- Email: [email protected]
Recurrent Menorrhagia in an Adolescent with a Platelet Secretion Defect
Case Report Recurrent Menorrhagia in an Adolescent with a Platelet Secretion Defect Xiomara M. Santos MD 1,3,*, Jennifer L. Bercaw-Pratt MD 1,3, Donald L. Yee MD 2, Jennifer E. Dietrich MD, Msc 1,3 1
Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA 3 Division of Pediatric and Adolescent Gynecology 2
a b s t r a c t Background: Although von Willebrand disease is the most common inherited bleeding disorder, platelet function disorders are less well recognized as a cause of bleeding. We report a case of menorrhagia caused by an unsuspected platelet secretion defect. Case: A 13-year-old Asian female, with unknown family history, presented with menorrhagia not responsive to intravenous conjugated estrogens, requiring transfusion of 7 units of packed red blood cells. Initial screening tests for bleeding disorders were normal; however, due to high clinical suspicion, further specific testing with platelet aggregometry was performed, which revealed a platelet secretion defect. Summary and Conclusion: The prevalence of platelet secretion defects in adolescents with menorrhagia is unknown, but may be higher than currently recognized. When screening tests are normal, yet suspicion remains high for an underlying hemostatic disorder, platelet aggregometry must be performed. Key Words: Menorrhagia, Dysfunctional uterine bleeding, Bleeding disorder, Platelet function disorder, Platelet secretion defect, Adolescent
Introduction
The prevalence of bleeding disorders among adult women with menorrhagia has been reported to be 10e20%.1,2 While most studies focus on adult patients, one study evaluating 115 women, of whom 25 were adolescents with menorrhagia in a non-acute setting, found that adolescents were just as likely to have hemostatic defects as were older reproductive-aged women.3 While von Willebrand disease is the most common inherited bleeding disorder, platelet function disorders are less well recognized as a cause of bleeding,4,5 although some data suggest that the prevalence of these two classes of disorders may actually be comparable.6 Abnormalities in any of the three phases of platelet plug formation (adhesion, extension, and aggregation/cohesion) will result in platelet dysfunction,4 which can manifest as mucocutaneous bleeding, including menorrhagia. We present an interesting case of menorrhagia caused by an unsuspected platelet secretion defect. Case
A 13-year-old Asian female, without significant past medical history, presented to the emergency room (ER) with vaginal bleeding for 15 days. Menarche occurred at age 10, with regular periods, but at least two episodes of heavy bleeding in the past, lasting up to 10 days in duration. A normal pelvic ultrasound was performed at an outside hospital a few months prior to presentation. The patient * Address correspondence to: Xiomara M. Santos, MD, Department of Obstetrics and Gynecology Baylor College of Medicine 6620 Main St., Ste 1450 Houston, Texas, 77030. E-mail address: [email protected] (X.M. Santos).
denied epistaxis, gum bleeding, or easy bruising. Since she was adopted, no family history was known. After heavy menses one month prior to her presentation, oral contraceptive pills (OCPs) were prescribed by an outside clinic. When her bleeding became heavier, taper instructions were recommended, which consisted of OCPs every six hours until bleeding stopped, with initial improvement in bleeding. After missing several doses, her bleeding resumed, resulting in pad changes every one to two hours, for which the patient presented to the ER. Initial hemoglobin/hematocrit (Hb/HCT) on presentation was 7.1/20.6 gm/dl and platelets were 156 103/mL (Table 1). She was placed on scheduled intravenous (IV) conjugated estrogens every six hours. Her Hb/HCT dropped to 5.8/16.8 gm/dl less than 12 hours after admission for which she received 2 units of packed red blood cells. Oral aminocaproic acid (an antifibrinolytic) was initiated; however, due to continued heavy bleeding and nausea, this was changed to IV. An underlying hemostatic disorder was initially screened for using standard coagulation screening tests (PT, PTT, fibrinogen, platelet count), von Willebrand factor testing, platelet function analyzer (PFA-100; Dade Behring, Inc, Deerfield, IL) testing (a screen for platelet function disorders that lacks high sensitivity) and thromboelastography (which attempts to provide a global assessment of hemostatic function but lacks conclusive validation studies). The results were not suggestive of a hemostatic problem. Subsequently, a pelvic magnetic resonance imaging/angiography was ordered, and did not reveal any structural abnormalities. However, due to the requirement for significant blood products and lack of response to IV conjugated estrogens, a platelet aggregation study was performed, revealing normal aggregation responses, but profound
