Two cases of myomectomy complicated by intravascular hemolysis and renal failure: disseminated intravascular coagulation or hemolytic uremic syndrome?

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1 CASE REPORT Two cases of myomectomy complicated by intravascular hemolysis and renal failure: disseminated intravascular coagulation or hemolytic uremic syndrome? Ioannis Tsimpanakos, M.D., a John Connolly, Ph.D., b Kyriaki S. Alatzoglou, M.Sc., c Camilla Rowan, M.B., B.S., B.Sc., d and Adam Magos, M.D., B.Sc., M.B., B.S., a a Minimally Invasive Therapy Unit and Endoscopy Training Centre, University Department of Obstetrics and Gynaecology, Royal Free Hospital, Hampstead; b Department of Nephrology, Royal Free Hospital, Hampstead; c UCL Institute of Child Health; and d Department of Histopathology, Royal Free Hospital, Hampstead, London, United Kingdom Objective: To present two cases of myomectomy complicated by intravascular hemolysis leading to acute renal failure and discuss the differential diagnosis and possible mechanism. Design: Case report. Setting: Minimally Invasive Therapy Unit, University Department of Obstetrics and Gynecology. Patient(s): Two premenopausal patients with uterine fibroids. Intervention(s): Both patients underwent otherwise uncomplicated myomectomies, one by laparotomy and one by laparoscopy, with tourniquets around the uterine and ovarian vessels being used to control intraoperative bleeding. Main Outcome Measure(s): Renal function in the postoperative period. Result(s): Both patients developed a very rare complication after surgery of severe thrombocytopenia with microangiopathic hemolytic anemia leading to acute renal failure. One patient made a full recovery within weeks but the other still has reduced renal function almost 2 years after the surgery. The differential diagnosis consisted of disseminated intravascular coagulation or hemolytic uremic syndrome. Conclusion(s): The etiology of thrombotic microangiopathy in these patients was unclear, but disruption and manipulation of fibroids during surgery may have led to the dissemination of pro-coagulant tissue factor containing particles leading to disseminated intravascular coagulation or hemolytic uremic syndrome, perhaps aggravated by utero-ovarian ischemia caused by the tourniquets. (Fertil Steril Ò 2010;93:2075.e11 e15. Ó2010 by American Society for Reproductive Medicine.) Key Words: Myomectomy, fibroids, renal failure, hemolytic uremic syndrome, coagulopathy Received August 31, 2009; revised November 9, 2009; accepted November 10, 2009; published online January 13, I.T. has nothing to disclose. J.C. has nothing to disclose. K.S.A. has nothing to disclose. C.R. has nothing to disclose. A.M. has nothing to disclose. Reprint requests: Adam Magos, B.Sc., M.B., B.S., M.D., FRCOG, Minimally Invasive Therapy Unit and Endoscopy Training Centre, University Department of Obstetrics and Gynaecology, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, UK (FAX: þ 44 (0) ; a.magos@medsch.ucl.ac.uk). Uterine leiomyomas are common benign tumors with a reported incidence of almost 80% in women of Afro-Caribbean origin (1). For women who wish to retain their fertility, myomectomy still remains the treatment of choice, and in many cases this means undergoing laparotomy or less often laparoscopic surgery depending on the size, number, and site of the fibroids. In the United States, for instance, >40,000 myomectomies are performed annually, with about 2,000 in the United Kingdom (2, 3). The major risk of myomectomy is intraoperative hemorrhage, sometimes necessitating hysterectomy. Various strategies are available to reduce this risk, of which the use of triple tourniquets to occlude the uterine blood supply during surgery has been found to be the most effective (4, 5). If intraoperative bleeding is excessive despite these measures, immediate blood replacement is an effective treatment. It is known that a possible complication of massive hemorrhage is disseminated intravascular coagulation (DIC) with hemolysis and acute renal failure (6, 7). To our knowledge, there have been two reports of acute renal failure following uncomplicated myomectomies, one thought to be secondary to DIC, the other to hemolytic uremic syndrome (HUS) (8, 9). We present two patients who underwent otherwise uncomplicated myomectomies, one by laparotomy one by laparoscopy, who developed severe microangiopathic hemolytic anemia postoperatively, leading to acute renal failure. We discuss the possible mechanisms involved, and the difficulty of distinguishing DIC from HUS. CASE 1 A 45-year-old nulliparous woman presented to the gynecology clinic with a history of menorrhagia for 5 years and acute urinary /10/$36.00 Fertility and Sterility â Vol. 93, No. 6, April e11 doi: /j.fertnstert Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc.

