|Year : 2019 | Volume
| Issue : 1 | Page : 1-9
Management of Glanzmann's Thrombasthenia – Guidelines based on an expert panel consensus from gulf cooperation council countries
Ahmad Tarawah1, Tarek Owaidah2, Naima Al-Mulla3, Muhammad Faisal Khanani4, Jehan Elhazmi1, Muneer Albagshi5, Yaser Wali6, Shikah AlMohareb7, Abdulkareem Almomen8
1 Department of Hematology, Maternity and Children Hospital, King Abdullah Medical City, Madinah, Saudi Arabia
2 King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
3 Department of Hematology, Hamad Medical Corporation, Doha, Qatar
4 Department of Hematology, Tawam Hospital, Alain, UAE
5 Department of Gynecology, Hereditary Blood Diseases Center, Alhassa, Saudi Arabia
6 Department of Hematology, Sultan Qabos University, Masqat, Oman
7 Department of Hematology, Kuwait University, Kuwait
8 National Blood and Cancer Center, Riyadh, Saudi Arabia
|Date of Web Publication||30-Apr-2019|
Dr. Ahmad Tarawah
Maternity and Children Hospital, King Abdullah Medical City, Madinah
Source of Support: None, Conflict of Interest: None
Glanzmann thrombasthenia is a rare disorder, due to quantitative and/or qualitative abnormalities of the platelet integrin αIIbβ3 and/or αIIbβ3. Although it is considered a rare disorder with a global incidence of 1/1,000,000 population, the case is different at the Gulf Cooperation Council countries, where prevalence rate as high as 1/40,000 in Madinah, Saudi Arabia. This makes it necessary to develop patient's management guidelines. Due to limited resources in the literature, experts' consensus was important to develop such guidelines. Experts panel elected to use recombinant activated factor VII (rFVIIa) as the first line of treatment of acute bleeds and reserve platelets transfusion for nonresponding patients or severe bleeds, rFVIIa at high dose (270 μg/kg body weight) may tried upfront. rFVIIa may be tried as prophylactic treatment in patients with frequents bleeds. Experts panel elected to allow girls with Glanzmann thrombasthenia to have menstruation and to adapt a special protocol for this purpose (Madinah protocol). Pregnancy should be managed carefully, where normal delivery encouraged under coverage of rFVIIa. Risk of bleeding should be expected in neonates. Minor surgeries and dental workup can be managed under coverage of rFVIIa. Glanzmann thrombasthenia patients with severe disease should be encouraged for hematopoietic stem cell transplant.
Keywords: Glanzmann, platelets, recombinant activated factor VII, thrombasthenia, treatment guidelines
|How to cite this article:|
Tarawah A, Owaidah T, Al-Mulla N, Khanani MF, Elhazmi J, Albagshi M, Wali Y, AlMohareb S, Almomen A. Management of Glanzmann's Thrombasthenia – Guidelines based on an expert panel consensus from gulf cooperation council countries. J Appl Hematol 2019;10:1-9
|How to cite this URL:|
Tarawah A, Owaidah T, Al-Mulla N, Khanani MF, Elhazmi J, Albagshi M, Wali Y, AlMohareb S, Almomen A. Management of Glanzmann's Thrombasthenia – Guidelines based on an expert panel consensus from gulf cooperation council countries. J Appl Hematol [serial online] 2019 [cited 2021 Jan 23];10:1-9. Available from: https://www.jahjournal.org/text.asp?2019/10/1/1/257471
| Introduction|| |
Glanzmann thrombasthenia (GT) is a rare, autosomal, recessive platelet function defect that causes lifelong bleeding. GT was first described by Edward Glanzmann in 1918 as “hereditary hemorrhagic thrombasthenia.” The defects that cause GT are quantitative and/or qualitative abnormalities of the platelet integrin αIIbβ3 (glycoprotein IIb/IIIa). αIIbβ3 are receptors present on the surface of platelets and mediate platelet aggregation.,, GT can be classified according to αIIbβ3 integrin. Type 1 GT is the most common type, where αIIbβ3 integrin is absent or present in trace amounts (0%–5%). In Type 2 GT, the αIIbβ3 integrin is present in reduced amounts (5%–20%). The αIIbβ3 integrin is qualitatively defective in Type 3 GT., Bleeding phenotype in GT is heterogeneous and has not been linked to type or genetic mutations. A total of 419 mutations have been registered in the GT database at Icahn School of Medicine at Mount Sinai. According to the Glanzmann's Thrombasthenia Registry (GTR), bleeding episodes are typically mucocutaneous, such as easy bruising, purpura, epistaxis, gingival, and mouth bleeding. Less commonly, gastrointestinal bleeding, hemarthrosis, or central nervous system bleeding has been identified in GT patients., Menorrhagia is a common manifestation among women with GT and can be critical enough to require transfusion at menarche.
