INTRODUCTION — Disorders of platelet function include several rare congenital disorders [1], as well as a myriad of common acquired conditions (eg, aspirin use, effects of other drugs, liver disease, uremia). The consultant Hematologist is often asked to evaluate patients with a bleeding disorder with clinical characteristics suggesting the presence of a qualitative and/or quantitative platelet disorder (eg, mucocutaneous bleeding and petechiae) (table 1).
This review will briefly summarize normal platelet function as well as available tests of platelet function. The major emphasis will be on the etiology, clinical evaluation, and available therapeutic options in patients with disorders of platelet function. General approaches to the patient with thrombocytopenia, thrombocytosis, or a bleeding disorder are discussed separately. (See "Diagnostic approach to the adult with unexplained thrombocytopenia" and "Approach to the patient with thrombocytosis" and "Approach to the adult with a suspected bleeding disorder" and "Preoperative assessment of hemostasis".)
NORMAL PLATELET FUNCTION — A review of normal platelet function is required to understand functional platelet disorders, especially with the increasing number of therapeutic agents available that specifically target various stages of platelet function. (See "Overview of hemostasis", section on 'Formation of the platelet plug' and "Overview of hemostasis", section on 'Clotting cascade and propagation of the clot' and "Platelet biology".)
Platelet adherence — Platelet-mediated hemostasis is initiated by exposure of the vascular subendothelium following injury to the endothelial surface. Circulating platelets are recruited to the site of injury and bind to exposed components of the subendothelium, including collagen, fibronectin, von Willebrand factor (VWF), fibrinogen, and thrombospondin via glycoprotein (GP) receptors on the platelet surface including GPIb/IX, GPIa/IIa, and integrin αIIbβ3 (integrin alphaIIbbeta3; previously known as GPIIb/IIIa) (figure 1) [2-4].
Platelet activation — Platelets can be activated by a variety of agonists including thrombin, epinephrine, adenosine diphosphate (ADP), and collagen.
Each agonist binds to its distinct cell surface receptor leading to platelet activation ("outside-in signaling"), resulting in calcium-dependent cytoskeletal changes in the platelet giving rise to platelet shape change, conformational change in integrin αIIbβ3 on the platelet surface, and the release of intracellular substances from two sources. (See "Megakaryocyte biology and the production of platelets", section on 'Specific platelet granules'.)
●Platelet alpha granules (VWF, platelet factor 4, thrombospondin, fibrinogen, beta-thromboglobulin, and platelet-derived growth factor)
●Platelet dense granules (ADP and serotonin)
Platelet aggregation — The integrin alphaIIbbeta3 (αIIbβ3; previously known as GPIIb/IIIa) conformational change ("inside-out signaling") allows the third step in platelet-mediated hemostasis: platelet aggregation. Fibrinogen binds to the conformationally altered integrin αIIbβ3 receptor on two or more adjacent platelets (figure 1), resulting in platelet aggregation and accumulation at the site of the vascular injury.
Interaction with coagulation factors — Finally, platelets interact with circulating coagulation factors by providing a scaffold for the activation of phospholipid-dependent coagulation factors. Activation of platelets alters their phospholipid membranes, allowing enhanced binding of coagulation factor complexes, including the tenase and prothrombinase complexes. This underlies the importance of platelets in arterial thrombus formation.
ASSESSMENT OF PLATELET FUNCTION — Numerous tests are available to the clinician to help in the evaluation of platelet function. These are noted below. Chief among them, however, is an examination of the peripheral blood smear.
CBC and peripheral smear examination — Since functional platelet disorders may be associated with normal, reduced, or elevated platelet counts, the initial evaluation of a patient with a possible functional platelet disorder should include a complete blood count, including a platelet count, white blood cell differential, and examination of the peripheral blood smear.
Specific conditions associated with platelet dysfunction, such as myeloproliferative, myelodysplastic (table 2), and plasma cell disorders (picture 1), often have characteristic morphologic features evident when looking at the blood smear (see "Evaluation of the peripheral blood smear").
The presence of large platelets on the peripheral smear suggests accelerated platelet turnover, while the presence of exceedingly large platelets (picture 2), often as large as, or larger than, a normal red cell, in a patient with thrombocytopenia (macrothrombocytopenia) can be seen in patients with Bernard-Soulier disease or in other giant platelet syndromes (see 'Giant platelet disorders' below). Small platelets are characteristic of other congenital disorders, such as Wiskott-Aldrich syndrome.
So-called "gray" platelets appear pale and hypogranulated on the blood smear and can indicate a congenital deficiency in alpha granules [5,6]. They are also often seen in acquired disorders, including the myelodysplastic syndrome.
