The hemostatic process has two important components: platelet-associated primary hemostasis (response of platelets to endothelial damage and plug formation) and coagulation factor-associated secondary hemostasis (coagulation cascade and fibrin formation) . In particular, platelets play an essential role in the appropriate initiation of hemostasis. Platelet dysfunction is characterized by mucocutaneous bleeding, including easy and extensive bruising, severe epistaxis, menorrhagia, postpartum bleeding, or unexpected bleeding after procedures despite a normal platelet count [2,3].
Platelets play an important role via the following mechanisms: adhesion, activation, granule secretion, aggregation, and procoagulant activity [4,5]. Thus, inherited platelet function disorders (IPFDs) can be classified according to the role of platelets [4,5]. The features of each disease classified under IPFDs include primary hemostatic defects with significant phenotypic heterogeneity and inherited transmission. However, due to the extremely low incidence of IPFDs, medical personnel can overlook these conditions . In this article, the normal physiological function of platelets, causes and clinical/laboratory characteristics of major representative IPFDs, and available therapeutic modalities were reviwed. The normal physiological platelet function and respective IPFDs are shown in Fig. 1, and the algorithm of access in patients with platelet dysfunction is depicted in Fig. 2. Meanwhile, Table 1 presents the outline and classification of the major IPFDs, and Table 2 shows the available therapeutic modalities for IPFDs.
The normal platelet function in primary hemostasis at the damaged vessel wall and the associated IPFDs are depicted in Fig. 1. Platelets are small, fragmented anucleate cells derived from megakaryocytes in bone marrow . Moreover, they play fundamental roles in primary hemostasis after vascular damage and are involved in innate immune response, inflammatory reaction, wound healing, and hematogenic metastasis . The process of primary hemostasis occurs in multiple steps via several molecules. When a blood vessel is injured, circulating platelets adhere to the exposed subendothelium to stop the leak . This process is mediated by the interaction between adhesive proteins and receptors on the platelet surface, including von Willebrand factor (vWF) which bind to glycoprotein (GP) Ibα in the GPIb/V/IX complex at high shear rates and collagen on the subendothelium binding to GPIa/IIa (integrin α2β1) at low shear rates . After adhesion, agonist substances, adenosine diphosphate (ADP) or thromboxane A2 (TXA2), activate platelets via the signal transduction of tyrosine kinase, G-protein coupled receptors, or GPIIb/IIIa (integrin αIIbβ3) . Activated platelets change shape with the formation of pseudopodia and the centralization of granules . The α-granules contain adhesive glycoproteins, such as vWF and fibrinogen, mitogenic/angiogenic factors, and coagulation factors . Dense granules (also known as d-granules) contain calcium, adenosine triphosphate, ADP, serotonin, and epinephrine . The contents of these granules secreted via exocytosis promote the activation of platelets and the recruitment of circulating platelets into the initial plug . Via cross-linking between the ligands (fibrinogen and vWF) and the receptor GPIIb/IIIa, aggregated platelets become firmly connected . Moreover, coagulation factors bind to phosphatidylserine (PS) on the platelet phospholipid bilayer membrane of aggregated platelets to generate thrombin in secondary hemostasis. Owing to thrombin formation on the platelet surface, a more stable hemostatic plug can be formed .
Although there are no standardized guidelines for the evaluation of IPFDs, clinical history can provide the most important information for the diagnosis of IPFDs [2,11,12]. Patients with secondary hemostatic disorder present with delayed, deep muscular bleeding. By contrast, those with platelet dysfunction commonly experience immediate, mucocutaneous bleeding after an injury or procedure . The common symptoms include easy bruising, epistaxis, gingival bleeding, menorrhagia, and postpartum bleeding, and the severity of symptoms can be heterogeneous even among patients with the same defect . Various tools for the assessment of the severity of bleeding tendency are available . Not only platelet function disorders but also acquired platelet dysfunction must be considered in patients with a bleeding tendency [14,15]. The algorithm of access for patients with platelet dysfunction is shown in Fig. 2.
