Platelet storage pool disease in women

JOURNAL OF ADOLESCENT HEALTH CARE 3:264-270, 1983

Platelet Storage Pool Disease in Women R I C H A R D W. W A L K E R , JR., M.D. A N D LILLIAN P. G U S T A V S O N , M.D.

Menstrual abnormalities in adolescents are usually diagnosed as dysfunctional uterine bleeding. It is generally regarded as characteristic of the young hypophyseal-pituitary system, which with time will stop naturally. The possibility of platelet Storage pool diseases as a cause of irregular bleeding is often overlooked. We have treated five patients with proven or suspected piatelet storage pool disease who had a history of adolescent hypermenorrhea and other bleeding. Patients with this type of history should have a comprehensive hematologic evaluation because platelet storage pool disease is not demonstrated by convelitional coagulation studies. Our patients were treated with medroxyprogesterone acetate, oral contraceptives, and an avoidance of aspirin. KEY WORDS:

Dysfunctional uterine bleeding Abnormal uterine bleeding Defects in hemostasis Platelets Diathesis

Bleeding disorders are more common in women than in men. This is, in part, due to the decrease in the platelet count of w o m e n 14 days before the onset of the menses (1,2). Menstrual abnormalities are frequent in adolescents; most are diagnosed as dysfunctional uterine bleeding (DUB). Claessans and Cowell (3) report a diagnosis of DUB in 74% of their adolescent patients, coagulopathy in 19%, and other pathologic conditions in 7%. Although hematologic disorders are seldom found in adolescent girls, the

From the Department of Obstetrics and Gynecologt/ and the Department of Pediatrics, The University of Texas Medical Branch at Galveston, Galveston, Texas. Address reprint requests to: Richard W. Walker, Jr., M.D., Instructor and Director, Teenage Pregnancy Clinic, Subdivision of MaternalFetal Medicine and Pediatric/Adolescent Gynecology Clinic, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas 77550. Manuscript accepted June 14, 1982. 264 0197-0070/83/010264 + 07503.0(/

possibility should be considered in all patients with abnormal bleeding. The initial assessment of these patients should include a hematologic laboratory screening: blood smear, hematocrit and hemoglobin counts, prothrombin time, partial thromboplastin time, piatelet count, bleeding time, and thyroid studies (4); and a medical history designed to educe evidence of a hematologic disorder (i.e., easy bruising, epistaxis, gingival bleeding, family history, intraoperative hemorrhage, obstetrical hemorrhage, early and prolonged occurrence of abnormal uterine or menstrual bleeding). The disorders grouped under platelet storage pool disease (PSPD), which are not detected by conventional hematologic evaluation, are classified according to the defect respOnsible for the inability of platelets to aggregate. The conditions can be caused by a deficiency in the nonmetabolic pool of adenosine diphosphate (ADP), which is stored in the densebody organelles of the platelet, or a defective mechanism for ADP release from these organelles. In either case, the result is a defect in phase two of platelet aggregation (5-9). The incidence of PSPD in adolescent girls is unknown, but the disease has been found in adolescent gynecologic patients (5,10). This paper reports five patients with proven or suspected PSPD who were treated in the gynecology clinics of The University of Texas Medical Branch at Galveston (UTMB).

Case Reports Case 1 The patient was the mother of three of the other patients. She was a 35-year-old woman, gravida 5, para 4, abortus 1. She reported a major bleeding episode after she broke a tooth at age 2 years, Bleeding was minimal at the time the tooth was treated. On that occasion she awoke "almost choking to death" with her mouth filled with blood and blood clots. She stated that "the blood had to be taken

© Society for Adolescent Medicine, 1983 Published by Elsevier Science Publishing Co., Inc., 52 Vanderbilt Ave., New York, NY 10017