Platelet aggregation assays — Traditional platelet aggregation assays employ a panel of platelet agonists to measure platelet activation and aggregation in vitro. Either whole blood or platelet-rich plasma is used depending on the technique. Since many common medications can affect platelet function, care must be taken to avoid their use in patients prior to testing. Common agonists used in these assays include ADP, arachidonic acid, collagen, epinephrine, thrombin, and ristocetin. (See "Platelet function testing", section on 'Platelet aggregometry'.)
Normal platelet aggregation in vitro in response to ADP and epinephrine involves a biphasic response. The first wave of aggregation reflects activation of integrin αIIbβ3 and subsequent crosslinking of platelets via fibrinogen binding (figure 1). The second wave reflects platelet degranulation and enhanced aggregation due to the release of additional platelet agonists (figure 2). Arachidonic acid, collagen and thrombin provoke only a single burst of aggregation. Results expected with specific disorders are summarized in the table (table 3).
Automated platelet function screening tests — There are several newer technologies in current clinical use measuring various aspects of platelet function [7-11].
Platelet Function Analyzer (PFA-100) — The most widely tested is the PFA-100 device [8-11]. This device uses two separate cartridges that distinguish between an aspirin-induced defect and more severe platelet dysfunction. (See "Platelet function testing", section on 'PFA-100'.)
One study compared results with the PFA-100 and standard platelet aggregometry in subjects with abnormal platelet function [10]. The sensitivity (94 versus 95 percent) and specificity (88 versus 89 percent) of the two tests were remarkably similar. An aspirin-induced defect was detected with a sensitivity of 96 versus 100 percent and von Willebrand disease and Glanzmann thrombasthenia were confirmed with sensitivities of 96 percent for the PFA-100 versus 80 percent with standard aggregometry. The PFA-100 is less sensitive to other specific platelet disorders such as storage pool disease [11].
In a study involving 113 patients, both the bleeding time (BT) and PFA-100 were used and showed concordant results in 74 percent of patients [12]. In the 29 patients with discordant results, 23 had abnormal findings with the PFA-100 but a normal BT. When platelet aggregometry was performed, 17 of these 23 patients had a defect consistent with aspirin effect. A second study concluded that the PFA-100 was as sensitive to the effects of aspirin on platelet function as the template BT, with less variability and fewer false positive results [13].
There are numerous studies clearly showing superior sensitivity of the PFA-100 versus the BT in screening for VWD [8]. In several studies, the sensitivity of the PFA-100 was uniformly higher than the BT (84 to 97 percent versus 48 to 66 percent), although the sensitivity of the PFA-100 varied with the severity of the VWD [14-16].
While the PFA-100 is very sensitive to aspirin's effect on platelets, it is insensitive to other therapeutic anti-platelet agents, including COX-2 inhibitors, ticlopidine, clopidogrel, and heparin [17,18]. In contrast, COX-1 inhibitors and the integrin αIIbβ3 antagonists greatly affect the PFA-100 [17,19,20].
Other devices — The Ultegra is an automated whole blood assay that can be used at the bedside [21]. It measures platelet aggregation based on the binding of activated platelets to fibrinogen. It is marketed to specifically measure the effects of the integrin αIIbβ3 antagonists abciximab, tirofiban, and eptifibatide. It is insensitive to aspirin, clopidogrel, and ticlopidine and is not useful in screening for VWD.
Bleeding time — The bleeding time (BT) was previously used as a screening test for platelet function [7,22]. However, there are many variables that can influence its accuracy and it is no longer used in routine practice. It is not useful as a preoperative screening test in patients without a history of bleeding and it cannot accurately assess platelet dysfunction in the presence of thrombocytopenia. There is also general consensus that the BT should not be routinely used preoperatively [23]. (See "Preoperative assessment of hemostasis", section on 'PFA-100'.)
THERAPEUTIC ANTIPLATELET AGENTS — The most common clinical circumstances leading to disordered platelet function include either a desired therapeutic effect or an adverse medication effect. Aspirin has been well documented to cause increased bleeding associated with altered platelet function [24]. Inhibitors of integrin αIIbβ3 (integrin alphaIIbbeta3; previously known as glycoprotein [GP]IIb/IIIa) can also lead to bleeding complications, due to their profound inhibition of platelet aggregation. (See "Platelet biology", section on 'GPIIb/IIIa inhibitors'.)
Thrombocytopenia has also been reported following use of these agents, with an incidence of 2 to 13 percent. Additional evidence suggests that the thrombocytopenia may be due to an immune-mediated mechanism [25]. (See "Drug-induced immune thrombocytopenia", section on 'GP IIb/IIIa inhibitors'.)
Aspirin — Aspirin is the most common of the therapeutic antiplatelet agents and certainly the most extensively studied drug, due to its role in prevention of thrombotic cardiovascular events. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".)
