Inherited platelet function disorders (IPFDs)

INTRODUCTION — Platelet function disorders include heritable and acquired conditions of varying severity. Some are associated with thrombocytopenia, and some have a normal platelet count.

Evaluation can be challenging. These disorders are rare, bleeding severity varies, and clinicians are often unfamiliar with the appropriate evaluation and treatment.

This topic reviews inherited platelet disorders, with a focus on inherited platelet function disorders (IPFDs).

Separate topics discuss:

●Biology of platelets and anti-platelet drugs – (See "Platelet biology and mechanism of anti-platelet drugs".)

●Platelet function testing – (See "Platelet function testing".)

●Thrombocytopenia evaluation (child) – (See "Approach to the child with unexplained thrombocytopenia".)

●Thrombocytopenia evaluation (adult) – (See "Diagnostic approach to thrombocytopenia in adults".)

●Bleeding evaluation (child) – (See "Approach to the child with bleeding symptoms".)

●Bleeding evaluation (adult) – (See "Approach to the adult with a suspected bleeding disorder".)

CONCEPTUAL FRAMEWORK — IPFDs can be categorized according to clinical phenotype (platelet size and morphology; associated with or without thrombocytopenia, and/or syndromic features) or mechanism (which gene variants cause the disorder and/or which aspect of platelet function they disrupt).

Severity of bleeding is important clinically but can vary widely, even among individuals with the same IPFD, possibly due to the specific genetic variant, other heritable variants that may influence bleeding risk, comorbidities, and the bleeding challenges to which the individual has been exposed.

Mechanisms and gene variants — Platelets mediate the first phase of hemostasis (also called primary hemostasis). Different subpopulations of platelets at the site of injury may carry out different functions [1]. Ultimately a platelet plug forms at the site of blood vessel injury and provides a phospholipid surface (the external surface of the platelet plasma membrane) for activation of blood coagulation factors. (See "Overview of hemostasis", section on 'Formation of the platelet plug'.)

There are four major steps in primary hemostasis; these are illustrated in the figure (figure 1):

●Platelet adhesion to the vascular subendothelium at the site of injury

●Platelet activation and secretion of granule contents

●Aggregation of multiple platelets

●Platelet interactions with clotting factors, resulting in thrombin generation

Many genes have been implicated in inherited disorders of platelet number and/or function.

Some IPFDs impair platelet function, with or without a low platelet count, whereas other conditions manifest predominantly as an inherited thrombocytopenia. For conditions with few reported cases (<50 cases worldwide), there can be uncertainty about the phenotypes, and a genetic variant identified after panel testing may be identified as a variant of uncertain significance (VUS) if there is not sufficient previously published literature confirming causality.

●Adhesion – Platelets adhere to the vascular subendothelium and von Willebrand factor (VWF) via glycoprotein (GP) receptors on the platelet surface (figure 1) [2-9]. Subendothelial components involved in platelet adhesive mechanisms include:

•Collagen – Receptors are integrin alpha2beta1 (previously called GPIa/IIa), and GPVI.

•VWF – VWF binds to collagen, augmenting adhesion though binding to platelet GPIb/IX/V. GpIb/IX/V also contributes to platelet aggregation at high shear rates. Platelet interactions with VWF are further stabilized by integrin alphaIIbbeta3 (previously called GPIIb/IIIa).

•Fibrinogen – Receptor is integrin alphaIIbbeta3.

•Fibronectin – Receptors are alpha5beta1 and alphaIIbbeta3.

•Thrombospondin – Receptor is CD36 (also called thrombospondin receptor and macrophage scavenger receptor).

Disorders of platelet surface receptors include Glanzmann thrombasthenia (pathogenic variants in ITGA2B or ITGB3, leading to deficiency of integrin alphaIIbbeta3) and Bernard-Soulier syndrome (pathogenic variants in GP1BA, GP1BB, or GP9, leading to deficiency of GP Ib/IX/V). (See 'Glanzmann thrombasthenia' below and 'Bernard-Soulier syndrome' below.)

IPFDs due to disorders in platelet collagen receptors are rare.

●Activation and aggregation – Activation is the process by which signaling pathways lead to shape change, altered surface receptors, and release of platelet granule contents. This causes platelets to aggregate with other platelets and form the primary hemostatic plug. (See "Overview of hemostasis", section on 'Platelet aggregation'.)

Platelets can be activated by a variety of agonists including thrombin, epinephrine, adenosine diphosphate (ADP), synthetic analogues of thromboxane A₂, collagen, and epinephrine. Pathogenic variants causing IPFDs have been reported in some of the genes for these agonist receptors, including the receptors for ADP, collagen, and thromboxane A₂. Ristocetin agglutinates platelets by promoting VWF binding to GP Ib/IX/V, which leads to "outside-in signaling" that triggers aggregation. Platelet aggregation in response to agonists and ristocetin are evaluated by platelet aggregometry (figure 2). (See "Platelet function testing", section on 'Platelet aggregometry'.)

•Agonists and second messenger signaling – Each agonist binds to its distinct cell surface receptor, leading to multiple downstream effects. (See "Platelet biology and mechanism of anti-platelet drugs", section on 'Platelet receptors and their agonists' and "Platelet biology and mechanism of anti-platelet drugs", section on 'Second messenger signaling'.)

Steps include:

-Platelet activation ("outside-in signaling") results in calcium-dependent cytoskeletal changes and alters platelet shape.

-Conformational changes in integrin alphaIIbbeta3 ("inside out signaling") allows it to bind fibrinogen on adjacent platelets and mediate low shear aggregation.

-Release of granule contents furthers activation.

Glanzmann thrombasthenia platelets do not aggregate with most agonists and only agglutinate with ristocetin, so the "aggregation" wave with ristocetin is reduced. (See 'Glanzmann thrombasthenia' below.)

Bernard-Soulier platelets do not bind to VWF and do not agglutinate and aggregate with ristocetin, but they have normal alphaIIbbeta3-mediated aggregation responses. (See 'Bernard-Soulier syndrome' below.)

•Granules – Granule biogenesis is discussed separately. (See "Megakaryocyte biology and platelet production", section on 'Granules'.)

-Alpha granules – Alpha granules are the protein storage organelle of platelets. They contain VWF, factor V, multimerin 1, platelet factor 4, thrombospondin, fibrinogen, beta-thromboglobulin, platelet-derived growth factor, P-selectin, and other proteins.

-Dense granules – Dense granules contain calcium, ADP, ATP, serotonin, polyphosphate, and P-selectin [10]. Polyphosphate released from dense granules promotes coagulation via enhancing effects on factors XII and XI (contact factors) and factor V, and inhibiting tissue factor pathway inhibitor (TFPI) and thrombin activatable fibrinolysis inhibitor (TAFI) [1]. (See "Overview of hemostasis", section on 'Control mechanisms and termination of clotting'.)

Platelet granule disorders (also called "storage pool disorders") include:

-Gray platelet syndrome, in which alpha granules are deficient. (See 'Gray platelet syndrome' below.)

-Dense (or delta) granule deficiency, the most common storage pool disorder. There are nonsyndromic and syndromic forms; the syndromic forms (which are rarer) include Chediak-Higashi syndrome and Hermansky-Pudlak syndrome. (See 'Chediak-Higashi syndrome' below and 'Hermansky-Pudlak syndrome' below.)

-Combined alpha-delta storage pool deficiency is an IPFD with thrombocytopenia that has both dominant and recessive forms.

-Quebec platelet disorder. This is a different type of storage pool disorder that leads to abnormal, plasmin-mediated proteolysis of diverse proteins (including factor V) stored in platelet alpha granules. This is due to overexpression and increased storage of urokinase-type plasminogen activator (uPA) within megakaryocytes and platelets. It causes a platelet-dependent gain-of-function defect in fibrinolysis. (See 'Quebec platelet disorder' below.)

•Membrane changes – Some IPFDs impair the ability of platelets to promote coagulation [1]. The activation of platelets by strong agonists (eg, combined stimulation by thrombin and collagen) alters the phospholipid distribution on platelet membranes and promotes the assembly of phospholipid-dependent coagulation factor complexes on the platelet surface. This procoagulant change involves the loss of platelet membrane phospholipid asymmetry, with movement of the negatively charged phospholipids phosphatidyl serine (PS) and phosphatidyl ethanolamine (PE) that are normally sequestered on the inner leaflet of the platelet membrane to the outer membrane leaflet, which promotes assembly of tenase and prothrombinase complexes [1].

-The most severe is in Scott syndrome, which results from deficiency of the "flippase" enzyme that normally redistributes PS and PE to the outer leaflet of the platelet membrane with activation. (See 'Scott syndrome' below.)

-Less-severe platelet procoagulant function disorders include Quebec platelet disorder, Hermansky-Pudlak syndrome, and commonly encountered platelet disorders that impair aggregation responses to multiple agonists and/or cause dense granule deficiency, including familial platelet disorder with predisposition to myeloid malignancy. (See 'Quebec platelet disorder' below and 'Hermansky-Pudlak syndrome' below and "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Familial platelet disorder with propensity to myeloid malignancies (FPD)'.)

Some IPFDs are extremely rare recessive disorders (with <50 patients worldwide), including those caused by pathogenic variants in SLFN14 (encodes a protein of unclear function), P2RY12 (encodes platelet P2Y₁₂ receptor), FYB1 (encodes a protein involved in platelet activation), and EPHB2 (encodes a receptor tyrosine kinase in platelets) [11-15]. Many of the more commonly encountered IPFDs that increase risks for bleeding have an unknown genetic cause [16].

Clinical spectrum (thrombocytopenia, platelet size, syndromic features) — Many IPFDs are associated with thrombocytopenia (and/or low normal platelet counts in some affected persons), whereas some have a normal platelet count.

●Bleeding risk – Bleeding scores are higher in IPFDs than in inherited thrombocytopenias without defective platelet function [17].

The absence of thrombocytopenia cannot be used to determine bleeding risk as some IPFDs with a normal platelet count have severe platelet dysfunction (eg, Glanzmann thrombasthenia). An inherited cause should be suspected if there is longstanding bleeding that is disproportionate to the thrombocytopenia and/or other features suggestive of an IPFD (syndromic features, multiple relatives with thrombocytopenia).

