Treatment of inherited platelet disorders
Uri Seligsohn, Amakia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center,
Tel Hashomer, Ramat Gan, Israel 52621
Tel: +972 3 530 2104; fax: +972 3 535 1568;
Summary. For patients affected by severe inherited platelet dysfunctions, e.g. Glanzmann thrombasthenia (GT) or Bernard-Soulier syndrome (BSS), platelet transfusion is frequently needed for controlling spontaneous bleeding, and is always needed when trauma occurs or surgery is performed. For the mild-to-moderate bleeding entities, e.g. storage pool disease, thrombaxane A2 receptor defect, platelet transfusion is usually unnecessary. Transfusion of platelets should be used selectively and sparingly because of the substantial risk of alloimmunization against HLA antigens and/or platelet glycoproteins (GP) αIIb, β3, or αIIbβ3 in GT, and GPI-IX-V in BSS, which may lead to refractoriness to therapy. To reduce the risk, HLA-matched single donors of platelets should be used. If such donors are unavailable, leucocyte-depleted blood components should be used. Therapy other than platelet transfusion includes: (i) Prevention (vaccination against hepatitis B, avoidance of non-steroidal anti-inflammatory drugs, preservation of dental hygiene, correction of iron deficiency and prenatal diagnosis). (ii) Topical measures (compression with gauze soaked with tranexamic acid, fibrin sealants, splints for dental extractions and packing for nose bleeds). (iii) Antifibrinolytic agents that are useful for minor surgery and as adjuncts for other treatment modalities. (iv) Desmopressin that increases plasma levels of von Willebrand factor and factor VIII giving rise to increased platelet adhesiveness and aggregation associated with shortened bleeding time. (v) Recombinant factor VIIa (rFVIIa). GT patients have been treated for bleeding episodes by rFVIIa with partial success. The mechanism by which rFVIIa arrests bleeding is probably related to increased thrombin generation by a tissue factor-independent process, enhanced platelet adhesion and restoration of platelet aggregation. (vi) Female hormones. Excessive bleeding during menarche in patients with GT or BSS can be controlled by high doses of oestrogen followed by high doses of oral oestrogen–progestin. Menorrhagia later in life can be managed by continuous oral contraceptives. Depo-medroxyprogesterone acetate administered every 3 months is an alternative when combined oral contraceptives are contraindicated.
Inherited platelet dysfunctions are rare disorders manifested in affected patients by mild-to-severe mucocutaneous bleeding tendencies. For patients affected by severe platelet dysfunctions, e.g. Glanzmann thrombasthenia (GT) or Bernard-Soulier syndrome (BSS), therapy is frequently needed for controlling spontaneous bleeding manifestations such as menorrhagia, epistaxis and peripartum or gastrointestinal bleeding, and is always needed when trauma occurs or surgery is performed. For the mild-to-moderate bleeding entities, e.g. storage pool disease, thromboxane A2 receptor defect, therapy is frequently unnecessary yet is essential when trauma is inflicted. Transfusion of platelet concentrates is a reasonable therapeutic modality, but should be used selectively and sparingly because of the risk of alloimmunization against HLA antigens and/or platelet glycoproteins, potential transmission of infectious agents and allergic reactions. Instead, using preventive measures and alternative treatment modalities, such as desmopressin or recombinant factor VIIa (rFVIIa), might be effective and sufficient. None of the currently used treatment protocols is backed up by rigorous evidence. However, guidance for management of inherited platelet dysfunctions is available [1,2].
Patients affected by inherited platelet dysfunction should preferably be managed in centres that can provide advanced laboratory and transfusion medicine services. Patients should be guided not to engage in contact sports, be vaccinated against hepatitis B, avoid using non-steroidal antiinflammatory drugs, preserve dental hygiene to minimize gingival bleeding, visit a dentist every 6 months, take iron pills when iron stores are decreased and always keep a haemoglobin level higher than 10 G dL−1. Girls and family members should be guided what to do when menarche accompanied by excessive bleeding is imminent. Families with members affected by GT or BSS should be counselled regarding the possibility of prenatal diagnosis when the genotype of the index case is known.
Management by topical measures
Superficial wounds can be managed by compression or use of gelatin sponge or gauze soaked in tranexamic acid. Fibrin sealants containing human fibrinogen and thrombin with or without tranexamic acid can be effective in arresting bleeding. For dental extractions, splints of soft acrylic assist in achieving haemostasis when used together with other means such as fibrin sealants, tranexamic acid given orally, or intravenous administration of rFVIIa or desmopressin (see below). Control of epistaxis, particularly in patients with GT and BSS, can be difficult. In many cases, anterior or posterior packing is necessary apart from using other haemostatic measures. Removal of nose packing should be carried out very gently because of a substantial risk of rebleeding.