Aspirin acetylates cyclooxygenase-1 (COX-1) irreversibly and thereby inhibits the first step in prostanoid synthesis (figure 3). By blocking thromboxane A2 production, platelet aggregation and vasoconstriction are inhibited. Much larger doses of aspirin are required for anti-inflammatory effects (mediated by COX-2) as compared with antiplatelet activity (COX-1), due to aspirin's greater inhibition of COX-1 compared with COX-2 (table 4). (See "NSAIDs: Pharmacology and mechanism of action", section on 'Cyclooxygenase inhibition'.)
Aspirin has been shown to be effective as an antithrombotic agent at doses of 50 to 1500 mg/day but the lower doses (50 to 100 mg/day) are as effective as the higher doses, and are associated with fewer side effects. Bleeding risk is quite small; in placebo-controlled trials demonstrating the benefit of aspirin in primary prevention of myocardial infarction, the absolute increase in major bleeding events varied between 0.3 and 1.7 per 1000 patient-years. A large observational study found a 2.3-fold increased risk of hospitalization for upper gastrointestinal bleeding due to low dose aspirin therapy [26].
The combined use of aspirin and clopidogrel, or aspirin and warfarin, is associated with an increased rate of bleeding at gastrointestinal and other sites [27]. Management of such bleeding patients can be challenging when cessation of these medications can lead to an increased risk of thrombosis (eg, stent thrombosis, recurrent VTE, embolic stroke) [28].
Non-aspirin NSAIDs — Non-aspirin nonsteroidal antiinflammatory drugs (NSAIDs) reversibly inhibit COX-1, generally to a lesser degree than aspirin [20]. This may explain their apparent lack of efficacy in preventing ischemic cardiac events as well as their ability to potentially block the beneficial effect of aspirin on atherothrombosis. (See "Aspirin in the primary prevention of cardiovascular disease and cancer" and "NSAIDs: Adverse cardiovascular effects", section on 'Aspirin and other antithrombotic agents'.)
The main bleeding risk associated with their use is upper GI bleeding.
The COX-2 selective NSAIDs may be associated with less GI bleeding. They do not appear to alter platelet function. (See "Overview of COX-2 selective NSAIDs", section on 'Lack of platelet inhibition and use during anticoagulation'.)
Dipyridamole — Dipyridamole is another antiplatelet agent in clinical use. Its exact mechanism of action is unclear. Randomized trials with a single exception have not shown clinical efficacy as an antithrombotic agent. The one exception was the ESPS-2 trial that demonstrated that the combination of dipyridamole and low-dose aspirin (25 mg twice daily) reduced recurrent stroke by 37 percent while aspirin alone led to only an 18 percent reduction and dipyridamole alone 16 percent [29]. This study used a higher than usual dose of dipyridamole (200 mg twice daily). In addition, the dipyridamole was a modified-release formulation with better bioavailability.
P2Y12 receptor antagonists — The platelet P2Y12 purinergic receptor is naturally stimulated by ADP [30]. This receptor can be inhibited by several agents, including the thienopyridine clopidogrel, and the direct P2Y12 receptor blockers such as ticagrelor. (See "Platelet biology", section on 'P2Y1 and P2Y12 (ADP receptors)'.)
The clinical use of these drugs is described separately. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'P2Y12 use' and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Clopidogrel' and "Acute ST-elevation myocardial infarction: Antiplatelet therapy".)
The use of genetic testing and platelet aggregometry to determine the in vitro effect of clopidogrel on platelet function are discussed separately. (See "Clopidogrel resistance and clopidogrel treatment failure", section on 'Variation in clopidogrel metabolism'.)
Integrin αIIbβ3 receptor antagonists — Blockade of the integrin alphaIIbbeta3 (αIIbβ3) receptor with agents such as abciximab and eptifibatide leads to a thrombasthenic state with profound inhibition of platelet aggregation, independent of the initial platelet stimulus. Their utility as therapeutic agents has been extensively studied and is reviewed separately. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy" and "Acute ST-elevation myocardial infarction: Antiplatelet therapy".)
Excessive bleeding has been noted in several trials. Less common is severe thrombocytopenia that may be immune mediated, also leading to significant bleeding [31]. (See "Drug-induced immune thrombocytopenia", section on 'GP IIb/IIIa inhibitors'.)
Other medications — Other medications used to treat cardiovascular conditions have been shown to inhibit platelet activation and/or aggregation in vitro. These agents and their proposed mechanisms of action include the following:
●Nitrates – Nitric oxide-induced reductions in platelet reactivity, adhesion, and aggregation
●Calcium channel blockers – Reduced platelet aggregation and adhesion
●Heparin – Reduced platelet adhesion
It remains unclear whether interference with platelet function contributes to the therapeutic effects of these agents.
ACQUIRED PLATELET FUNCTIONAL DISORDERS
Liver disease — The liver plays an important role in hemostasis, as it is responsible for the synthesis of clotting factors and many of their inhibitors. Liver disease often leads to impairment of hemostasis by a variety of mechanisms, not simply due to decreased production of clotting factors [32]. It has long been recognized that both quantitative and qualitative platelet disorders are a consequence of not only chronic, but also acute liver damage.