●Platelet count

•IPFDs with thrombocytopenia (platelet count may be normal in some of these, as indicated):

-ANKRD26-related thrombocytopenia

-ARPC1B deficiency (may have normal platelet count)

-Bernard-Soulier syndrome

-Congenital autosomal recessive small-platelet thrombocytopenia

-Erythrokeratosis with thrombocytopenia syndrome

-ETV6-related thrombocytopenia and leukemia predisposition (may have normal platelet count)

-Familial platelet disorder with predisposition to myeloid malignancy (may have normal platelet count)

-FLNA-related thrombocytopenia

-GALE-related thrombocytopenia

-GATA1 X-linked thrombocytopenia with dyserythropoietic anemia

-GFI1b-related thrombocytopenia

-GNE myopathy with congenital thrombocytopenia

-GPVI-related disease (may have normal platelet count)

-Gray platelet syndrome

-ITGA2/ITG3B-related thrombocytopenia

-MYH9-related disease

-Paris-Trousseau and Jacobsen syndrome

-Platelet-type von Willebrand disease (may have normal platelet count)

-PTPRJ-related thrombocytopenia

-PRKACG-related thrombocytopenia

-Noonan syndrome (may have normal platelet count)

-Quebec platelet disorder (may have normal platelet count)

-SLC35A1-related thrombocytopenia

-SLFN14-related thrombocytopenia

-Stormorken syndrome

-Stormorken syndrome/York platelet syndrome

-Thrombocytopenia with absent radius syndrome

-Thrombocytopenia-2

-Thrombocytopenia, anemia and myelofibrosis syndrome

-TPM4-related thrombocytopenia (may have normal platelet count)

-TRPM7-related thrombocytopenia

-TUBB1-related thrombocytopenia

-Wiskott-Aldrich syndrome/X-linked thrombocytopenia

-Wiskott-Aldrich syndrome 2

•IPFDs with normal platelet counts [18]:

-Arthrogryposis-renal dysfunction-cholestasis syndrome

-Autism with platelet dense granule defect

-Aspirin-like syndrome

-Chediak-Higashi syndrome

-Cytosolic phospholipase A2 syndrome

-Ephrin type-B receptor 2-related disease

-Glanzmann thrombasthenia

-Ghosal syndrome

-Hermansky-Pudlak syndrome

-Leukocyte adhesion deficiency-III

-P2Y12-related disease

-Scott syndrome

-TxA₂ receptor-related disease

●Platelet size - IPFDs can be categorized by platelet size (which is a hereditary trait) since some are associated with giant platelets and some with small platelets. However, platelet size is not always reported on complete blood count (CBC) results, it may be unreliable, and in many cases the clinician will not have access to timely review of the peripheral blood smear. Sometimes the blood smear report will mention large platelets or megathrombocytes (platelet similar in size or larger than red blood cells). Some automated CBC machines may incorrectly count very large platelets as other cell types, which can affect platelet count and platelet size results. (See "Automated complete blood count (CBC)", section on 'Platelet parameters'.)

•Large platelets (high mean platelet volume [MPV]):

-Bernard-Soulier syndrome

-FLNA-related thrombocytopenia

-GFI1b-related thrombocytopenia

-Gale-related thrombocytopenia

-GNE myopathy with congenital thrombocytopenia

-Gray platelet syndrome

-ITGA2/ITGB3-related thrombocytopenia

-MYH9-related disease

-Paris-Trousseau syndrome

-Thrombocytopenia, anemia, and myelofibrosis syndrome

-SLC35A1-related thrombocytopenia

-SLFN14-related thrombocytopenia

-TPM4-related thrombocytopenia

-TRPM7-related thrombocytopenia

-TUBB1-related thrombocytopenia

•Small platelets (low MPV):

-ARPC1B deficiency

-Congenital autosomal recessive small-platelet thrombocytopenia

-PTPRJ-related thrombocytopenia

-Wiskott-Aldrich syndrome (but not Wiskott-Aldrich syndrome 2)

•Normal size platelets:

-Most IPFDs with normal platelet counts

●Syndromic features – Some IPFDs only affect platelets, whereas others affect other cells or organs and present with syndromic features (some or all syndromic features may be present) [19]:

•ANKRD-26-related thrombocytopenia – Leukocytosis, polycythemia, leukemia predisposition

•ARPC1B deficiency – Allergies, autoimmunity, eczema, vasculitis

•Arthrogryposis-renal dysfunction-cholestasis syndrome – Arthrogryposis, renal dysfunction, cholestasis, growth failure, cardiac defects, ichthyosis, infections

•Autism with platelet dense granule deficiency – Autism

•Chediak-Higashi syndrome – Hypopigmentation, immunodeficiency, ataxia, neuropathy

•ETV6-related thrombocytopenia and leukemia predisposition – Macrocytosis, leukemia predisposition

•Familial platelet disorder with predisposition to myeloid malignancy – Myeloid malignancy

•FLNA-related thrombocytopenia – Otopalatodigital syndrome, brain malformation (periventricular nodular heterotopia)

•GALE-related thrombocytopenia – Neutropenia

•GATA1 X-linked thrombocytopenia with dyserythropoietic hemolytic anemia with similarity to beta-thalassemia

•Ghosal syndrome – Osteopetrosis

•GPVI-related disease – Possible autoimmune manifestations

•Hermansky-Pudlak syndrome – Hypopigmentation, pulmonary fibrosis, colitis, neutropenia, immunodeficiency

•Jacobsen syndrome (larger deletion that also causes Paris-Trousseau syndrome) – Growth and developmental delay, intellectual disability, cardiac defects, skull dysmorphism

•MYH9-related disease – Sensorineural hearing loss, kidney disease, cataracts

•Noonan syndrome – Cardiac defects, facial dysmorphism, short stature, skeletal malformations

•SLC35A1-related thrombocytopenia – Delayed psychomotor development, ataxia, choreiform movements, epilepsy, microcephaly

•Stormorken syndrome – Immunodeficiency, muscular hypotonia, ectodermal dysplasia

•Stormorken syndrome/York platelet syndrome – Immunodeficiency, asplenia, facial dysmorphism, ichthyosis, intellectual disability, myopathy

•Thrombocytopenia absent radius (TAR) – Radial dysplasia, upper and lower limb abnormalities, cardiac, renal and central nervous system malformations

•Thrombocytopenia, anemia and myelofibrosis syndrome – Hepatosplenomegaly, anemia, myelofibrosis

•Wiskott-Aldrich syndrome and X-linked thrombocytopenia – Immunodeficiency, autoimmunity, eczema, malignancy

•Wiskott-Aldrich syndrome 2 – Autoimmunity, eczema, malignancy

EVALUATION

When to suspect — An IPFD may be suspected when there is a bleeding phenotype despite normal screening tests of hemostasis, bleeding disproportionate to the degree of thrombocytopenia, thrombocytopenia unresponsive to immune thrombocytopenia (ITP) therapies, multiple affected relatives, and/or syndromic features suggestive of a particular IPFD.

●Bleeding – Includes excess bleeding or bruising (particularly numerous, large, and/or spontaneous bruises), epistaxis, heavy menstrual bleeding, and/or excessive bleeding with childbirth, invasive procedures or dental extractions [20]. Typically, IPFDs are associated with mucocutaneous bleeding and bruising, beginning soon after trauma, rather than joint and muscle bleeds or delayed soft tissue hematomas (table 1); Quebec platelet disorder is an exception that causes delayed bleeding [21]. All patients should be evaluated with a bleeding assessment tool (BAT) such as the ISTH-BAT.

Some IPFDs have minimal bleeding symptoms, whereas others are associated with bleeding disproportionate to the degree of thrombocytopenia. IPFDs with severe bleeding typically have bleeding every hemostatic challenge, whereas milder IPFDs may have variable bleeding with hemostatic challenges.

In general, bleeding due to an IPFD is identified earlier and more frequently in females. Females with IPFD have higher bleeding scores than males and more skin bleeding [16,22]. They also have increased bleeding related to menses and childbirth. Males may only present after bleeding with hemostatic challenges. (See 'History and examination' below.)

Sometimes patients are referred to the bleeding disorders specialist based on their clinical history, and sometimes the primary clinician or hematologist may have done an initial evaluation and documented normal coagulation studies and negative testing for von Willebrand disease (VWD) despite excessive or disproportionate bleeding. (See "Approach to the adult with a suspected bleeding disorder", section on 'Positive bleeding history and normal initial testing'.)

●Thrombocytopenia or abnormal platelet morphology – Some IPFDs are associated with thrombocytopenia. However, absence of thrombocytopenia does not exclude an IPFD, since some IPFDs have normal platelet counts. IPFDs with thrombocytopenia are sometimes erroneously presumed to be ITP, which is a diagnosis of exclusion. Thrombocytopenia unresponsive to ITP therapies is a clue to the diagnosis of an IPFD. (See 'Clinical spectrum (thrombocytopenia, platelet size, syndromic features)' above and "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis", section on 'Differential diagnosis'.)

An IPFD may be suspected if the platelet morphology (or other blood smear finding) is abnormal. Examples include agranular (gray) platelets, megathrombocytes, or Döhle bodies in neutrophils. While the blood smear can provide important clues to an IPFD, most IPFDs show normal findings on the blood smear. (See 'CBC, blood smear, coagulation testing' below and "Evaluation of the peripheral blood smear", section on 'Platelets'.)

●Syndromic features – Some IPFDs are associated with other findings and non-hematologic features. (See 'Clinical spectrum (thrombocytopenia, platelet size, syndromic features)' above and 'Specific disorders' below.)

●IPFD in a relative – Multiple affected relatives strongly suggests a heritable disorder. (See 'Implications for first-degree relatives' below.)

History and examination

●BAT – The bleeding history is best documented using a bleeding assessment tool (BAT) such as one available online from the International Society on Thrombosis and Haemostasis (ISTH-BAT). Other BATs have been used to collect standardized data on IPFD symptoms and estimate the bleeding risks as likelihood or odds ratios, relative to the general population or unaffected relatives, as some bleeding symptoms are common in the general population [16,21].

Advice on use of the BAT is discussed separately. (See "Approach to the adult with a suspected bleeding disorder", section on 'Bleeding score' and "Clinical presentation and diagnosis of von Willebrand disease", section on 'Evaluation'.)

●Syndromic features – History of syndromic features may suggest a specific IPFD. (See 'Clinical spectrum (thrombocytopenia, platelet size, syndromic features)' above.)

●Family history – The family history is an important consideration. IPFDs are much more common in populations where consanguinity is prevalent, and their incidence is also influenced by founder effects and (for recessive disorders) the number of carriers in the population.

●Examination – The examination should evaluate for evidence of bleeding, bruising, and anemia, as well as syndromic features such as skeletal, joint, or skin abnormalities (hypopigmentation, eczema, ichthyosis). An abdominal examination including liver and spleen size, as well as stigmata of chronic liver disease, may suggest a specific IPFD (eg, hepatosplenomegaly is seen with thrombocytopenia, anemia, and myelofibrosis syndrome) or an alternative diagnosis. (See 'Differential diagnosis' below.)

