Abstract
Bleeding into the corpus luteum following ovulation rarely has clinical significance in healthy women, but may lead to life-threatening hemorrhage in women with congenital or acquired bleeding disorders. Women who are at an increased risk for corpus luteum hemorrhage (CLH) can be divided in two categories; first, those taking anticoagulants because of a thrombotic disorder; and second, women with congenital bleeding disorders. The management and prevention of CLH is still unsettled and the literature dealing with this problem is based on case reports only. This review focuses on the pathophysiology, clinical presentation, diagnosis and treatment options of an acute bleeding event and prevention modalities of CLH in women with bleeding disorders.
Pathophysiology & diagnosis
In healthy women, spontaneous bleeding during ovulation into the corpus luteum is usually a minor event and, generally, is of no clinical significance or sequella. Characteristically, hemorrhage occurs during midmenstrual cycle subsequent to the vascularization phase following ovulation. The corpus luteum may become cystic and fill with blood and as the intraluminal pressure rises, rupture of the corpus luteum will occur resulting in intraperitoneal bleeding. The other mechanism for corpus luteum hemorrhage (CLH) is when the ovum is extruded from the Graafian follicle to form the corpus luteum [1].
While rupture of the corpus luteum may go unnoticed in healthy women, it may lead to a life-threatening intraperitoneal hemorrhage in women with congenital or acquired bleeding disorders. The clinical presentation is typical; the appearance of acute onset of abdominal pain at midmenstrual cycle, sometimes with evidence of circulatory compromise (syncope, hypotension and/or severe anemia). The differential diagnosis is broad and includes ectopic pregnancy, acute appendicitis, bowel perforation, adnexal torsion, endometriosis and CLH in pregnancy. Notably, the right ovary is usually involved [1].
Diagnosis of CLH is made by transabdominal or transvaginal ultrasound, CT scan, MRI, laparoscopy or explorative laparotomy. CLH should always be suspected whenever a premenopausal woman has an acute lower abdominal pain at her midcycle with a negative pregnancy test, new onset anemia and a personal or family history of congenital bleeding disorders or in women receiving anticoagulant (AC) treatment. Thus, women who are at increased risk for CLH can be divided in two categories:
Women taking ACs because of thrombotic disorders
Women with congenital or acquired bleeding disorders
In regard to the pathogenesis, as with other types of bleeding episodes in patients prone to bleeding, an important point regarding the site and severity of a hemorrhagic event is a possible underlying injured area that augments bleeding in the presence of hemostatic failure. Such is the case in a ruptured corpus luteum cyst or during oocyte expulsion from the Graafian follicle.
Management & prevention
The incidence of CLH is unknown as there are only case reports in the literature. The first case of hemoperitoneum in a women receiving AC treatment was reported in 1957 by Wesely et al. [2]. Since then, there have been numerous reports of CLH episodes in women taking ACs, most often with warfarin [3–7]. The indications for warfarin in those women were venous thromboembolism, atrial fibrillation, recurrent thrombotic episodes, thrombophilic disorders, antiphospholipid syndrome and postmechanical heart valve replacement.
Corpus luteum hemorrhage resulting in hemoperitoneum has also been described in various congenital and acquired bleeding disorders, such as hemophilia A and B, afibrinogenemia, Factor X, XIII, V, II and VII deficiencies, Von Willebrand disease (VWD) and thrombocytopenia (
Case report of corpus luteum hemorrhage in bleeding disorders.
APLS: Antiphospholipid antibody syndrome; FFP: Fresh-frozen plasma; MHVR: Mechanical heart valve replacement; OCP: Oral contraceptive pill; PC: Packed cells; PCC: Prothrombin complex concentrates; SPD: Storage pool disease; VWD: Von Willebrand disease.
The management of acute bleeding in both categories (AC treatment and bleeding disorders) is virtually the same, at least at the onset of the bleeding episode. This includes stopping AC treatment, and circulatory stabilization by fluids and blood transfusion. In addition, reversal of the AC effect is carried out by administering fresh-frozen plasma or prothrombin complex concentrates (PCC) in cases of severe bleeding with supratherapeutic international normalized ratio (INR) levels. In women with congenital clotting factor deficiencies, a specific factor therapy is the appropriate way to secure hemostasis. Sometimes, the conservative approach is sufficient to control the bleeding event without the need for surgical intervention and is of course, the preferred way of management. The surgical modality of treatment includes laparotomy or laparoscopic oophorectomy with or without salpingectomy to control the source of bleeding. Another way to control bleeding is corpus luteum cystectomy and local hemostasis to preserve the ovary. The best modality we would suggest is the conservative one if the patient can be stabilized properly. Otherwise, a laparoscopic intervention with limited hemostatic control is preferred [17].
Regarding the prevention of recurrences, suppression of ovulation with the use of hormonal agents, such as oral contraceptives, gonadotropin-releasing hormone analogues or progestatins, is an effective method.
In the following section we present some illustrative case reports that describe and demonstrate the management of CLH episodes. Payne et al. describe three women presenting with hemoperitoneum in association with Factor VII and X deficiencies [8]. These patients were managed with blood products and factor concentrate (recombinant factor VIIa and PCC, accordingly), which was successful in avoiding surgery in two out of three bleeding episodes. The patients were then started on a combined oral contraceptive pill (OCP) that prevented further bleeding episodes. In a recent case report [15], three patients were described. One patient with a prosthetic heart replacement was administered AC therapy (warfarin and aspirin) and bled owing to corpus luteum rupture. She underwent emergency laparatomy and salpingoophorectomy and was discharged with preventive OCP. Another patient in this report had antiphospholipid syndrome and was administered warfarin. She had two CLH episodes and underwent laparatomy and oophorectomy in both episodes. The patient restarted warfarin after discharge. Sönmezer et al. investigated the safety of depot medroxyprogesterone acetate (DMPA) in women with prosthetic heart values as well as the impact of DMPA on the prevention of CLH in these patients [16]. This prospective study enrolled 13 patients, and DMPA was initiated after a first bleeding episode. Over a mean follow-up of 40 months, 12 women remained well with no hemorrhagic corpus luteum under therapeutic INR. The authors concluded that DMPA is an effective contraceptive agent to suppress ovulation in anticoagulated women with prosthetic heart valves and can be used to prevent CLH.
