Menoufia Medical Journal

REVIEW ARTICLE
Year
: 2020  |  Volume : 33  |  Issue : 3  |  Page : 723--728

Studies on inherited platelet disorder: a systematic review


Sabry A Shoieb1, Mohammed A Abdelhafez2, Alaa E. A. El-Hameed1, Bassam H Ramadan Alemam3,  
1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Diagnostic Radiology, Faculty of Medicine, Tanta University, Tanta, Egypt
3 Department of Internal Medicine, Ministry of Health, Tanta, Egypt

Correspondence Address:
Bassam H Ramadan Alemam
Tanta City, Al Gharbia Governorate
Egypt

Abstract

Objective The aim was to review the studies on clinical presentation, diagnosis, and management of inherited platelet disorder (IPD). Materials and methods A systematic search of MEDLINE (PubMed, Medscape, Science Direct, EMF-Portal) and internet was conducted on all articles published from 1997 to 2016. English language reports of perianal fistula were assessed. The initial search presented 150 articles where 26 satisfied the inclusion criteria. Articles not reporting on IPD in the title or abstract were not included. A total of 11 independent investigators extracted data on methods. Comparisons were made by structured review, with the results tabulated. Eight authors emphasized clinical presentation of IPD, nine about diagnosis of IPD, and nine about management of IPD. Findings Common symptoms include ecchymosis, epistaxis, menorrhagia, and excessive bleeding with childbirth, surgery, dental procedures, and trauma. IPD diagnosis is straightforward in the major platelet function disorders such as Bernard-Soulier Syndrome (BSS) and Glanzmann thrombasthenia (GT). Establishing a conclusive molecular diagnosis is the bedrock of good hematological practice, because it informs optimal treatment and can provide clarity about disease progression. The management of patients with IPDs usually consists of general measures aimed at avoiding bleeding and the use of supportive therapy to control hemorrhagic episodes. Conclusion IPDs are important causes of bleeding that can quantitatively and qualitatively alter platelets, impairing their function. The management of patients with IPDs usually consists of general measures aimed at avoiding bleeding and the use of supportive therapy to control hemorrhagic episodes. Moreover, patients and their parents must be instructed about drugs that impair platelet functions.



How to cite this article:
Shoieb SA, Abdelhafez MA, El-Hameed AE, Ramadan Alemam BH. Studies on inherited platelet disorder: a systematic review.Menoufia Med J 2020;33:723-728


How to cite this URL:
Shoieb SA, Abdelhafez MA, El-Hameed AE, Ramadan Alemam BH. Studies on inherited platelet disorder: a systematic review. Menoufia Med J [serial online] 2020 [cited 2020 Dec 2 ];33:723-728
Available from: http://www.mmj.eg.net/text.asp?2020/33/3/723/296679