Thrombocytopenia can be a manifestation of acute hepatitis; rarely it can be quite severe, as in aplastic anemia-associated acute hepatitis [33]. Chronic liver disease with cirrhosis often leads to modest thrombocytopenia due to portal hypertension and splenic sequestration of platelets, as well as decreased thrombopoietin production.
Dysfunctional platelets in the absence of thrombocytopenia may also contribute to bleeding risk in patients with liver disease. Platelet aggregation may be abnormal and the bleeding time prolonged. However, a prolonged bleeding time is not predictive of bleeding risk in this population [34,35]. The interpretation of a prolonged bleeding time may be confounded by co-existing thrombocytopenia. In practice, the bleeding time should not be used as a screening test prior to liver biopsy or liver transplant. There is only cursory data utilizing the PFA-100 in this setting. (See "Gastrointestinal endoscopy in patients with disorders of hemostasis", section on 'Acquired disorders' and "Hemostatic abnormalities in patients with liver disease", section on 'Thrombocytopenia and platelet dysfunction'.)
Cardiopulmonary bypass — Cardiopulmonary bypass (CPB) causes significant platelet dysfunction due to numerous factors, including the interaction of platelets with the non-physiologic surface components of the bypass machine. Hypothermia during bypass, complement activation, release of cytokines, and thrombin generation may also contribute [36]. Platelets are activated, their granular contents are secreted, and their adhesive properties are compromised due to alteration in surface glycoprotein expression. Glycoproteins Ib and IIb/IIIa and PECAM-1 are decreased, leading to decreased platelet-endothelial adhesiveness and decreased platelet aggregation. The activated platelets secrete alpha-granule proteins, including P-selectin and beta-thromboglobulin. Upregulation of P-selectin expression on platelets may mediate the formation of platelet-neutrophil and platelet-monocyte conjugates. These complexes are thought to be important in the pathogenesis of the post-CPB inflammatory syndrome, a complication that can cause acute pulmonary injury.
Thrombocytopenia is also a common occurrence due to both hemodilution from the priming of the extracorporeal circuit prior to bypass and adherence of platelets to the artificial surfaces of the bypass machine. (See "Extracorporeal membrane oxygenation (ECMO) in adults".)
Uremia — Uremia associated with chronic renal failure has long been associated with increased clinical bleeding [37]. Ecchymoses, epistaxis, gastrointestinal and genitourinary bleeding are common manifestations, and may reflect underlying platelet dysfunction. (See "Uremic platelet dysfunction".)
Alternatively, many of the bleeding problems in the uremic patient may be explained by co-existing coagulopathies, the use of heparin with dialysis, or anatomical abnormalities, including common conditions such as gastritis. Certainly, the routine use of dialysis to control uremia has decreased the incidence of spontaneous mucocutaneous bleeding. The pathophysiologic mechanisms have been extensively studied with a wide range of proposed etiologies. These include intrinsic platelet metabolic defects, deficiencies in platelet-endothelial interactions and the influence of anemia on normal platelet function.
Severity of renal failure does not correlate with abnormal platelet aggregation, unlike the degree of anemia, which is directly related. Correction of the anemia with erythropoietin may decrease the incidence of bleeding. (See "Uremic platelet dysfunction".)
Dysproteinemia — Patients with multiple myeloma or Waldenstrom macroglobulinemia may have platelet dysfunction. The abnormal paraproteins found in these conditions can affect all stages of platelet function including adherence, activation, aggregation, and procoagulant activity. However, most bleeding complications are due to the effects of hyperviscosity or acquired von Willebrand disease. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Platelet function and blood coagulation' and "Pathophysiology of von Willebrand disease", section on 'Causes of reduced VWF in acquired VWS'.)
Specificity of the paraprotein for glycoprotein (GP)IIIa has been described in a patient with multiple myeloma and acquired thrombasthenia [38].
Myeloproliferative disorders — The reported incidence of bleeding complications in patients with myeloproliferative disorders is quite variable. One review cites several studies with an incidence ranging from 3 to 59 percent and mortality due to bleeding in zero to 30 percent of cases [39]. (See "Diagnosis and clinical manifestations of essential thrombocythemia", section on 'Thrombosis and hemorrhage'.)
The nature of the bleeding is characteristic of platelet or vascular defects [40]. Symptoms include gingival hemorrhage, epistaxis, gastrointestinal bleeding, and bruising. Although a variety of mechanisms of platelet impairment have been described, the prediction of risk for an individual patient remains imprecise [41]. Often, impairment in epinephrine-induced aggregation is the sole abnormality and mimics the pattern seen when alpha 2 adrenergic receptors are deficient [42]. The magnitude of thrombocytosis, bleeding time prolongation, or results of platelet function testing are not predictive of bleeding risk [39].
