Platelets are circulating cells that adhere to the vascular wall, aggregating together and protecting against bleeding. Platelets are formed in 2 distinct stages: megakaryopoiesis and thrombopoiesis (see if against figure). Platelets can be : – insufficient in number in the case of thrombocytopenia – or non-functional in the case of thrombopathy.
Constitutional thrombocytopenia
Thrombocytopenia is defined as a reduction in the platelet count in the blood to below the low normal value for the population (150 G/L). Acquired thrombocytopenia is very common. Constitutional thrombocytopenia is a rare disease, the prevalence of which is probably underestimated, with wide geographical variations. They are present from birth and are generally stable throughout life.
The nature of thrombocytopenia and its usual clinical manifestations
The origin of constitutional thrombocytopenia is genetic. The mutations, which vary widely, are far from all being identified to date. Thrombocytopenia results from a defect in platelet production or accelerated platelet elimination. In the first, most frequent category, thrombocytopenia results from abnormalities in genes involved in the differentiation or maturation of megakaryocytes in the bone marrow, or in the subsequent release of platelets from megakaryocytes into the blood. In the second category, thrombocytopenia is associated with rare metabolic diseases, or diseases affecting von Willebrand factor (certain Willebrand 2B diseases or congenital ADAMTS13 deficiencies). Constitutional thrombocytopenias are generally expressed by a tendency to spontaneous cutaneous-mucosal haemorrhage, or to haemorrhage induced by trauma or invasive procedures. While major thrombocytopenias, below 20 G/L, almost always have a severe clinical expression, with a risk of deep bleeding, moderate thrombocytopenias have an expression that is not directly proportional to the platelet level. Platelet volume is one of the susceptibility factors, but comorbidities or the association with a platelet functional defect (“thrombopathy”) can explain the sometimes severe hemorrhagic tendency of very moderate thrombocytopenias (100-150 G/L). Some constitutional thrombocytopenias are accompanied by symptoms affecting other functions, depending on the gene involved: sensory disorders, immune deficiencies, renal failure, abnormal bone or mental development, anemia, and some thrombocytopenias predispose to the development of hematological malignancies. These are known as “syndromic” thrombocytopenias.
Diagnostic steps
Thrombocytopenia is diagnosed on the basis of platelet counts obtained as part of a complete blood count (CBC). The constitutional nature of thrombocytopenia is suggested by stable platelet counts over a long period, a possible family history, the presence of symptoms suggestive of a syndromic pathology, and particular platelet or leukocyte morphology (giant platelets, cytoplasmic leukocyte inclusions). While each of these elements, and a fortiori their combination, are in favor of a constitutional nature, their absence does not rule it out. The diagnosis is sometimes made late in the course of several failed treatments for acquired immunological thrombocytopenia, with which it was initially confused. The diagnosis is confirmed, with the patient’s formal agreement, by clinically-directed molecular analysis of candidate gene clusters. To date, some thirty different genes have been identified as being involved.
Care and maintenance
Once a precise diagnosis has been made, the patient is informed by the MHEMO referral physician and the Hereditary Platelet Diseases Reference Center of the preventive measures common to hemorrhagic diseases in general, and of the specific features of his disease (possible course, monitoring). The referring physician intervenes on numerous occasions throughout the patient’s life. He or she coordinates the management of emergencies (bleeding, trauma, surgery) with the health professionals close to the patient (general practitioner, pediatrician, nurses) and the emergency services. Together with the specialists concerned, they draw up individual protocols for scheduled risk situations (invasive diagnostic or therapeutic procedures, pregnancy). It discusses with prescribers the indications for common treatments (non-steroidal anti-inflammatory drugs, anticoagulants, antiplatelet agents) likely to increase the risk of bleeding in patients with moderate forms of thrombocytopenia.
Treatments
Treatment of constitutional thrombocytopenia involves the usual symptomatic therapies for bleeding disorders (anti-fibrinolytics for ENT and oral bleeding, hormonal therapy for gynaecological bleeding) and/or mechanical haemostasis. When bleeding cannot be controlled by these means, the only recourse is the preventive or curative administration of platelet concentrates. Their efficacy is excellent in the majority of cases, but a minority of patients may develop antibodies against HLA or platelet antigens, which reduce the amplitude and duration of the effect of transfused platelets. Their safety and tolerance are very good, apart from possible transfusion reactions of low intensity and easily controllable. Emergency availability of platelet concentrates is generally good in hospitals. Neither first-line drugs for immunological thrombocytopenia (corticosteroids, intravenous immunoglobulins) nor splenectomy are permanently effective.
Transmission and genetic counseling
Depending on the rules of Mendelian transmission, the disease may or may not be present in a direct relative, and may affect both sexes or only males. Genetic counseling is facilitated by knowledge of the mutation involved, but family investigation, including at birth, is generally based on platelet count alone. Genetic research using new-generation sequencing methods is developing rapidly, enabling the discovery of new mutations and mechanisms of constitutional thrombocytopenia.
Clinical research
Therapeutic research concerns thrombopoietin hormone analogues (romiplostim subcutaneously, eltrombopag orally), which stimulate megakaryocytes to produce platelets. These drugs, used in the treatment of certain acquired thrombocytopenias, appear to be able to attenuate spontaneous bleeding symptoms and correct thrombocytopenia, at least transiently, but their benefit and safety need to be confirmed, and their use is not currently authorized in constitutional thrombocytopenia, outside of clinical trials. Finally, cell therapy (allogeneic hematopoietic stem cell transplants) and even gene therapy can only be used in rare, severe forms, notably those associated with life-threatening immune deficiency.