Full Text



 Introduction



Inherited platelet disorders (IPDs) are rare bleeding diseases. They can be classified as hereditary macrothrombocytopenias/microthrombocytopenia, and disorders of platelet signaling defects, platelet granules, platelet membrane, and defective platelet coagulant function [1]. The main role of platelets is to maintain vascular system integrity and normal hemostasis. These functions rely on the ability of the platelets to provide particular receptors to interact with the exposed extracellular matrix such as type 1 collagen and von Willebrand factor to activate signaling pathways. It has been shown that von Willebrand factor, fibronectin, fibrinogen, and collagen are capable of stimulating platelet adhesion and aggregation [1] Platelets are generated and activated by locally produced agonists to induce a change in their shape from discs to tiny spheres with reorganized cytoskeleton and filopodia [2]. These activated platelets release their alpha and dense granule contents such as P-selectin and ADP. P-selectin is expressed on the surface of activated platelets where it basically mediates the rolling and tethering of leukocytes that are needed for strong extravasation and adhesion. Upon the release of ADP and thromboxane A2, further platelet activation is stimulated and results in the aggregation of platelets that eventually form platelet plugs at injury sites to arrest bleeding [3]. These platelet agonists bind to their respective receptors such as G-protein-coupled receptor in a manner that modulates intracellular mechanisms. Thrombin plays an important role in platelet activation via GPIbα binding of thrombin to position it for efficient cleavage of the N-terminal end of protease-activated receptor molecules, particularly protease-activated receptor-1 in humans. This induces G-protein-coupled receptor signaling pathways that are essential in platelet activation [4]. In contrast, ADP is largely kept at high concentrations in dense granules. It is released in reaction to ADP purinergic receptors, P2Y1 and P2Y12, to mediate platelet activation. In addition, platelet procoagulant activity is activated by these two receptors [5]. The platelets are abnormally large defined by an increased mean platelet volume and an additional peak in the white blood cell analysis. Some of these syndromes also have symptoms of nephritis or sensory problem of deafness. MYH9 gene mutations are also known to play a role in the pathogenesis of several related disorders involving macrothrombocytopenia and leukocyte inclusions, including Sebastian, Fechner, and Epstein syndromes [6]. Therefore, the aim of this work was to provide an overview of IPDs that are caused by heritable gene mutations and/or defective platelet function and signaling pathways.

 Materials and Methods



Data sources

A systematic search on clinical presentation, diagnosis, and management of IPD, using MEDLINE (PubMed, Medscape, Science Direct, EMF-Portal) and internet was conducted on all articles published from 1997 to 2016. The research focused on IPD/clinical presentation of IPD/diagnosis/treatment of IPD as searching terms. Additional records were identified by reference lists in retrieved articles. The search was established in the electronic databases from 1997 to 2016.

Study selection

Eligible articles were published in peer-reviewed journals and written in English. Articles not reporting on clinical presentation, diagnosis, and management of IPD in the title or abstract were not included. Full-text articles were screened, and the final inclusion decisions were made according to the following criteria: original studies; systematic reviews or meta-analyses; primary or first-line treatment and, if necessary, secondary treatment described; and treatment success, complications, and adverse effects described.

Data extraction

Articles not reporting on IPD in the title or abstract were not included. A total of 11 independent investigators extracted data on methods, health outcomes, and traditional protocol. Surveys about symptoms and health without exposure assessment, report without peer-review, not within national research program, letters/comments/editorials/news, and studies not focused on clinical presentation, diagnosis, and management of IPD were excluded as well.

The analyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM in addition to the evidence pyramid [7].

US Preventive Services Task Force [7] classification is as follows:

Level I: evidence obtained from at least one properly designed randomized controlled trialLevel II-1: evidence obtained from well-designed controlled trials without randomizationLevel II-2: evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research groupLevel II-3: evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidenceLevel III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

Study quality assessment

Quality of all the studies was assessed. Important factors included, study design, ethical approval, calculation of evidence power, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.

Data synthesis

A structured systematic review was done with the results tabulated. Eight authors emphasized clinical presentation of IPD, nine studies about diagnosis of IPD, and nine studies emphasized management of IPD.

 Results



Study selection and characteristics

A systematic search on IPD using MEDLINE (PubMed, Medscape, Science Direct, EMF-Portal) and internet was conducted on all articles published from 1997 to 2016. Articles not reporting on clinical presentation, diagnosis, and management of IPD in the title or abstract were not included. A total of 11 independent investigators extracted data on methods, health outcomes, and traditional protocol. Potentially relevant publications were identified, and 113 articles were excluded as they are away from our inclusion criteria. A total of 26 studies were reviewed as they met the inclusion criteria. Eight studies about clinical presentation of IPD, nine studies about diagnosis of IPD, and nine studies emphasized management of IPD.