Diabetes mellitus — The platelets of patients with diabetes mellitus (DM) are characterized by dysregulation of several signaling pathways, both receptor (eg, increased expression) and intracellular downstream signaling abnormalities, leading to increased platelet reactivity, with intensified adhesion, activation, and aggregation [43,44]. These abnormalities may play a role in the higher risk of developing the acute coronary syndrome, as well as in the larger proportion of DM patients with inadequate response to antiplatelet agents (eg, clopidogrel, aspirin) compared with non-DM patients. (See "Clopidogrel resistance and clopidogrel treatment failure", section on 'Diabetes mellitus'.)
Trauma — While the coagulopathy associated with trauma is multifactorial, there is evidence that platelet dysfunction is present early after injury, before substantial fluid or blood transfusion has been given [45]. (See "Coagulopathy in trauma patients", section on 'Etiologies'.)
Acquired Glanzmann thrombasthenia — Acquired Glanzmann thrombasthenia with clinical bleeding is an uncommon condition but can occur, usually associated with allo- or auto-antibodies to the platelet integrin αIIbβ3 (integrin alphaIIbbeta3; previously known as GPIIb/III). These include pregnancy, autoimmune conditions (eg, systemic lupus erythematosus, immune thrombocytopenia), and the use of therapeutic antagonists of integrin αIIbβ3 (eg, abciximab, eptifibatide) [46-52]. Clinical manifestations are similar to the inherited disorder. (See 'Glanzmann thrombasthenia' below.)
INHERITED DISORDERS OF PLATELET FUNCTION — The inherited disorders of platelet function are composed of a large number of rare conditions [1,53-55]. The most common inherited platelet function disorders are summarized in the table (table 5) and described below. A listing of genes implicated in inherited platelet disorders is also available (table 6).
Giant platelet disorders — Inherited platelet disorders with giant platelets are quite rare (picture 2 and algorithm 1 and table 3) [56,57]. These include platelet glycoprotein abnormalities (eg, Bernard-Soulier syndrome [58,59]), deficiency of platelet alpha granules (eg, gray platelet syndrome) [6], the May-Hegglin anomaly, which also involves the presence of abnormal neutrophil inclusions (ie, Döhle-like bodies [60]), and some kindreds with type 2B von Willebrand disease (the Montreal platelet syndrome) [61-65]. (See "Diagnostic approach to the adult with unexplained thrombocytopenia", section on 'Causes of thrombocytopenia' and "Pathophysiology of von Willebrand disease", section on 'Type 2 (dysfunctional protein; 2A, 2B, 2M, 2N)'.)
The pathophysiology of many of these disorders has been explained by defects in hematopoietic transcription factors [66]:
●Rare families have an X-linked thrombocytopenic disorder with GATA-binding protein 1 (GATA1) mutations and an associated thalassemic or dyserythropoietic blood picture. These conditions have been variably termed "X-linked thrombocytopenia with thalassemia" or "X-linked gray platelet syndrome" [67]. A tubulin mutation has been described in one patient with congenital macrothrombocytopenia [68].
●Some disorders are associated with glomerulonephritis, sensorineural deafness, or cataracts and a mutation of the gene encoding the heavy chain of non-muscle myosin-9 (MYH9-related disease, MYH9-RD) [69].
●The gray platelet syndrome has been associated with progressive thrombocytopenia, myelofibrosis, splenomegaly, and elevated serum B12 levels [6]. A mutation in the region of chromosome 3p21 involving NBEAL2, a gene critical for the development of platelet alpha granules, has been implicated in the autosomal recessive form of the disease [70]. A mutation in the gene encoding growth factor independent 1B (GFI1B), involved in megakaryopoiesis, was found in a family with autosomal dominant gray platelet syndrome [71].
●Disorders of Filamin A, an essential component of the cell cytoskeleton, have been associated with hemorrhage, coagulopathy, and macrothrombocytopenia [72].
It has been suggested that immunofluorescence analysis of circulating platelets may be useful for distinguishing among these various conditions, as follows [72]:
●The presence of myosin precipitates favors presence of a MYH9 syndrome
●Platelet aggregates and von Willebrand factor at the periphery of the platelets favors type 2B VWD
●A severe reduction in alpha granules confirms the grey platelet syndrome
●Abnormal Filamin A with a population of negative platelets suggest disorders of Filamin A
Patients with these disorders who have bleeding diatheses are usually treated with platelet transfusions. In a small study in subjects with MYH9-RD and platelet counts <50,000/microL, treatment with the non-peptide thrombopoietin receptor agonist eltrombopag resulted in major responses (ie, platelet counts of at least 100,000/microL or three times baseline) in 8 of the 12 so treated [73]. Bleeding tendency disappeared in 8 of the 10 subjects with bleeding symptoms at baseline. (See "Approach to the child with bleeding symptoms", section on 'Platelet function disorders'.)
