Platelet Function Disorders

Platelets (or thrombocytes) are essential components of the blood. Along with coagulation factors, these tiny (roughly 2 – 3 µm in diameter) discoid-shaped bodies react to bleeding from blood vessel injury by clumping, thereby initiating a blood clot.

In an adult, the ‘normal’ platelet count is 150 and 450 x 109/L, so there are 150,000 – 450,000 platelets per microliter of blood (or nearly one trillion in total). Platelets are not affected by intact epithelium but if vascular injury to the endothelium lining blood vessels exposes the subendothelial matrix, they adhere to the site due to interactions between proteins on their surface, von Willebrand factor and other agents in the matrix. Interaction with collagen in the vessel wall activates the platelet, which undergoes ‘shape change’ from a disc to a spiny sphere; it secretes cytokines, activating more platelets which then aggregate to form a plug at the site of injury. This culminates in binding with fibrinogen and the formation of a thrombus. These events are associated with interactions with many other molecules in the blood and tissues that further affect platelet function and modulate inflammation and immunity.

Inherited platelet function disorders (PFDs) are rare and much less common than bleeding disorders due to clotting factor deficiencies, though it is believed that the statistics underestimate the true picture because many affected people go undiagnosed. In 2015/16, the UK National Haemophilia Database included 2,432 patients with ‘platelet disorders’ compared with 7,700 with haemophilia A, 1,707 with haemophilia B and 10,598 with von Willebrand disease (vWD). The UK National Haemophilia Centres Doctors Organisation 2006 guideline on the management of inherited platelet disorders estimated that even the more common disorders each affected fewer than 100 people in the UK and the rarer ones affected fewer than 10 each [Bolton-Maggs et al, 2006]. PFDs that are acquired (e.g. due to drugs or systemic disorders [Casari et al, 2016]) are much more common than inherited disorders.

Inherited PFDs can arise from a range of mechanisms (Table 1 [Rao et al, 2013]). As well as a defect of the platelet itself, function may be compromised by other factors: examples include vWD, which is due to a deficiency or defect in plasma von Willebrand factor (a protein essential for platelet adhesion) (vWD is not discussed further in this review), and Bernard-Soulier syndrome, which is due to a deficiency or defect in glycoprotein 1b, the receptor for von Willebrand factor.

Table 1. Inherited platelet function disorders [Rao et al, 2013]

Defects in platelet-platelet interaction (disorders of aggregation)



Congenital afibrinogenemia (deficiency of plasma fibrinogen)

Glanzmann thrombasthenia (deficiency or defect in GPIIb-IIIa)

Disorders of platelet secretion and abnormalities of granules Storage pool deficiency (d, a, ad)*

Quebec platelet disorder

Disorders of platelet secretion and signal transduction Defects in platelet-agonist interaction (receptor defects) (ADP, thromboxane A2, collagen, epinephrine)

Defects in G-proteins (Gaq, Gas, Gai abnormalities)

Defects in phosphatidylinositol metabolism and protein phosphorylation (phospholipase C-b2 deficiency, PKC-q deficiency)

Abnormalities in arachidonic acid pathways and thromboxane A2 synthesis (phospholipase A2 deficiency, cyclooxygenase deficiency, thromboxane synthase deficiency)

Disorders of platelet coagulant-protein interaction Scott syndrome
Defects related to cytoskeletal/structural proteins Wiskott-Aldrich syndrome

b1 tubulin deficiency

Kindlin-3 deficiency (leukocyte adhesion defect-III)

Abnormalities of transcription factors leading to functional defects RUNX1 (familial platelet dysfunction with predisposition to acute myelogenous leukaemia);


* Storage poolrefers to deficiencies in the contents of alpha and dense granules, not the storage of platelets


Signs and symptoms

The bleeding disorders associated with inherited PFDs are generally considered to be mild to moderate but some are severe (Table 2). Bleeding severity also varies between patients diagnosed with the same PFD.

Table 2. Characteristics of selected PFDs [Rao et al, 2013; Matthews, 2013; Podda et al, 2012]

Bernard–Soulier syndrome Prevalence 1 per million

Quantitative or qualitative defects of the platelet glycoprotein complex (the von Willebrand factor receptor)

Associated with giant platelets, decreased platelet adhesion to subendothelium, shortened survival and abnormal prothrombin consumption

Autosomal recessive inheritance*

Bleeding severe

Glanzmann thrombasthenia <1,000 cases worldwide

Defects in glycoproteins that bind fibrinogen, essential for aggregation

Platelet size and count normal

Autosomal recessive inheritance

Bleeding severe

Scott syndrome Very rare

Impaired migration across platelet membrane of phosphatidylserine, a procoagulant, during activation

Platelet structure and function otherwise normal

Autosomal recessive inheritance

Causes defective wound healing

Storage pool disorders
Dense granule Variable severity, often mild to moderate bleeding diathesis associated with a prolonged bleeding time

Variable abnormalities of aggregation

Autosomal recessive or dominant inheritance*

Alpha granule (Grey platelet syndrome)


Variable bleeding severity, impaired aggregation

Platelets appear grey, may be large, associated with mild thrombocytopenia and splenomegaly