2 TABLE 1 Laboratory results for Case 1. Normal range Pre-Op Day 1 Day 2 Day 4 Day 6 Day 9 Day 11 Day 13 Day 15 Day 20 Hb g/dL Platelets /L WBC /L Reticulocytes % Haptoglobin g/L <0.2 <0.2 < INR Ratio PT seconds APTT seconds Na mmol/l K mmol/l 4.3 High High High Urea mmol/l Creatinine mmol/l LDH U/L 2, Hemodialysis <-* * * * * *-> Plasma exchange < > Pre-Op ¼ before laparotomy; LDH ¼ lactate dehydrogenase; INR, international normalized ratio; WBC, white blood cell; APPT ¼ activated partial thromboplastin time; PT ¼ prothrombin time; *denotes day of hemodyalisis; <-> period of plasma exchange. retention. Pelvic ultrasound examination confirmed a fibroid uterus with the presence of three intramural fibroids, the largest one measuring mm. The patient had a family history of venous thromboembolism; following investigation it was noted that she had low levels of protein-c and protein-s, which were normalized after treatment with vitamin K supplements (10 mg twice weekly for 2 weeks). There was no evidence of abnormality of factor V-Leiden or of prothrombin 3-UTR, and the full blood count and renal function tests were normal. She underwent open myomectomy via a low transverse incision when the uterus was found to be enlarged to the size of a 16-week pregnancy. Triple vicryl tourniquets were tied around the cervix (to occlude the uterine vessels) and both infundibulopelvic ligaments (to occlude the ovarian vessels) for hemostasis. Three fibroids were excised weighing a total of 502 g. All three tourniquets were removed after 25 minutes. The estimated blood loss was 300 ml, and there were no complications. A size 10 Redovac drain was left in the pouch of Douglas, with minimal output until it was removed after 2 days. The patient was hemodynamically stable following surgery, with a urine output of 720 ml in the first 24 hours (average 30 ml/h). A routine full blood count on the day after surgery revealed severe thrombocytopenia, with a platelet count of /L and a hemoglobin of 9.5 g/dl. Examination of the blood film showed features of microangiopathic hemolytic anemia with thrombocytopenia, numerous red cell fragments, occasional spherocytes, and irregularly contracted cells. The serum lactate dehydrogenase (LDH) was up to 2,875 U/L and haptoglobin reduced <0.2 g/l. Clotting time was deranged, with an international normalized ratio (INR) of 1.5, Prothromgin time (PT) 20.1 seconds and activated partial thromboplastin time (APTT) 32.4 seconds. The patient developed oliguria and acute renal failure with urea up to 23.1 mmol/l and creatinine up to 450 mmol/l. Results are shown in detail on Table 1. There was no evidence of postoperative hemorrhage. A differential diagnosis of DIC or HUS was made. She was transfused blood and fresh frozen plasma (FFP), underwent daily plasma exchange for 8 days (from the 2nd to 10th postoperative day), and had six sessions of hemodialysis. After 8 days, the LDH fell to 811 U/L and the platelet count rose to /L. Serum ADAMTS-13 was >50% (normal range 60% 120%). Urine output returned and renal function improved with creatinine of 338 mmol/l on day 20. She discharged from the hospital on the 20th postoperative day when hematologic and biochemical markers were normal. CASE 2 A 39-year-old nulliparous woman presented to the gynecology clinic with a history of menorrhagia for almost 2 years. She was found to be anemic with hemoglobin of 9.2 g/dl and pelvic ultrasound showed a single posterior intramural fibroid measuring cm. She was treated with iron supplements and oral progestogens. The patient agreed to undergo laparoscopic myomectomy, and by the time of her admission her hemoglobin had improved 11.8 g/dl; all other full blood count indices were normal (Table 2). Laparoscopic myomectomy was performed using triple vicryl tourniquets for hemostasis (10), and a large fundal posterior fibroid was excised weighing 302 g. The two ovarian tourniquets were removed after 90 minutes once the uterine defect had been repaired, but the uterine tourniquet was left in situ to dissolve over the ensuing weeks. The estimated intraoperative blood loss was 300 ml, and there were no complications. A size 10 Redovac drain was left in the Pouch of Douglas. Six hours after surgery, the patient complained of abdominal pain and there was hemorrhagic leakage from the drain site. Her hemoglobin was found to be 10.5 g/dl with a platelet count of /L. Her vital signs remained stable at this time, and she had passed 980 ml of urine. Overnight, however, she became hypotensive and tachycardic, and was also noted to be anuric. Twelve hours later her hemoglobin and platelet count dropped to 5.3 g/dl and /L, respectively, and she had deranged clotting studies with an 2075.e12 Tsimpanakos et al. Intravascular hemolysis after myomectomy Vol. 93, No. 6, April 2010