1083-3188/$ - see front matter Ó 2011 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. doi:10.1016/j.jpag.2010.11.004
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X.M. Santos et al. / J Pediatr Adolesc Gynecol 24 (2011) e35ee38
Table 1 Laboratory Results Lab
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Hb/HCT (gm/dl, %) Platelets (103/mL) PTT/PT/INR Fibrinogen (mg/dL)
7.1/20.6/5.8/16.8 156/132 -
8.1/23.8 144 30.8/15.2/1.2 252
5.6/16.3 142 -
7.2/20.7/6.5/18.9 147/159 28.1/15.8/1.2 154
8.9/25.7/9.1/26.2 101/117 28.6/14.0/1.0 290
8.5/24.5 -
platelet secretion defects with each tested agonist (Table 2). Platelet aggregometry measures changes in physical properties of the blood or plasma specimen (either electrical impedance or light transmittance, respectively) that accompany platelet activation and aggregation after different platelet agonists (e.g., arachidonic acid, collagen) are added. The method can also measure enzymatically the release of platelet granule contents in response to different agonists, reflecting the presence or absence of platelet secretion defects. The patient’s bleeding eventually improved on a regimen that included conjugated estrogens, IV aminocaproic acid, cryoprecipitate and vitamin K. By day 5, bleeding ceased. She was discharged home on an OCP taper, which consisted of a high dose combination OCP containing 50 mcg ethinyl estradiol, every eight hours for one week, then twice a day for a week, then daily, skipping placebo pills. She remains on extended cycle OCPs without any significant bleeding since hospital discharge. Subsequent platelet electron microscopy studies did not reveal any ultrastructural abnormalities. As an outpatient, repeat platelet aggregometry confirmed the presence of a platelet secretion defect, which improved after administration of intranasal desmopressin. In addition to oral antifibrinolytics, intranasal desmopressin acetate is planned as rescue therapy for future breakthrough bleeds. Summary and Conclusion
Breakthrough bleeding with missed doses of OCPs is a common problem, which we initially believed was the major contributing factor in this case. Other common sources of abnormal uterine bleeding in adolescents include Table 2 Whole Blood Platelet Aggregation Results Component
Results
Reference Range
Explanation
ADP aggregation Arach acidþ aggregation Collagen high aggregation Collagen low aggregation Ristocetin high aggregation Ristocetin low aggregation ADP secretion Arach acid* secretion Collagen low secretion Collagen high secretion Thrombin secretion
27 33 (H) 36 (H) 22 26 2 0.00 (L) 0.00 (L) 0.00 (L) 0.15 (L) 0.39 (L)
6e33z 9e22z 9e30z 8e26z 10e47z !3z 0.38e1.71x 0.50e1.96x 0.40e1.62x 0.67e1.90x 0.62e1.65x
Normal Increased risk of stent thrombosisy Normal Normal Normal Suggestive of platelet secretion defect, such as storage pool deficiency
Arachadonic acid; H, high; L, low. Platelet aggregation was increased in response to arachadonic acid and high dose collagen. Result not clinically significant in this setting, but this has been associated with increased risk of stent thrombosis after coronary stenting.7 z ohms. x nmoles. * y
