Drugs represent the most common cause of platelet dysfunction in our overmedicated society. While acetylsalicylic acid (aspirin), adenosine diphosphate receptor antagonists (clopidogrel and prasugrel), and integrin αIIbβ3 (GPIIb-IIIa) receptor blockers (abciximab, eptifibatide, and tirofiban) are well-known prototypes of antiplatelet drugs, other widely used agents such as nonsteroidal anti-inflammatory drugs, antibiotics, cardiovascular and lipid-lowering drugs, selective serotonin reuptake inhibitors, and volume expanders can also impair platelet function and thus cause or aggravate hemorrhages in certain clinical settings. Therefore, induction of a bleeding diathesis remains a significant concern. This is especially relevant in patients with preexisting hemostatic defects of any kind, which may remain compensated as long as platelet function (and/or coagulation) is not inhibited pharmacologically. Identification of individual patients with preexisting hemostatic defects remains crucial (1) to prevent otherwise unexpected bleeding complications, (2) to manage hemorrhagic symptoms adequately, (3) to minimize the risk from invasive procedures, and (4) to avoid unnecessary patient exposure to blood products. This article provides a review of the large variety of agents that have not been designed for antiplatelet therapy but nevertheless interfere with platelet reactivity or induce platelet inhibition. In particular, drug interactions and mechanisms by which these agents can trigger or cause platelet dysfunction are detailed.

Drugs that affect platelet function.

Glanzmann's thrombasthenia (GT) is an autosomal recessive inherited bleeding disorder due to a defect in platelet function. The hallmark of this disease is severely reduced/absent platelet aggregation in response to multiple physiological agonists. Bleeding signs in GT include epistaxis, bruising, gingival hemorrhage, gastrointestinal hemorrhage, hematuria, menorrhagia, and hemarthrosis. Homozygous or compound heterozygous mutations in the genes of GPIIb and GPIIIa lead to GT. A patient with GT, with no possible causative mutations in GPIIb and GPIIIa genes, may harbor defects in a regulatory element affecting the transcription of these 2 genes. GT occurs in high frequency in certain ethnic populations with an increased incidence of consanguinity such as in Indians, Iranians, Iraqi Jews, Palestinian and Jordanian Arabs, and French Gypsies. Carrier detection in GT is important to control the disorder in family members. Carrier detection can be done both by protein analysis and direct gene analysis.

https://journals.sagepub.com/doi/pdf/10.1177/1076029608326165

Glanzmann's thrombasthenia: an overview.

In clinical daily practice the definition of a bleeding tendency is rather subjective. Clinical manifestations usually include hematoma, epistaxis, menorrhagia, and severe bleeding episodes after surgery or injuries. The most common causes are disorders of primary hemostasis that occur sometimes due to platelet function disorders. Inherited thrombocytopathies are much less frequent in comparison to acquired platelet function disorders. However, congenital disorders can lead to severe bleeding tendency and are often not diagnosed. They are induced by different platelet defects based on disorders of platelet adhesion, receptors, secretion, and signal transduction. In some cases, they are associated with thrombocytopenias, giant platelets, and various comorbidities. This article gives an overview of the different defects, their diagnosis, and treatment options.

