indicating that the defect is not in the synthesis of a-granule proteins.414 Studies of the megakaryocytes in patients with the gray platelet syndrome identified von Willebrand factor, platelet-derived growth factor, and platelet factor 4 in early megakaryocytes, but a failure of the proteins to be retained in a granules as the megakaryocytes matured.272 It has been postulated that the leakage of platelet-derived growth factor, and perhaps collagenase, from platelet a granules may be responsible for the mild reticulin fibrosis that has been observed in some patients,417,419,427,432 leading to splenomegaly in at least one patient.427 The fibrosis does not, however, appear to be progressive. An association with pulmonary fibrosis has also been reported,424 raising the possibility of leakage of growth factors from megakaryocytes in the lung, but this remains speculative.
The primary defect responsible for abnormal granule formation has not been identified, but it could involve membrane production, protein targeting, granule formation, or protein retention. The evidence for a constant recycling of a granules to and from the plasma membrane adds additional loci where defects may result in abnormalities in a granules.433
Hemorrhagic manifestations are usually mild in the gray platelet syndrome, but severe bleeding has been noted in a patient with head trauma.420
Platelets appear as larger-than-normal, pale, ghostlike, oval forms on blood films. Often they can be extremely difficult to identify. Thrombocytopenia is common and can be moderately severe, with the count dropping below 50,000/µl. Platelet aggregation abnormalities are present, but the reported abnormalities vary considerably. ADP and epinephrine-induced aggregation is normal or nearly normal. Collagen and thrombin-induced aggregation tends to be more abnormal, but this is not a consistent finding.421,425,434 The abnormal thrombin-induced aggregation was studied further in one patient; abnormal platelet aggregation in response to thrombin receptor activating peptide and normal numbers of thrombin PAR-1 receptors were found.425 Additional abnormalities in phosphoinositide metabolism, protein phosphorylation, calcium mobilization, platelet factor Va, and platelet secretion have been described.435,436 and 437 Thus, it is unclear whether the a-granule protein deficiency, the defects in signal transduction, or both are responsible for the platelet aggregation abnormalities. The failure of a-granule proteins to fully correct the aggregation defects suggests that the signal transduction defects may be significant.421
Gray platelets are deficient in a-granule contents, including fibrinogen, von Willebrand factor, thrombospondin, platelet factor 4, b-thromboglobulin, and platelet derived growth factor; these can be analyzed by immunologic assays or polyacrylamide gel electrophoresis. Platelet IgG and albumin are less severely affected. Electron microscopy confirms a selective absence of a granules, with normal numbers of dense granules.365,419,431
See “Differential Diagnosis” for Glanzmann thrombasthenia. Degranulated platelets are sometimes observed in myelodysplastic and myeloproliferative disorders, but the clinical setting should provide enough information to establish the diagnosis. Some EDTA-dependent phenomena can cause platelets to degranulate in vitro and appear gray on smear.438
THERAPY, COURSE, AND PROGNOSIS
The general measures for treating this disorder are similar to those for Glanzmann thrombasthenia. Desmopressin produces inconsistent correction of the bleeding time,418,439 but hemostasis after a tooth extraction was acceptable after desmopressin treatment in one patient, even without correction of the bleeding time.418 Antifibrinolytic therapy may also be beneficial.420 Platelet transfusions are rarely needed but should be given for serious hemorrhage.
Thrombocytopenia can contribute to the hemostatic defect. Glucocorticoid therapy may or may not increase the platelet count but usually does not result in a normal count.413,418 The mechanism for this effect is unknown, but it raises the possibility that an immune mechanism may contribute to the thrombocytopenia in some patients. Splenectomy resulted in normalization of the platelet count in two patients soon after the surgery,413,427 but in one of them the count slowly decreased thereafter.414
a,d-STORAGE POOL DEFICIENCY
This rare disorder is characterized by moderate to severe defects in both a and d granules, with heterogeneous expression in the few patients in whom it has been reported.368,440 One severely affected patient also had decreased platelet P-selectin (CD62P), a point of distinction from other patients with the disorder and patients with gray platelet syndrome.441 Clinical and laboratory features are similar to those of d-storage pool deficiency. In general, the defect in dense granules is more severe than the defect in a granules. Decreased a 2-adrenergic receptors442 and increased platelet GPIV (CD36)443 have been reported in isolated cases, as has an association with hematologic malignancy.377
QUEBEC PLATELET DISORDER
Originally described as factor V Quebec, the early description of this autosomal dominant disorder included severe bleeding after trauma, mild thrombocytopenia, decreased functional platelet factor V, and normal plasma factor V (see Chap. 122).444,445 Subsequent studies demonstrated that the platelets of these patients had markedly reduced levels of multimerin and thrombospondin (see Chap. 111), and both reduced levels and proteolysis of a number of a-granule proteins, including factor V, fibrinogen, von Willebrand factor, and osteonectin.446 Platelet factor 4 and b-thromboglobulin, which are also a-granule proteins, did not, however, show evidence of proteolysis. Thus, these patients’ platelets have a generalized defect that results in excessive proteolysis of select a-granule proteins. The mechanism of the defect in these patients, and whether the multimerin deficiency plays an etiologic role, remain unknown. Since the platelet factor V abnormality is prominent, this defect may also be classified as a defect in platelet coagulant activity (see “Abnormalities of Platelet Coagulant Activity” below).