3 TABLE 2 Laboratory results for Case 2. Day of surgery Normal range Pre-Op 6 hours 24 hours Day 1 Day 2 Day 4 Day 8 Day 10 Day 17 Day 24 Day 26 Hb g/dL Platelets /L WBC /L Reticulocyte % 4.9 Haptoglobin g/l <0.2 < INR < ratio PT seconds APTT seconds TT seconds 13.9 Fibrinogen g/l Na mmol/l K mmol/l Urea mmol/l Creatinine mmol/l LDH U/L 2,886 2,379 2, Hemodialysis < -* * * * * * > Pre-Op ¼ before laparoscopy; Day 1: first day after the laparoscopy; < > ¼ start of hemodialysis, which continued after discharge from hospital. * ¼ day of hemodialysis; LDH ¼ lactate dehydrogenase; INR, international normalized ratio; WBC, white blood cell; APPT ¼ activated partial thromboplastin time; PT ¼ prothrombin time. elevated INR (1.7) and reduced fibrinogen (1.2 g/l). She had evidence of acute kidney injury with elevated urea (8.8 mmol/l) and creatinine (239 mmol/l). A diagnosis of intraabdominal bleeding was made and she underwent immediate laparotomy with appropriate resuscitation with intravenous fluids, blood, FFP, and platelets. At laparotomy, an estimated 400 ml of blood was found in the peritoneal cavity and there was no evidence of active arterial bleeding from the uterine incisions. The uterine tourniquet was removed and the uterus was resutured. The total estimated blood loss during surgery was 2,000 ml, including blood already present in the abdominal cavity, and the patient received four units of blood and one unit of FFP. Postoperatively, her hemoglobin was 9.2 g/dl and her platelet count /L, and she was transferred to intensive therapy unit for further management. Despite resuscitation and support, she remained anuric and was started on renal replacement therapy on the second postoperative day, by which time her urea and creatinine had risen to 10.4 mmol/l and 298 mmol/l, respectively (Table 2). Further investigations showed that there were large platelets and platelet clumps but no red cell fragments on the blood. Clotting profile showed INR up to 1.7, PT 21.6 seconds, and APTT 31.0 seconds. A diagnosis of DIC was made. She remained stable on hemofiltration until the eighth day when she developed acute pulmonary edema. She remained thrombocytopenic and anemic, and was found to have elevated LDH at 2,886 U/L with undetectable haptoglobin (<0.2 g/l). A repeat blood film was performed showing features of a microangiopathic hemolytic anemia with red cell fragmentation. Investigations for predisposing thrombotic disorders were normal. A renal biopsy was performed on the 10th day and showed patchy cortical necrosis with the affected areas containing necrotic glomeruli, tubules, and interstitial tissues. Arteries and arterioles in these regions were necrotic and distended by thrombus (Fig. 1). These are features of renal cortical necrosis because of an acute thrombosing disorder such as DIC, HUS, or thrombotic thrombocytopenic purpura (TTP), the histologic appearances of which would be indistinguishable. A MAG3 renal scan showed poor renal function with little or no selective uptake. ADAMTs 13 assay was 74% (normal range 60% 120%). The patient was finally discharged from hospital 26 days after the myomectomy, still receiving regular hemodialysis. She remained on hemodialysis for a total of 2 months. At the time of writing 20 months after her surgery, her renal function is stable, with an isotopic glomerula filtration rate of 40 ml/min/1.73 m 2. DISCUSSION We have described two patients who developed severe microangiopathic hemolytic anemia (MAHA) and renal failure following myomectomy. These are not only extremely rare complications of this type of surgery, but our cases demonstrate the difficulties in identifying the precise cause of the microangiopathic hemolytic disorders. Thrombotic microangiopathy is a clinicopathologic syndrome characterized by the presence of hyaline thrombi in the microcirculation with resulting profound thrombocytopenia, microangiopathic hemolysis, and organ dysfunctions. In the patients described the findings of thrombocytopenia, anemia, increased LDH, and red cell fragmentation on blood film were compatible with thrombotic microangiopathy, the differential diagnosis including DIC, HUS, and TTP (11). Disseminated intravascular coagulation is characterized by the systemic activation of coagulation, microvascular deposition of fibrin, and resulting organ failure (12). The ongoing activation of the coagulation system and consumption of coagulation factors and platelets may result in bleeding from various sites. Disseminated intravascular coagulation may complicate a variety of disorders, the commonest of which are severe sepsis, trauma and hemorrhage, Fertility and Sterility â 2075.e13

