Glanzmann's thrombasthenia medical therapy
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Glanzmann's thrombasthenia |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2], Niyousha Danesh, MD-MPH
Overview
The mainstay of therapy for bleeding episodes in patients with Glanzmann’s thrombasthenia is to locally stop bleeding in the site of injury by means of gelatin sponges, fibrin sealants,compression or topical thrombin. An anti-fibrinolytic medication can also be added to the aforementioned therapy . This combination is specially beneficial for mucocutaneous bleeding, like bleeding during dental procedures. Tranexamic acid and epsilon aminocaproic acid are two anti-fibrinolytic medications.
If the bleeding persists rFVIIa can be combined with the anti-fibrinolytic agent in different sites of body. It can be used as prophylaxic treatment prior to minor surgical procedures and dental extractions. As well as treatment of menorrhagia, epistaxis, gingival bleeding.
In patients with hematuria anti-fibrinolytics drugs utilization is contraindicated, as the risk of clots formation in the urinary tract is high, likewise in patients undergoing procedures with high risk of thrombosis, these drugs should be administered cautiously.
Platelet transfusion should be considered in heavy or prolonged bleeding when the local hemostatic procedures and anti-fibrinolytic agents are unable to cease bleeding. It is also used as prophylaxis in GT patients prior to a major surgery.
As the risk of alloantibodies production against the HLA antigens and the platelet glycoproteins GPIIb/IIIa isotopes with repeated transfusions is high, it is recommended that HLA-matched platelet concentrates or platelet from a single-donor be used.
If the HLA-matched platelets are not attainable, leukocyte-reduced platelets should be administered, because of HLA immunization reduction.
Platelet transfusion should be continued until wound healing takes place in GT patients after a surgery and in a severe bleeding episodes the transfusion should be resumed for 48 hours after the bleeding cessation.
A GT patients with severe bleeding after delivery or a trauma may need multiple platelet or RBC transfusions. After appropriate amount of transfusions the PFA test would become normal.
Platelet isoantibodies cause relative or absolute platelet refractoriness. In this situation platelets are damaged rapidly and the platelet transfusions fail. The platelet refractoriness was used to be treated by means of plasmapheresis or IVIG.
However rFVIIa is nowadays recommended in GT patients, with diminished response to platelet transfusions, with or without the platelet isoantibodies in their blood. Although rFVIIa is not effective in all GT patients,it controls bleeding well in most patients. The US Food and Drug Administration (FDA) approved rFVIIa (NovoSeven RT) for prophylaxis of postoperative hemorrhage and of management bleeding episodes in both adults and children with Glanzmann thrombasthenia.
Recombinant factor VIIa (rFVIIa) was first used in 1996. It managed successfully a severe hemorrhage in a 2-year-old boy with Glanzmann’s thrombasthenia .
The reason why rFVIIa controls bleeding in some GT patients but not others is not fully understood. It may weakly bind to the platelets surface, activate factor IX and X, and enhance thrombin production.This function is not dependent to a tissue factor.
Thrombin production is increased significantly with doses of 90 mcg/kg and above. This vast thrombin generation develops platelet adhesion and promotes platelet aggregation, even in GPIIb/IIIa-lacking platelets.[1]
The other successful managements for the patients with acquired Glanzmann’s thrombasthenia include IVIG, plasmapheresis, systemic corticosteroids, protein A Sepharose immunoadsorption, cyclophosphamide, azathioprine, chemotherapy and rituximab.
Rituximab is a monoclonal antibody targeting CD20 antigen on B cells (also called anti-CD20), which is utilized in treating the antibody mediated hemostatic diseases and acquired immune cytopenia. 375 mg/m2/week administration of rituximab for four weeks would be beneficial for bleeding cessation and ecchymosis in acquired GT, following the normalized platelet aggregation.[2]
When persistent, severe bleeding episodes in patients with GT occur Hematopoietic stem cell transplantation (HSCT) is an option. HSCT is also recommended in patients, who are refractory to platelet transfusions due to isoantibodies. Siblings with identical HLA, matched relative donors and matched non-family donors must be considered in order to have a successful stem cell transplantations. Until now 19 successful transplantations from umbilical cord blood have been reported, the first one was a 4 year old boy in 1985. Cyclophosphamide and Busulfan must be added after transplantation. HSCT is however expensive and risky.
has no approved effect on GT treatment although it increases in plasma the tissue plasminogen activator (TPA),FVIII and VWF, but it has no significant effect on platelet disorders.[3] [4] [5] [6]
Medical Therapy
The treatment of bleeding episodes in patients with glanzmann’s thrombasthenia includes local measures with or without anti-fibrinolytic therapy first, followed by platelet transfusion, and rFVIIa if bleeding persists. However, The majority of cases of Glanzmann’s thrombasthenia are self-limited and only require supportive care.[7] Other options include:
- Desmopressin (DDAVP): Increases in plasma the tissue plasminogen activator (TPA),FVIII and VWF, but it has no significant effect on platelet disorders
- Rituximab: Anti-CD20
- Bevacizumab: Anti-VEGF antibody
- Hematopoietic stem cell transplantation
- Gene therapy[8]
References
- ↑ Bennett JS (2005). "Structure and function of the platelet integrin alphaIIbbeta3". J Clin Invest. 115 (12): 3363–9. doi:10.1172/JCI26989. PMC 1297263. PMID 16322781.
- ↑ Morel-Kopp MC, Melchior C, Chen P, Ammerlaan W, Lecompte T, Kaplan C; et al. (2001). "A naturally occurring point mutation in the beta3 integrin MIDAS-like domain affects differently alphavbeta3 and alphaIIIbbeta3 receptor function". Thromb Haemost. 86 (6): 1425–34. PMID 11776310.
- ↑ Diz-Küçükkaya R (2013). "Inherited platelet disorders including Glanzmann thrombasthenia and Bernard-Soulier syndrome". Hematology Am Soc Hematol Educ Program. 2013: 268–75. doi:10.1182/asheducation-2013.1.268. PMID 24319190.
- ↑ Fiore M, Nurden AT, Nurden P, Seligsohn U (2012). "Clinical utility gene card for: Glanzmann thrombasthenia". Eur J Hum Genet. 20 (10). doi:10.1038/ejhg.2012.151. PMC 3449071. PMID 22781097.
- ↑ Nurden AT, Ruan J, Pasquet JM, Gauthier B, Combrié R, Kunicki T; et al. (2002). "A novel 196Leu to Pro substitution in the beta3 subunit of the alphaIIbbeta3 integrin in a patient with a variant form of Glanzmann thrombasthenia". Platelets. 13 (2): 101–11. doi:10.1080/09537100220122466. PMID 11897046.
- ↑ Stevens RF, Meyer S (2002). "Fanconi and Glanzmann: the men and their works". Br J Haematol. 119 (4): 901–4. PMID 12472566.
- ↑ Solh T, Botsford A, Solh M (2015). "Glanzmann's thrombasthenia: pathogenesis, diagnosis, and current and emerging treatment options". J Blood Med. 6: 219–27. doi:10.2147/JBM.S71319. PMC 4501245. PMID 26185478.
- ↑ Solh T, Botsford A, Solh M (2015). "Glanzmann's thrombasthenia: pathogenesis, diagnosis, and current and emerging treatment options". J Blood Med. 6: 219–27. doi:10.2147/JBM.S71319. PMC 4501245. PMID 26185478.