Author Information
Vaidya A*, Hatkar PA**, Satia MN***, More V****.
(* Second year Resident, ** Associate Professor, **** Professor, *** Assistant Professor, Department of Obstetrics and Gynecology, Seth GS Medical College and KEM Hospital, Mumbai, India.)
Abstract
Glanzmann's thrombasthenia is a rare autosomal recessive bleeding diathesis.[1, 2] The platelet glycoprotein (GP) IIb/ IIIa complex is either absent or dysfunctional which causes a defect in platelet aggregation and hence the coagulation cascade. We are reporting an interesting case of conservative management done in a patient with puberty menorrhagia suffering with a variant of Glanzmann’s thrombasthenia.
Introduction
Glanzmann's thrombasthenia has been named after Dr. Eduard Glanzmann, a Swiss pediatrician. It is a platelet function disorder with defective clot retraction due to a dysfunctional aggregation of glycoprotein IIb/ IIIa. The incidence is 1 in 1 million.[3] It causes prolonged bleeding time and poor platelet aggregation that results in bleeding manifestations. Patients commonly present with episodes of bleeding from external orifices (epistaxis, menorrhagia, less commonly hematemesis, malena and hematuria) as well as generalized rash over the body (purpura, petechial hemorrhages, or gingival bleeding). Menorrhagia is seen in most female patients from the time of menarche and is a serious concern as they have heavy bleeding requiring transfusion of blood and blood products.
Case Report
A 13 year old unmarried girl presented to the emergency ward of our department at a tertiary care hospital with complaints of heavy bleeding per vaginum along with passage of clots during her 1st menstrual cycle. She was referred from a primary health center in view of her menorrhagia with severe anemia. She was a known case of Glanzmann thrombasthenia which was diagnosed when she was 8 years old during screening as her younger brother had died of the same disease. There was no history of consanguinity in her parents. She had history of epistaxis and easy bruising on and off since childhood. She came with complaints of soakage of 8-10 pads/ day for almost 10 days. Bleeding was not controlled with intravenous (IV) tranexamic acid that was started at the primary health center.
On examination she was markedly pale, her vital parameters were stable and there was no evidence of organomegaly on per abdomen findings. She was started on tablet medroxyprogesterone acetate (MPA) 10 mg tid, and IV tranexamic acid 500 mg tid. Both were continued for 3 days. Blood investigations like hemoglobin, coagulation profile, liver and renal function tests were sent and she was sent to hematologist for opinion where she was admitted. She had an initial hemoglobin level of 5.6 gm % for which she was given 2 units of blood transfusion. Repeat hemoglobin was 8.5 gm % which dropped to 3.5 gm % as her menorrhagia continued over a period of 3-4 days. She was given multiple blood transfusions for the same and serial monitoring of hemoglobin was done. In spite of this her menorrhagia persisted and finally the patient was started on combined oral contraceptive pills and injectable ethamsylate. In spite of oral contraceptive pills in the dose of 2 tablets tid for 5-6 days her heavy bleeding continued & therefore she was given injection testosterone enanthate 50 mg IM daily for 4 doses over 48 hours and Novo 7. Novo 7 which is Factor VII was given in the dose of 90 mcg/ kg. Single dose of 2500 mcg (with a half-life of 3 hours) was given IV every 3 hours for 5 days upto a total dose of 50 mg (20 doses) as advised by the hematologist. Since that failed to control bleeding, injection Leuprolide acetate 3.75 mg, was given with a view to completely suppress the hypothalamo-pituitary ovarian axis. Leuprolide acetate was actually contraindicated because of her age and premature suppression of HPO axis but it was used as a life saving medication. She was soaking around 8-10 pads/ day which was a subjective assessment but bleeding stopped completely in 2 days after starting injection Leuprolide. Her general condition improved & hemoglobin of 7.7g/dL was achieved at the time of discharge. Total of 25 blood transfusions, along with parenteral albumin transfusion for hypoproteinaemia along with the above mentioned medical management one after the other over 19 days were given. She was discharged and was advised to start on tablet tranexamic acid 500 mg tid from day 1 of her next menses and to follow up in emergency ward if bleeding is not controlled on oral tranexamic acid.