Laboratory testing — The details of the evaluation depend on the individual's presenting findings (bleeding score, thrombocytopenia, syndromic findings) and whether there is a known familial bleeding disorder (algorithm 1). Tests for common IPFDs and rare but important IPFDs may also be considered.

CBC, blood smear, coagulation testing — The complete blood count (CBC) documents presence or absence of thrombocytopenia and abnormalities of white blood cells (WBCs) and/or red blood cells (RBCs). The WBC count, RBC count, and hemoglobin are typically normal in IPFDs unless there is iron deficiency anemia or a disorder that also affects WBCs or RBCs. (See 'Specific disorders' below.)

●Platelet count – The platelet count helps distinguish IPFDs associated with thrombocytopenia from those without. The discussion above classified IPFDs according to whether thrombocytopenia is present. (See 'Clinical spectrum (thrombocytopenia, platelet size, syndromic features)' above.)

In some individuals, thrombocytopenia may be due to an acquired condition. (See 'Differential diagnosis' below.)

●Platelet size and blood smear review – Information about platelet size and granulation may be helpful if available, but some clinicians may not have access to this information (it may not be included in the automated CBC report) or the ability to review the blood smear themselves. The blood smear should be reviewed if possible, as it may show findings that help to narrow the diagnosis.

•Size

-Small platelets – Small platelets are characteristic of Wiskott-Aldrich syndrome, ARPC1B deficiency, congenital autosomal recessive small-platelet thrombocytopenia, and PTPRJ-related thrombocytopenia.

-Giant platelets – Giant platelets are often as large as or larger than a normal RBC (picture 1). Giant platelets are seen in Bernard-Soulier syndrome, gray platelet syndrome, MYH9-related disease, and Paris-Trousseau syndrome. (See 'Specific disorders' below.)

•Granules

-Hypogranulation – Hypogranulated, pale, or gray platelets can indicate alpha granule deficiency (a feature of Gray platelet syndrome) and alpha-delta storage pool deficiency [23-25]. (See 'Gray platelet syndrome' below.)

Pale platelets can also be seen in dense granule disorders including Chediak-Higashi syndrome and Hermansky-Pudlak syndrome. (See 'Chediak-Higashi syndrome' below and 'Hermansky-Pudlak syndrome' below.)

-Giant platelet granules – In Paris-Trousseau syndrome, some platelets may have very large alpha granules. (See 'Paris-Trousseau syndrome' below.)

-Giant granules in neutrophils – Some granule biogenesis disorders, including Chediak-Higashi syndrome, can have giant granules in other blood cells such as neutrophils (picture 2). (See 'Chediak-Higashi syndrome' below.)

●Basic metabolic panel, liver function tests, iron studies – This testing is appropriate if there is concern for possible kidney or liver disease contributing to thrombocytopenia or coagulation abnormalities, or as a syndromic feature of an IPFD. (See 'Clinical spectrum (thrombocytopenia, platelet size, syndromic features)' above.)

Iron deficiency is common in persons with IPFDs with increased iron losses or needs (from bleeding, menses, or pregnancy), particularly before menopause. Iron studies should be performed if there is any concern about iron deficiency. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)

●Coagulation testing – This is appropriate for any concerning bleeding history. It should include prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and VWD testing (performed sequentially or simultaneously). (See "Approach to the adult with a suspected bleeding disorder", section on 'Laboratory evaluation'.)

Platelet function testing — Appropriate for an individual with a bleeding phenotype or other reason to suspect platelet dysfunction. It is typically reserved until after an evaluation for more common bleeding disorders; it may be used to evaluate bleeding out of proportion to mild abnormalities detected on initial laboratory evaluation (algorithm 1). (See 'CBC, blood smear, coagulation testing' above.)

Platelet aggregometry is the gold standard test for diagnosing platelet function disorders. Traditional aggregation assays use a panel of platelet agonists to evaluate platelet activation and aggregation in vitro. Either whole blood or platelet-rich plasma is tested depending on the technique. Common agonists used include ADP, arachidonic acid, collagen, epinephrine, a thromboxane A₂ mimetic, and ristocetin. Thrombin or thrombin receptor activating peptides may sometimes be used. Since many common medications can affect platelet function, care must be taken to avoid their use for at least several days prior to testing. (See "Platelet function testing", section on 'Platelet aggregometry'.)

Normal platelet aggregation in response to ADP and epinephrine involves a biphasic response, although the visualization of two waves may require ADP titration. The first wave of aggregation reflects activation of integrin alphaIIbbeta3 and subsequent crosslinking of platelets via fibrinogen binding (figure 2). The second wave reflects platelet degranulation and enhanced aggregation due to the release of additional platelet agonists and thromboxane generation. Arachidonic acid, collagen, and thrombin provoke only a single burst of aggregation. Dilution of a strong agonist may result in tracings more typical of a weak agonist. With ristocetin, agglutination occurs before the close platelet contact triggers subsequent aggregation, but these two waves are often fused. De-aggregation is sometimes evident when there is reduced aggregation, particularly with the thromboxane analogue U46619 or reduced aggregation with ADP due to P2Y₁₂-related disease.

Documentation of the drug history (and drug discontinuation when appropriate) is important when testing platelet function; several classes of drugs can interfere with the results. (See 'Differential diagnosis' below and "Platelet function testing", section on 'Caveats with testing'.)

Results expected with specific disorders are summarized in the table (table 2). Findings should be examined for the following patterns:

●Lack of agglutination (or aggregation) with ristocetin – Seen in Bernard-Soulier syndrome; the response to other agonists is normal. (See 'Bernard-Soulier syndrome' below.)

●Minimal to absent aggregation to ADP, epinephrine, thrombin, and collagen – Seen in Glanzmann thrombasthenia; the response to ristocetin is reduced but present, as agglutination occurs without aggregation. (See 'Glanzmann thrombasthenia' below.)

Similar aggregation impairments occur in the related disorders ITGA2B/ITGB3-related thrombocytopenia (as activating mutations impair alphaIIbbeta3 expression and reduce their copy number on platelets) and leukocyte adhesion deficiency-III (as kindlin-3 defects impair alphaIIbbeta3 function).

●Impaired aggregation with arachidonic acid but not with thromboxane A2 mimetics (eg, U46619) – Seen in aspirin-like syndrome. As thromboxane generation augments some other agonist responses, there is typically also reduced aggregation with lower concentrations of collagen, absent secondary aggregation with epinephrine, and sometimes reduced aggregation with ristocetin.

●Impaired aggregation with ADP with extensive de-aggregation – Seen in P2Y₁₂-related disease or in patients taking a P2Y₁₂ inhibitor. (See "Platelet biology and mechanism of anti-platelet drugs", section on 'P2Y12 inhibitors'.)

●Impaired aggregation with arachidonic acid and thromboxane A2 mimetics – Seen in TBXA2 receptor related disease; can also be seen in other commonly encountered IPFDs without pathogenic variants in the thromboxane A2 receptor [16].

●Impaired aggregation with low concentrations of collagen, arachidonic acid, and thromboxane analog U46619 – Seen in persons with commonly encountered IPFDs that impair aggregation and/or cause nonsyndromic dense granule deficiency (which includes familial platelet disorder with predisposition to myeloid malignancy) [16]. Aggregation is more frequently impaired with low concentrations of collagen, arachidonic acid and thromboxane analog U46619, than with other agonists. Secondary aggregation with epinephrine is often absent or impaired.

●Impaired primary wave of epinephrine aggregation – Typical of Quebec platelet disorder, with absent secondary aggregation, with or without accompanying impaired aggregation with other agonists such as ADP and collagen [18]. (See 'Quebec platelet disorder' below.)

●Increased aggregation with low concentrations of ristocetin – Seen in platelet-type and type 2B VWD [18]. (See 'Platelet-type VWD' below and "Clinical presentation and diagnosis of von Willebrand disease", section on 'Summary of VWD types'.)

●Impaired ristocetin-induced platelet aggregation – Seen in VWD if there is a significant VWF deficiency or a loss of platelet-dependent VWF function. Can also be seen in IPFDs that impair multiple agonist responses, as aggregation follows ristocetin-induced agglutination. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Ristocetin-induced platelet aggregation (RIPA)'.)

Single abnormalities with a single agonist (except ristocetin) can be a false positive and are not predictive of a bleeding disorder, whereas impaired aggregation with multiple agonists is predictive of a bleeding disorder [26,27]. Isolated aggregation abnormalities with collagen can be a false positive as IPFDs affecting platelet collagen receptors are rare [18].

Repeat testing to confirm diagnostic findings is a good practice when assessing for IPFDs and to help in excluding false-positive findings.

If possible, patients undergoing testing for an IPFD should be evaluated for platelet dense granule deficiency, as it has a prevalence similar to VWD, and confirmed dense granule deficiency is highly predictive of a bleeding disorder [28]. In dense granule deficiency, aggregation findings are nondiagnostic in approximately one-half of the cases, and aggregation testing is not an adequate test. Access to testing with electron microscopy may be limited. (See "Platelet function testing", section on 'Tests not commonly used'.)

There are controversies about the use of platelet secretion testing for IPFD diagnosis, including its usefulness if aggregation studies are normal [29,30]. Flow cytometry can be useful if an IPFD associated with glycoprotein deficiency is suspected (Bernard-Soulier syndrome, Glanzmann thrombasthenia); it can also be used to evaluate platelet function if there is thrombocytopenia, and to assess for defects in activation, granule release, or expression of procoagulants [31]. (See "Platelet function testing", section on 'Other testing if aggregometry is not available'.)

Point of care tests may be more readily available than aggregometry at some centers (table 3), but most of these tests were developed for other purposes and do not have an established role in IPFD diagnosis. Closure times measured by the platelet function analyzer (PFA)-100 are abnormal in severe IPFDs, but normal findings do not exclude an IPFD as the test is insensitive to more common IPFDs [32,33]. Flow cytometry is useful for documenting platelet glycoprotein deficiencies (Bernard-Soulier syndrome or Glanzmann thrombasthenia) and can be used to assess platelet activation and procoagulant markers. Test limitations, performance considerations, and caveats are discussed separately. (See "Platelet function testing", section on 'Other testing if aggregometry is not available'.)

Genetic testing — Decisions about genetic testing should be made by the hematologist following a full clinical evaluation and appropriate platelet function testing.

Genetic testing can be very useful when it reveals a specific pathogenic variant in a platelet function gene and facilitates testing of first-degree relatives of a proband with an IPFD. (See 'Implications for first-degree relatives' below.)