anovulation, complications of pregnancy, sexually transmitted diseases, and bleeding disorders (Table 3).8,9 Factors that may help predict an underlying bleeding disorder include a personal or family history of easy bruising, epistaxis, gingival bleeding, menorrhagia, and/or excessive bleeding after trauma, surgical procedures, or parturition.2,4 A suggested algorithm for the evaluation of abnormal uterine bleeding in adolescents is included in Figure 1.9,10 While von Willebrand disease is currently recognized as the most common inherited bleeding disorder in women with menorrhagia, the prevalence of platelet secretion defects in adolescents with menorrhagia is unknown.5 One study done among adult women with menorrhagia found prolonged bleeding time in one third of women and abnormal platelet aggregation studies in almost half of all the women studied.5 Most case reports describing adolescents with similar presentations and an underlying platelet disorder, focus on classic (but quite rare) diagnoses such as Bernard-Soulier syndrome and Glanzmann thrombasthenia.11 The current case is unique in that a platelet secretion defect was identified, which may actually be quite common,6 although underrecognized and thus important for adolescent gynecologists to be aware of. Management principles for previously
Table 3 Differential Diagnosis of Abnormal Uterine Bleeding in Adolescents8,9 Complications of pregnancy Abortion, retained products Ectopic pregnancy Trophoblastic disease Anovulation DUB not attributable to underlying structural or systemic disease Immature hypothalamic-pituitary axis Thyroid disease Hyperandrogenic (PCOS, CAH) Sexual transmitted infections Bleeding disorders: Von Willebrand disease Coagulation factor deficiencies Platelet disorders4 Defective clot initiation Bernard-Soulier syndrome Defective clot extension Platelet storage pool defects Gray platelet syndrome Dense granule storage pool disease diak-Higashi syndrome Che Hermansky-Pudlak syndrome Defective cohesion/aggregation Glanzmann thrombasthenia Foreign body Genital trauma Systemic disease Medications Anticoagulants Less common sources: cervical or vaginal neoplasia, endometrial hyperplasia or malignancy, endometrial or cervical polyp, adenomyosis Abbreviations: DUB, dysfunctional uterine bleeding; PCOS, polycystic ovarian syndrome; CAH, congenital adrenal hyperplasia.
X.M. Santos et al. / J Pediatr Adolesc Gynecol 24 (2011) e35ee38
e37
Abnormal Uterine Bleeding
History: Key Questions: age at menarche, length of cycles, duration and quantity of bleeding, clots?, cramping?; sexual history; menstrual history of patient’s mother and any sisters
Menorrhagia?
Yes
No
Key Questions: personal or family history of bleeding problems during or after surgery, dental procedures, trauma, during childbirth, history of large bruises; bleeding disorder or hemophilia, easy bruising, epistaxis, anemia requiring treatment or blood transfusion, heavy menses characterized by changing pad or tampon hourly, and/or resulting in anemia or low iron, female family members with history of hysterectomy due to heavy cycles
Physical Examination -Special attention to orthostatics, bruises, signs of hyperandrogenism (acne, hirsutism, clitoromegaly), acanthosis nigricans, striae, thyromegaly, pubertal stage (Tanner stage)
Non-sexually Active Only external pelvic examination; recto-abdominal exam can assess pelvic structures if necessary, also ultrasound. If massive bleeding and vaginal laceration suspected despite denial of sexual activity exam under anesthesia
Sexually Active Speculum exam, testing for N. gonorrhoea, C. trachomatis, wet prep (if no active bleeding), bimanual exam
CBC, PT, PTT, fibrinogen, UPT, ultrasound
If indicated by H&P: TSH, LH, FSH, prolactin, androgens
If bleeding disorder suspected by H&P: VWF ristocetin cofactor activity, VWF antigen, clotting factor VIII activity; consultation with Hematologist
Fig. 1. Evaluation of Abnormal Uterine Bleeding in Adolescents.9,10Ă
described cases of these more classic platelet disorders were similar to the approach taken for our patient: hormonal therapy, antifibrinolytics, and blood product replacement.11 Platelet dysfunction results from abnormalities in any of the three phases of platelet plug formation: adhesion, extension, and aggregation/cohesion.4 Prototypical platelet disorders include rare membrane receptor deficiencies such as Bernard-Soulier syndrome, which affects platelet adhesion, and Glanzmann thrombasthenia, which affects aggregation.4 However, the most common congenital platelet function disorders appear to be secretion defects, such as in our patient, which affect the extension phase of platelet plug formation.6 Many of these disorders share common treatments (e.g., hormonal suppression, antifibrinolytics, desmopressin acetate, platelet transfusion) and much effort is being put into techniques to more rapidly and accurately diagnose these disorders.4 Platelet function abnormalities are likely under-recognized due to mildness of symptoms and absence of the surgical or other significant hemostatic challenges that may be required
