General Considerations
Because treatment options are similar for platelet function defects, this section briefly reviews the common therapeutic regimens utilized in these syndromes. Additional treatments unique to a particular disorder are further described in the Treatment section.
The first step in treatment and prevention of bleeding is always the education of patients and their families. Affected individuals should be informed that mucocutaneous bleeding is the major type of hemorrhage associated with these conditions. Common examples include epistaxis, gingival bleeding, hematochezia, hematuria, and menorrhagia. Serious hemorrhage is always a potential risk within the gastrointestinal tract and can also occur after trauma or surgery, at childbirth or during the postpartum period.
Patients should be provided with both a reliable method to contact their hematologist and a treatment plan that is transmitted to the primary care physician, surgeons or emergency room in the event prophylaxis is needed or serious bleeding occurs.
In addition, patients should be advised to avoid medications that interfere with platelet function, notably aspirin, certain nonsteroidal anti-inflammatory drugs (NSAIDs), certain antidepressants (serotonin reuptake inhibitors), such as paroxetine,59-61 and high doses of fish oils containing omega-3 polyunsaturated fatty acids.62 As an additional precaution, all medications, whether prescribed or over the counter, should be reviewed with the hematology team or pharmacist to ensure there is no inhibition of platelet function.
Women with menorrhagia may benefit from hormonal suppression to prevent or limit menses; in the most extreme and life-threatening cases, affected women may undergo uterine ablation or hysterectomy. Management of these patients should also involve a gynecologist with experience in the care of patients with bleeding disorders.63,64
Certain nonspecific agents can be used to minimize or control mucosal bleeding and for prophylactic treatment during the course of minor surgical interventions.
Antifibrinolytic agents, such as aminocaproic acid (Amicar®) or tranexamic acid (Cyklokapron®, Lysteda®), reduce mucosal bleeding associated with epistaxis, menses or mucosal bleeding resulting from dental procedures.
Desmopressin acetate (DDAVP) effectively prevents bleeding in certain platelet dysfunction syndromes, likely due to its ability to induce release of endothelial cell VWF.65 A preliminary trial of DDAVP, similar to DDAVP (Stimate®) trials in von Willebrand disease, should be undertaken to determine individual response before its recommended use, since DDAVP has been found to trigger fibrinolysis in certain patients. The physician should evaluate effectiveness based on correction of the abnormal laboratory assay. When the platelet function analysis or platelet mapping assays are abnormal, we will use these as indicators because they are quick and easy to perform in the laboratory. However, if only the aggregation studies are abnormal, we will look for correction using only the agonists that were most impacted. In the initial paper documenting the effectiveness of DDAVP, the bleeding time was used;65 however, few centers have the equipment or trained staff to perform this test, and we have found our approach to be equally predictive of DDAVP effectiveness.
Activated recombinant factor VII (rFVIIa or NovoSeven®) is used to ameliorate or prevent bleeding associated with platelet dysfunction.66-68 When used in combination with antifibrinolytic agents, minor bleeding can be controlled in certain patients. This treatment is often used prior to platelet transfusion to avoid blood product exposure and isoimmunization. In 2004, the European Medical Evaluation Agency (EMEA) approved the use of rFVIIa to treat patients in the European Union who have Glanzmann thrombasthenia with platelet antibodies and past and/or current history of platelet refractoriness.67 In 2014 the Food and Drug Administration (FDA) approved the use of rFVIIa to treat patients with Glanzmann thrombasthenia with refractoriness to platelet transfusions, with or without antibodies.
According to recent data, Thrombopoietin (TPO) receptor agonists may help in the management of patients with inherited thrombocytopenias.69,70 Some efficacy was observed in increasing platelet counts in certain disorders, including MYH9-related disorders and amegakaryocytic thrombocytopenia (CAMT), but results are highly variable in CAMT, most likely owing to the heterogeneous pathophysiology of this disease.24
Platelet transfusion therapy will correct the bleeding defect in most cases of life-threatening bleeding episodes, even if only one single-donor apheresis unit is administered. Leukodepleted apheresis units (equivalent to approximately 6-8 pooled random donor units) are strongly recommended and preferred, to minimize multiple donor exposure and to decrease the risk of sensitization and a subsequent platelet refractory state.
To minimize long-term sensitization to human leukocyte antigen (HLA) class I proteins expressed on platelets, blood products should always be leuko-poor or leukodepleted.
In syndromes with complete absence of a membrane receptor, such as Glanzmann thrombasthenia or BSS, management strategies should include avoidance of excessive exposure to normal platelets due to the increased risk of development of isoantibodies specific for the missing receptor glycoproteins. Although isoimmunization in Glanzmann thrombasthenia is rare, the risk of alloimmunization remains a major concern. Isoantibodies are usually specific for multiple epitopes, some of which are functionally important sites of the receptor, and they bind to and neutralize these functional sites on any subsequently transfused normal platelets, rendering them ineffective.
Alloantibodies, on the other hand, are specific for polymorphisms in the receptor protein sequence, such as histidinol phosphate aminotransferase 1 (HPA-1, PlA1) on integrin b3. While these can cause immune clearance of alloantigen-positive, transfused platelets, donors can be selected who are genetically negative for the alloantigen(s) in question. Nonetheless, antibodies specific for platelet alloantigens or HLA Class I antigens have the potential to eventually make the multi-transfused patient completely refractory to future transfusions.
Rare Coagulation Disorders Resource Room, an extension of the RBDD Registry (eu.rbdd.org), was developed in collaboration with the Indiana Hemophilia & Thrombosis Center (www.innovativehematology.org).
The Resource Room serves as a platform to promote international collaboration to increase knowledge of these very rare disorders and to improve the care of affected individuals. The international RBDD mission, under the leadership of Dr. Peyvandi, will continue to be expanded over time.
The Resource Room thanks all contributing authors of the website articles that have made this valuable information available to the global community of both individuals affected with rare coagulation disorders and their healthcare providers.