Wiskott-Aldrich syndrome — This X-linked recessive disorder is characterized by immunodeficiency, severely dysfunctional platelets, and thrombocytopenia with microthrombocytes rather than macrothrombocytes [74]. These patients have a storage pool-like disorder (see below) with platelets that are unable to aggregate [75].
This condition and its treatment are discussed in depth separately. If platelets are given, HLA-selected platelets should be used to avoid sensitization [1]. Because of the immunodeficiency, blood products should be irradiated and CMV negative. (See "Wiskott-Aldrich syndrome".)
Storage pool disorders — In addition to the gray platelet syndrome with deficiency of alpha granules, there are dense granule deficiencies that are often part of other congenital disorders. Wiskott-Aldrich syndrome is one such example. Chediak-Higashi syndrome (picture 3), Hermansky-Pudlak syndrome, and thrombocytopenia-absent radius syndrome are others. Decreased platelet dense granules can be detected by electron microscopy.
In the storage pool disorders, platelet aggregation studies are highly variable, and may be normal (table 3). Clinical bleeding is variable but can be quite severe.
Glanzmann thrombasthenia — Glanzmann thrombasthenia is an autosomal recessive bleeding disorder characterized by a defect in the platelet integrin αIIbβ3 (integrin alphaIIbbeta3; previously known as glycoprotein [GP]IIb/IIIa) [76-78]; clinical manifestations are limited to bleeding, which is mostly mucocutaneous. The presence of mucocutaneous bleeding and a normal platelet count but with single isolated platelets without any platelet clumping on examination of a non-anticoagulated peripheral blood smear should raise the possibility of this disorder (algorithm 1) [79]. Platelet aggregometry is distinctly abnormal (table 3).
This disorder may also occur in combination with defects in leukocyte function in the disorder leukocyte adhesion deficiency III, and should be suspected in infants with concomitant leukocytosis, delayed separation of the umbilical cord, or severe bacterial infections. (See "Leukocyte-adhesion deficiency", section on 'LAD III'.)
Antibodies to integrin αIIbβ3 and/or HLA antigens may occur in subjects with Glanzmann thrombasthenia who have received multiple platelet transfusions, resulting in refractoriness to such transfusions. (See "Refractoriness to platelet transfusion", section on 'Alloimmunization'.)
The use of recombinant factor VIIa and other hemostatic agents in such settings has been helpful in controlling bleeding, although controlled efficacy studies are lacking [80]. (See 'Recombinant factor VIIa' below and "Refractoriness to platelet transfusion", section on 'Treatment of bleeding' and "Recombinant factor VIIa: Administration and adverse effects", section on 'Glanzmann thrombasthenia'.)
Hematopoietic cell transplantation has been successfully employed in some patients with severe bleeding and/or development of antiplatelet antibodies [81].
Platelet release disorders — Platelet signal transduction disorders are a heterogeneous group that can present with clinical bleeding. They have in common either abnormal primary or secondary platelet aggregation and decreased platelet granule release without actual deficiency of platelet granules. Deficiencies of platelet agonist receptors including epinephrine, ADP, collagen, and thromboxane have been described. Patients with abnormal thromboxane A2 synthesis will have an aspirin-like defect noted with platelet aggregation testing [82]. Abnormal primary and/or secondary aggregation is seen with these disorders. Characterization of the specific defect in a patient requires specialized testing not generally available in clinical laboratories.
Glycoprotein VI defects — Congenital or acquired defects involving platelet glycoprotein VI, the platelet collagen receptor, are uncommon, and have been associated with a bleeding disorder varying from mild to severe, mild degrees of thrombocytopenia, absent platelet aggregation in vitro to high concentrations of collagen, and an association with immune dysfunction or autoimmune disease [83]. (See "Platelet biology", section on 'Glycoprotein VI'.)
Sticky platelet syndrome — Sticky platelet syndrome is the name given to an autosomal dominant platelet disorder associated with arterial and venous thromboembolic events [84-86]. It has been characterized in vitro by exaggerated platelet aggregation in response to low dose platelet agonists (eg, ADP, epinephrine) and clinically by episodes of otherwise unexplained arterial or venous occlusion (eg, myocardial infarction or angina pectoris without identifiable coronary artery disease, stroke or transient ischemic attacks (TIAs) in younger patients and children, idiopathic ischemic optic neuropathy), often in association with stress [87-89].
There are no large reported series of patients with this condition, and whether this represents a real clinical syndrome remains uncertain. The underlying defect is not known. Anecdotally, treatment with low-dose aspirin (eg, 81 to 100 mg/day) has been associated with return of the platelet aggregation pattern to normal and relief from the thrombotic symptoms [84,85,90].