to elicit them. In addition, the specialized expertise required to perform and interpret platelet function testing probably contributes to the underdiagnosis of these disorders.4 Although data suggest that a wide variety of agents can affect platelet function results,12,13 including hormones and antifibrinolytics, this patient’s abnormalities were confirmed on repeat testing performed several weeks after her acute presentation and treatment. Nevertheless, accurate interpretation of platelet function testing is best accomplished in close consultation with a hematologist. Additional potential pitfalls of platelet function testing include concerns about its reproducibility.12 Since it has been shown that experienced laboratories can generate very reproducible aggregometry results,14 having such testing performed at a reliable testing facility is also of paramount importance. The reproducibility of testing results performed weeks apart on our patient speaks to the reliability of her diagnosis; a similar approach is recommended to confirm suspected platelet dysfunction. Closure time, measured by PFA-100, has been used as part of the diagnostic evaluation of platelet disorders and
e38
X.M. Santos et al. / J Pediatr Adolesc Gynecol 24 (2011) e35ee38
platelet function. However, the available evidence shows that it has insufficient sensitivity and specificity to screen reliably for platelet function disorders, especially in the case of platelet secretion defects.15 Normal closure time can be helpful in excluding some severe platelet defects and severe von Willebrand disease.15 However, when other screening tests are normal, including PFA-100, yet clinical suspicion remains high for an underlying hemostatic disorder, further testing, including platelet aggregometry performed in a reliable facility and in collaboration with an experienced hematologist, is recommended. References 1. Dilley A, Drews C, Miller C, et al: von Willebrand disease and other inherited bleeding disorders in women with diagnosed menorrhagia. Obstet Gynecol 2001; 97:630 2. Kadir RA, Economides DL, Sabin CA, et al: Frequency of inherited bleeding disorders in women with menorrhagia. Lancet 1998; 351:485 3. Philipp CS, Faiz A, Dowling N, et al: Age and the prevalence of bleeding disorders in women with menorrhagia. Obstet Gynecol 2005; 105:61 4. Simon D, Kunicki T, Nugent D: Platelet function defects. Haemophilia 2008; 14:1240
5. Philipp CS, Dilley A, Miller CH, et al: Platelet functional defects in women with unexplained menorrhagia. J Thromb Haemost 2003; 1:477 6. Hayward CP: Diagnostic approach to platelet function disorders. Transfus Apher Sci 2008; 38:65 7. Cuisset T, Frere C, Quilici J, et al: Predictive values of post-treatment adenosine diphosphate-induced aggregation and vasodilator-stimulated phosphoprotein index for stent thrombosis after acute coronary syndrome in clopidogreltreated patients. Am J Cardiol 2009; 104:1078 8. Casablanca Y: Management of dysfunctional uterine bleeding. Obstet Gynecol Clin North Am 2008; 35:219 9. Strickland J, Gibson EJ, Levine SB: Dysfunctional uterine bleeding in adolescents. J Pediatr Adolesc Gynecol 2006; 19:49 10. James AH, Manco-Johnson MJ, Yawn BP, et al: Von Willebrand disease: key points from the 2008 National Heart, Lung, and Blood Institute guidelines. Obstet Gynecol 2009; 114:674 11. Aydinok Y, Egemen A, Balkan C: Menorrhagia due to abnormalities of the platelet function: evaluation of two young patients. Pediatr Int 2007; 49:106 12. George JN, Shattil SJ: The clinical importance of acquired abnormalities of platelet function. N Engl J Med 1991; 324:27 13. Bar J, Tepper R, Fuchs J, et al: The effect of estrogen replacement therapy on platelet aggregation and adenosine triphosphate release in postmenopausal women. Obstet Gynecol 1993; 81:261 14. Yee DL, Sun CW, Bergeron AL, et al: Aggregometry detects platelet hyperreactivity in healthy individuals. Blood 2005; 106:2723 15. Hayward CP, Harrison P, Cattaneo M, et al: Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis: Platelet function analyzer (PFA)-100 closure time in the evaluation of platelet disorders and platelet function. J Thromb Haemost 2006; 4:312
Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA 3 Division of Pediatric and Adolescent Gynecology 2
a b s t r a c t Background: Although von Willebrand disease is the most common inherited bleeding disorder, platelet function disorders are less well recognized as a cause of bleeding. We report a case of menorrhagia caused by an unsuspected platelet secretion defect. Case: A 13-year-old Asian female, with unknown family history, presented with menorrhagia not responsive to intravenous conjugated estrogens, requiring transfusion of 7 units of packed red blood cells. Initial screening tests for bleeding disorders were normal; however, due to high clinical suspicion, further specific testing with platelet aggregometry was performed, which revealed a platelet secretion defect. Summary and Conclusion: The prevalence of platelet secretion defects in adolescents with menorrhagia is unknown, but may be higher than currently recognized. When screening tests are normal, yet suspicion remains high for an underlying hemostatic disorder, platelet aggregometry must be performed. Key Words: Menorrhagia, Dysfunctional uterine bleeding, Bleeding disorder, Platelet function disorder, Platelet secretion defect, Adolescent
Introduction
The prevalence of bleeding disorders among adult women with menorrhagia has been reported to be 10e20%.1,2 While most studies focus on adult patients, one study evaluating 115 women, of whom 25 were adolescents with menorrhagia in a non-acute setting, found that adolescents were just as likely to have hemostatic defects as were older reproductive-aged women.3 While von Willebrand disease is the most common inherited bleeding disorder, platelet function disorders are less well recognized as a cause of bleeding,4,5 although some data suggest that the prevalence of these two classes of disorders may actually be comparable.6 Abnormalities in any of the three phases of platelet plug formation (adhesion, extension, and aggregation/cohesion) will result in platelet dysfunction,4 which can manifest as mucocutaneous bleeding, including menorrhagia. We present an interesting case of menorrhagia caused by an unsuspected platelet secretion defect. Case
A 13-year-old Asian female, without significant past medical history, presented to the emergency room (ER) with vaginal bleeding for 15 days. Menarche occurred at age 10, with regular periods, but at least two episodes of heavy bleeding in the past, lasting up to 10 days in duration. A normal pelvic ultrasound was performed at an outside hospital a few months prior to presentation. The patient * Address correspondence to: Xiomara M. Santos, MD, Department of Obstetrics and Gynecology Baylor College of Medicine 6620 Main St., Ste 1450 Houston, Texas, 77030. E-mail address: [email protected] (X.M. Santos).
denied epistaxis, gum bleeding, or easy bruising. Since she was adopted, no family history was known. After heavy menses one month prior to her presentation, oral contraceptive pills (OCPs) were prescribed by an outside clinic. When her bleeding became heavier, taper instructions were recommended, which consisted of OCPs every six hours until bleeding stopped, with initial improvement in bleeding. After missing several doses, her bleeding resumed, resulting in pad changes every one to two hours, for which the patient presented to the ER. Initial hemoglobin/hematocrit (Hb/HCT) on presentation was 7.1/20.6 gm/dl and platelets were 156 103/mL (Table 1). She was placed on scheduled intravenous (IV) conjugated estrogens every six hours. Her Hb/HCT dropped to 5.8/16.8 gm/dl less than 12 hours after admission for which she received 2 units of packed red blood cells. Oral aminocaproic acid (an antifibrinolytic) was initiated; however, due to continued heavy bleeding and nausea, this was changed to IV. An underlying hemostatic disorder was initially screened for using standard coagulation screening tests (PT, PTT, fibrinogen, platelet count), von Willebrand factor testing, platelet function analyzer (PFA-100; Dade Behring, Inc, Deerfield, IL) testing (a screen for platelet function disorders that lacks high sensitivity) and thromboelastography (which attempts to provide a global assessment of hemostatic function but lacks conclusive validation studies). The results were not suggestive of a hemostatic problem. Subsequently, a pelvic magnetic resonance imaging/angiography was ordered, and did not reveal any structural abnormalities. However, due to the requirement for significant blood products and lack of response to IV conjugated estrogens, a platelet aggregation study was performed, revealing normal aggregation responses, but profound