January 1983

PSPD IN ADOLESCENTS WITH UTERINE BLEEDING

out of my mouth with a spoon." Another major bleeding episode occurred later in childhood when she hemorrhaged after a tooth extraction. Menarche occurred at age 16 years. Bleeding was heavy during each period. When she was 18 years old her first pregnancy terminated in a spontaneous abortion, which caused a hemorrhage that necessitated a 6-unit transfusion. She continued to hemorrhage with each menses during which she usually used two boxes of sanitary napkins (60 pads) in two days. Birth control pills were given in an effort to control her bleeding, but hemorrhage continued during each withdrawal period. She had four children born in quick succession, with only 11 or 12 months separating each. She had no abnormal bleeding during pregnancy or delivery, but hemorrhaged when a tubal ligation was performed after the birth of her fourth child. The patient is treated with an injection of medroxyprogesterone acetate (Depo-Provera) every 3 months and avoids aspirin-containing and other platelet-inhibitory drugs. She has not had any menstrual hemorrhaging for several years, except during a time when she received another platelet-inhibitory, nonsteroidal, antiinflammatory drug for arthritis. On progestational drugs, her coagulation screen was normal. Her bleeding time was within the upper limits of normal at 8.5 minutes, tourniquet test results were negative, and results of platelet aggregation studies (as outlined for case 2; see below) were normal. The values for factor VIII-C (0.9/xg/ml), factor VIII-Ag (1.32/xg/ml), factor VIII-von Willebrand (Ristocetin cofactor) (1.16/xg/ml) were also normal. Platelet retention in a glass-bead column was at the borderline of normal values (74%). No further work except completion of platelet aggregation studies is considered until she can discontinue hormone therapy for an extended period of time, a circumstance not presently acceptable. All studies will be repeated at that time.

at 6 minutes, Factor VIII-C (1.23/xg/ml), VIII-Ag (1.06/xg/ ml), VIII-von Willebrand's (Ristocetin cofactor) (0.86 tLg/ ml), and platelet aggregation-to-ristocetin values were normal, and aggregation to ADP and epinephrine as described in case 5 (see below). Aggregation to strong collagen was normal; weak collagen and arachidonic acid tests were not done. She was considered to have a mild form of platelet storage pool disease. Menstrual bleeding is now controlled by oral contraceptives and medroxyprogesterone acetate (10 mg/day for the last 15 days of each menstrual cycle), and she does not use aspirin-containing drugs or other platelet-inhibitory drugs.

Case 2

This patient was the 14-year-old daughter of patient 1. As a child, she often bled for several hours from scratches or minor cuts. Menarche occurred at 13 years of age with a bleeding episode that lasted for 6 weeks. She had been taking 2 aspirins twice daily for the 3 days before being seen. Her subsequent menses were irregular and heavy. Laboratory study values were: hemoglobin, 9.4 g/dl; hemotocrit, 28.3%; MCV, 76.4; MCH, 25.3; platelet count, 335,000/mm3; partial thromboplastin time, 34/34 s; prothrombin time, 12.0/11.6 s. A reticulocyte count the following morning was 12.8%. Values for premenarchal hemoglobin had been 12.6 g/dl, reticulocytes 1%, and hemoglobin electrophoresis normal. The bleeding time was 15 minutes, tourniquet test results were negative, and platelet aggregation study values reflected the acquired aspirin-induced release defect, but aggregation was normal to ristocetin, making a diagnosis of von Willebrand's disease less likely. After recovery, her standard coagulation screen test result was normal, as was bleeding time

265

Case 3

This patient was the 13-year-old daughter of the first patient. At 5 years of age, she was struck by an automobile and had a massive hemorrhage requiring multiple blood transfusions. She remained in a coma for 3 weeks. She developed a spastic hemiplegia on the right side that was thought to be the result of a cerebrovascular accident. Menarche occurred at 11 years of age, and like her mother and sister she had irregular heavy menses. She was given medroxyprogesterone acetate for a while, but is not now taking any hormones. Her menses are normal and she also avoids taking aspirin. Her coagulation screening study values were normal, as were values for factors VIII-C (0.7 /xg/ml), VIII-Ag (0.66 /xg/ml), and VIII-von Willebrand's (0.84/,g/ml). Her bleeding time was normal at 6 minutes, tourniquet test results were negative, and platelet aggregation study values (as outlined for case 2) were normal. Her ptatelet retention result in a glass-bead column was decreased at 45%. Case 4