Usually autosomal recessive inheritance

Alpha and dense granule Heterogenous disorder with clinical effects similar to dense and alpha storage pool disorders

Platelet count normal

Autosomal dominant or recessive inheritance

NB: autosomal recessive: both parents must pass on the abnormal gene; autosomal dominant: the disorder occurs if the abnormal gene is inherited from only one parent

The usual symptoms are mucocutaneous bleeding (bruising, epistaxis, menorrhagia) that may also affect the oropharynx or gastrointestinal tract, and bleeding from surgical sites. Unlike haemophilia, PFDs are not generally associated with musculoskeletal bleeding or deep ecchymoses though rare variants associated with severe bleeding, such as Scott syndrome and Quebec platelet disorder, may cause joint bleeds. Because the tendency to bleed spontaneously is often mild to moderate, a PFD may not be diagnosed until excessive bleeding occurs when a child becomes mobile, a girl reaches puberty and develops menorrhagia, or an individual undergoes surgery [Matthews, 2015].


The assessment of a patient with excessive bleeding and prolonged bleeding time involves a detailed personal and family history, review of drug treatment (to exclude acquired PFDs) and enquiry about comorbidities that are associated with bleeding disorders (including hearing loss, structural abnormalities of the heart, face or bone, ocular involvement, Down syndrome and skin discoloration). Standard laboratory investigations such as full blood count, prothrombin time, activated partial thromboplastin time and screening for von Willebrand factor often suggest an alternative diagnosis to a PFD.

The gold standard test for platelet function is measurement of platelet aggregation using light transmission aggregometry [Matthews, 2015]. If a PFD is suspected, further assessment requires a stepped approach to platelet phenotyping. This includes assessment of appearance, size and structure, granule release and surface glycoproteins, and the aggregatory response after exposure to several agents. The information obtained at this step can define the type of PFD – for example, aggregation abnormalities and defective expression of glycoproteins on the platelet surface are characteristic of Glanzmann’s thrombasthenia whereas Chediak-Higashi syndrome is associated with defective dense granule release and structural abnormalities in other blood cells.

If these investigations are inconclusive, the second step involves further assessment of aggregation, granule content and surface proteins, and electron microscopy. Where the diagnosis remains uncertain, a third tier of investigations such as biochemical tests, receptor binding assays and genetic testing are available from specialist centres. Detailed guidance on the laboratory diagnosis of PFDs has been published by the International Society on Thrombosis and Haemostasis  [Gresele, 2015].


In the UK, most people with PFDs are referred to a haemophilia centre where the full range of interventions and support, including genetic counselling, should be available (Table 3).


Table 3. General management of PFDs [Matthews, 2015; Gresele, 2015; Seligsohn, 2012]

Lifestyle Minimise risk from activities that may cause injury – e.g. contact sports

Maintain good dental care

Drugs Avoid NSAIDs, aspirin and other antiplatelet agents, anticoagulants and other drugs that may increase bleeding risk

Avoid intramuscular injection

Epistaxis Ensure patient and family know how to manage nose bleeds

Consider use of topical and room humidifiers and intranasal saline to prevent nasal dryness

Severe epistaxis requires packing, which increases risk of recurrence on removal

Minor wounds May be controlled by compression, gelatin sponge or gauze soaked in tranexamic acid solution

Tranexamic acid mouthwash for gingival bleeding

Menorrhagia Options to reduce bleeding include oral contraceptives and intrauterine levonorgestrel-releasing device (Mirena®)

Heavy bleeding may cause anaemia – consider iron supplementation

Antifibrinolytic therapy Oral tranexamic acid for 5 – 10 days
Surgery Prophylaxis with intranasal desmopressin

Fibrin sealants

Acute bleeding Intravenous desmopressin may shorten bleeding time but effectiveness is variable in patients with storage pool disorders and it is usually ineffective in those with Glanzmann thrombasthenia

Recombinant Factor VIIa (NovoSeven) is licensed for the treatment of patients with Glanzmann’s thrombasthenia with antibodies to GP IIb – IIIa and/or HLA, and with past or present refractoriness to platelet transfusions; it may also be effective patients with Bernard Soulier syndrome or storage pool disorders. Serious adverse effects include venous and arterial thrombosis.

Platelet transfusion is effective but associated with a risk of alloimmunisation

Stem cell transplantation Has been successful in children with Glanzmann thrombasthenia but risk of adverse effects is high [Poon et al, 2016]

The principles of lifestyle change, prevention and the management of minor bleeding are applicable to most people with a PFD but, because some abnormalities render platelets unresponsive to certain drugs, treatment to control acute bleeding is selected according to the specific disorder (Table 4). Platelet transfusion and recombinant Factor VIIa are associated with significant risk of serious adverse effects, and the effectiveness of FVIIa is variable. The risks and benefits of treatment therefore need to be carefully weighed for each individual.