Regarding these studies, three prospective studies [8],[9],[10] were in level II-2 or level B. In these studies, we found that in recent years, a growing number of inherited, qualitative platelet disorders have been recognized, and in some, the molecular genetic abnormality of the 'thrombocytopathy' has been elucidated. Moreover, four randomized case–control studies [1],[3],[11],[12] were in level I or level A, which reported that most patients have symptoms that are clinically indistinguishable from the symptoms of von Willebrand disease, as well as common symptoms include ecchymosis, epistaxis, menorrhagia, and excessive bleeding with childbirth, surgery, dental procedures, and trauma. Furthermore, one was a cases' analysis [13] that comes in the second level regarding the pyramid of EBM, and it reported that although women recognized to have congenital platelet disorders frequently outnumber men owing to the hemostatic challenges associated with menses and childbirth, the mode inheritance of IPDs ranges from X-linked to autosomal dominant and autosomal recessive [Table 1]. Additionally, three randomized case–control studies [14],[15],[16] were in level I or level A and reported that IPD diagnosis is straightforward in the major platelet function disorders such as BSS and GT, which often present with severe bleeding symptoms early in life and are easily recognized by the pattern of platelet aggregation defects. Moreover, four prospective studies [6],[8],[17],[18] were in level II-2 or level B and found that in some IPDs, the platelet function defect and impaired hemostasis are part of well-defined syndromes, for example, Chediak Higashi syndrome and HPS. Moreover, two cases' analyses [19],[20] were in the second level regarding the pyramid of EBM and reported that current guidelines favor a tiered approach to IPD diagnosis. DNA analysis by Sanger sequencing is at the fourth and final tier and often not applied because of its limited availability and costs [Table 2]. Regarding management of IPDs, there were three randomized case–control studies [21],[22],[23] that come in level I or level A, and they estimated that the management of patients with IPDs usually consists of general measures aimed at avoiding bleeding and the use of supportive therapy to control hemorrhagic episodes. However, as the type and severity of bleeding vary in different patients, therapeutic approaches must be personalized. However, two cases analyses [4],[6] were in the second level regarding the pyramid of EBM, and these reported that people with IPDs should be immunized against hepatitis A and B, have baseline liver function tests performed at diagnosis, and these should be routinely monitored especially in those who receive blood products. Moreover, four cohort studies [6],[11],[17],[24] were in level II-2 or level B and indicated that recombinant factor VIIa is particularly useful as an alternative to platelet transfusion to prevent patients from developing antibodies to platelets, or to continue treatment in cases where antibodies have already developed, as well as fibrin sealants (also called fibrin glue) can be used to treat external wounds and during dental work such as tooth extraction [Table 3].{Table 1}{Table 2}{Table 3}

 Discussion



IPDs are important causes of bleeding that can quantitatively and qualitatively alter platelets, impairing their function [8]. In recent years, a growing number of inherited, qualitative platelet disorders have been recognized, and in some, the molecular genetic abnormality of the 'thrombocytopathy' has been elucidated [9]. These conditions are important causes of bleeding, and there is considerable heterogeneity in their features. Congenital platelet disorders are often suspected in individuals with unexplained bleeding problems, which suggest a defect in primary hemostasis rather than a coagulation factor deficiency [10]. Most patients have symptoms that are clinically indistinguishable from the symptoms of von Willebrand disease [11]. Common symptoms include ecchymosis, epistaxis, menorrhagia, and excessive bleeding with childbirth, surgery, dental procedures, and trauma [3]. With the exception of the Quebec platelet disorder, IPDs are typically manifested by immediate bleeding upon exposure to hemostatic challenges [12]. The severity of bleeding symptoms, even among affected family members with a known defect, can be variable [1]. Although women recognized to have congenital platelet disorders frequently outnumber men owing to the hemostatic challenges associated with menses and childbirth, the mode inheritance of IPDs ranges from X-linked to autosomal dominant and autosomal recessive [13].