The fourth patient is the 12-year-old daughter of the first patient; she is premenarchial. During a recovery from a tonsillectomy several years ago, she required 3 units of blood and 2 units of fresh frozen plasma. On the seventh day after surgery, 24 hours after having been sent home in good condition, she hemorrhaged and went into shock. No bleeding site was identified until the day after transfusion when a second hemorrhage occurred upon which, under anesthesia, a small artery was found bleeding and was ligated. She has had no further problems. Because she was at the time the only member of the family not menstruating or receiving hormone therapy, she was elected to take the aspirin-tolerance test. Preadministration bleeding time was 6½ minutes; 2 hours after receiving 450 mg of aspirin, bleeding time was 17 minutes, and at 24 hours, it was 12 minutes. These seem excessively long when compared to similar and larger doses of aspirin as studied by others. Her coagulation screen and platelet aggregation study values, as outlined for case 2, were normal, as were the values for factor VIII-C (1.36 /xg/ml), factor VIII-Ag (0.84/xg/ml), and VIII-yon Witlebrand's (0.8/xg/ml). Platelet retention value was at the borderline of normal values (77%).

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clot retraction (these make up our coagulation screening battery); also normal were values for factor VIII-C (0.67 /zg/ml; 9.6-1.7 normal) factor VII&Ag (0.84/zg/ml; 0.5-1.7 normal), and VIII-von Willebrand's (1.24/zg/ml; Ristocetin cofactor, 0.4-1.6 normal). Platelet function screening study results were: bleeding time >1 h (<9 rain normal), tourniquet test results were negative. Other platelet study values were: platelet retention in a glass-bead column 90% (normal, >79%), platelet retention in a standard wound (Borchgrevink test) 0%, with venous platelet count of 101,000 mm 3 and wound counts of 162,000 mm 3 (slowutilization in wound--the expected reduction of wound blood below venous blood is at least 25%). Aggregation studies over a period of several years consistently showed the absence of a second-wave response to ADP and epinephrine, absent response to weak collagen, defective response to strong collagen, normal response to ristocetin, and absent response to arachidonic acid (Figures 1, 2, 3). The electron micrographs made of the platelets undergo-

Case 5

The fifth patient is a 13-year-old girl. She had a history of easy bruising and epistaxis. No one else in her family had such a history. When she was I year old, she experienced prolonged bleeding after her family physician lanced a furuncle. At 2 years of age, the diagnosis of idiopathic thrombocytic purpura was made. Screening for coagulation disorders revealed a prolonged bleeding time and mild thrombocytopenia (76,000-176,000/mm3). An examination was also made when she was 4 years old because of her history of easy bruising. At that time, laboratory studies revealed a normal prothrombin time, partial thromboplastin time, and clot retraction. She continued to have nosebleeds and easy bruising. At age 9 years, she experienced heavy bleeding after a tonsillectomy, even though her platelet count was normal. She had no more problems until she was 12 years old, when she was hospitalized for idiopathic abdominal pain, which subsided uneventfully. Her diagnostic examination includes the following normal coagulation parameters: whole-blood Euglobulin lysis time, fibrin split products, fibrinogen, factor XIII stability, partial thromboplastin time, protbrombin time, prothrombin consumption time, Russell's viper venom (Stypven) time, thrombin time, whole blood clotting time,

Figure 1. A. Aggregation to epinephrine (10 tu~d): (g) patient 5; (h) control. B. Aggregation to collagen: (i) patient 5, weak collagen; (j) patient 5, strong collagen; (k) control, weak collagen, strong collagen similar.

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ing these responses confirmed the presence of dense bodies and their defective release. The final studies, yet to be done, involve liberating the platelet organelles and studying them for content of ADP, adenosine triphosphatase, serotonin, and platelet factor 3. Currently, the results of the physical examination of all five patients are normal.