ABNORMALITIES OF PLATELET COAGULANT ACTIVITY
DEFINITION AND HISTORY
Patients whose platelets fail to facilitate thrombin generation are defined as having defects in platelet coagulant activity (see Chap. 111). Only a few patients have been described with isolated defects in platelet coagulant activity,447,448,449,450 and 451 but minor defects in coagulant activity secondary to abnormalities in platelet aggregation are more common. The patient Scott, described by Weiss and colleagues in 1979, has been studied in detail,447,448 and thus patients with isolated abnormalities in platelet coagulant activity are commonly referred to as having Scott syndrome.449,450 and 451
ETIOLOGY AND PATHOGENESIS
The primary abnormality in the patient Scott appears to be a failure of platelets to undergo normal microvesiculation in response to several different stimuli.448,452 This is thought to be responsible for the decreased translocation of phosphatidylserine to the platelet’s outer membrane leaflet, which in turn is presumed to be responsible for decreased binding of factors Va-Xa and VIIIa-IXa.452,453,454 and 455 Without platelet binding of these intermediates in blood coagulation, the reactions do not proceed at their normal rate. This patient’s defect was not confined to platelets, since her erythrocytes demonstrated a similar defect in microvesicle formation.456
Complementation studies using the patient’s lymphocytes and a myeloma cell line suggested that the patient’s cells lack a functional gene product.457 Two other patients with sporadic defects in platelet coagulant activity have been described, and in both cases, the most significant abnormality was in collagen + thrombin-induced prothrombinase activity in the absence of added factor Va. In one of these patients, this may have been due to a defect in a granule factor V distinct from the abnormality found in the Quebec platelet syndrome (see “Quebec Platelet Syndrome” above).450 A French family with Scott syndrome has been reported in which the propositus, who had a significant bleeding diathesis, was the product of a first-cousin mating; her two sisters had already died from hemorrhage and thus could not be studied. Her platelets and transformed lymphocytes demonstrated severe abnormalities in platelet coagulant activity, whereas platelets from her son and daughter, who were asymptomatic, had partial abnormalities in platelet coagulant activity. This suggests an autosomal recessive inheritance in this family.449 The propositus’ platelets were found to have a defect in protein tyrosine phosphorylation in response to thrombin and collagen + thrombin, especially of an Mr 40,000 protein, suggesting that a defect in signal transduction may be responsible for the abnormality in coagulant activity.451
Platelet coagulant defects differ from other platelet function disorders in that the hemorrhagic manifestations are not primarily mucocutaneous. For example, the patient Scott447,448 did not have easy bruising or excessive bleeding after superficial cuts. She did, however, have variably severe bleeding after tooth extractions, menorrhagia, severe postpartum hemorrhage requiring transfusions and hysterectomy, and a spontaneous pelvic hematoma. Bleeding after surgery was present in the two sporadic cases, but epistaxis and easy bruising were only present in one of the two patients.450 In the French family, the 71-year-old female propositus had epistaxis, trauma-related hematomas, and bleeding after tooth extractions and childbirth.449 Her two older sisters died from hemorrhage during childbirth.
The bleeding time is usually normal, which distinguishes platelet coagulant defects from other qualitative platelet abnormalities.448,449 and 450 The serum prothrombin time, which reflects the completeness of clotting of whole blood as reflected in consumption of prothrombin, is consistently abnormal and serves as a convenient screening assay.447,449,450 More specific assays of “platelet factor 3,” the phenomenologic designation of all of the platelet’s contributions to accelerating clot formation, are also abnormal. There are a number of different techniques used to measure platelet factor 3, however, and so the results vary considerably.458
The patient Scott452,454,455,459 had normal platelet aggregation, normal platelet phospholipid content, normal to enhanced platelet adhesion to subendothelium with diminished thrombus formation, severely impaired fibrin formation on subendothelium, diminished factor Va binding to platelets and platelet microparticles, diminished platelet acceleration of both factor X activation and prothrombin activation, decreased microparticle formation, and decreased activation-dependent exposure of negatively charged phospholipids. Platelet calpain and aminophospholipid translocase, enzymes that might potentially contribute to the functional abnormalities, were normal. Abnormalities in exposure of negatively charged phospholipids and shedding of microparticles, measured by any one of several techniques, including the binding of annexin V to the surface of platelets and microparticles, have been consistent findings in all of the patients described.449,450 and 451
The normal bleeding time, abnormal serum prothrombin time, and in several of the reported cases, the lack of the characteristic mucocutaneous pattern of bleeding, distinguish platelet coagulant defects from the other qualitative platelet disorders. See “Differential Diagnosis” for Glanzmann thrombasthenia.
THERAPY, COURSE, AND PROGNOSIS
Platelet or whole blood transfusions have been effective as prophylaxis and as therapy for bleeding episodes.447,448,449 and 450 Prothrombin complex concentrates, which may contain activated coagulation species that can bypass some of the activation steps, have also been reported to be effective in the patient Scott.368 These preparations may induce thrombosis, however, and thus should be reserved for serious hemorrhagic episodes.