Although GT is considered a rare disorder with a global incidence of 1/1,000,000 population, its incidence is much higher in the countries that make up the Gulf Cooperation Council (GCC): the Kingdom of Bahrain, the State of Kuwait, the Sultanate of Oman, the State of Qatar, the Kingdom of Saudi Arabia, and the United Arab Emirates.,,,, Based on hospital records, [Table 1] shows the prevalence of GT in GCC countries ranges from 1/100,000 to 1/400,000 population (unpublished data, 12). The rate of GT is 1/40,000 individuals in Madinah region, Saudi Arabia.,,
|Table 1: Prevalence of Glanzmann thrombasthenia in the Gulf Cooperation Council Countries|
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Although there is a dearth of evidence available for the treatment of GT patients, there are a few guidelines or recommendations based on expert opinions.,,, The higher rate of GT in GCC countries has made management guidelines necessary. A group of experts in coagulation disorders from GCC countries joined hands to write consensus guidelines. These guidelines are a proposal for the management of GT patients based on GCC country experts' recommendations and currently available evidence and experience.
| Diagnosis|| |
The diagnosis of platelet disorders is very challenging and requires technical and medical expertise. Platelet function testing is time-consuming and affected by preanalytical and analytical variables. The diagnosis of GT is more problematic because of the specific laboratory diagnostic features.
History is a cornerstone in the diagnosis of patients with hereditary platelets disorders. The first step for diagnosis is a careful clinical evaluation of the following:
- Bleeding history: Manifestations of atypical of platelet function may include unexplained or extensive bruising, epistaxis causing anemia or requiring hospital admission, menorrhagia, oral cavity bleeding, bleeding during childbirth, bleeding following invasive procedures, and bleeding following dental extraction
- Site, severity, frequency of bleeding episodes, and response to therapy
- Requirement for blood transfusion
- Severe disease is likely to present at early childhood, including the neonatal period. Presentation may include Intracranial hemorrhage (ICH) following delivery. Excessive bleeding from the umbilical stump or postcircumcision, easy or extensive bruising. Later in life Prolonged epistaxis and menorrhagia may encountered
- Bleeding from hereditary platelets disorders occurs at the time of trauma rather than after a delayed onset. Hemarthrosis or muscle bleeds are less likely
- Family history of bleeding disorder and consanguinity
- Evaluation of drugs or foods possibly interfering with platelet function.
The use of a bleeding assessment tool (BAT) is strongly encouraged; however, the International Society of Bleeding and Thrombosis–BAT (ISTH-BAT) has not been evaluated sufficiently for GT.
Screening tests for a bleeding patient include the following:
- Complete blood count (CBC) and peripheral blood morphology are essential to examine platelet count, size, and morphology. Evaluation of white blood cell (WBC) count is important to exclude platelet disorders with WBC inclusions. The presence of anemia may influence testing, particularly for the platelet function analyzer (PFA-100)
- Routine coagulation tests, such as prothrombin time, activated partial thromboplastin time, and thrombin time, are usually normal
- Screening of platelet function is best done by in vitro techniques such as PFA-100, measuring closure time using cartridges first coated with collagen and adenosine diphosphate (ADP), and then collagen and epinephrine. Bleeding time tests are discouraged because of lack of standardization, patient trauma, and poor positive predictive values.