Discussion Clinical and historical data for all five patients were consistent with a hematologic disorder. Three of the patient s had had menstrual irregularities from the time of menarche, but a bleeding disorder had not been demonstrated by conventional coagulation studies. Southam and Richart (8) reviewed the cases of all adolescents with DUB and oligomenorrhea seen at Columbia-Presbyterian Medical Center over a 25-

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year period. They discovered that 50% of the 291 adolescents continued with their problem for more than 4 years after menarche, but they noted that the prognosis was better if bleeding became normal within 2 years of menarche. Claessens and Cowell (3) demonstrated that defective hemostatic mechanisms were partly responsible for DUB and acute menorrhagia in their adolescent patients. These authors concluded that one in five adolescents with acute menorrhagia has a hemostatic disorder serious enough to require hospitalization. In the 11 cases of acute adolescent menorrhagia (3) these patients were found to have primary coagulation disorders: four had idiopathic thrombocytopenic purpura, three had von Willebrand's disease, two had Glanzmann disease (thrombocytopenia), and there was one case each of Thalassemia major and Fanconi's anemia. In the same study it was found that of the adolescents with coagulation disorders resulting in acute menorrhagia, one in four had hemoglobin counts of less than 10 g/dl, one in three patients required a

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JOURNAL OF ADOLESCENT HEALTH CARE VoI. 3, No. 4

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transfusion, and one in two patients hemorrhaged at menarche. The prognosis for patients with abnormal menses tends to depend on the clinical history and duration of the problem. The incidence of subsequent morbidity (conditions that require transfusions, dilatation and curettage, and laparotomy), infertility (11), and carcinoma of the endometrium (11,12) appears to be higher in patients who begin to hemorrhage at menarche and continue to have DUB. Adolescents with DUB and acute menorrhagia with a history of bleeding should be evaluated for PSPD. The results of the conventional bleeding parameters, with the probable exception of the bleeding time, will be normal. If the patient's bleeding time is prolonged, or if she has a history of bleeding, the patient should be referred to a hematologist for a comprehensive evaluation to include a screen for factor XIII deficiency, for von Willebrand's disease, and for functional platelet disorders (13,14) by observing platelet aggregation in response to collagen, ADP, epinephrine, and arachidonic acid. The storage pool disorders are distinguished most simply by their

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ability to aggregate normally in response to strong stimuli and their inability to demonstrate with weak stimuli, such as epinephrine and critical concentrations of ADP and collagen, that they can recruit a full-scale response via the release of their internal organelles. The latter requires functional organelles to be present and an intact arachidonic acid-cyclooxygenase-prostaglandin endoperoxidase-thromboxane A2 pathway. It is seen as a second wave of activity after the initial response in the aggregometer tracing with ADP and epinephrine, and the single response after a lag phase with collagen. If these responses are lacking and there is no response, or a defective response, with arachidonic acid, then the problem lies with the release mechanism pathway (Figures 1, 2, and 3). Currently, patients with PSPD are advised to avoid aspirin or aspirinlike drugs because salicylates prevent cyclooxygenase from converting arachidonic acid

January 1983

PSPD IN ADOLESCENTSWITH UTERINEBLEEDING

269

into thromboxane and prostaglandin by acetylating its binding sites. Most of the congenital coagulation disorders can be treated by replacement of the deficient protein component; in the case of PSPD, however, replacement therapy with plasma or plasma fractions is not beneficial (12,13). Transfusions of platelets should be restricted to use during surgical procedures and for hemorrhages not responding to the usual methods of securing hemostasis. Patients with PSPD may not need platelet transfusions for sutured wounds or wounds where adequate pressure can be applied. They may however, hemorrhage from the wounds of dilatation and curettage or parturition. Several approaches can be taken to the treatment of PSPD hypermenorrhea. Our first patient was treated with medroxyprogesterone acetate to induce endometrial atrophy. For our second patient, w h o had never required a transfusion, oral contraceptives were effective until late in her menstrual cycle, when she experienced breakthrough bleeding and then hemorrhaged. In this case, the breakthrough bleeding was caused by insufficient progestin and androgen. When additional progesterone was prescribed in combination With the oral contraceptives her cycles became regular. Platelet-enriched plasma or platelet conCentrates should be given to patients With PSPD before surgery. Platelet transfusions should not be used routinely in these patients because they may result in the development of antiplatelet antibodies (14). Other forms of PSPD treatment may be considered. Dietary control (15) was considered because prostaglandins are known to be important in platelet aggregation and are derived from arachidonic acid. Increased dietary intake of meat and fish may raise the level of prostaglandins (PG) D2, E2, G2, I2, and H2. Unfortunately, some of these 20-carbon moieties have antagonistic effects. The PGD2 and PGI2, which are metabolized in vessel walls, are potent vasodilators and antiaggregators of platelets, whereas the thromboxane A2j PGE2, PGG2, and PGH2 formed on plateletS are strong platelet aggregators and vasoconstrictors (16). At present, the ability to manipulate the diet selectively has not been effectively demonstrated. Another potential therapy is danazol, a 2,3-isoxazole derivative of 17-ethynyltestosterone, which is used for the treatment of DUB, menorrhagia, endometriosis, precocious puberty, and cystic mastitis. Danazol is postulated to affect the estrogen and progesterone receptors of the endometrium (17), thus