ABNORMALITIES OF PLATELET AGONIST RECEPTORS, SIGNAL TRANSDUCTION, AND SECRETION
Platelet activation is a complex phenomenon involving agonist binding to receptors; signal transduction through G-protein-coupled receptors and other types of receptors; phosphoinositol metabolism resulting in calcium mobilization and phosphorylation of target proteins; arachidonic acid metabolism leading to thromboxane A2 production; activation of the GPIIb/IIIa receptor, and release of granule contents (see Chap. 111). Defects involving any of these phenomena can result in impaired platelet function.368,460
Abnormalities in signal transduction usually produce only a minor hemorrhagic tendency, comparable to that caused by aspirin ingestion. Therapy is not usually necessary, but if it is, desmopressin may be helpful. It is likely, therefore, that many patients with these defects do not come to medical attention. In addition, only a small percentage of patients with defects in signal transduction have had their abnormalities defined at the molecular level.
DEFECTS IN PLATELET AGONIST RECEPTORS OR AGONIST-SPECIFIC SIGNAL TRANSDUCTION
A mutation in the thromboxane A2 receptor (Arg60Leu) has been described as causing a dominantly inherited bleeding disorder in two unrelated families from Japan.461 The mutation is in the first cytoplasmic loop of the receptor, and studies with recombinant mutated receptor indicate a defect in signal initiation rather than ligand binding. The proposed dominant inheritance suggests the possibility that the abnormal receptor acts in a dominant negative fashion.
Abnormalities in one or more of the ADP receptors on platelets, or ADP-specific signal transduction, have been described in patients with bleeding disorders.462,463 and 464
Abnormalities of a-adrenergic receptors or a-adrenergic-specific signal transduction have been described in several patients.460,465,466 and 467
A defect in the platelet activating factor receptor or platelet activating factor–specific signal transduction has been reported.468
DEFECTS IN SIGNAL TRANSDUCTION
DEFECTS IN ARACHIDONIC ACID METABOLISM AND THROMBOXANE PRODUCTION
Arachidonic Acid Release from Phospholipids Several patients have been described whose platelets aggregated normally in response to arachidonic acid but not to ADP, epinephrine, and/or collagen. The patients’ platelets did not release arachidonic acid normally in response to thrombin but appeared to have normal phospholipase A2 activity, suggesting a defect in moblizing sufficient calcium to activate the phopholipase.469,470 A patient with Hermansky-Pudlak syndrome whose platelets had d-storage pool deficiency and abnormal phospholipase A2 activity has also been reported.471 Another patient whose platelets failed to release arachidonic acid normally has also been identified.472
Cyclooxygenase (Prostaglandin H2 Synthase-1) Deficiency Deficient platelet cyclooxygenase (prostaglandin H2 synthase-1) activity leading to impaired platelet function has been identified in a number of patients.473,474,475,476,477 and 478 Platelets from such patients cannot make thromboxane from arachidonic acid but can make it from cyclic endoperoxides. If cyclooxygenase activity is also deficient in endothelial cells, prostacyclin production will also be impaired, as was demonstrated in one patient.475 The clinical manifestations of patients with cyclooxygenase deficiency are, therefore, of considerable interest, since they presumably reflect the competing influences of thromboxane A2 and prostacyclin. One patient had a mild bleeding disorder,475 whereas another476 had evidence of a thrombotic vascular disease, including a transient ischemic attack.
Thromboxane Synthase Deficiency Presumed platelet thromboxane synthase deficiencies have been identified in two families based on the failure of cyclic endoperoxides to be converted into thromboxane A2.479,480 An otherwise mild bleeding disorder associated with one life-threatening hemorrhage and a variably prolonged bleeding time was found in one patient.480
DEFECTS IN PHOSPHOLIPASE C, Ga q, CALCIUM MOBILIZATION, AND CALCIUM RESPONSIVENESS
Defects in platelet secretion and the second wave of platelet aggregation with weak agonists such as epinephrine and ADP, but not strong agonists such as high-dose collagen or thrombin, are commonly encountered. When aspirin ingestion is excluded and the platelets are found to be capable of making thromboxane A2 in response to the weak agonists, it has been inferred that the platelets’ diminished response is due to one or more abnormalities of the thromboxane A2 receptor (discussed above), the signal transduction pathway involved in calcium mobilization, or the calcium-responsive mechanisms involved in platelet activation.460,465,470,481,482,483,484,485,486,487 and 488 Since ADP acts synergistically with thromboxane A2, some of these abnormalities may reflect a contribution from diminished ADP secretion or responsiveness as well.470
A defect in phospholipase C activation489 has been described as has a primary selective deficiency in phospholipase C-b2.490 In addition, a selective deficiency of Gaq, a G protein implicated in signal transduction, has been described in association with a mild bleeding disorder and abnormal platelet aggregation and secretion.491 This last defect is of particular interest, since mice lacking Gaq also have been reported to have abnormal platelet function.492
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn