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);
GATA-1 |
* 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].
Diagnosis
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].
Treatment
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 Desmopressin 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. (www.wfh.org/en/page.aspx?pid=654)
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 www.uk-itp.org/qolsurvey.htm) 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.
Summary
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.