1083-3188/$ - see front matter Ó 2011 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. doi:10.1016/j.jpag.2010.11.004
e36
X.M. Santos et al. / J Pediatr Adolesc Gynecol 24 (2011) e35ee38
Table 1 Laboratory Results Lab
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Hb/HCT (gm/dl, %) Platelets (103/mL) PTT/PT/INR Fibrinogen (mg/dL)
7.1/20.6/5.8/16.8 156/132 -
8.1/23.8 144 30.8/15.2/1.2 252
5.6/16.3 142 -
7.2/20.7/6.5/18.9 147/159 28.1/15.8/1.2 154
8.9/25.7/9.1/26.2 101/117 28.6/14.0/1.0 290
8.5/24.5 -
platelet secretion defects with each tested agonist (Table 2). Platelet aggregometry measures changes in physical properties of the blood or plasma specimen (either electrical impedance or light transmittance, respectively) that accompany platelet activation and aggregation after different platelet agonists (e.g., arachidonic acid, collagen) are added. The method can also measure enzymatically the release of platelet granule contents in response to different agonists, reflecting the presence or absence of platelet secretion defects. The patient’s bleeding eventually improved on a regimen that included conjugated estrogens, IV aminocaproic acid, cryoprecipitate and vitamin K. By day 5, bleeding ceased. She was discharged home on an OCP taper, which consisted of a high dose combination OCP containing 50 mcg ethinyl estradiol, every eight hours for one week, then twice a day for a week, then daily, skipping placebo pills. She remains on extended cycle OCPs without any significant bleeding since hospital discharge. Subsequent platelet electron microscopy studies did not reveal any ultrastructural abnormalities. As an outpatient, repeat platelet aggregometry confirmed the presence of a platelet secretion defect, which improved after administration of intranasal desmopressin. In addition to oral antifibrinolytics, intranasal desmopressin acetate is planned as rescue therapy for future breakthrough bleeds. Summary and Conclusion
Breakthrough bleeding with missed doses of OCPs is a common problem, which we initially believed was the major contributing factor in this case. Other common sources of abnormal uterine bleeding in adolescents include Table 2 Whole Blood Platelet Aggregation Results Component
Results
Reference Range
Explanation
ADP aggregation Arach acidþ aggregation Collagen high aggregation Collagen low aggregation Ristocetin high aggregation Ristocetin low aggregation ADP secretion Arach acid* secretion Collagen low secretion Collagen high secretion Thrombin secretion
27 33 (H) 36 (H) 22 26 2 0.00 (L) 0.00 (L) 0.00 (L) 0.15 (L) 0.39 (L)
6e33z 9e22z 9e30z 8e26z 10e47z !3z 0.38e1.71x 0.50e1.96x 0.40e1.62x 0.67e1.90x 0.62e1.65x
Normal Increased risk of stent thrombosisy Normal Normal Normal Suggestive of platelet secretion defect, such as storage pool deficiency
Arachadonic acid; H, high; L, low. Platelet aggregation was increased in response to arachadonic acid and high dose collagen. Result not clinically significant in this setting, but this has been associated with increased risk of stent thrombosis after coronary stenting.7 z ohms. x nmoles. * y
anovulation, complications of pregnancy, sexually transmitted diseases, and bleeding disorders (Table 3).8,9 Factors that may help predict an underlying bleeding disorder include a personal or family history of easy bruising, epistaxis, gingival bleeding, menorrhagia, and/or excessive bleeding after trauma, surgical procedures, or parturition.2,4 A suggested algorithm for the evaluation of abnormal uterine bleeding in adolescents is included in Figure 1.9,10 While von Willebrand disease is currently recognized as the most common inherited bleeding disorder in women with menorrhagia, the prevalence of platelet secretion defects in adolescents with menorrhagia is unknown.5 One study done among adult women with menorrhagia found prolonged bleeding time in one third of women and abnormal platelet aggregation studies in almost half of all the women studied.5 Most case reports describing adolescents with similar presentations and an underlying platelet disorder, focus on classic (but quite rare) diagnoses such as Bernard-Soulier syndrome and Glanzmann thrombasthenia.11 The current case is unique in that a platelet secretion defect was identified, which may actually be quite common,6 although underrecognized and thus important for adolescent gynecologists to be aware of. Management principles for previously