causing amenOrrhea or oligomenorrhea. Danazol may significantly reduce the amount of menstrual blood (18,19). Danazol, however, is expensive, and it may be associated with side effects such as weight gain and musculoskeletal pain. Although it has been used for some inpatients with hypermenorrhea, none have had a known coagulopathy. In conclusion, the following procedure is recommended: An adolescent patient who hemorrhages at menarche and has a history of bleeding problems should have a hematologic evaluation. The measurement of bleeding time may identify those patients with von Willebrand's disease and PSPD. Many of the patients found to have defective hemostasis can be treated with hormones.

References 1. Pohle FJ: The blood platelet count in relation to menstrual cycle in normal women. Am J Med Sci 197:40-47, 1939 2. Dameshek W, Rheingold JJ: Idiopathic thrombocytopenic purpura and menorrhagia mistakenly treated for local disease: Report of 4 cases, lAMA 139:993-996, 1949 3. Claessens EA, Cowell CA: Acute adolescent menorrhagia. Am JObstet Gynecol 139:227-280, 1981 4. Radman HM: Blood dyscrasia as a causative factor in abnormal uterine bleeding. A m J Obstet GyneCol 79:1-4, 1960 5. Adashi E, Farber M, Mitchell GW, Jr: Congenital release thrombocytopathy: Pathophysiology and management. Obstet Gynecol 48:403-406, 1976 6. Holmsen H, Weiss HJ: Hereditary defect in the platelet release reaction caused by a deficiency in the storage pool of platelet adenine nucleotides. Br J Haematol 19:643-649, 1970 7. Bloch B, Dort H: Thrombocytopathia as a cause of menorrhagia: Two case reports. Br J Obstet Gynecol 84:956-957, 1977 8. Southam AL, Richart RM: The prognosis for adolescents with menstrual abnormalities. Am JObstet Gynecol 94:637-643, 1966 9. Altchek A: Dysfunctional uterine bleeding in adolescence. Clin Obstet Gynecol 20:633-650, 1977 10. Bachmann F: Diagnostic approach to mild bleeding disorders. Semin Hamatol 17:292-305, 1980 11. Smith JB, Ingerman C, Docsis lJ, Silver MI: Formation of an intermediate in prostaglandir~ biosynthesis and its association with the platelet release reaction. J Clin Invest 53:1468-1472, 1974 12. Romney SL, et al.: Gynecology and obstetrics: The health care of women. 2nd ed. New York, McGraw-Hill, 1980 13. Miale JB: Laboratory medicine hematology. 5th ed. St. Louis, CV Mosby, 1977 14. Cash JD: Platelet transfusion therapy. Clin Haematol 1:395411, 1972 15. Remuzzi G, Mecca G, de Gaetano C (eds): Hemostasis, pros° taglandins and renal disease. New York, Raven Press, 1980 16. Greenblatt RB, Oettinger M, Borestein R, Bohler C: Influence of danazol (100rag) on conception and contraception. J Reprod Med 13:201-203, 1974

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17. Guillebaud J, Fraser IS, Thorburn GD, Jenkin G: Endocrine effects of danazol in menstruating women. J lnt Med Res 5(Suppl 3).:57-66, 1977 18. Chimbira TH, Cope E, Anderson ABM, Bolton FG: The effect of danazol on menorrhagia, coagulation mechanisms, he-

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matoiogical indices and body weight. Br. j Obstet Gynecol 86:46-50, 1979 19. Cope E: Danazol in the treatment of menorrhagia. Drugs 19:342-348, 1980