IPD diagnosis is straightforward in the major platelet function disorders such as BSS and GT, which often present with severe bleeding symptoms early in life and are easily recognized by the pattern of platelet aggregation defects. This is often supplemented by assessment of the storage pool either directly by nucleotide assay or lumiaggregometry [14]. In some IPDs, the platelet function defect and impaired hemostasis are part of well-defined syndromes, for example, Chediak Higashi syndrome and HPS, where the platelet-granule defect is typically associated with immune deficiency or ocular albinism, respectively [17]. The presence of syndromic features can help in recognition and diagnosis, but diagnosis remains challenging for most IPDs, which often have a mild platelet phenotype and are clinically heterogeneous [15]. Diagnosis is further complicated by the fact that for many IPDs, the platelet count is within normal ranges and the disorder may only become apparent after a hemostatic challenge or if cases present with accompanying pathologies in other organ systems, including malignancies [16]. Establishing a conclusive molecular diagnosis is the bedrock of good hematological practice because it informs optimal treatment and can provide clarity about disease progression. [6]. Thrombocytopenias caused by variants in RUNX1, ETV6, and ANKRD26 are associated with increased risk of myeloid malignancy, whereas for WAS and a megakaryocytic thrombocytopenia caused by MPL variants, treatment by allogeneic hematopoietic stem cell transplant or gene therapy may require consideration. Moreover, genetic counseling can be provided if the diagnosis is confirmed at the DNA level [19]. Current guidelines favor a tiered approach to IPD diagnosis. DNA analysis by Sanger sequencing is at the fourth and final tier and often not applied because of its limited availability and costs [20]. Moreover, it is used primarily to confirm an already clinically suspected genetic diagnosis and targets only a single or small group of genes [18]. In most IPDs, a single candidate gene is not readily apparent from standard laboratory tests. Consequently, a molecular diagnosis is given in only a minority of patients, and even when a genetic defect is identified, the number of independent cases remains small for most IPDs [8].

The management of patients with IPDs usually consists of general measures aimed at avoiding bleeding and the use of supportive therapy to control hemorrhagic episodes. However, as the type and severity of bleeding vary in different patients, therapeutic approaches must be personalized [21]. Advice should be given where necessary about life-style issues (e.g. individuals with severe disorders should avoid contact sports), and patients with severe platelet disorders should avoid medication that interferes with platelet function, that is, salicylates and other NSAIDs. The use of such drugs must be balanced against the risks [22]. People with IPDs should be immunized against hepatitis A and B, have baseline liver function tests performed at diagnosis, and these should be routinely monitored especially in those who receive blood products [4]. Education of patients is of great importance. Patients and their parents must be instructed about drugs that impair platelet functions, such as acetylsalicylic acid-containing medications, regular dental care, and the use of oral contraceptives to prevent menorrhagia. Local measures, such as the application of firm pressure in the case of epistaxis, will usually be sufficient to stop cases of mild bleeding [21]. The antifibrinolytic drugs tranexamic acid and aminocaproic acid are used to prevent the breakdown of a clot in certain parts of the body, such as the mouth, bladder, and uterus [6]. Recombinant factor VIIa is particularly useful as an alternative to platelet transfusion to prevent patients from developing antibodies to platelets, or to continue treatment in cases where antibodies have already developed [24]. Fibrin sealants (also called fibrin glue) can be used to treat external wounds and during dental work such as tooth extraction [11]. Iron replacements can be taken as needed to treat anemia, or iron deficiency without anemia, caused by excessive or prolonged bleeding [23]. Platelet transfusions, using platelets from HLA matched donors when available, are used to control severe hemorrhage in thrombocytopenic patients or in individuals with thrombocytopathies [17]. Splenectomy has no effect in congenital platelet disorders except in WAS. Allogeneic hematopoietic stem cell transplantation could be effective for IPDs, restoring normal megakaryocytopoiesis, but the risk of such procedures is still high [6].

 Conclusion



This review found that IPDs are important causes of bleeding that can quantitatively and qualitatively alter platelets, impairing their function. The management of patients with IPDs usually consists of general measures aimed at avoiding bleeding and the use of supportive therapy to control hemorrhagic episodes. Moreover, patients and their parents must be instructed about drugs that impair platelet functions.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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