/pdf/diagnosis-and-management-of-inherited-platelet-disorders-1ts7kpz66q.pdf

Diagnosis and Management of Inherited Platelet Disorders

Platelet function can be abnormally increased, as in association with acute vascular events, or defective, as in a variety of clinical settings. Acquired platelet dysfunction may occur at any age and range in severity from mild to life-threatening haemorrhages. Diagnostic work-up of platelet disorders requires meticulous evaluation of medical history, specifically of any drugs interfering with platelet function, careful clinical examination and a staged laboratory protocol to assess the underlying platelet defect(s). To identify hyperactive platelets ex vivo, costly procedures may be required using flow cytometry and distict epitope-specific monoclonal antibodies. Currently, this approach can be recommended for research purposes only. Drugs represent the most common cause of platelet dysfunction in our overmedicated society. While aspirin, clopigogrel (more recently also prasugrel) and integrin αIIbβ3 (GPIIb-IIIa) receptor antagonists (abciximab, eptifibatide and tirofiban) are well-known prototypes of antiplatelet drugs, other widely used agents (e.g. nonsteroidal anti-inflammatory drugs, antibiotics, serotonin reuptake inhibitors and volume expanders) can also impair platelet function and thus cause or aggravate hemorrhages. Identification of individual patients with pre-existing hemostatic defects remains crucial (i) to prevent bleeding complications, (ii) to manage symptoms adequately, (iii) to minimize the risk from invasive procedures, and (iv) to avoid unnecassary exposure to blood products. Screening for platelet dysfunction can be performed by point-of-care testing followed by platelet aggregometry in response to various agonists. While mild bleeding episodes due to antiplatelet therapy can be managed by withdrawal of the drug(s), severe hemorrhages may require immediate platelet transfusions. Apart from that, the prohemostatic armamentarium is limited to desmopressin, antifibrinolytic agents, and recombinant factor VIIa.

The impact and management of acquired platelet dysfunction.

Antiplatelet agents and anticoagulants are effective in the prevention and treatment of a variety of thrombotic disorders. Several clinical settings require more intense antithrombotic regimens. These can be provided by combining (i) two antiplatelet drugs, (ii) antiplatelet monotherapy with an anticoagulant, or (iii) anticoagulation with dual antiplatelet treatment (triple therapy). A major side effect of all antithrombotic regimens, however, is the induction of a bleeding diathesis. This is especially true in patients with preexisting haemostatic defects of any kind that may remain compensated, unless platelet function and/or coagulation are not inhibited pharmacologically. To address the dilemma of the “double-edged sword” between thrombosis and bleeding, several strategies are currently under study, including (i) identification of high-risk patients, (ii) stratification of patient subgroups, (iii) individualized decision making, and (iv) administration of “tailor-made” risk-adapted regimens. Nonetheless, prevention and protection from bleeding in patients using antithrombotic agents remain an enduring challenge. For high-risk patients on antiplatelet agents with urgent need of surgery, an algorithm is discussed that allows short-term interruption of oral antithrombotic therapy and i.v. administration of a GPIIb-IIIa receptor antagonist for bridging without increasing perioperative bleeding. When individual patients, using antiplatelet or anticoagulant agents, experience serious or even life-threatening haemorrhages, haemotherapy with platelet units or prothrombin complex concentrates remains an integral part of the clinical management.

Behandlung von Patienten mit Blutungen unter antithrombotischer Therapie – Prädiktion, Prävention, Protektion, problemorientierte Intervention

Apart from on-label indications, recombinant factor VIIa (rFVIIa) is increasingly administered for treatment of life threatening bleeding events when appropriate standard therapy fails. Case reports and short treatment series document the efficacy and safety of rFVIIa to achieve haemostasis in patients with platelet function disorders and thrombocytopenias of various origin. An established on-label indication for the use of rFVIIa is given in patients with Glanzmann thrombasthenia with refractoriness to transfusions of platelet concentrates. Bolus applications of rFVIIa at dosages between 80 and 120 microg/kg body weight every 1.5 to 3 h are also administered successfully in patients with Bernard-Soulier syndrome, platelet storage pool defects, and other acquired platelet function disorders. In patients with Glanzmann thrombasthenia, at least three bolus injections are required to achieve effective haemostasis. In approximately half of the patients with thrombocytopenias, a single bolus of rFVIIa has been shown to be sufficient in managing otherwise untreatable bleeding complications. In these patients, haemostasis was achieved even at platelet counts <20,000/microl, although the efficacy of rFVIIa increases at higher platelet concentrations.

Recombinant factor VIIa in patients with platelet function disorders or thrombocytopenia

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Recombinant factor VIIa in patients with platelet function disorders or thrombocytopenia