Epsilon aminocarpoic acid or tranexamic acid given alone can be very useful in arresting or diminishing haemorrhage in patients with epistaxis, gingival bleeding or menorrhagia. These agents are also useful for prevention of bleeding following minor surgical procedures, and can be employed as adjuncts of other treatment modalities such as rFVIIa, desmopressin and platelet transfusion. Patients should be guided to commence oral treatment with an antifibrinolytic agent whenever troublesome bleeding occurs and thereafter seek medical attention if necessary. Both agents can be administered intravenously or orally [1,2]. For oral use of epsilon aminocaproic acid, a dose of 60–80 mg Kg−1 3–4 times a day is given, and for tranexamic acid, a dose of 15–25 mg Kg−1 3–4 times a day is recommended. A mouth wash with tranexamic acid (10 mL of a 5% solution) 4–6 times a day can also be beneficial for controlling gingival bleeding.
Management by desmopressin
Desmopressin is a synthetic analogue of the antidiuretic hormone – vasopressin that increases the plasma concentrations of von Willebrand factor (VWF) and factor VIII and has been used successfully in patients with mild von Willebrand disease and mild haemophilia A . The mechanism of desmopressin action has not been elucidated. In 1984, Kobrinsky et al.  showed that desmopressin is also effective in patients with inherited platelet dysfunctions. In that study, the bleeding time was shortened in all patients examined and haemostasis was secured in 8 patients undergoing surgery albeit with the aid of epsilon aminocaproic acid administration. Since then, several small series of desmopressin-treated patients with variable inherited platelet dysfunctions have been reported [5–10] and comprehensively reviewed [11,12]. Although it is questionable whether shortening of the bleeding time means adequate haemostasis during surgery, it is notable that in a subset of patients with inherited platelet dysfunctions and shortening of bleeding time following desmopressin administration, no excessive bleeding occurred during surgery when it was preceded by desmopressin infusion [5,6,9,10]. Entities for which unequivocal evidence indicates that bleeding time shortens after desmopressin include delta-storage pool disease, disorders of granule secretion, unexplained prolonged bleeding time, May-Hegglin anomaly, signal transduction disorders and thromboxane receptor anomaly [12,13]. Equivocal evidence was provided for BSS, Hermansky-Pudlak syndrome and arachidonate metabolism defects [11,12]. Of nine patients with GT, only one exhibited shortening of the bleeding time after desmopressin infusion .
Desmopressin at a dose of 0.3 μG Kg−1 (but not exceeding a total dose of 20 μG) is usually administered intravenously in 50 mL saline over 30 min. Peak levels of VWF are usually obtained 30 min after infusion. When desmopressin is used for surgery, strict timing should be coordinated with the surgeon. Side effects can occur sometimes and include tachycardia, hypotension, facial flushing and headache. Fluid retention and severe hyponatremia with seizures can occur and hence fluid intake should be restricted for 24 h after desmopressin infusion. Several studies, but not all, have indicated that desmopressin infusion confers a risk of arterial thrombosis . Consequently, treatment by esmopressin should be cautiously considered in elderly patients and in patients with cardiovascular disease.
The augmented haemostasis following desmopressin infusion has been attributed to increased platelet adhesiveness to the subendothelium, and increased platelet aggregation at high shear rate . These findings were probably related to increased plasma VWF levels, appearance of ultra-large multimers in the circulation and secretion of VWF abluminally from endothelial cells. However, these mechanisms do not explain the shortening of bleeding time observed in patients with BSS who lack glycoprotein Ibα, the receptor of VWF, and raise the possibility that desmopressin exerts an additional VWF-independent effect on haemostasis.
Management by rFVIIa
In 1996, Tengborn and Petruson reported a 2-year-old boy with GT in whom high dose rFVIIa administration resulted in controlling severe epistaxis . Since then, additional cases, mostly with GT, have been treated for bleeding episodes by rFVIIa with partial success [16,17]. The mechanism by which rFVIIa arrests bleeding in a fraction of patients with GT has not been rigorously elucidated, but has been attributed to: (i) Increased thrombin generation related to direct activation of factor X by rFVIIa bound to platelet surfaces by a tissue factor-independent mechanism . (ii) Enhanced adhesion of platelets to endothelial extracellular matrix and collagen under flow conditions by the generated thrombin . (iii) Restoration of platelet aggregation in the presence of factor X, factor II and fibrinogen by polymerizing fibrin formed by the tissue factor-independent thrombin generation .
The use of r-FVIIa in patients with inherited platelet dysfunction has not been examined by randomized controlled studies. The largest experience has been obtained in patients with GT by Poon et al. [16,17,21]. These investigators organized an international survey the objective of which was to examine the efficacy of rFVIIa infusion in GT patients. Fifty-nine patients were enrolled in 49 medical centres and were treated with rFVIIa during 108 bleeding episodes and during 34 surgical procedures. For the bleeding episodes, the success rate was 69/108 (75%), and for the surgical procedures, 29/34 (94%). The regimen used in most patients consisted of at least 80 μG Kg−1 rFVIIa administered intravenously every 2.5 h. The success rate in patients with gastrointestinal bleeding was low 8/17 (47%) and for dental extraction, it was high 9/9 (100%).