Once the initial screening tests suggest an inherited platelet disorder, more specific tests are needed to confirm the diagnosis and classify the disease. Specific tests for platelets dysfunction include the following:
- There are different methods for evaluation of platelet aggregation. The most common and widely used method is light transmission aggregometry (LTA), using platelet-rich plasma (PRP) to measure the change in light transmission in real time when agonists, such as ADP, collagen, arachidonic acid, and ristocetin, are added to PRP or washed platelets. Whole blood aggregometry can be also used. The LTA is considered to be the gold standard method; however, it is technically demanding and requires a significant amount of blood, which can be difficult for young children. Multiple electrode aggregometry (MEA) has recently been developed for rapid assessment of platelet function using pairs of electrodes to measures electrical resistance. It requires small blood volumes with standardized reagents. Recently, published research has validated using MEA to diagnose GT
- Platelet flow cytometry is used to evaluate the glycoproteins GPIa/IIa (CD31 and CD49b), GPIV (CD36), and GPVI to identify deficiency and help to identify GT typing and variants
- Transmission electron microscopy is recommended only when there is suspicion of platelet storage defects
- Molecular analysis of the ITGA2B and ITGB3 genes is indicated for confirmation of difficult cases, particularly the GT variants, prenatal screening, prenatal genetic diagnosis, and prevention of GT.
| Management|| |
Antifibrinolytic agents, such as epsilon-aminocaproic acid and tranexamic acid, act through inhibition of plasminogen conversion to plasmin and subsequent fibrinolysis inhibition. They have shown effectiveness in controlling surgical and nonsurgical bleeds, particularly mouth bleeds and menorrhagia., It is not recommended for treatment of renal bleeding or in case of disseminated intravascular coagulation.
- Epsilon-aminocaproic acid:
- 50–100 mg/kg (maximum 6 g) every 4–6 h (maximum 24 g per 24 h).
- Tranexamic acid:
- Oral: 25 mg/kg every 8 h
- IV: 10 mg/kg every 8 h
- Mouthwashes (can be prepared by diluting 5 mL of tranexamic acid with 5 mL of sterile water or 500 mg tablets placed into 10–20 mL of water) 10 mL every 6–8 h.
Desmopressin (DDAVP) has been shown to be effective in many bleeding disorders, including inherited platelet function disorders. Although DDAVP efficacy among GT patients has not been established, clinical efficacy has been observed.
- Intravenous infusion: 0.3 μg/kg diluted to 30–50 ml in saline over 30 min
- Subcutaneous injection: 0.3 μg/kg
- Intranasal spray:
Platelet transfusions are the gold standard treatment for uncontrolled bleeding in GT, preferably, human leukocyte antigen (HLA)-matched single-donor and leukocyte-reduced apheresis platelets. Between 25% and 80% of GT patients develop antiplatelet antibodies, particularly against αIIbβ3, and antibodies develop more frequently in homozygous patients., This is a serious risk in GT patients, and hence, the development of these platelets specific antibodies should be minimized by avoidance of platelet transfusions particularly for minor bleeds such as gingival oozing. Platelet refractoriness has been reported in about 50% of patients with anti-HLA antibodies., Although the risk of viral transmission of human immunodeficiency virus, hepatitis C virus, and hepatitis B virus is very low now, other viruses or bacterial contamination still exist., Transfusion-related acute lung injury is another risk of platelet transfusion. In GT patients, consumption of platelets due to surgery or bleeding is increased, in turn, platelet transfusion needs to be given more frequently. Another issue of concern is the availability of platelet units, particularly HLA-matched single donor.
- Single-donor aphaeresis: one unit
- Random donor 4–6 units
Recombinant activated factor VII
An international survey evaluating the use of recombinant activated factor VII (rFVIIa) in 59 GT patients, published in 2004, found as follows:
- The success of rFVIIa bolus injections was highest when used at optimal regimens, which were defined as rFVIIa at dosage ≥80 μg/kg at intervals of ≥2.5 h, for at least 3 doses
- Earlier treatments yielded better results.