To obtain an accurate diagnosis of IPFDs, several laboratory tests should be performed. According to the recent worldwide survey, laboratories frequently use platelet count, peripheral blood (PB) smear, platelet function analysis, and light-transmission aggregometry as the first-step tests of IPFDs, and flow cytometry, electron microscopy, and genetic tests as the second-step tests .
Complete blood count (CBC) and PB smears are suitable for the initial workup of IPFDs since they provide important information about the number, size, and morphology of blood cells [2,17]. Some IPFDs are characterized by abnormal findings based on CBC and/or PB smears, which include large platelets in Bernard–Soulier syndrome (BSS) [12,18,19]. In addition, the presence of thrombocytopenia itself cannot rule out IPFDs; thus, further evaluations must be conducted on patients suspected with these conditions .
Platelet function analyzer (PFA)-100 is a simple and rapid screening tool used to assess platelet function by obtaining in vitro bleeding time using a membrane coated with collagen/epinephrine or collagen/ADP [20,21]. The results should be cautiously interpreted because they are affected by several variables, including platelet function, vWF level, platelet count, and hematocrit level .
The platelet aggregation test with a light transmission aggregometer is the most widely used platelet function test, and it can identify the patterns of aggregation of platelet-rich plasma to agonist panels, such as ADP, epinephrine, ristocetin, and collagen . Several IPFDs, including Glanzmann thrombasthenia (GT), BSS, pseudo-vWD, ADP receptor defect, and gray platelet syndrome, can be diagnosed using the characteristic patterns of aggregation [12,19,22]. However, the test requires at least 15 mL of blood even in young children and thrombocytopenic patients .
Flow cytometry is a method used for measuring the expression of molecules, including glycoprotein, phospholipid, and granules of platelets . This technique is effective in the diagnosis of surface glycoprotein defects, such as GT and BSS . In addition, it is advantageous as only a small amount of blood is required .
Electron microscopy can be used in the diagnosis of platelet structure and granule defects .
Although genetic tests are available in few laboratories, the genetic tests are essential in the diagnosis of IPFDs and genetic alterations in family members should be identified [2,19]. In particular, next-generation sequencing, including targeted gene panels, is effective in the diagnosis and differential diagnosis of IPFDs .
BSS is also known as hemorrhagiparous thrombocytic dystrophy . In 1948, Jean Bernard and Jean-Pierre Soulier first described a male patient with bleeding tendency characterized by prolonged bleeding time, low platelet count, and large platelets (macrothrombocytopenia) . BSS is an extremely rare type of IPFD, with a prevalence of 1/1,000,000 individuals. However, the actual rate may be higher due to the misdiagnosis or underreporting of such condition . This disease can be misdiagnosed as immune thrombocytopenia (idiopathic thrombocytopenic purpura, ITP) based on clinical manifestations alone, and the standard therapy for ITP may not be effective . In Korea, no BSS cases have been reported yet. In patients with BSS, the platelets have defects in the surface expression of GPIb/V/IX complex (receptor of vWF) for platelet adhesion at the vascular injury site [27,28]. The associated genes coding for the subunits of the GPIb/V/IX complex are
The clinical manifestations and laboratory test findings between vWD type 2B and pseudo-vWD, also known as platelet-type vWD, are extremely similar. The vWD type 2B is an autosomal dominant disorder caused by functionally defective vWF due to a mutation in the
P2Y1 and P2Y12 are the two G protein-coupled ADP receptors expressed in human platelets. The concomitant activation of both P2Y receptors is required for normal responses to ADP and platelet activation . The P2Y12 receptor defect, which was first described in 1991, is an extremely rare type of IPFD . To date, only anecdotal cases with P2Y12 receptor defects have been described worldwide, and the actual incidence is not known . No cases have been reported in Korea. The P2Y12 receptor defect is caused by mutations in the
The TXA2 receptor is also included in the G protein-coupled receptor family and plays an important role in interacting with TXA2, resulting in platelet aggregation . The TXA2 receptor defect was first reported in 1994, and is caused by a mutation of
Gray platelet syndrome (GPS) is an α-storage pool disease among IPFDs. Recently, the condition had found to be caused by
Jacobsen syndrome (JS) and Paris–Trousseau syndrome (PTS) are rare autosomal dominant IPFDs with giant α-granule abnormalities caused by microdeletion of chromosome 11q [51,52]. Chromosome 11q23.3 includes the
Chediak-Higashi syndrome (CHS) was first reported about 60 years ago, and it is a syndromic dense storage pool deficiency caused by mutations in the
In 1918, Eduard Glanzmann first described GT as a bleeding disorder characterized by hereditary hemorrhagic thrombasthenia without reduction in platelet numbers . There are quantitative or qualitative defects in the platelet GPIIb/IIIa complex in GT patients, which is the binding receptor for fibrinogen and vWF [72,73]. GT generally develops due to the loss-of-function variants of
Scott syndrome is an extremely rare autosomal recessive IPFD, and it was first reported as an isolated deficiency of platelet procoagulant activity in 1979 [79,80]. Recently, the condition was found to be caused by a homozygous mutation in the
Patients with platelet function disorders should be managed in centers that can provide accurate diagnosis and specialized management to treat and prevent bleeding and related complications. The accessible therapeutic modalities for IPFDs are summarized in Table 2.