Table 3 Differential Diagnosis of Abnormal Uterine Bleeding in Adolescents8,9 Complications of pregnancy Abortion, retained products Ectopic pregnancy Trophoblastic disease Anovulation DUB not attributable to underlying structural or systemic disease Immature hypothalamic-pituitary axis Thyroid disease Hyperandrogenic (PCOS, CAH) Sexual transmitted infections Bleeding disorders: Von Willebrand disease Coagulation factor deficiencies Platelet disorders4 Defective clot initiation Bernard-Soulier syndrome Defective clot extension Platelet storage pool defects Gray platelet syndrome Dense granule storage pool disease diak-Higashi syndrome Che Hermansky-Pudlak syndrome Defective cohesion/aggregation Glanzmann thrombasthenia Foreign body Genital trauma Systemic disease Medications Anticoagulants Less common sources: cervical or vaginal neoplasia, endometrial hyperplasia or malignancy, endometrial or cervical polyp, adenomyosis Abbreviations: DUB, dysfunctional uterine bleeding; PCOS, polycystic ovarian syndrome; CAH, congenital adrenal hyperplasia.
X.M. Santos et al. / J Pediatr Adolesc Gynecol 24 (2011) e35ee38
e37
Abnormal Uterine Bleeding
History: Key Questions: age at menarche, length of cycles, duration and quantity of bleeding, clots?, cramping?; sexual history; menstrual history of patient’s mother and any sisters
Menorrhagia?
Yes
No
Key Questions: personal or family history of bleeding problems during or after surgery, dental procedures, trauma, during childbirth, history of large bruises; bleeding disorder or hemophilia, easy bruising, epistaxis, anemia requiring treatment or blood transfusion, heavy menses characterized by changing pad or tampon hourly, and/or resulting in anemia or low iron, female family members with history of hysterectomy due to heavy cycles
Physical Examination -Special attention to orthostatics, bruises, signs of hyperandrogenism (acne, hirsutism, clitoromegaly), acanthosis nigricans, striae, thyromegaly, pubertal stage (Tanner stage)
Non-sexually Active Only external pelvic examination; recto-abdominal exam can assess pelvic structures if necessary, also ultrasound. If massive bleeding and vaginal laceration suspected despite denial of sexual activity exam under anesthesia
Sexually Active Speculum exam, testing for N. gonorrhoea, C. trachomatis, wet prep (if no active bleeding), bimanual exam
CBC, PT, PTT, fibrinogen, UPT, ultrasound
If indicated by H&P: TSH, LH, FSH, prolactin, androgens
If bleeding disorder suspected by H&P: VWF ristocetin cofactor activity, VWF antigen, clotting factor VIII activity; consultation with Hematologist
Fig. 1. Evaluation of Abnormal Uterine Bleeding in Adolescents.9,10Ă
described cases of these more classic platelet disorders were similar to the approach taken for our patient: hormonal therapy, antifibrinolytics, and blood product replacement.11 Platelet dysfunction results from abnormalities in any of the three phases of platelet plug formation: adhesion, extension, and aggregation/cohesion.4 Prototypical platelet disorders include rare membrane receptor deficiencies such as Bernard-Soulier syndrome, which affects platelet adhesion, and Glanzmann thrombasthenia, which affects aggregation.4 However, the most common congenital platelet function disorders appear to be secretion defects, such as in our patient, which affect the extension phase of platelet plug formation.6 Many of these disorders share common treatments (e.g., hormonal suppression, antifibrinolytics, desmopressin acetate, platelet transfusion) and much effort is being put into techniques to more rapidly and accurately diagnose these disorders.4 Platelet function abnormalities are likely under-recognized due to mildness of symptoms and absence of the surgical or other significant hemostatic challenges that may be required