However, genetic testing has many caveats, especially when whole exome sequencing is performed for rare disorders for which the pathogenicity of many gene variants is uncertain. If a gene panel was performed in an individual with a suspected IPFD and did not reveal a pathogenic variant in platelet function genes, consultation with a platelet function disorders expert may help to determine whether relevant genes were omitted. This is especially important when relevant genes have not been fully characterized.

There may be value in repeating genetic testing or reevaluating the interpretation if a causative gene variant was not identified initially as information about pathogenicity continues to emerge. In a 2014 series of 111 patients with excessive bleeding who underwent genetic testing, approximately 60 percent had a specific genetic variant associated with an IPFD identified [34]. The yield was much lower (9 percent) for a single-center consecutive case cohort study that evaluated cases of commonly encountered IPFDs without a suspected or known cause and with impaired aggregation to multiple agonists and/or nonsyndromic dense granule deficiency [16].

Differential diagnosis — The differential diagnosis includes other hereditary bleeding disorders as well as acquired causes of platelet dysfunction and thrombocytopenia.

●Kidney or liver disease – Uremia or chronic liver disease (including due to chronic excess alcohol) can cause platelet dysfunction. Like IPFDs, bleeding can be mucocutaneous. Unlike IPFDs, there will be laboratory abnormalities showing abnormal kidney or liver function. Acute alcohol intake (binge-related drinking) is unlikely to cause major changes in platelet function testing. (See "Uremic platelet dysfunction" and "Hemostatic abnormalities in patients with liver disease".)

●Dysproteinemias or MPNs – Abnormal paraproteins in multiple myeloma or Waldenstrom macroglobulinemia can cause acquired platelet dysfunction. Hyperviscosity or acquired von Willebrand syndrome can also contribute to bleeding. Platelet dysfunction and bleeding can occur in myeloproliferative neoplasms (MPNs), which can also cause acquired von Willebrand syndrome [35-38]. Like IPFDs, there may be thrombocytopenia; unlike IPFDs, there will be non-platelet abnormalities on the CBC, and the platelet dysfunction may respond to treatment of the underlying disorder. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Overview' and "Overview of the myeloproliferative neoplasms", section on 'Thrombosis and bleeding'.)

●Drug-induced platelet dysfunction or thrombocytopenia – Numerous drugs inhibit platelet function.

•Aspirin – Irreversibly inhibits cyclooxygenase-1, causing aggregation abnormalities similar to inherited aspirin-like defects.

•NSAIDs – Many nonsteroidal antiinflammatory drugs (NSAIDs) reversibly inhibit cyclooxygenase-1 and cause abnormal platelet aggregation similar to aspirin. (See "NSAIDs (including aspirin): Pharmacology and mechanism of action".)

•P2Y₁₂ inhibitors – Impair ADP aggregation responses. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'P2Y12 use'.)

•BTK inhibitors – Inhibitors of Bruton tyrosine kinase (BTK), used for lymphoid malignancies, can increase bleeding risk due to platelet dysfunction.

•SSRIs – Selective serotonin reuptake inhibitors (SSRIs) are not considered a major cause of platelet dysfunction, although some agents have been reported to interfere with certain aggregometry tests [39-41]. High quality randomized trials have not shown a statistically significant increase in clinical bleeding, although they may not have been adequately powered to detect small increases. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Bleeding'.)

•Other inhibitors – Agents that inhibit integrin alphaIIbbeta3 (previously called GPIIb/IIIa) can induce Glanzmann thrombasthenia-like abnormalities in platelet function. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'Glycoprotein IIb/IIIa inhibitors' and "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Glycoprotein IIb/IIIa inhibitors'.)

Like IPFDs, these drugs may cause abnormalities in platelet aggregometry testing. Additionally, drugs that inhibit platelet function may worsen or unmask an IPFD. Drug-induced platelet dysfunction should be suspected when a patient develops symptoms after a drug is started, irrespective of the indication for the drug. Unlike IPFDs, drug-induced platelet dysfunction resolves upon drug discontinuation (although the prescriber should be consulted before drug discontinuation, unless there is significant bleeding).

Numerous other medications can cause thrombocytopenia without altering platelet function, either by an immune-mediated mechanism, direct bone marrow toxicity, or other mechanisms. Unlike IPFDs, the thrombocytopenia will resolve upon drug discontinuation (although the prescriber should be consulted before drug discontinuation, unless there is significant bleeding). (See "Drug-induced immune thrombocytopenia".)

●Other hereditary bleeding disorders – Mild forms of some factor deficiencies or VWD can have normal initial laboratory testing. Other clotting factor deficiencies and vascular disorders are not always apparent from initial testing. Like IPFDs, these disorders are present from birth, and there may be positive family history. Unlike IPFDs, these disorders have other diagnostic testing and show normal platelet function on platelet function testing. (See "Approach to the child with bleeding symptoms", section on 'Normal initial testing' and "Approach to the adult with a suspected bleeding disorder", section on 'Positive bleeding history and normal initial testing'.)

TREATMENT

Counseling and communication — Individuals with IPFDs should be offered the opportunity to learn about and understand their specific disorder. When possible, referral to a service with relevant expertise, such as a hemophilia treatment center, is appropriate to evaluate and treat an IPFD.

The patient should be aware of the following general guidance [19]:

●Drugs and medications to avoid, such as anti-platelet drugs, unless there is an important indication.

●Planning is needed to treat and prevent bleeding from hemostatic challenges.

●For some IPFDs with significant bleeding, avoidance of contact sports may be appropriate. These decisions are made on a case-by-case basis.

●Good dental hygiene is important to limit the need for future dental procedures.

●Routine cancer screening should be done according to clinical care guidelines so that problems can be identified early.

●Related health issues requiring consideration include iron deficiency and health risks from syndromic features of some IPFDs. (See 'Iron deficiency' below and 'Other treatments' below.)

Individuals with IPFDs should notify any clinician caring for them about their disorder, especially surgeons, obstetricians, dentists, and others performing procedures. Patients can be provided with a wallet card or letter that explains their condition and recommended treatments. Registration with national databases where available can be extremely helpful to ensure all treating clinicians are aware of the bleeding disorder, specific findings, and appropriate treatment(s).

Major bleeding or major surgery — Major bleeding in individuals with IPFDs is often triggered by invasive surgical or dental procedures or trauma. All management should be carried out in close collaboration and consultation with the specialized clinic, hemophilia treatment center, or a hemostasis expert [42]. Most treatments of IPFD do not require laboratory monitoring.

Available treatments for preventing and treating acute bleeding in IPFDs include:

●Desmopressin – Desmopressin (DDAVP) is the most commonly used treatment; it is used for many IPFDs. (See 'Desmopressin' below.)

●Platelet transfusions – Platelet transfusions are used for bleeding that is not adequately controlled by medical therapies, particularly for severe IPFDs or platelet dysfunction unlikely to be corrected by medications, such as Scott syndrome. Carry risks of transfusion reactions and alloimmunization, including the development of platelet antibodies that may limit future responses. (See 'Platelet transfusion' below.)

●Recombinant factor VIIa (rFVIIa) – rFVIIa is effective for some IPFDs; it carries risks of thrombosis, and cost is high. (See 'Recombinant factor VIIa' below.)

●Antifibrinolytic agents – Antifibrinolytic agents such as tranexamic acid are effective for heavy menstrual bleeding and epistaxis. They are increasingly considered as adjunctive treatment, given the growing evidence they reduce blood loss with cardiac surgery, major orthopedic surgery, severe trauma, and postpartum hemorrhage. Antifibrinolytic therapy is the treatment of choice for bleeding and bleeding prophylaxis in Quebec platelet disorder. (See 'Antifibrinolytic agents' below.)

●Local therapies – Local therapies may also be used when bleeding sites are accessible. (See 'Local therapies' below.)

●TPO-RAs – Short-term thrombopoietin receptor agonist (TPO-RA) therapy has been used for temporary improvement of the platelet count in some IPFDs with significant thrombocytopenia when there is sufficient time for advance planning [19,43]. (See 'Other treatments' below.)

●Treatments for heavy menstrual bleeding – Treatments for heavy menstrual bleeding in IPFDs are similar to that of other bleeding disorders. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management".)

Platelet transfusion

●Indications and mechanism – Platelet transfusions should be considered for serious bleeding and major surgery in patients with more severe IPFDs (such as Scott syndrome), and when other treatments such as DDAVP do not adequately control bleeding [19,42,44]. For less-severe IPFDs and less-severe bleeding, medical therapies can be used to avoid the risk of platelet alloimmunization and other complications of platelet transfusion including platelet refractoriness and transfusion reactions. (See 'Conceptual framework' above.)

Platelet transfusions are often not necessary for managing less severe IPFDs, as patients with commonly encountered IPFDs report bleeding mainly for hemostatic challenges done without prophylactic medications to reduce bleeding [16].

Recombinant factor VIIa (rFVIIa) has been used to treat and prevent bleeding, and to spare platelet transfusions, mainly in severe IPFDs with significant risks for forming platelet antibodies, as discussed below [45]. (See 'Recombinant factor VIIa' below.)

●Dosing and irradiation – The number of transfusions required depends on the severity of bleeding, degree of platelet dysfunction, and platelet count. Dosing and the duration of platelet transfusion support requires clinical judgement, particularly for IPFDs without thrombocytopenia.

•Dosing

-Typically, one apheresis unit or six units of whole blood derived platelets are transfused, with clinical assessment and repeat platelet count to determine if more transfusions are needed. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Ordering platelets'.)

For IPFDs that impair aggregation or activation but not initial platelet adhesion (eg, Glanzmann thrombasthenia and RASGRP2-related disease [also called platelet-type bleeding disorder-18]), animal models suggest there is in vivo competition between transfused platelets and the patient's dysfunctional platelets [46]; dosing needs for those disorders may be fourfold greater.

-If there is massive bleeding requiring massive transfusion, platelets, plasma, and red blood cells are typically transfused in a 1:1:1 ratio. (See "Massive blood transfusion", section on 'Component ratio (1:1:1)'.)

•Irradiation – Irradiated blood products (including platelets) must be used for all patients at risk for transfusion-associated graft-versus-host disease (TA-GVHD) [47]. This includes IPFDs associated with immunodeficiency, including:

-ARPC1B deficiency

-Chediak-Higashi syndrome

-Hermansky-Pudlak syndrome

-Stormorken syndrome

-Wiskott-Aldrich syndrome/X-linked thrombocytopenia

-Wiskott-Aldrich syndrome 2

Leukoreduction is not sufficient to prevent TA-GVHD. Some pathogen inactivation process may be effective, although supporting data are less extensive. (See "Transfusion-associated graft-versus-host disease", section on 'Prevention' and "Pathogen inactivation of blood products", section on 'Preventing transfusion-associated graft-versus-host disease'.)