Discussion
Glanzmann’s thrombasthenia (GT) is a genetic disorder which is autosomal recessive most commonly seen in patients who give positive history of consanguineous marriages. Heterozygotes are asymptomatic with normal platelet function tests. The glycoprotein complex IIb/ IIIa binds to fibrinogen when activated in normal coagulation pathways and bridges the platelets in the presence of calcium to form platelet aggregates which are responsible for the clotting mechanism. In patients with GT this complex is deficient and hence the pathology. In spite of normal platelet counts patient exhibits bleeding manifestations. Three groups of this disease are found. Type I have less than 5 % of the normal GP IIb/ IIIa complex and clot retraction is absent. Type II have 5-20 % of the normal complex and clot retraction is impaired. Type III are variants who have normal receptor levels but defective receptor function.[5] Our patient was a case of Type I GT as diagnosed by flow cytometry.
The severity of bleeding is independent of the type of the disease. Carriers or heterozygotes have normal hemostatic function. Epistaxis, gingival bleeding, purpura and menorrhagia in women are recurrent features seen in Glanzmann’s thrombasthenia. Bleeding time is prolonged. Normal platelet count, morphology and a normal coagulation profile is usually seen on laboratory evaluation. These patients have abnormal clot retraction time and when the test is performed using collagen and ADP epinephrine then platelet aggregation test results are abnormal due to dependence of these agents on fibrinogen. Fibrinogen attachment to the platelets is essential for these factors to cause aggregation. Platelet aggregation occurs in response to ristocetin because of its independence from fibrinogen.[6] Receptor assay using flow cytometry can be done to detect the presence of the GP IIb-IIIa complex, GP IIb (CD 41), GP IIIa, (CD 61) and fibrinogen by using monoclonal antibodies. The same method is used to detect the carrier status of family members with this disorder.[7] The goal of treatment for patients with factor VII deficiency is to control bleeding episodes. Recommended treatment is platelet transfusions. However, about 15-30 % of patients do not respond to these transfusions and this may be because they have developed antibodies to GP IIb-IIIa and/ or HLA antibodies. They have also developed presently or in the past refractoriness to platelet transfusions. The management of patients with GT is challenging and requires multidisciplinary approach. If the bleeding is serious then vigorous treatment should be initiated to reduce further life threatening complications. Thus the step wise management is an initial trial of anti-fibrinolytics (tranexamic acid or ethamsylate) followed by hormonal support (high dose progestins or combined oral contraceptive pills) for maintenance. Blood and blood products are administered to correct anemia.
Every transfusion increases the risk of alloimmunization. Repeated platelet transfusions lead to platelet refractoriness by formation of platelet glycoprotein antibodies and Human Leucocyte Antigen (HLA) immunization. This increases the susceptibility to a massive hemorrhage.[8] All patients need to be vaccinated against Hepatitis B and medications affecting platelet function should be avoided. Such cases benefit from newer modalities of treatment such as Factor VIIa therapy. Factor VIIa therapy was initially used for treatment of Hemophilia but now has been successfully used to treat hemorrhage from bleeding disorders such as Glanzmann Thrombasthenia.[9, 10] Patients with Glanzmann's thrombasthenia have antibodies to GP IIb-IIIa and/ or HLA along with past or present refractoriness to platelet transfusions. Factor VIIa (Novo7) is essential for the treatment of bleeding episodes and for the prevention of bleeding during surgery or invasive procedures. The recommended dosage is 90 mcg/ kg; range is 80- 12 mcg/ kg by intravenous injection every 2 hours; range is 1.5- 2.5 hours. To secure hemostasis at least three doses should be administered. Factor VIIa has been used with good effectiveness in Glanzmann's thrombasthenia patients. It has low risk of transmission of hepatitis virus or retroviruses as it is free of human plasma and protein (albumin). If the patient has already developed alloimmunization the only treatment option remaining is plasmapheresis.
As far as management is concerned, it is advisable to avoid intramuscular injections as well as NSAIDS in these patients. Platelet transfusion should be given only if bleeding is life threatening and not for minor petechiae.
Conclusion
Glanzmann’s thrombasthenia patients do well with necessary supportive care. Spontaneous bleeding is not common. Post traumatic bleeding can occur, which can be serious and even life threatening. The need for immediate and appropriate individualized medical measures forms the mainstay of management in rare coagulation disorders like Glanzmann thrombasthenia.
References
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Vaidya A, Hatkar PA, Satia MN, More V. Puberty Menorrhagia Due To Glanzmann’s Thrombasthenia. JPGO 2017. Volume 4 No.5. Available from: http://www.jpgo.org/2017/05/puberty-menorrhagia-due-to-glanzmanns.html