Table 4. Summary of treatment options for selected PFDs

Bernard-Soulier syndrome Antifibrinolytic drugs

Recombinant factor VIIa


Fibrin sealants

Hormonal contraceptives to control excessive menstrual bleeding

Iron replacement for anaemia secondary to excessive bleeding

Platelet transfusions if bleeding is severe

Glanzmann thrombasthenia Antifibrinolytic drugs

Recombinant factor VIIa

Desmopressin is not usually effective

Fibrin sealants

Hormonal contraceptives to control excessive menstrual bleeding

Iron replacement for anaemia secondary to excessive bleeding

Platelet transfusions if bleeding is severe

Storage pool deficiencies Antifibrinolytic drugs

Desmopressin (may not be useful in alpha granule deficiency)

Platelet transfusions

Adapted from World Federation of Hemophilia. Inherited Platelet Disorders. (


Living with a PFD

There appears to be no published systematic assessment of the impact of a PFD on the person and family or carers, perhaps because they constitute a small minority of patients in haemophilia centres; there may also be an assumption that they share the experiences of people with more common bleeding disorders. However, their experience is distinct from that of people with haemophilia or vWD – for example, pain is a major determinant of quality of life in people with those disorders [McLaughlin et al, 2017], whereas pain does not appear to be common or intrusive for most people with a PFD. By contrast, menorrhagia is associated with impaired quality of life in girls with vWD [Re et al, 2013] and this is also a frequent effect of PFDs. Further, the impact of PFDs is likely to vary with the severity of bleeding risk and what may be relevant to people with one form of PFD may not be important to others. When so few people are affected by a PFD, generalisation is difficult.

Haemnet’s qualitative Study Of LIving with a platelet Function disordEr (SO-LIFE) was the first initiative to describe the impact of PFDs on children and their families [Woollard et al, 2017]Children and young people with PFDs, all of whom were prone to serious bleeding, were invited (with their families) to an informal meeting to discuss their experiences. They were also asked to complete the Kids ITP questionnaire (a quality of life tool developed for children with immune thrombocytopenic purpura – see to evaluate whether it accurately captured their thoughts and feelings.

The study showed that several families had experienced prolonged delays in diagnosis of PFD, with some reporting misdiagnosis (e.g. of vWD). Affected children and young people appeared to lack knowledge and clear understanding of their condition; they expressed concern about how it might affect their future. There was an acute awareness of the need to avoid high risk behaviour such as contact sports and siblings were very protective of their affected brothers and sisters. Families reported no contact with patient support groups. Although families consistently expressed gratitude for the support and advice they received from health services it was clear that many of their needs were unmet. As a result of this project, Haemnet made the following video, which patients might find helpful. It provides some simple information about platelet disorders, the symptoms you can expect, and the importance of communicating with your care team to ensure you receive the right treatment.

SO-LIFE also showed that Kids ITP is not suitable for assessing quality of life or burden of disease in people with a PFD.


Inherited PFDs are a group of rare bleeding disorders with very different effects on individuals. Management is provided through haemophilia centres that can offer a full range of support and drug treatment. Little is known about the impact of PFDs on patients and their families and there is no validated tool for assessing quality of life. The SO-LIFE study suggests that families and patients don’t know enough about PFDs and are concerned about the future. There are clearly unmet needs in both social and clinical support.



Bolton-Maggs PH, Chalmers EA, Collins PW et al. A review of inherited platelet disorders with guidelines for their management on behalf of the UKHCDO. Br J Haematol 2006;135:603-33.
Casari C, Bergmeier W. Acquired platelet disorders. Thromb Res 2016;141 Suppl 2:S73-5.
Gresele P; Subcommittee on Platelet Physiology of the International Society on Thrombosis and Hemostasis. Diagnosis of inherited platelet function disorders: guidance from the SSC of the ISTH. J Thromb Haemost 2015;13:314-22.
Matthews DC. Inherited disorders of platelet function. Pediatr Clin North Am 2013;60:1475-88.
McLaughlin JM, Munn JE, Anderson TL et al. Predictors of quality of life among adolescents and young adults with a bleeding disorder. Health Qual Life Outcomes 2017;15:67. doi:10.1186/s12955-017-0643-7.
Podda G, Femia EA, Pugliano M et al. Congenital defects of platelet function. Platelets 2012;23:552-63.
Poon MC, Di Minno G, d’Oiron R et al. New insights into the treatment of Glanzmann thrombasthenia. Transfus Med Rev 2016;30:92-9.
Rao AK. Inherited platelet function disorders. overview and disorders of granules, secretion, and signal transduction. Hematol Oncol Clin N Am 2013;27:585–611.
Rae C, Furlong W, Horsman J et al. Bleeding disorders, menorrhagia and iron deficiency: impacts on health-related quality of life. Haemophilia 2013;19:385-91.
Seligsohn U. Treatment of inherited platelet disorders. Haemophilia 2012;18 Suppl 4:161-5.
UK Haemophilia Centres Doctors Organisation. Bleeding disorder statistics for April2015 to March 2016. A report from the UK National Haemophilia Database. (; accessed August 2017)
Woollard L, Holland M, Dodgson S et al. Children with platelet function disorders: an unmet need. 10thAnnual Congress of the European Association of Haemophilia and Allied Disorders. Paris, 2017. Abstract 1160.