●Evidence for efficacy – Most evidence for platelet transfusion comes from clinical experience; many IPFDs are too rare to study systematically, and more evidence for efficacy is needed. Among IPFDs, more evidence for effectiveness of platelet transfusion is available for the thrombocytopenic disorders [46].

●Adverse effects

•Acute transfusion reactions – Platelet transfusions carry risks of acute transfusion reactions (allergic, immunologic, transfusion-associated circulatory overload, transfusion-related acute lung injury, transfusion-transmitted bacterial infection). (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Complications' and "Approach to the patient with a suspected acute transfusion reaction".)

•Immunodeficiency and TA-GVHD – Transfusion-associated graft-versus-host disease (TA-GVHD) is a life-threatening transfusion reaction with an extremely high mortality rate (almost always fatal) [47]. In TA-GVHD, lymphocytes in the transfused product attack the recipient's immune system, including skin, gut, and bone marrow, resulting in bone marrow aplasia within 4 to 30 days after transfusion. (See "Transfusion-associated graft-versus-host disease".)

IPFDs associated with immunodeficiency can be considered risk factors for TA-GVHD and an indication for irradiated blood products (or in some cases, leukoreduced blood products. (See "Transfusion-associated graft-versus-host disease", section on 'Immunodeficiency'.)

•Alloimmunization and refractoriness to platelet transfusion – The risk of alloimmunization against platelet glycoproteins or HLA antigens in specific IPFDs is challenging to determine. It is most likely in disorders requiring repeated transfusions and with deficiency of a major platelet glycoprotein, such as Glanzmann thrombasthenia and Bernard-Soulier syndrome. Alloimmunization can lead to refractoriness to platelet transfusion and reduced efficacy of platelet transfusions; during pregnancy this can also pose risks to the fetus. (See "Refractoriness to platelet transfusion".)

Recombinant factor VIIa

●Indications and mechanism – Recombinant activated factor VII (rFVIIa) is a "bypassing therapy" originally developed for hemophilia that can promote clotting by activating a later step in the coagulation cascade. It is thought to promote thrombin generation at sites of vascular damage in patients with IPFDs [48-52]. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'Background and mechanism of action'.)

Treatment with rFVIIa is especially appealing in individuals who are at risk for developing alloantibodies to platelet antigens, including anti-HLA, anti-alphaIIbbeta3 in Glanzmann thrombasthenia, or anti-GP Ib/IX/V in Bernard-Soulier syndrome. Bleeding in patients with several severe IPFDs has been successfully treated with rFVIIa, and the rFVIIa product NovoSeven is approved for Glanzmann thrombasthenia. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'Glanzmann thrombasthenia'.)

●Dosing and efficacy – A 2021 review of rFVIIa use in patients with Glanzmann thrombasthenia identified 333 instances of administration for bleeding and 157 for surgical procedures [45]. Overall efficacy was 79 percent for bleeding and 88 percent for surgery; it was effective in individuals with or without anti-platelet alloantibodies. Dosing was variable (range, 28 to 450 mcg/kg; median, 90 mcg/kg); most individuals received from one to three doses per admission. Therapy was well-tolerated, with only one episode of deep vein thrombosis (DVT) among all the reports.

Smaller series have also described rFVIIa use in Bernard-Soulier syndrome, typically in combination with platelet transfusions [53].

Rare descriptions of other schedules and preventive therapy have been reported, including weekly low-dose rFVIIa for a patient with Glanzmann thrombasthenia and refractory bleeding [54,55].

●Adverse effects – Possible benefits of rFVIIa must be balanced against the risk of thrombosis and the cost. Further details of the dosing and thromboembolic risk are discussed separately. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'Thromboembolic complications'.)

Minor bleeding or minor procedures — Management should be carried out in close collaboration and consultation with an expert service, such as a hemophilia treatment center [42].

Local therapies — Local therapies may be particularly effective for bleeding from sites that can be easily accessed, such as [19]:

●Epistaxis – Nasal packing and/or endoscopic cauterization can be used.

●Dental extractions – Tranexamic acid can be applied as mouthwash or soaked gauze (after dissolving tranexamic acid tablets in water) [19]. (See 'Antifibrinolytic agents' below.)

●Heavy menstrual bleeding – Evaluate for anatomic causes of bleeding such as polyps or uterine fibroids that could be treated locally. Endometrial ablation can be used if future pregnancies are not desired. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis" and "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management".)

●Superficial wounds – Topical tranexamic acid can be administered on gelatin sponges or gauzes [19]. (See 'Antifibrinolytic agents' below.)

Desmopressin

●Indications – Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is commonly used to treat or prevent bleeding in less severe IPFDs. There is considerable experience with using DDAVP to treat minor bleeding in individuals with von Willebrand disease (VWD), where it leads to release of endogenous VWF from platelets and endothelial cells [56,57]. DDAVP also increases plasma VWF and factor VIII levels in individuals with IPFDs [58]. (See "von Willebrand disease (VWD): Treatment of minor bleeding, use of DDAVP, and routine preventive care", section on 'DDAVP'.)

●Dosing – DDAVP can be given subcutaneously, intranasally, or intravenously. A DDAVP trial is not performed for individuals with IPFDs, as the only relevant endpoint is reduction in bleeding or prevention of challenge-related bleeding. Dosing is similar to dosing for VWD. (See "von Willebrand disease (VWD): Treatment of minor bleeding, use of DDAVP, and routine preventive care", section on 'DDAVP'.)

●Adverse effects – Tachyphylaxis and hyponatremia can occur. Instructions and orders for fluid restriction (maximum intake of 1 to 1.5 liters of free water during the 24 hours after DDAVP) are important to limit the risks for water intoxication, as potent fluid retention lasts for 12 to 24 hours.

●Evidence for efficacy – Efficacy of DDAVP to prevent bleeding after dental extraction and minor surgery has been reported in mild IPFDs [42,59,60]. In vitro studies suggest DDAVP improves platelet procoagulant function in IPFDs without altering platelet activation, adhesive, or aggregation function [1].

Antifibrinolytic agents

●Indications – An antifibrinolytic agent (tranexamic acid or epsilon aminocaproic acid) may be helpful in reducing bleeding, especially if bleeding is mucosal, such as with:

•Dental extractions [42]

•Epistaxis

•Heavy menstrual bleeding

Tranexamic acid is more commonly used in patients without bleeding disorders to reduce surgical, traumatic, or postpartum hemorrhage. It is the treatment of choice for bleeding and bleeding prophylaxis in Quebec platelet disorder. (See 'Quebec platelet disorder' below.)

●Dosing – Typical tranexamic acid dosing for IPFDs is similar to other bleeding disorders and non-bleeding disorder uses (with adjustments if kidney function is impaired). (See "von Willebrand disease (VWD): Treatment of minor bleeding, use of DDAVP, and routine preventive care", section on 'Antifibrinolytic agents'.)

•Tranexamic acid, 25 mg/kg per dose orally every six to eight hours or 10 mg/kg intravenously three times per day.

•Aminocaproic acid, 25 to 50 mg/kg per dose orally (maximum 5 g dose) four times per day.

●Duration – The duration of antifibrinolytic therapy is uncertain. Treatment can be provided on the day of surgery, trauma, or postpartum hemorrhage and extended if bleeding continues. An antifibrinolytic agent can be combined with other therapies and is generally well-tolerated.

●Adverse effects – Short-term use of these agents, or their use for treatment of heavy menstrual bleeding, is not associated with an increase in the risk of thrombosis [61]. However, thrombosis has occurred in individuals with Quebec platelet disorder during periods of high risk for thrombosis due to atrial fibrillation, or when fibrinolytic inhibitor therapy was necessary to treat bleeding during a period of high thrombotic risk [21,62]. Combined antifibrinolytic and anticoagulant therapy has been tried to mitigate these risks for persons with Quebec platelet disorder [62,63]. Tranexamic acid treatment leads to increased platelet counts in Quebec platelet disorder, suggesting the underlying fibrinolytic defect is responsible for the lower platelet counts of affected individuals.

Other treatments

●Hormonal contraceptives – Suppression of menses or use of hormonal contraception methods, including medicated intrauterine devices, may reduce menstrual blood loss in IPFD. (See "Hormonal contraception for menstrual suppression" and "von Willebrand disease (VWD): Gynecologic and obstetric considerations", section on 'Interventions for HMB'.)

●TPO-RAs – A thrombopoietin receptor agonist (TPO-RA; such as eltrombopag or romiplostim) may temporarily increase platelet counts. TPO-RAs have been used in several thrombocytopenic IPFDs including MYH9-related disease, Wiskott-Aldrich syndrome/X-linked thrombocytopenia, Bernard-Soulier syndrome, and ANKRD26-related thrombocytopenia [19,43]. A TPO-RA would only be expected to raise the platelet count, not to correct the underlying platelet dysfunction.

Small studies of chronic TPO-RA use in IPFDs have reported good efficacy in increasing the platelet count without significant safety concerns [64-67]. As an example, in a study involving 12 patients with MYH9-related disease and platelet counts <50,000/microL, eltrombopag increased platelet counts to ≥100,000/microL or three times baseline in 8 of the 12 and reduced bleeding in 8 of 10 with bleeding symptoms at baseline [68].

●Hematopoietic stem cell transplant and gene therapy – Individuals with some severe forms of IPFDs who have frequent major bleeding episodes may be treated with more aggressive (and potentially curative) therapy, such as allogeneic hematopoietic stem cell transplantation (HSCT).

•Allogeneic HSCT has been used for Glanzmann thrombasthenia. (See 'Glanzmann thrombasthenia' below.)

•HSCT is an important treatment for congenital amegakaryocytic thrombocytopenia (CAMT) as it evolves to bone marrow failure. HSCT may be warranted for malignant progression of familial platelet disorder with germline predisposition to hematological malignancy; if the donor is related, they must test negative for the causative germline gene variant(s) [69].

•Allogeneic HSCT is also appropriate treatment for syndromic conditions in which other hematologic complications can be life-threatening. Examples include Chediak-Higashi syndrome and Wiskott-Aldrich syndrome. In Wiskott-Aldrich syndrome, outcomes are better for children transplanted before five years of age [70]. (See 'Chediak-Higashi syndrome' below and 'Wiskott-Aldrich syndrome' below.)

Single gene disorders are also potentially amenable to autologous HSCT using gene therapy to restore normal gene function to autologous hematopoietic stem cells, but this has not yet been studied in most IPFDs, with the exception of Wiskott-Aldrich syndrome. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Inherited single gene disorders' and "Wiskott-Aldrich syndrome", section on 'Gene therapy'.)