The international, prospective GTR, published in 2015, studied 184 GT patients with 829 bleeding episodes and 96 GT patients with 206 surgical interventions. They found as follows:,
- rFVIIa in a dose of ≥80 μg/kg at intervals of 2.5 h or less were observed to be safe and effective in nonsurgical bleeds, minor and major procedures in patients with or without antibodies, and/or refractoriness
- rFVIIa was used more frequently than platelets.
rFVIIa at a high dose could activate FX to FXa directly, resulting in a burst of thrombin generation through GT platelet adhesion and aggregation improvement. This also improves fibrin clot structure.
- Conventional dose:
- ≥80 μg/kg (may repeated at interval of 2.5 h)
- High dose:
Due to multiple issues related to platelet transfusion (see above) and the desire of GT patients to conceive, panel elected to consider rFVIIa as the first line of therapy in order to save platelets for more severe or non-responsive bleeds. High doses have been successful, particularly if used early and upfront.,,, Prophylaxis for patients with frequent severe bleeding may be recommended, with an rFVIIa does of 270 μg/kg daily or every other day.
- Sports and exercises should be encouraged. Contact sports should be avoided for individuals with severe bleeding patterns
- Avoid agents that may cause platelet dysfunction, such as acetylsalicylic acid (aspirin). Nonsteroidal anti-inflammatory agents should be used with caution
- Treat a suspected life-threatening hemorrhage immediately, for example, ICH, without waiting for further investigation
- Treat veins with care. Never cut down, except in a dire emergency, as a cut down destroys veins
- Baseline tests such as liver function, renal function, virology status, and iron status should be done at diagnosis
- Iron deficiency should be monitored and treated
- Maintain dental hygiene
- Keep immunizations updated
- Patients should be encouraged to keep a record of all bleeding episodes.
All patients should carry identification cards indicating the diagnosis, special instructions if exist such as platelets, immunization, and severity, and contact information for the treating physician or clinic. Treatment of acute episodes may be added on the back.
Local and conservative measures
- Nasal packing
- Topical hemostatics
- Fibrin glue
- YAG laser for nasal mucosal
- Topical thrombin
- Prevention of nose dryness using saline sprays several times a day
- Lubricants to nasal mucosa.
Treatment of minor bleeding episodes
- Local measures and antifibrinolytic drugs.
- rFVIIa ≥80 μg/kg single dose and repeat as necessary.
Platelet transfusions are usually unnecessary.
Treatment of severe bleeding episodes
- Local measures and antifibrinolytic drugs should be started at home and continued at the hospital
- Early start of rFVIIa, either a single high dose or a conventional dose every 2.5 h for 3 doses.
- rFVIIa ≥80 μg/kg every 2–4 h to control bleeding. Dose spacing can be made once bleeding is controlled
- If rFVIIa cannot stop bleeding, platelet transfusions can be used as a single dose and can be repeated as necessary with continuation of rFVIIa.
Treatment of minor surgery
Minor surgery defined as a surgery that only manipulates skin, mucous membranes, or superficial connective tissue.
- Correction of anemia to acceptable level for each patient baseline
- Disease and plan of management should be explained in writing to the surgeon
- Every effort should be made to minimize bleeding risk
- Antifibrinolytic should be started 2-h preoperative
- Single-dose rFVIIa ≥80 μg/kg 10-min preoperative.
- Monitoring of bleeding
- rFVIIa ≥80 μg/kg may be repeated as necessary at intervals of 2.5 h.
- Control of bleeding risk through local control measures
- Antifibrinolytic should be continued until hemostasis is established
- rFVIIa ≥80 μg/kg every 2–4 h if needed.
- If rFVIIa cannot stop bleeding, platelet transfusions can be used as a single dose and can be repeated if necessary with continuation of rFVIIa.
Treatment of major surgery
Major surgery defined as a surgery that may cross a mesenchymal barrier, remove an organ, alter a normal anatomy, open a facial plane, or enter a body cavity.
- Correction of anemia to acceptable level for each patient and based on surgery type
- Disease and plan of management should be explained in writing to the surgeon
- Every effort should be made to minimize bleeding risk
- Antifibrinolytic should be started 2-h preoperative
- rFVIIa ≥80 μg/kg 10-min preoperative
- Platelet transfusion 1–2-h presurgery
- Keep 3 doses of platelet units ready.