4 FIGURE 1 Cortex from renal biopsy from patient 2 showing extensive cortical necrosis with a necrotic artery (arrow) and a thrombosed glomerulus (arrowhead). solid tumors, and hematologic malignancies, or obstetric causes such as placental abruption and amniotic fluid emboli (12). These conditions may result in the release of inflammatory cytokines (e.g., IL-6) and the induced expression of tissue factor on activated vascular endothelial and mononuclear cells. In addition, it seems that in DIC there is impairment of natural anticoagulant pathways such as antithrombin III, protein-c system and tissue factor pathway inhibitor, which further propagates coagulation and intravascular deposition of fibrin (13). Unfortunately, no single laboratory test is sufficiently accurate to allow a definite diagnosis of DIC (14). For instance, tests for the detection of fibrin degradation products have a sensitivity of 90% to 100%, but generally a low specificity and measurement of fibrinogen may not be helpful. As fibrinogen is an acute phase reactant, its concentration may remain within the normal range and hypofibrinogenemia is only detected in a relatively small percentage of DIC cases (15). The International Society of Thrombosis and Hemostasis has developed a scoring system for the diagnosis of DIC that takes this into account and scores the platelet count, fibrin degradation products, or D-dimer, PTT, and fibrinogen concentration. A score of >5 is compatible with overt DIC (16). Disseminated intravascular coagulation is usually distinguished from HUS and TTP by the laboratory sings of coagulation activation, fibrinolysis, and high plasma levels of D-dimers (17). Recent studies have demonstrated that patients with TTP are deficient in ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor; inherited or acquired deficiency in ADAMTS13 will result in intravascular platelet aggregation (18). HUS is characterized by normal ADAMTS 13 and the presence of renal impairment (19). Although diarrhea-associated HUS (Dþ HUS) occurs mainly in children and is the commonest form (>90%) caused in most cases by Shiga-toxin producing Escherichia coli (O157:H7), 5% to 10% of patients with HUS do not have antecedent gastrointestinal infection (D HUS). D HUS is heterogeneous with regard to its age of onset and etiology. It may be associated with complement dysregulation caused by mutations in factors involved in the alternative complement pathway. In both our cases, ADAMTS-13 were within the normal range (>50% and 74%, respectively), which goes against the diagnosis of TTP. The differential diagnosis between DIC and D HUS is more difficult. In the first case, D-dimers were not assayed but the profound thrombocytopenia (< L) and prolonged PT time (20 seconds) would result in borderline DIC score of 4 according to the above-mentioned scoring system. However, we think that this patient may indeed have had DIC, as the history of protein C-deficiency should also be taken into account. This is an aggravating factor, and may have contributed to the systemic activation of coagulation and the development of DIC. In the second case there were grossly elevated D-dimers (>1,000 ng/ml), prolonged PT (21 seconds) and low platelets ( /L) resulting in a score of 6, which is consistent with DIC. However, in this case there was severe and early renal impairment. Renal biopsy showed patchy cortical necrosis because of acute thrombosing disorder, but histologic appearances do not allow differentiation between HUS and DIC. We can only make assumptions for the etiology of thrombotic microangiopathy in our patients. Although DIC and consumptive coagulopathy can be the result of severe trauma and extensive surgery, it seems that the operative course has not been complicated by significant blood loss, and there was no indication of a hematoma. Neither were there signs of severe sepsis and no pathogenic organisms were isolated from cultures. It is known that high levels of tissue factor are present in the uterus. Therefore, there is the possibility that disruption and manipulation of fibroids during surgery may have led to the dissemination of pro-coagulant tissue factor containing particles and precipitated DIC. However, this hypothesis is difficult to prove. Another possibility is that uterine ischemia caused by the use of tourniquets precipitated and aggravated tissue factor release, resulting in microangiopathic endothelial damage, although a 25-minute tourniquet use in one case is not generally considered prolonged. In addition, in the first case, the possible underlying thrombotic tendency could have exacerbated DIC driven by tissue factor release. These two cases represent very rare complications that occurred in a large series of patients operated on in our hospital over the years. We suggest that gynecologists should be aware of their occurrence and monitor all patients carefully in the first postoperative hours. Early detection of a drop in platelet count and hemoglobin may be the first indication of this severe but rare complication, even in cases that did not seem to be surgically challenging. REFERENCES 1. Jacobson GF, Shaber RE, Armstrong MA, Hung Y-Y. Changes in rates of hysterectomy and uterine conserving procedures for treatment of uterine leiomyoma. Am J Obstet Gynecol 2007;196:601.e Data from the National Uterine Fibroids Foundation. Available at e14 Tsimpanakos et al. Intravascular hemolysis after myomectomy Vol. 93, No. 6, April 2010

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