Other platelet defects
●Individuals with a congenital deficiency of the ADP receptor P2Y12 display a mild to moderate bleeding diathesis, characterized by mucocutaneous bleeding and excessive post-surgical and post-traumatic blood loss. Defects in P2Y12 should be suspected when ADP, even at very high concentrations, is unable to induce full, irreversible platelet aggregation [91]. (See "Platelet biology", section on 'P2Y1 and P2Y12 (ADP receptors)'.)
●Scott syndrome is an autosomal recessive disorder associated with prolonged bleeding and reduced thrombosis. The underlying defect is a failure of platelet membrane phospholipid reorganization (ie, a “scramblase” defect) in response to platelet activation signals. (See "Overview of hemostasis", section on 'Multicomponent complexes'.)
●A family has been described with mild autosomal dominant thrombocytopenia and dysregulated platelet formation, presumably due to an inherited cytochrome c variant with enhanced in vitro apoptotic activity and caspase activation [92]. In this condition, platelets appear to be prematurely released from megakaryocytes into the bone marrow space, rather than the sinusoids, and cannot reach the bloodstream as effectively.
●A family has been described with an autosomal recessive bleeding disorder due to a pathogenic variant in the FYB gene, which encodes a protein involved in platelet activation and integrin-mediated cell adhesion [93]. Affected individuals had small platelets and moderate to severe thrombocytopenia since birth (platelet counts often below 25,000/microL), without abnormalities of growth and development [94]. This condition was termed congenital autosomal recessive small-platelet thrombocytopenia (CARST).
●A family has been described with an autosomal recessive bleeding disorder due to a variant in the EPHB2 gene, which encodes a transmembrane receptor tyrosine kinase that binds to transmembrane ephrin ligands [95]. Two affected siblings had spontaneous bleeding (eg, subcutaneous, gastrointestinal) and heavy bleeding after minor injuries during childhood. Platelet counts and platelet size were normal, but mild thrombocytopenia developed in one individual during early adulthood; platelet morphology was mildly abnormal with occasional thin or elongated shapes. There was decreased platelet aggregation in response to ADP, arachidonic acid, and collagen, with a normal response to ristocetin. Additional testing demonstrated impaired GPVI signaling.
THERAPY — Therapeutic decisions should not be based solely on laboratory testing, since abnormalities in platelet function as measured by the tests mentioned above are not necessarily predictive of the presence or absence of clinical bleeding. Since medications such as aspirin are the most common causes of platelet dysfunction, a careful history of medication use, including use of over-the-counter aspirin-containing preparations, is crucial. The most prudent decision prior to an operation or other invasive procedure may simply be to withhold any medication in question prior to the procedure.
Specific tests of platelet function may not have much of a role in clinical decision-making in these situations. However, if a patient has a history of clinically significant bleeding suggestive of platelet dysfunction, whether provoked or spontaneous, appropriate platelet function tests should be obtained so that risk for bleeding can be adequately assessed and therapy chosen more rationally. However, there are a limited number of therapeutic options available if specific treatment is required to correct platelet dysfunction [96]. This is especially true for most of the inherited platelet disorders, in which there is little evidence from randomized trials upon which to base recommendations for management [1,97].
Desmopressin — Desmopressin (DDAVP) is commonly used to correct the hemostatic defect in von Willebrand disease (VWD) [98,99]. In the case of VWD, DDAVP releases endogenous VWF from the endothelium. (See "von Willebrand disease (VWD): Treatment of minor bleeding, use of DDAVP, and routine preventive care", section on 'DDAVP'.)
Treatment with DDAVP has been reported to be effective in preventing bleeding after dental extraction and minor surgery in patients with milder platelet defects, including storage pool disease [1,100,101].
Its use has also been studied in patients with acquired platelet dysfunction [37,98,102,103]. One study demonstrated correction of an abnormal bleeding time in seven of nine patients with acquired platelet dysfunction [98]. This correction did not correlate with changes in VWF levels and interestingly, there was no improvement in tests of in vitro platelet aggregation. Similarly, DDAVP can shorten the bleeding time in patients with cirrhosis or uremia, although this correction does not necessarily correlate with a decline in bleeding risk [37,102]. (See "Uremic platelet dysfunction".)
In patients undergoing cardiopulmonary bypass, two well-designed studies came to opposite conclusions in two different patient populations concerning the value of this agent for treatment of the bleeding diathesis that often complicates open-heart surgery:
●In a double-blind, randomized, placebo-controlled trial, 150 consecutive patients undergoing coronary-artery bypass grafting received intravenous DDAVP or placebo [104]. The median amount of postoperative blood loss within the first 24 hours after operation was similar in the two groups as was the postoperative use of blood replacement products. The authors concluded that most patients who undergo elective cardiac surgery do not benefit from the use of DDAVP.
●A second double-blind, randomized study included 70 patients [105]. Unlike the above study, patients undergoing uncomplicated primary coronary-artery bypass grafting were not included. DDAVP significantly reduced mean operative and early postoperative blood loss. Plasma levels of von Willebrand factor were higher after desmopressin administration than following placebo.