Constitutional thrombopathies
Thrombopathies are pathologies linked to abnormal platelet function. They are therefore unable to fulfil their role of stopping bleeding by filling a vascular breach (primary haemostasis) and enabling plasma coagulation to take place rapidly and efficiently. Platelet count is usually normal, but some thrombopathies are accompanied by a reduction in platelet count (thrombocytopenia).
Nature of thrombopathies and common clinical manifestations
Before suspecting constitutional thrombopathy, it is essential to ensure that there is no “acquired” cause of platelet function abnormality. The most common cause is aspirin, non-steroidal anti-inflammatory drugs and even serotonin reuptake inhibitors. We must also rule out the use of medications often considered harmless (herbal remedies, herbal teas, etc.) which may contain extracts that interfere with platelet function. Lastly, certain pathologies may also be responsible for platelet functional abnormalities, such as renal failure, liver cirrhosis, myeloproliferative disorders, certain dysglobulinemias, etc.
Constitutional thrombopathies may be responsible for a more or less marked hemorrhagic tendency. Symptoms are mainly mucocutaneous (ecchymosis, haematomas, epistaxis, gingivorrhagia), appearing either spontaneously or after shocks or vulgarizing gestures. More serious signs can sometimes be present in the most severe pathologies (deep haematomas, haemarthrosis). Severity varies widely from one pathology to another, as does inter-individual variability. The most severe thrombopathies are mainly aggregation abnormalities (Glanzmann Thrombasthenia) and adhesion abnormalities (Bernard-Soulier Disease), which are much less frequent.
Transmission
Constitutional thrombopathies are pathologies of genetic origin. The genes involved are numerous (and the list is certainly still incomplete) and may be involved in various stages of platelet function: platelet adhesion to the subendothelium (part of a vessel exposed during a vascular wound), primary platelet aggregation, agonist receptor abnormality, secretion abnormality, intracellular signaling abnormality and phospholipid exposure abnormality. Disorders of secretion, often referred to as “empty pool syndrome”, are the most frequent anomalies.
Because of this genetic nature, the discovery of a pathology in the family often leads to a family investigation. Fortunately, transmission of the most severe diseases is mainly autosomal recessive, and the children of sufferers often carry only one copy of the disease gene (“heterozygotes”), but are not sick themselves.
Diagnostic steps
The diagnosis of thrombopathy is a difficult one, and few tests can be performed in primary care laboratories. What’s more, these first-line tests often lack sensitivity and/or specificity. In most cases, the patient will need to seek specialist advice from the constitutional platelet pathology reference center.
At this stage, several analyses can be carried out to establish the diagnosis: microscopic examination of platelets to look for morphological anomalies (large size, abnormal granulations, etc.), study of platelet functions (light-aggregometry), quantification of platelet surface receptors (flow cytometry) and, in some cases, study of secretion, intra-platelet signalling, electron microscopy and finally genetic analyses with the patient’s agreement.
In any case, there are a significant number of patients with minor platelet function abnormalities, at low risk of spontaneous hemorrhage (but at high risk in surgical situations) for whom no precise diagnosis can yet be proposed, but who require medical management and follow-up.
Care and maintenance
Because of its complexity, in most cases the diagnosis is made at a referral center in the MHEMO network, and the referring physician sets up regular follow-up with the patient. In addition to scheduled follow-up, the referring doctor also works with other healthcare professionals (GP, school doctor, occupational physician, anesthetist, surgeon, nurse, etc.) to set up care protocols for emergencies or invasive procedures (invasive procedures, surgery), and to provide advice in specific situations (genetic counseling, pregnancies, antithrombotic treatments, in consultation with the disciplines concerned).
Treatments
From a therapeutic point of view, the treatment of choice for thrombopathies remains the transfusion of platelet concentrates, of which there are two main types: MCPS (Mixture of Standard Platelet Concentrates) and CPA (Platelet Concentrate Apheresis), each of which has its own advantages and disadvantages, and is chosen on a case-by-case basis by the prescribing physician.
Other treatments include desmopressin for minor thrombopathies and recombinant activated factor VII in very special cases of Glanzmann Thrombasthenia. Finally, tranexamic acid, which makes the clot more resistant by inhibiting its physiological destruction, is proving very useful, particularly in cases of mucous hemorrhage.
On the other hand, certain drugs (aspirin, antiplatelet agents, non-steroidal anti-inflammatory drugs, etc.) are not recommended, or even contraindicated, because they impair platelet function. If their prescription is medically justified, a discussion between the prescriber and the referring physician will help define the best way to proceed. Bone marrow transplants for severe forms are exceptional.
Clinical research on these diseases
Clinical research into these diseases focuses on epidemiological studies and new cell therapy modalities. Genome scanning is rapidly developing to search for the genes involved in the many thrombopathies whose origin is still unknown.
More information on platelet pathologies is available on the website :
https://maladies-plaquettes.orgOr visit the MHEMO website by clicking on the following link:
https://mhemo.fr/les-pathologies/les-pathologies-plaquettaires/