- Monitoring of bleeding
- rFVIIa ≥80 μg/kg every 2.5 h
- Platelets transfusion if necessary.
- Control of bleeding risk through local control measures
- Antifibrinolytic to be continued until hemostasis is established
- rFVIIa ≥80 μg/kg every 2–4 h
- Continue rFVIIa ≥80 μg/kg with decreasing frequency until proper hemostasis is achieved
- Platelet transfusion daily or when necessary for the first 3 days.
Management of pregnancy
- Pregnancy should be managed at a hospital where hemophilia services are available, with a written management plan for pregnancy, delivery, and management of the neonate
- Regional anesthesia in patients with GT is contraindicated
- Ventouse extraction and high forceps are contraindicated; fetal scalp monitoring and blood sampling should be avoided as the fetus is at risk of bleeding
- Neonates are at risk of thrombocytopenia as maternal antiplatelet antibodies may cross the placenta
- Vaginal delivery is preferred unless contraindicated from an obstetrics point of view.
- Carries a risk of hemorrhage
- Avoid using platelet transfusion due to the associated risk of formation of isoantibodies that may increase the chance of neonatal alloimmune thrombocytopenia
- Antifibrinolytic should be started during the first stage and continued every 6 h
- rFVIIa ≥80 μg/kg every 2.5 h starting at the active labor phase, or earlier if a vaginal bleed takes place, and continue until the risk of bleeding has elapsed
- Keep 3 doses of platelet units ready
- If no bleeding occurs, control with rFVIIa platelets transfusion may be used.
- Postpartum hemorrhage may occur 1–2 weeks after delivery
- Tranexamic acid should be continued for at least 2-week postdelivery
- If postpartum hemorrhage occurs, it should be treated as a bleeding episode mentioned above.
- Cesarean section should be treated as any major surgical procedure.
- The father should be screened genetically; if the father is a carrier, the neonate is at risk of severe platelet dysfunction
- If the neonate is at risk, ventouse and instrumental delivery and fetal scalp monitoring are contraindicated
- Neonates are at risk for thrombocytopenia as maternal antiplatelet antibodies may cross the placenta, which can result in fatal intrauterine hemorrhage
- In such neonates, platelet transfusion should be ABO and RhD antigen identical
- All neonates should be screened (CBC, PFA).
| Menorrhagia|| |
Menorrhagia, or heavy menstrual bleeding, is a common and debilitating condition falling under the larger category of abnormal uterine bleeding. It is defined as excessive uterine bleeding occurring at regular intervals or prolonged uterine bleeding lasting more than 7 days. The classic definition of menorrhagia is “>80 mL of blood loss per cycle.” Menorrhagia is caused by structural abnormalities in the reproductive tract, such as anovulation, bleeding disorders, cancer of the reproductive tract, infection, pregnancy-related bleeding, systemic diseases, hormone imbalance, and among others.
Menorrhagia is a major bleeding problem for women with GT after puberty. The incidence of menorrhagia ranges from 13% to 100%.,, The use of oral contraceptives can regulate the menstrual bleed. Antifibrinolytic agents have been shown to be successful in controlling menstrual bleeds. Menorrhagia usually affects the quality of life of women with GT. Since dilation and curettage (D and C), laparoscopy, or endometrial biopsy may worsen blood loss and may lead to hysterectomy, such procedures should be avoided.