The prevention of hemorrhagic events is the most important management for IPFDs. Patients should be educated to prevent performing hard core exercises and intake of medications that can affect hemostasis; nonsteroidal anti-inflammatory drugs or salicylate . Regular dental examination and good oral hygiene every 6 months can help prevent dental and periodontal diseases that cause chronic gum bleeding and require invasive procedures . Prior to invasive dental procedures, preventive medication can be used for reducing the bleeding risk . Vaccination against transfusion-transmitted infections, such as hepatitis A and B, should be provided on schedule. In terms of route of administration, subcutaneous injection is the preferred over intramuscular injection . Oral or intravenous iron replacement is required for patients with anemia to maintain a hemoglobin level >10 g/dL . Genetic counseling is required for the family members of patients with inherited disorders who are planning to get pregnant. Moreover, obstetricians should cautiously manage pregnancy in collaboration with neonatologists or pediatric hematologists .
Antifibrinolytics, for example, tranexamic acid and aminocaproic acid, are effective in managing mucosal bleeding and preventing bleeding in minor surgical procedures . Furthermore, they are used in adjunctive therapy for treating major bleeding . Either oral or intravenous preparation of the drug is available.(2) Desmopressin
Desmopressin, a synthetic analogue of antidiuretic hormone vasopressin, is effective for managing mild/moderate bleeding in patients with IPFDs although its efficacy is limited in GT . This mechanism is believed to be correlated to the enhancement of platelet subendothelial interaction and procoagulant abilities of platelets . After the administration of desmopressin, fluid intake should be restricted for the next 24 hours due to the risk of fluid retention.(3) Recombinant activated factor VII (rFVIIa, NovosevenⓇ)
The rFVIIa, alone or in combination with platelets and/or antifibrinolytics, is an effective and safe treatment for all patients with GT . In South Korea, the use of rFVIIa at 90 (80-120) mg/kg/dose at intervals of 2 (1.5-2.5) hours has been approved for the treatment of bleeding and use prior to invasive procedures in patients with GT with platelet antibodies or platelet refractoriness. In addition, there are several cases that report the efficacy of rFVIIa in other platelet function disorders, including BSS, platelet storage pool defect, Wiskott–Aldrich syndrome, and pseuso-vWD .(4) Platelet transfusion
In patients with IPFDs, platelet transfusion is the standard management for severe or uncontrolled bleeding and is helpful in perioperative care. Adverse reactions, including allergic reactions, transfusion-transmitted infections, and development of antibodies to HLA antigens or platelet surface proteins, should be considered. HLA-matched single donor leukocyte-depleted platelets are the most effective products that can reduce the risk of developing alloimmunization .(5) Hematopoietic stem cell transplantation
Some patients with GT and BSS underwent successful transplantations [4,30]. In patients with platelet disorders associated with severe bleeding problems or progressive marrow aplasia or high potential for malignant transformation, hematopoietic stem cell transplantation can be considered as a curative treatment . In case of CHS or HPS, treatment is hematopoietic stem cell transplantation that is effective for hematologic and immunologic recovery .