Platelet transfusion — Transfusion of platelets may be required in patients with disordered platelet function. Platelet transfusions are particularly indicated in cases of severe, uncontrolled bleeding, when prior treatments (eg, DDAVP, estrogen) have been unsuccessful, and/or in the presence of, or anticipation of, excessive traumatic or surgical bleeding. (See "Coagulopathy in trauma patients", section on 'Thromboelastography-based transfusion' and "Platelet transfusion: Indications, ordering, and associated risks", section on 'Platelet function disorders'.)
Antifibrinolytic agents — The use of antifibrinolytic agents (eg, tranexamic acid, epsilon aminocaproic acid) may be helpful in reducing bleeding in patients with disordered platelet function following dental extraction [1].
Recombinant factor VIIa — Recombinant factor VIIa (rFVIIa) has had some success for the treatment of bleeding in patients with congenital platelet disorders [106]. Potential mechanisms include a local procoagulant effect at sites of vascular damage or tissue factor-independent thrombin generation induced by binding of rFVIIa to the surface of activated platelets [107-111].
Patients who cannot receive platelet transfusions because of alloimmunization or antibody formation to the absent platelet glycoprotein (eg, Glanzmann thrombasthenia and Bernard-Soulier syndrome) may benefit from rFVIIa. This use was evaluated in a review of observational studies and case reports that included 165 bleeding episodes and 56 surgical procedures in patients with Glanzmann thrombasthenia. Approximately half had a history of or concern for platelet isoimmunization. Patients treated with rFVIIa typically received one or more bolus infusions of approximately 90 to 100 mcg/kg. Most patients had resolution of or prevention of excessive bleeding; it was difficult to determine if efficacy was solely due to rFVIIa as many patients received other therapies as well. There were four thromboembolic events that may have been related to rFVIIa administration. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'Glanzmann thrombasthenia'.)
The rFVIIa product is approved in Europe for use in patients with Glanzmann thrombasthenia refractory to platelet transfusions. (See "Refractoriness to platelet transfusion", section on 'Treatment of bleeding'.)
Benefits of rFVIIa must be balanced against the risk of thrombosis. Further details of the thromboembolic risk, including factors such as the dose of rFVIIa and underlying prothrombotic risk, are discussed in detail separately. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'Thromboembolic complications'.)
Estrogens — In the past, conjugated estrogens have been used to treat some platelet disorders, such as uremic bleeding [112] or in patients with mild to moderate type 1 von Willebrand disease. Dosing included intravenous estrogen, 0.6 mg/kg daily for five days, oral estrogen, 2.5 to 25 mg orally per day, or transdermal estradiol, 50 to 100 mcg twice weekly, particularly for gastrointestinal bleeding. (See "von Willebrand disease (VWD): Treatment of minor bleeding, use of DDAVP, and routine preventive care", section on 'Estrogens'.)
Subsequently, erythropoietin has been used successfully in uremic patients to both reduce and prevent bleeding. (See 'Uremia' above.)
The use of hormonal therapies to treat bleeding in hereditary hemorrhagic telangiectasia (HHT) is presented separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Tamoxifen and other non-guideline approaches'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Immune thrombocytopenia (ITP) and other platelet disorders".)
SUMMARY
●Platelets, which are important in achieving hemostasis, can have disordered function due to either acquired or congenital defects. (See 'Normal platelet function' above.)
●Acquired platelet function defects are seen most commonly in patients treated with antiplatelet medications; or with hepatic or renal disease, post-cardiopulmonary bypass, myeloproliferative neoplasms, diabetes mellitus. (See 'Therapeutic antiplatelet agents' above and 'Acquired platelet functional disorders' above.)
●Congenital platelet function defects are less common, and include giant platelet disorders (eg, Bernard Soulier syndrome), Wiskott-Aldrich syndrome, Glanzmann thrombasthenia, and storage pool disorders (table 5); genes involved in many of these disorders have been identified (table 6). (See 'Inherited disorders of platelet function' above.)
●Platelet function testing should begin with examination of platelet morphology on the peripheral blood smear. More specific testing is available through platelet aggregometry (table 3) and the Platelet Function Analyzer (table 7). The bleeding time is no longer routinely employed due to poor sensitivity, specificity, and reproducibility, its invasive nature, and lack of personnel trained in its use. (See 'Assessment of platelet function' above and "Platelet function testing" and "Approach to the adult with a suspected bleeding disorder", section on 'Laboratory evaluation'.)
●Several modalities are available for treatment/prevention of bleeding in patients with abnormal platelet function. These include desmopressin (DDAVP), estrogens, platelet transfusion, antifibrinolytic agents, and recombinant human factor VIIa. (See 'Therapy' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Steven Coutre, MD (deceased), who contributed to an earlier version of this topic review.