Obstetric considerations — Pregnancy should be managed in close collaboration with a hemophilia treatment center or hemostasis expert [42]. This should include discussions about options for avoiding an IPFD in offspring (if the disorder is severe), screening for and treatment of iron deficiency, and management of pregnancy and delivery (including pain control if neuraxial anesthesia will not be used). Ideally, the hemophilia treatment center should become familiar with the patient prior to conception or early in the pregnancy to allow a close review of the patient's case and to help plan treatment during the pregnancy. (See "Anemia in pregnancy", section on 'Iron deficiency'.)

●Risks – Childbirth poses bleeding risks for individuals with IPFDs; rates of excessive bleeding with delivery have been as high as 40 to 50 percent for some IPFDs [71,72]. One study found that individuals with commonly encountered IPFDs (that manifest with aggregation defects and/or dense granule deficiency) have increased risks for excessive bleeding with childbirth/miscarriage (odds ratio [OR] 17) and prolonged menses (OR 7) [16]. Compared with unaffected relatives, individuals with Quebec platelet disorder also have increased risks for bleeding with childbirth (OR 12) and prolonged menses (OR 14) [21]. These increased risks largely reflect bleeding with bleeding challenges in untreated individuals.

Another risk in some disorders is that maternal anti-platelet antibodies could cross the placenta and cause fetal or neonatal alloimmune thrombocytopenia (NAIT). Maternal antibodies may be induced by prior transfusions or transplacental hemorrhage with sensitization to fetal platelet antigens, and the likelihood of NAIT increases if existing anti-platelet antibodies are increased by an anamnestic response [42]. (See "Fetal and neonatal alloimmune thrombocytopenia: Parental evaluation and pregnancy management".)

●Likelihood of IPFD in offspring – Some IPFDs are autosomal dominant, meaning offspring have a 50 percent chance of inheriting the gene variant associated with disease and a 50 percent chance of being unaffected.

For autosomal recessive conditions, if the parents are both heterozygous carriers and have had an affected child, the chance of having another affected child is 25 percent for each pregnancy. The risks for rare autosomal recessive IPFDs are higher in kindreds with consanguinity.

Individuals with IPFDs, including those who do not have a known gene variant associated with their IPFD, should be offered the opportunity to speak with an expert in IPFDs or to have genetic testing and counseling prior to attempted conception. (See "Genetic counseling: Family history interpretation and risk assessment", section on 'Resources for genetic counseling'.)

Reproductive options to avoid having an affected offspring are rarely needed; these include preimplantation genetic testing (PGT) of embryos conceived by in vitro fertilization (IVF), use of donor gametes (donor sperm or donor egg), or adoption. (See "Preimplantation genetic testing" and "In vitro fertilization: Overview of clinical issues and questions" and "Donor insemination" and "Adoption".)

●Preconception – Prior to conception, individuals with IPFDs should have the opportunity to discuss maternal and fetal risks and approaches to minimizing these risks. Preimplantation genetic testing of embryos is a consideration for some monogenic disorders, but use has not been reported for IPFDs. (See "Preimplantation genetic testing" and "In vitro fertilization: Overview of clinical issues and questions" and "Donor insemination".)

Screening for (and treating) iron deficiency is especially important for individuals with IPFDs during early pregnancy. (See "Anemia in pregnancy", section on 'How to screen for iron deficiency'.)

●Pregnancy – Bleeding during pregnancy in IPFDs is rare, unlike bleeding with delivery and postpartum. Management and planning for delivery should involve the hemophilia treatment center and a high-risk obstetrician.

Data on the safety of TPO-RAs during the third trimester to increase the platelet count prior to delivery are very limited, with a small series describing their use for individuals with immune thrombocytopenia and one individual with MYH9-related disease [19]. (See 'Other treatments' above.)

●Delivery and postpartum – The risk of maternal hemorrhage is greatest at the time of delivery and postpartum [71,72]. Postpartum hemorrhage can occur up to one to two weeks following delivery, and individuals with IPFDs may have very prolonged postpartum bleeding. Treatment is individualized.

•Vaginal delivery – For vaginal delivery, some experts treat with desmopressin (DDAVP), and for more severe IPFDs, rFVIIa and tranexamic acid at the time of delivery, as a way to improve hemostasis and avoid platelet transfusions. (See 'Recombinant factor VIIa' above and 'Antifibrinolytic agents' above.)

The use of DDAVP during pregnancy and childbirth requires clinical judgement as there are no randomized trials on the effectiveness and safety.

If there is thrombocytopenia, the target minimum platelet count is often >50,000/microL for a surgical or interventional delivery. This may be accomplished by administration of HLA-matched platelet transfusion (to reduce alloimmunization), or with tranexamic acid to further reduce bleeding risk. (See 'Platelet transfusion' above and 'Antifibrinolytic agents' above.)

If the fetus is diagnosed with or at risk for an IPFD or there is concern for NAIT, forceps should not be used [42].

•Cesarean delivery – Cesarean delivery is treated as a major surgical procedure. For severe IPFDs, HLA-selected platelets and tranexamic acid are recommended. For thrombocytopenic IPFD, the optimal platelet count is generally determined by the obstetric team and hematologists taking care of the patient.

•Anesthesia – Neuraxial anesthesia is generally not used in individuals with mild or severe IPFDs due to concerns about spinal epidural hematoma and uncertainties about sustained, adequate hemostatic correction. Some reviews state that neuraxial anesthesia is contraindicated (for Glanzmann thrombasthenia), although there are limited case reports describing platelet transfusion to cover neuraxial anesthesia (eg, for MYH9-related disease) [71,72]. A plan for labor anesthesia should be discussed prior to labor, and options for pain relief should also be planned and discussed. (See "Adverse effects of neuraxial analgesia and anesthesia for obstetrics", section on 'Neuraxial analgesia and low platelets'.)

Iron deficiency — Individuals with pregnancies or who have severe and/or frequent bleeding (epistaxis, heavy menstrual bleeding) are at greater risk of developing iron deficiency.

Periodic screening with ferritin is appropriate, with iron replacement (oral or parenteral iron) as required to treat iron deficiency anemia as well as iron deficiency without anemia, which may be symptomatic, and to improve iron stores before surgery, pregnancy, or delivery. The frequency of screening and the route of iron administration are individualized. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)

Implications for first-degree relatives — First-degree relatives should have the option to be evaluated, starting with a thorough bleeding history. (See 'History and examination' above.)

Relatives with a positive bleeding history and a known family history of an IPFD should undergo testing for that disorder. For some disorders, testing of umbilical cord blood had been used to identify infants at high risk of an IPFD (eg, a child of a parent with Quebec platelet disorder).

For mild disorders, testing may be delayed until older school age, since the volume of blood needed for platelet function testing can be large (approximately 40 mL), and this allows the child to be involved in decision-making around testing. These decisions are made on a case-by-case basis depending on the child's bleeding symptoms and need for surgical procedures or dental extractions.

SPECIFIC DISORDERS — IPFDs include many rare conditions [42,73-75]. Selected disorders are described below.

Some of these disorders affect platelet count, some affect platelet size, and some are associated with syndromic features that may be more clinically impactful than the platelet dysfunction. (See 'Clinical spectrum (thrombocytopenia, platelet size, syndromic features)' above.)

With thrombocyopenia

Bernard-Soulier syndrome

●Genetics and pathophysiology – Bernard-Soulier syndrome (BSS) is caused by pathogenic variants in GP9, GP1BA, or GP1BB [76,77]. These genes encode components of the GPIb/IX complex, which serves as one of the platelet receptors for von Willebrand factor (VWF). BSS platelets have reduced adherence to VWF at sites of vascular injury (but they can still adhere via integrin alphaIIbbeta3).

●Prevalence and inheritance – The prevalence is approximately 1 in 1 million. Transmission is usually autosomal recessive, but autosomal dominant forms also exist.

●Clinical features and evaluation – BSS generally presents with a bleeding phenotype with mild to moderate thrombocytopenia and large platelets. The bleeding phenotype is highly variable from mild to severe [78]. There are no other syndromic features. The diagnosis can be made by platelet aggregometry. BSS platelets do not agglutinate or aggregate in response to ristocetin (table 2).

●Management – Other than standard management discussed above, there are no BSS-specific recommendations. (See 'Treatment' above.)

Gray platelet syndrome

●Genetics and pathophysiology – Gray platelet syndrome (a form of alpha granule deficiency) is caused by pathogenic variants in NBEAL2, which encodes a protein important in alpha granule biogenesis [79]. Pathogenic variants in GFI1B have also been described to cause gray platelet syndrome. GFI1B encodes a transcriptional repressor active in megakaryocytes.

●Prevalence and inheritance – Gray platelet syndrome is very rare. Transmission is autosomal recessive for the NBEAL2-related form and autosomal dominant for the GFI1B-related form [24,79].

●Clinical features and evaluation – Gray platelet syndrome generally presents with progressive thrombocytopenia, myelofibrosis, splenomegaly, and elevated vitamin B12 levels [24]. Platelets are pale and lack azurophilic granules.

●Management – Standard management is discussed above. (See 'Treatment' above.)

GPVI deficiency

●Genetics and pathophysiology – Glycoprotein (GPVI) deficiency is caused by pathogenic variants in GP6, which encodes a platelet collagen receptor [80]. (See 'Mechanisms and gene variants' above and "Platelet biology and mechanism of anti-platelet drugs", section on 'Collagen receptors (GPIa/IIa and GPVI)'.)

●Prevalence and inheritance – GPVI deficiency is very rare. Transmission is autosomal recessive.

●Clinical features and evaluation – Platelet counts are variable, from severe thrombocytopenia to normal platelet count. Some individuals have had autoimmune manifestations, but the disorder is too rare to determine whether these are causally related or incidental findings [80].

●Management – Standard bleed management is discussed above. (See 'Treatment' above.)

MYH9-related disease

●Genetics and pathophysiology – MYH9-related disease is caused by pathogenic variants in MYH9, which encodes a heavy chain of non-muscle myosin. Before the responsible gene was identified, several separate syndromes were described, including May-Hegglin anomaly, Fechtner syndrome, Epstein syndrome, Sebastian syndrome, and others, but these are now considered to be the same disorder. The bleeding history can be minimal or significant. MYH9 is an intracellular protein in non-muscle cells that binds to actin and helps regulate changes in cell shape, adhesion, membrane protrusion, and migration [81]. Thrombocytopenia is thought to be due to reduced megakaryopoiesis, and platelet dysfunction may arise from abnormalities in activation [42].