to elicit them. In addition, the specialized expertise required to perform and interpret platelet function testing probably contributes to the underdiagnosis of these disorders.4 Although data suggest that a wide variety of agents can affect platelet function results,12,13 including hormones and antifibrinolytics, this patient’s abnormalities were confirmed on repeat testing performed several weeks after her acute presentation and treatment. Nevertheless, accurate interpretation of platelet function testing is best accomplished in close consultation with a hematologist. Additional potential pitfalls of platelet function testing include concerns about its reproducibility.12 Since it has been shown that experienced laboratories can generate very reproducible aggregometry results,14 having such testing performed at a reliable testing facility is also of paramount importance. The reproducibility of testing results performed weeks apart on our patient speaks to the reliability of her diagnosis; a similar approach is recommended to confirm suspected platelet dysfunction. Closure time, measured by PFA-100, has been used as part of the diagnostic evaluation of platelet disorders and
e38
X.M. Santos et al. / J Pediatr Adolesc Gynecol 24 (2011) e35ee38
platelet function. However, the available evidence shows that it has insufficient sensitivity and specificity to screen reliably for platelet function disorders, especially in the case of platelet secretion defects.15 Normal closure time can be helpful in excluding some severe platelet defects and severe von Willebrand disease.15 However, when other screening tests are normal, including PFA-100, yet clinical suspicion remains high for an underlying hemostatic disorder, further testing, including platelet aggregometry performed in a reliable facility and in collaboration with an experienced hematologist, is recommended. References 1. Dilley A, Drews C, Miller C, et al: von Willebrand disease and other inherited bleeding disorders in women with diagnosed menorrhagia. Obstet Gynecol 2001; 97:630 2. Kadir RA, Economides DL, Sabin CA, et al: Frequency of inherited bleeding disorders in women with menorrhagia. Lancet 1998; 351:485 3. Philipp CS, Faiz A, Dowling N, et al: Age and the prevalence of bleeding disorders in women with menorrhagia. Obstet Gynecol 2005; 105:61 4. Simon D, Kunicki T, Nugent D: Platelet function defects. Haemophilia 2008; 14:1240
5. Philipp CS, Dilley A, Miller CH, et al: Platelet functional defects in women with unexplained menorrhagia. J Thromb Haemost 2003; 1:477 6. Hayward CP: Diagnostic approach to platelet function disorders. Transfus Apher Sci 2008; 38:65 7. Cuisset T, Frere C, Quilici J, et al: Predictive values of post-treatment adenosine diphosphate-induced aggregation and vasodilator-stimulated phosphoprotein index for stent thrombosis after acute coronary syndrome in clopidogreltreated patients. Am J Cardiol 2009; 104:1078 8. Casablanca Y: Management of dysfunctional uterine bleeding. Obstet Gynecol Clin North Am 2008; 35:219 9. Strickland J, Gibson EJ, Levine SB: Dysfunctional uterine bleeding in adolescents. J Pediatr Adolesc Gynecol 2006; 19:49 10. James AH, Manco-Johnson MJ, Yawn BP, et al: Von Willebrand disease: key points from the 2008 National Heart, Lung, and Blood Institute guidelines. Obstet Gynecol 2009; 114:674 11. Aydinok Y, Egemen A, Balkan C: Menorrhagia due to abnormalities of the platelet function: evaluation of two young patients. Pediatr Int 2007; 49:106 12. George JN, Shattil SJ: The clinical importance of acquired abnormalities of platelet function. N Engl J Med 1991; 324:27 13. Bar J, Tepper R, Fuchs J, et al: The effect of estrogen replacement therapy on platelet aggregation and adenosine triphosphate release in postmenopausal women. Obstet Gynecol 1993; 81:261 14. Yee DL, Sun CW, Bergeron AL, et al: Aggregometry detects platelet hyperreactivity in healthy individuals. Blood 2005; 106:2723 15. Hayward CP, Harrison P, Cattaneo M, et al: Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis: Platelet function analyzer (PFA)-100 closure time in the evaluation of platelet disorders and platelet function. J Thromb Haemost 2006; 4:312