In another study of seven children with GT (five patients), BSS (one patient) and storage pool disease (one patient), the success rate of rFVIIa infusion alone during bleeding episodes was only 10/28 (36%) . Response was excellent during three bleeding episodes in the patient with BSS and during two bleeding episodes in the patient with storage pool disease. These results are less promising than the results of the international survey and thus further studies are warranted.
Severe adverse events including myocardial infarction, ischaemic stroke and venous thromboembolism have been reported in approximately 1% of 700 000 rFVIIa doses given to haemophilic patients with inhibitors . Also, among the 59 patients with GT of the international survey, two patients who received a high dose of rFVIIa given as a continuous infusion supplemented by an antifibrinolytic agent, developed pulmonary embolism and a ureteric clot, respectively . Consequently, the use of rFVIIa should be carefully considered particularly in patients with cardiovascular disease.
The use of rFVIIa was approved by the European Medicines Agency in 2004 for the use in patients with GT who became refractory to platelet transfusions or have developed antiplatelet antibodies.
Transfusion of platelets has been the most efficient mode of therapy for bleeding episodes and prophylaxis during surgery in patients with GT or BSS. For patients with the milder inherited platelet dysfunctions, platelet transfusions are rarely needed. The major concerns regarding the use of blood components in patients with the severe types of platelet dysfunction are the potential development of allo-immune antibodies against HLA antigens and/or against the missing platelet glycoproteins (GP), αIIb, β3 or αIIbβ3 in GT and GPI-IX-V in BSS. In one study of GT patients who were exposed to blood components, the frequencies of HLA antibodies were 8/54 (14.8%), for αIIbβ3 antibodies, the frequency was 16/54 (29.6%), and for antibodies against both HLA and αIIbβ3, 5/54 (9.3%) . In a smaller study of 16 patients with GT, the frequency of HLA-alloantibodies was quite similar. However, for anti-αIIbβ3 antibodies, the frequency was substantially lower than in the larger study (12.5% vs. 39%) . Additional risks of blood component therapy include allergic reactions, transmission of infectious agents, Rh immunization in Rh-negative patients, and on rare occasions – haemolytic transfusion reactions when the donor is type O and recipient is type A . For partial circumvention of the problems related to platelet transfusion, HLA and ABO-matched donors should be sought. If such donors are unavailable, leucocyte-depleted blood components should be used because it was shown to be effective in reducing the rate of HLA allo-immunization. Use of platelet pheresis from single donors reduces the risk of allo-immunization against αIIbβ3, thereby diminishing the risk of refractoriness to platelet transfusions. Rh negative patients in the child-bearing age, in whom transfusion of Rh positive blood components is unavoidable, should receive anti-D therapy to neutralize the D-antigen. Using family members for donation of platelets is usually convenient, but should not be done if stem-cell transplantation in the affected patient(s) is considered. Blood from family members should be irradiated to prevent transfusion-related graft-versus-host disease.
Platelet transfusions after surgery should be continued until wound healing has been achieved  and for at least 2 days after severe bleeding episodes have abated. Monitoring therapy can be performed by platelet aggregation tests, by determination of the closure time of the aperture of a collagen-coated membrane in the presence of ADP (PFA-100), or by bedside devices .
Management by female hormones and during pregnancy
Menarche, particularly in patients with GT and BSS, is frequently associated with excessive bleeding necessitating blood transfusions. This may result from prolonged oestrogen stimulation of unovulatory cycles with extensive endometrial proliferation leading to breakthrough bleeding . Haemostasis in such cases can be achieved by intravenous infusion of high-dose conjugated oestrogen for 24–48 h followed by high doses of oral oestrogen–progestin. Thereafter, a combined oral contraceptive can be given continuously for 2–3 months.
Menorrhagia later in life is also frequent in patients with GT and BSS. If antifibrinolytic agents fail to decrease the blood loss, continuous oral contraceptives can be useful in eliminating menses and should be considered especially in women with anaemia due to iron depletion . Depo-medroxyprogesterone acetate administered every 3 months is an alternative when combined oral contraceptives are contraindicated. Another agent used for suppressing menses is gonadotrophin-releasing hormone analogue that causes hypoestrogenism. However, its administration is associated with menopausal symptoms.
Two excellent reviews of pregnancies in patients with BSS and GT have recently been published [30,31]. Primary and secondary postpartum haemorrhage was observed in over 50% of these cases and thus, prophylactic platelet transfusions for 1–2 weeks should be considered.
Haematopoietic stem-cell transplantation
To date, 14 patients with severe GT and three patients with BSS have been successfully transplanted with stem cells of HLA-identical siblings, matched unrelated donors, or matched family donors . Careful evaluation of the risk–benefit ratio of this procedure must be assessed in each individual.
The authors stated that they had no interests which might be perceived as posing a conflict or bias.