●Prevalence and inheritance – The prevalence is unknown; it has been estimated to be as high as 1 in 25,000, although only a few hundred kindreds have been described [82]. Transmission is autosomal dominant.

●Clinical features and evaluation – Clinical features include thrombocytopenia (platelet count varies by kindred), large platelets, and Döhle body-like inclusions in neutrophils. Different gene variants have different manifestations in other organs (sensorineural hearing loss, glomerulonephritis, cataracts) [42,81,83,84]. Aggregation findings are typically normal.

●Management – Standard management is discussed above. (See 'Treatment' above.)

One report described improvement in platelet counts with a thrombopoietin receptor agonist (TPO-RA) in a small number of patients with baseline platelet counts <50,000/microL and significant bleeding; bleeding was also reduced [68]. The need for other interventions depends on the bleeding history and other disease manifestations. (See 'Other treatments' above.)

Paris-Trousseau syndrome

●Genetics and pathophysiology – Paris-Trousseau syndrome is caused by pathogenic variants in FLI1, which encodes a transcription factor important in hematopoietic cells.

Jacobsen syndrome is a very rare chromosomal microdeletion syndrome that deletes FLI1 and other genes in the same chromosomal region. (See "Microdeletion syndromes (chromosomes 1 to 11)", section on '11q24.1 deletion syndrome (Jacobsen syndrome)'.)

●Prevalence and inheritance – The prevalence is unknown. Transmission is autosomal dominant.

●Clinical features and evaluation – Clinical features include mild to moderate thrombocytopenia and large platelets, some of which may show abnormally large alpha granules. Other syndromic features may include intellectual disability; dysmorphic craniofacial features; and congenital anomalies affecting the heart, kidneys, and gastrointestinal tract. (See "Causes of thrombocytopenia in children", section on 'Large or giant platelets' and "Microdeletion syndromes (chromosomes 1 to 11)", section on '11q24.1 deletion syndrome (Jacobsen syndrome)'.)

●Management – Standard bleed management is discussed above. (See 'Treatment' above.)

Management of syndromic features depends on the specific findings; multidisciplinary input is required.

Platelet-type VWD

●Genetics and pathophysiology – Platelet-type von Willebrand disease (VWD) is caused by gain-of-function mutations in the GP1BA gene, which encodes a component of the GPIb/IX/V complex, a receptor for VWF. These variants cause increased binding of VWF to platelets and rapid clearance of the GPIb/IX/V-VWF complex, leading to thrombocytopenia and low VWF activity [85]. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Differential diagnosis'.)

●Prevalence and inheritance – The prevalence is unknown. The disorder is autosomal dominant, but fewer than 100 cases are reported worldwide, and there is significant potential for misdiagnosis as other conditions [85].

●Clinical features and evaluation – Clinical features are similar to other IPFDs. Features that should raise suspicion of this disorder include reduced VWF activity, a low ratio of VWF activity to VWF antigen, loss of high molecular weight VWF multimers, and increased aggregation with low concentrations of ristocetin [85]. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Laboratory testing'.)

A 2020 expert opinion practice guideline from the International Society on Haemostasis and Thrombosis (ISTH) recommends testing ristocetin-induced platelet activation (RIPA), followed by genetic testing [85]. In mixing studies, type 2B VWD plasma, but not platelet-type VWD plasma, increases the aggregation of control platelets by low concentrations of ristocetin.

●Management – Standard management is discussed above; major bleeding can be treated with platelet transfusions [85]. For major bleeding that does not respond to platelet transfusions (or if transfusions are not available), rFVIIa can be used [85]. Minor bleeding can be treated with antifibrinolytic therapy and/or desmopressin (DDAVP).

If VWF activity is low, VWF concentrate is added. The target VWF activity is 50 to 60 percent for major bleeding or surgery and 30 to 50 percent for minor bleeding or surgery. (See "von Willebrand disease (VWD): Treatment of major bleeding and major surgery", section on 'VWF concentrates for major bleeding'.)

Quebec platelet disorder

●Genetics and pathophysiology – Quebec platelet disorder (QPD; originally called factor V Quebec) is caused by a pathogenic variant consisting of a duplication on chromosome 10 that includes PLAU and repositions a downstream megakaryocyte-specific enhancer that "rewires" PLAU to increase its expression selectively in megakaryocytes and platelets [86-88]. PLAU encodes the urokinase-type plasminogen activator (uPA), which cleaves plasminogen to plasmin. Generation of plasmin within platelets causes degradation of alpha granule contents including factor V, multimerin 1, VWF, and fibrinogen. QPD causes a gain-of-function defect in fibrinolysis as the release of uPA from QPD platelets accelerates fibrinolysis. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'Quebec platelet disorder'.)

●Prevalence and inheritance – QPD affects approximately 1 in 200,000 French Canadians; all affected individuals share the same pathogenic variant [21]. Transmission is autosomal dominant.

●Clinical features and evaluation – Patients with QPD have delayed-onset bleeding, including large hematomas and muscle and joint bleeding. Mild thrombocytopenia may be present, and platelet aggregometry shows reduced aggregation and absent secondary aggregation with epinephrine, with or without other aggregation abnormalities (reduced aggregation with ADP and collagen). (See 'Platelet function testing' above.)

●Management – The only effective treatment for QPD bleeding is antifibrinolytic therapy [21]. As several persons with QPD have developed thrombosis, concurrent anticoagulation and antifibrinolytic therapy should be considered during situations with high bleeding and high thrombotic risks including atrial fibrillation, pelvic fracture, and hip or knee replacement surgery [62,63]. (See 'Treatment' above.)

Thrombocytopenia absent radius (TAR) syndrome

●Genetics and pathophysiology – Thrombocytopenia absent radius (TAR) syndrome is caused by pathogenic variants in the gene RBM8A, which encodes an mRNA binding protein involved in nuclear export of mRNA in many cell types.

●Prevalence and inheritance – TAR is extremely rare, with only a few hundred cases reported worldwide. Transmission is autosomal recessive.

●Clinical features and evaluation – Radii are absent; thumbs are present. There may be other skeletal abnormalities, heart and genitourinary anomalies, and cow's milk intolerance. (See "Microdeletion syndromes (chromosomes 1 to 11)", section on 'Proximal 1q21.1 deletion syndrome (Thrombocytopenia absent radius syndrome)'.)

Thrombocytopenia is initially severe (platelet counts <50,000/microL) but gradually improves over time [42]. Bleeding risk may be greater than expected based on the platelet count.

●Management – Standard management is discussed above. Platelet transfusions are often required during early infancy and may also be required perioperatively, even in individuals whose platelet counts have improved [42]. (See 'Treatment' above.)

Wiskott-Aldrich syndrome

●Genetics and pathophysiology – Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) are caused by pathogenic variants in the WAS gene, which regulates actin cytoskeleton remodeling and cell polarization. WAS is a type of granule disorder (also called storage pool disorder). (See "Wiskott-Aldrich syndrome", section on 'Pathogenesis' and "Wiskott-Aldrich syndrome", section on 'Genetics'.)

●Prevalence and inheritance – The prevalence has been estimated at 1 to 10 per 1 million; it occurs almost exclusively in males. Transmission is X-linked. (See "Wiskott-Aldrich syndrome", section on 'Epidemiology'.)

●Clinical features and evaluation – Classical WAS is an immunodeficiency syndrome with T-cell dysfunction, autoimmunity, eczema, and an increased risk of hematologic malignancies. XLT is a less-severe form characterized mostly by thrombocytopenia and mild eczema.

For both classical WAS and XLT, the complete blood count (CBC) and blood smear show a thrombocytopenia (platelet counts <70,000/microL) and small platelets. (See 'CBC, blood smear, coagulation testing' above.)

●Management

•Treatment and prevention of bleeding – Standard management for bleeding is discussed above. (See 'Treatment' above.)

Patients with WAS are immunosuppressed. If platelet transfusions (or other blood product transfusions) are used, all products should be irradiated to avoid transfusion-associated graft-versus-host disease (TA-GVHD). Platelet transfusions should also be HLA-matched if possible, to avoid platelet alloimmunization [42]. (See "Transfusion-associated graft-versus-host disease", section on 'Prevention' and "Refractoriness to platelet transfusion", section on 'Prevention'.)

Splenectomy may improve platelet counts but carries a risk of further immunosuppression and sepsis from encapsulated organisms [19,42]. Infection prevention and other considerations are discussed separately [42]. (See "Elective (diagnostic or therapeutic) splenectomy".)

•Treatment of immunodeficiency – Management of immunodeficiency in WAS is discussed in detail separately. (See "Wiskott-Aldrich syndrome", section on 'Treatment'.)

Normal platelet count

Chediak-Higashi syndrome

●Genetics and pathophysiology – Chediak-Higashi syndrome (CHS) is caused by pathogenic variants in the LYST gene, which encodes a protein involved in lysosomal trafficking in many cell types. Manifestations are due to impaired vesicle trafficking. (See "Chediak-Higashi syndrome", section on 'Pathogenesis'.)

●Prevalence and inheritance – CHS is extremely rare with only a few hundred cases reported worldwide. Transmission is autosomal recessive.

●Clinical features and evaluation – Clinical features include easy bruising and bleeding. White blood cells (WBCs) contain abnormally large cytoplasmic granules (picture 2).

Patients with CHS have hypopigmentation (also called oculocutaneous albinism) and recurrent bacterial infections due to impaired immune function; some individuals may develop ataxia or neuropathies [89].

Disease progression to hemophagocytic lymphohistiocytosis (HLH) is common and often triggered by infection. This is referred to as the "accelerated phase" of CHS. HLH is a disorder of massive immune dysregulation with lymphohistiocytic infiltration of virtually all organ systems, fever, hepatosplenomegaly and lymphadenopathy, pancytopenia, and bleeding with hypofibrinogenemia. HLH is often fatal. (See "Chediak-Higashi syndrome", section on 'Hemophagocytic lymphohistiocytosis/accelerated phase' and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

●Management

•Treatment and prevention of bleeding – Standard bleeding management and prevention are discussed above. (See 'Treatment' above.)

•Treatment of immunodeficiency – Management of immune dysfunction mainly focuses on identification and treatment of infections. Hematopoietic stem cell transplant can be curative for the hematologic manifestations but not the neurologic complications. (See 'Other treatments' above and "Chediak-Higashi syndrome", section on 'Treatment' and "Chediak-Higashi syndrome", section on 'Prognosis'.)