Another study prospectively compared the differences between laparoscopy and laparotomy in managing women with CLH and hemoperitoneum [17]. This prospective study demonstrated that laparoscopic surgery had significant advantages over laparotomy as a diagnostic and therapeutic procedure, mostly owing to shorter hospitalization. In our center, we have encountered six women with 11 episodes of CLH between 1996 and 2008 in total. Four women were treated with ACs (including low molecular weight heparin), one woman had VWD type II and the other FVII deficiency. Eight of the 11 CLH episodes occurred in women taking ACs and three episodes occurred in woman with a bleeding diathesis. The INR in two bleeding episodes was supratherapeutic and in four episodes it was in the therapeutic range.
Among the cases, a 12-year-old girl with severe FVII deficiency (FVII antigen and activity <1%), with lifelong threatening bleeding episodes was treated with FVII concentrate on demand. In the last 3 years, she was administered FVII prophylactic regimen: 600 international units (IU) of human factor VII (Baxter Healthcare, IL, USA) three times a week. She was admitted to the children's department on her first menstrual cycle because of excessive bleeding. Transabdominal ultrasound showed a CLH of the right ovary with hemoperitoneum. She was hemodynamically stable and was managed with tranexamic acid 1 g three times a day and 600 IU of human FVII concentrate. She was released with combined OCPs in order to prevent recurrences for a period of 6 months. This is the first report of a 12-year-old girl with FVII deficiency who suffered from CLH in her first menstrual cycle. In our series, we have treated protein S-deficient women with an INR of 6 with PCC to normalize the INR, and another women with VWD was treated with VWD concentrate (Hemate P) to support her hemostatic failure (
Rambam medical center experience (1996–2008).
AC: Anticoagulant; APS: Antiphospholipid syndrome; AT: Antithrombin; CLH: Corpus luteum hemorrhage; FFP: Fresh-frozen plasma; FVII: Factor VII; FVL: Factor V-Leiden; Homo: Homozygous; INR: International normalized ratio; PC: Packed cells; PCC: Prothrombin complex concentrate; VWD: von Willebrand disease.
Although numerous reports exist, since there are only retrospective case reports in the literature, it is difficult to draw conclusions regarding the management or prevention of those potentially catastrophic bleeding events, but from these reports we can nevertheless highlight several important observations:
A single woman may have several episodes of CLH during her reproductive life;
The INR, which reflects the intensity of warfarin effect, can be in the therapeutic range during a bleeding episode, instead of being supratherapeutic;
CLH may occur under other AC treatment except warfarin (e.g., low molecular weight heparin or aspirin).
The problematic issues regarding CLH are:
The magnitude of the problem is unknown;
The management of an acute bleeding episode in both categories: AC treatment and bleeding disorders (congenital or acquired) is not well defined;
The appropriate timing of resuming AC treatment following an acute episode is unclear;
The prevention of recurrences during ovulations, especially in the case of AC therapy because of thrombophilia or recurrent thromboembolism, is problematic since OCPs are potentially thrombogenic. Is it safe to give both AC therapy with hormonal agents?
How to manage difficult situations such as bleeding in women with high thrombotic risks (e.g., heart valve replacement, antiphospholipid syndrome and recurrent thrombosis);
The role of tranexamic acid or prophylactic factor concentrates during ovulations has yet to be explored;
The proper management of a woman with bleeding diathesis who wants to be pregnant and has to stop OC is unclear. Should we advise her to seek other means of getting pregnant (e.g., IVF)?
Future perspective
Since CLH is a potentially life threatening bleeding event in premenopausal women with acquired or congenital bleeding disorders, we have to define the exact incidence of the problem and determine the optimum management in the setting of an acute event as well as modes of prevention.
In order to gather information about cases of CLH, we have suggested an International Registry. This suggestion has been presented at the Scientific and Standardization Committee meeting that was held in Vienna on July 2008, in the subcommittee of Women Health Issues, and this Registry will be soon available at the International Society on Thrombosis and Haemostasis website. This registry will cover all aspects of CLH episodes, such as modes of diagnosis and treatment, types of AC agents causing the bleeding and modes of prevention. From the information gathered, we will be able to learn more about the best ways of dealing with the problem of CLH.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Executive summary
Bleeding into corpus luteum cavity following ovulation rarely has clinical significance in healthy women.
Rupture of corpus luteum may lead to life-threatening hemorrhage (hemoperitoneum) in women with congenital or acquired bleeding disorders.
The basis for corpus luteum hemorrhage (CLH) is an underlying hemostatic failure when the ovum is extruded from the Graafian follicle or an ovarian cyst rupture.
There are two categories of women at risk: those who are treated with anticoagulants because of thrombotic disorders, and those with bleeding disorders.
The incidence of CLH is unknown as there are only case reports in the literature.
The management of an acute episode is conservative (circulatory stabilization and replacement of clotting factors) or surgical (oophorectomy with or without salpingecotmy by laparotomy or laparoscopy).
The principle way to prevent recurrences is to suppress ovulation by hormonal agents.
In order to gain more information and draw specific conclusions about the optimal management, especially in difficult situations such as in high thrombotic risks situations, an international registry is underway and will be published at the International Society on Thrombosis and Haemostasis website.