Due to cultural and social issues related to the menstrual cycle in GCC nations, the cessation of menstruation as a treatment for bleeding disorders, including GT, has not been accepted by young patients and their families. A panel decided to adapt the Madinah protocol for menstrual cycle control in young patients with GT [Figure 1] and [Figure 2]. Based on the judgment of the treating physician, once young patients with GT start menstruation, they will be admitted to the protocol. The first three menstruation cycles are monitored for the amount of menstrual bleed; if the menstrual bleed is within an acceptable amount, the protocol is continued. If bleeding is massive, young patients will be discharged from the protocol and begin hormonal therapy. Readmission to the protocol is possible based on the judgment of the treating physician and the patient's decision. If three nongynecologically explained massive menstruations occur, patients with GT will be discharged from the protocol and continue on hormonal therapy, while readmission to the protocol is possible based on the judgment of the treating physician and the patient's decision. Two occasions of protocol discharge will lead to permanent discharge.
|Figure 1: Madinah protocol for menstrual cycle control: (1) Hormonal therapy will continue on a daily basis. (2) At proposed time of menstruation (assigned by patient and physician), hormonal therapy will be stopped. (3) Antifibrinolytic drugs will be started. (4) With the first bleed, one dose recombinant activated factor VII will be given. (5) Keep monitoring bleeding, if a massive bleed occurs, recombinant activated factor VII will be initiated, and platelet transfusions will be avoided unless needed. (6) Hormonal therapy will restart between days 3 and 5. Antifibrinolytic drugs will continue until there are no more bleeds|
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For women of child-bearing age who want to conceive, menstruation can be managed by antifibrinolytic drugs; rFVIIa may be used to control bleeding, but platelet transfusions should be avoided unless bleeding is not controlled by rFVIIa. A pregnancy plan for delivery and neonate management should be agreed in writing between the obstetrician and the hematologist.
- Good oral hygiene
- Teeth should be brushed at least twice daily with a medium texture bristle toothbrush or sponge toothbrush; toothpaste containing fluoride should be used
- Floss teeth daily
- A cold liquid or minced solids diet should be taken for 1 week after tooth extraction
- Regular dental checkups every 3–6 months
- Avoid accidental damage to oral mucosa during procedures
- Protection of soft tissues during restorative therapy
- Nerve blocks can be used, providing satisfactory measures taken
- Chlorhexidine and povidone-iodine mouthwash may be used pre- and postdental workup
- Topical thrombin soaks can be used as a local hemostatic agent.
Procedures with a low risk of bleeding (e.g., restorative procedures)
- Antifibrinolytic therapy should be started 2-h predental workup and continued until the risk of bleeding is alleviated
- If a nerve block is needed, rFVIIa ≥80 μg/kg 10-min preprocedure
- Local measures to control or prevent bleeding should be used
- If failed rFVIIa ≥80 μg/kg
- Routine examination and cleaning need no therapy.
Procedures with a high risk of bleeding (e.g., extractions and oral surgery)
- Extensive procedures may require hospitalization for proper management
- Dose rFVIIa ≥80 μg/kg 10-min preprocedure and continue for an additional 1 or 2 days at an interval of 2–4 h, if needed
- Antifibrinolytic should be used concomitantly to be continued for 7–10 days postprocedure
- Local measures to control or prevent bleeding should be used.
| Stem Cell Transplant|| |
Hematopoietic stem cell transplant (HSCT) is a curative treatment for GT. The available treatment strategies for GT are very effective. A small number of GT patient have frequent uncontrolled or life-threatening bleeding refractory to hemostatic treatments, especially patients with antibodies and refractoriness. HSCT can be considered for such patients, has been successfully performed, and has improved the quality of life.
At least 16 children have undergone HSCT (two from GCC countries), primarily for GT of a serious bleeding type.,,,,,,,, Between 1981 and 2015, 43 GT patients have undergone allogenic HSCT and have been registered with the Center for International Blood and Marrow Transplant Research, with various donors, graft sources, and conditioning regimens. As of October 16, 2015, 81% patients remained alive. There is clear evidence of the benefit of HSCT for selected patients with frequent uncontrolled or life-threatening bleeding. The decision for the transplant must be weighed against the risk associated with transplant. Full-intensity conditioning may also carry considerable adverse effects, such as infertility, growth issues, and secondary malignancy. Reduced-intensity conditioning may reduce morbidity and mortality, but the risk of graft rejection is higher.,,
The panel recommended HSCT for GT patients suffering from frequent severe bleeding, life-threatening bleeding, as frequent bleeding interferes with the quality of life. HSCT may be recommended for GT patients having refractoriness to platelet transfusions.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]