•Treatment of HLH – (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

Glanzmann thrombasthenia

●Genetics and pathophysiology – Glanzmann thrombasthenia (GT) is caused by pathogenic variants in ITGA2B and ITGB3. These genes encode components of the integrin alphaIIbbeta3 (previously called GPIIb/IIIa), which serves as one of the platelet receptors for VWF [90]. GT platelets have reduced adherence to VWF at sites of vascular injury (but they can still adhere via GPIb/IX). (See "Pathophysiology of von Willebrand disease", section on 'VWF functions'.)

Leukocyte adhesion deficiency III (LAD-III) is another rare disorder of integrin function, due to pathogenic variants in the gene FERMT3 (also called KINDLIN3), which has a role in integrin activation in hematopoietic cells. LAD-III is associated with reduced alphaIIbbeta3 expression and a GT phenotype [91]. (See "Leukocyte-adhesion deficiency", section on 'LAD III'.)

●Prevalence and inheritance – The prevalence is approximately 1 in 1 million. Transmission is autosomal recessive.

●Clinical features and evaluation – GT generally presents with a bleeding phenotype with a normal platelet count and normal platelet size. There are no other syndromic features. The diagnosis can be made by platelet aggregometry. GT platelets do not aggregate in response to ADP (first or second wave) or collagen; only ristocetin-induced aggregation is normal (table 2). This is the converse pattern of BSS. (See 'Bernard-Soulier syndrome' above.)

Individuals with GT who have received multiple platelet transfusions can sometimes develop alloantibodies to integrin alphaIIbbeta3 and/or HLA antigens, resulting in refractoriness to such transfusion. Rare cases of acquired GT due to allo- or autoantibodies have been reported [92-99]. (See "Refractoriness to platelet transfusion", section on 'Alloimmunization'.)

Infants with LAD-III can have leukocytosis, delayed separation of the umbilical cord, and severe bacterial infections. (See "Leukocyte-adhesion deficiency", section on 'LAD III'.)

●Management – Standard management decisions are discussed above. (See 'Treatment' above.)

Unique to GT is the risk of developing alloantibodies to integrin alphaIIbbeta3 and/or HLA antigens, resulting in refractoriness to platelet transfusions. This leads to the risk that a more serious bleeding event in the future could not be effectively treated with platelet transfusions. As a result, many clinicians will use recombinant activated factor VII (rFVIIa) for minor or less-serious bleeding in an attempt to "save" platelet transfusions for truly life-threatening bleeding. Dosing is discussed above, and the general approach is discussed in more detail separately. HLA-matched platelets are indicated, where available. (See 'Recombinant factor VIIa' above and "Recombinant factor VIIa: Administration and adverse effects", section on 'Glanzmann thrombasthenia'.)

Hematopoietic stem cell transplantation has been successfully used in some patients who have severe bleeding and/or development of antiplatelet antibodies [100-104]. (See 'Other treatments' above.)

Hermansky-Pudlak syndrome

●Genetics and pathophysiology – Hermansky-Pudlak syndrome (HPS) is caused by biallelic pathogenic variants in one of the genes listed in the table (table 4). These encode components of complexes involved in intracellular biogenesis and trafficking of lysosomes and lysosome-related organelles (LROS). (See "Hermansky-Pudlak syndrome", section on 'Pathogenesis'.)

●Prevalence and inheritance – The prevalence is approximately 1 in 1 million or slightly greater; there is a high carrier frequency in Puerto Rico. Transmission is autosomal recessive. (See "Hermansky-Pudlak syndrome", section on 'Epidemiology'.)

●Clinical features and evaluation – Hypopigmentation and platelet dysfunction are present in all individuals. Other manifestations are variable depending on the affected gene, including pulmonary fibrosis colitis, neutropenia, and immunodeficiency. (See "Hermansky-Pudlak syndrome", section on 'Clinical manifestations'.)

The platelet count is normal. The blood smear shows pale platelets.

●Management

•Treatment and prevention of bleeding – Standard bleed management is discussed above. (See 'Treatment' above.)

•Management of other manifestations (dermatologic, ophthalmic, gastrointestinal, respiratory) – (See "Hermansky-Pudlak syndrome", section on 'Management'.)

Scott syndrome

●Genetics and pathophysiology – Scott syndrome is caused by pathogenic variants in ANO6 (previously called TMEM16F). ANO6 encodes a calcium-activated transmembrane enzyme with "flippase" activity, which redistributes negatively charged phosphatidyl serine (PS) and phosphatidyl ethanolamine (PE) from the platelet membrane leaflet to the outer leaflet [105]. As a result, these membrane phospholipids cannot get redistributed to the outer membrane in response to platelet agonists and cannot form a phospholipid scaffold for assembly of the tenase and prothrombinase complexes [1]. (See "Overview of hemostasis", section on 'Multicomponent complexes'.)

●Prevalence and inheritance – The syndrome is extremely rare. Transmission is autosomal dominant.

●Clinical features and evaluation – Platelet count and platelet size are normal.

●Management – Standard management is discussed above. (See 'Treatment' above.)

Hereditary thrombocytopenia with normal platelet function — Hereditary disorders of decreased platelet production or increased platelet clearance cause thrombocytopenia without affecting platelet function.

●Congenital amegakaryocytic thrombocytopenia (CAMT) – Variants in the MPL gene, which encodes the thrombopoietin receptor, cause CAMT. (See "Causes of thrombocytopenia in children", section on 'Inherited platelet disorders'.)

●Montreal platelet syndrome (type 2B VWD) – Montreal platelet syndrome is a form of type 2B VWD caused by a V1316M mutation in the VWF gene [106]. (See "Pathophysiology of von Willebrand disease", section on 'Type 2 (dysfunctional protein; 2A, 2B, 2M, 2N)' and "Clinical presentation and diagnosis of von Willebrand disease", section on 'Summary of VWD types'.)

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 AND RECOMMENDATIONS

●Overview – Platelets bind collagen and von Willebrand factor (VWF) at sites of vascular injury, which triggers activation, secretion of granule contents, aggregation, binding to clotting factors, and thrombin generation. Inherited platelet function disorders (IPFDs) can affect any of these processes. Some disorders cause thrombocytopenia and/or alter platelet size; some are associated with syndromic features. (See 'Conceptual framework' above.)

●Evaluation

•When to suspect – IPFDs can present with excess bleeding (especially heavy menstrual bleeding), thrombocytopenia, abnormal platelet morphology, syndromic features, or after diagnosis in a relative. Diagnosis is frequently delayed. All evaluations should start with a bleeding assessment tool (ISTH-BAT). Syndromic features (hypopigmentation, eczema) should be assessed. (See 'When to suspect' above and 'History and examination' above.)

•Laboratory – Obtain a complete blood count (CBC), metabolic panel, liver function tests, clotting studies, fibrinogen, and VWD testing. If this is unrevealing (algorithm 1), platelet aggregometry is indicated (table 2). Genetic testing can be confirmatory and can facilitate testing of first-degree relatives if symptomatic. Aggregometry and genetic testing should be ordered by a hematologist or other hemostasis expert. (See 'Platelet function testing' above and 'Genetic testing' above and "Platelet function testing", section on 'Platelet aggregometry'.)

Iron deficiency may occur when bleeding has been significant. Serum ferritin is used to assess for iron deficiency. (See 'Iron deficiency' above.)

•Differential – The differential diagnosis includes other bleeding disorders, thrombocytopenias, and drug effects. (See "Approach to the child with bleeding symptoms" and "Approach to the adult with a suspected bleeding disorder" and "Approach to the child with unexplained thrombocytopenia" and "Diagnostic approach to thrombocytopenia in adults".)

●Management – Management should involve consultation with a hemophilia treatment center, ideally at the time of diagnosis to allow planning.

•Bleeding/surgery – Platelet transfusion is the main therapy for major bleeding or surgery. Recombinant activated factor VII (rFVIIa) may be used in selected cases. For individuals with Glanzmann thrombasthenia (GT) who have non-major bleeding, we suggest rFVIIa rather than platelet transfusions (Grade 2C). This preserves platelet transfusions for life-threatening bleeding or major surgery, since platelet transfusion can result in alloantibody formation that can render future transfusions less effective. This may apply to other IPFDs. (See 'Major bleeding or major surgery' above.)

Minor bleeding can be treated with local therapies (nasal packing, cautery), antifibrinolytic agents, and desmopressin (DDAVP). (See 'Major bleeding or major surgery' above and 'Minor bleeding or minor procedures' above.)

Thrombopoietin receptor agonists (TPO-RAs) are occasionally used for chronic therapy or elective surgery, but evidence is limited. Hematopoietic stem cell transplantation is reserved for severe frequent bleeding. Syndromic features may require separate interventions. (See 'Iron deficiency' above and 'Other treatments' above.)

•Pregnancy – Bleeding risk is greatest during delivery and postpartum; platelet transfusions may be required. All individuals should receive antifibrinolytic therapy. Neuraxial anesthesia will be associated with increased complication rates; consultation with anesthesia is recommended before delivery. Those with alloantibodies may have fetal and neonatal alloimmune thrombocytopenia (NAIT). (See 'Obstetric considerations' above.)

•Counseling – Individuals with IPFDs should be aware of drugs and medications to avoid and should inform clinicians about their disorder. Carrying a wallet card and/or registration with national databases can be helpful. First-degree relatives should have the opportunity to be evaluated. (See 'Counseling and communication' above and 'Implications for first-degree relatives' above.)

●Specific platelet function disorders – (See 'Specific disorders' above.)

•Thrombocytopenia

-BSS – (See 'Bernard-Soulier syndrome' above.)

-Gray platelet – (See 'Gray platelet syndrome' above.)

-GPVI – (See 'GPVI deficiency' above.)

-MYH9 – (See 'MYH9-related disease' above.)

-Paris-Trousseau – (See 'Paris-Trousseau syndrome' above.)

-Platelet-type VWD – (See 'Platelet-type VWD' above.)

-Quebec – (See 'Quebec platelet disorder' above.)

-TAR – (See 'Thrombocytopenia absent radius (TAR) syndrome' above.)

-Wiskott-Aldrich – (See 'Wiskott-Aldrich syndrome' above.)

•Normal platelet count

-Chediak-Higashi – (See 'Chediak-Higashi syndrome' above.)

-GT – (See 'Glanzmann thrombasthenia' above.)

-Hermansky-Pudlak – (See 'Hermansky-Pudlak syndrome' above.)

-Scott – (See 'Scott syndrome' above.)

ACKNOWLEDGMENTS

The UpToDate editorial staff acknowledges Steven Coutre, MD (deceased), who contributed to earlier versions of this topic review.

The UpToDate editorial staff also acknowledges Lawrence LK Leung, MD, who contributed to earlier versions of this topic review.