Studies on fibrinopeptide A, fibrinopeptide B beta 15-42 and inhibitors of blood coagulation and fibrinolysis during use of oral contraceptives]

To examine a change occurring in the coagulation-fibrinolytic system during oral contraceptive (OC) administration, the author measured fibrinopeptide A and Bbeta15-42 (FPA and FPBbeta15-42) over a long period of time. These are sensitive indicators of coagulation and fibrinolytic activity as well as coagulation fibrinolysis inhibiting factor plasma antithrombin III (AT III) and alpha2 plasmin inhibitor (alpha2 PI). The interesting results are listed as follows. 1) FPA showed almost no change during OC administration, nor was thrombin observed to have been produced. 2) FPB15-42 increased when the drug was administered 3-5 times and 11-12 times (p0.05) but showed significant difference when the drug was administered for the 18th and 24th times. 3) Plasma AT III activity decreased significantly (p0.05) when the drug was given for the 1st time but showed no change when the drug was administered 3-5 times. When administered 11-12 times, AT III was observed to decrease again, but repeat administrations did not cause AT III to decline; this was probably due to inurement. A similar change in immune activity concentration was observed but the change was slight. 4) When the drug was given 3-5 times following the 1st administration, a slight decrease (p0.1) occurred in alpha2 PI levels, but no change worth of mention was noted to occur thereafter. 5) In patients who received norethisterone 5 mg alone, no particular change was seen to occur in FPA, FPBbeta15-42, AT III, or alpha2 PI. Judging from the above results, especially that there was an increase in FPA, the decrease in AT III levels may be attributed not to a reduction in consumption but to a decrease in the AT III itself, due to estrogens. It is possible also that an increase in FPBbeta 15-42 led to plasmin production which was the reason so few thromboses were observed to form. (author's modified)     

Antithrombin III levels in normotensive and hypertensive pregnancy

Antithrombin III (AT III) is the main physiological inhibitor of blood coagulation. In a prospective study, plasma AT III was determined in 653 women during pregnancy, using an automated amidolytic technique. A control value 8 weeks after delivery was obtained in 192 of the women. In women with pregnancy-induced or aggravated hypertension a significant decrease in AT III levels was observed compared with normotensive controls of the same period of gestation and compared with the patients' own control values 6-8 weeks after delivery. No AT III depression occurred in patients with chronic hypertension during pregnancy. Patients with pregnancy hypertension and proteinuria had lower AT III levels than those without proteinuria, whose AT III levels were also depressed. Lowest AT III levels were seen in 2 eclamptic patients and in patients with severe preeclampsia, whose pregnancies were terminated for fetal distress while the infants were still preterm. Monitoring At III levels is of value in preeclampsia.     

Adjuvant CMF-chemotherapy and haemostasis. Effect of "classical" and "modified" adjuvant CMF-chemotherapy on blood coagulation fibrinolysis in patients with breast cancer

Effects of "classical" and "modified" adjuvant CMF-chemotherapy on haemostasis were studied in 22 patients with breast cancer receiving cyclophosphamide (100 mg/m2 p.o.; days 1-14 or 600 mg/m2 i.v.; days 1,8), methotrexate (40 mg/m2 i.v.; days 1,8) and 5-fluorouracil (600 mg/m2 i.v.; days 1,8). Blood collection was done prior to chemotherapy on day 1 and 8. A significant decrease of protein C antigen and activity associated with cumulative effects was observed from day 1 to 8. This effect was similar with "classical" and "modified" CMF-chemotherapy but the reduction of protein C was more pronounced with the oral application of cyclophosphamide. In absence of any significant cumulative decrease of other vitamin K-dependent blood coagulation proteins (factor VII, protein S), the simultaneous decrease of protein C activity and antigen indicates a specific influence of CMF-chemotherapy on vitamin K-dependent protein C-synthesis in the liver.     

Correlation between grade III placenta and plasma antithrombin III activity in full term pregnancy

We evaluated whether the presence of a grade III placenta correlates with blood hypercoagulability in pregnancy between 37 and 39 weeks of gestation. The placenta was graded by ultrasound in 155 healthy full-term women and the plasma levels of antithrombin III (AT III) activity, thrombin-antithrombin complex (TAT) and D-dimer were correlated with each placental grade. AT III activity levels tended to decrease with advancing placental grade from I to III (p < 0.05). D-dimer showed the same tendency while TAT did not. The incidence of reduced AT III activity levels (<70%) in women with a grade III placenta was about twice those in women with a grade II or I placenta, and that of AT III <80% was 3-fold greater. We concluded that the presence of a grade III placenta in full-term pregnancies correlates with blood hypercoagulability.     

The changes of alpha 2-plasmin inhibitor, and notably urokinase activities in blood measured by synthetic chromogenic substrates S-2444 after urokinase administration

Thrombolytic therapy with Urokinase (UK) has often been successful but it is very difficult to determine the effective dosage of UK. It is reported that after UK administration, plasmin fibrinolytic activity was immediately inhibited by alpha 2-Plasmin inhibitor (alpha 2-PI). In this study, we used UK on patients with myoma to prevent the occurrence of thrombosis after operation and the initial decrease in alpha 2-PI activities following UK administration was investigated to determine the minimum effective dosage of UK required to suppress alpha 2-PI. An attempt was also made to measure UK activity in blood by means of chromogenic substrate S-2444, and in some cases by administering 60,000 I.U. UK, alpha 1-Antitrypsin (alpha 1-AT), alpha 2-Macroglobulin (alpha 2-M), Antithrombin III (AT III) and Plasminogen (Plg) were measured at the same time. The results were as follows: 1) By the drip infusion method. In all doses, alpha 2-PI and UK activity showed no remarkable change. 2) By the one shot method. a) A decrease in alpha 2-PI was observed following both 48,000 and 60,000 I.U. UK administration. It was noted that in the case of 48,000 I.U. UK, alpha 2-PI showed the lowest level, 60% of the pre-administration level. b) UK activity showed a gradual increase in the case of 60,000 I.U. UK only and large changes in the other cases. c) alpha 1-AT, alpha 2-M, AT III and Plg produced no remarkable changes. This indicated that the effective dosage of UK for suppressing alpha 2-PI was at least 48,000 I.U. UK with the one shot method, and alpha 2-PI is a reliable indicator of the effectiveness of UK therapy.     

Studies on inhibitors of blood coagulation and fibrinolysis during use of oral contraceptives]

The authors studied antithrombin 3 (AT3), alpha1 antitrypsin (alpha1 AT), and alpha2 macroglobulin (alpha2 M) in Japanese women taking oral contraceptives (OCs). These are the results. 1) In women receiving combined OCs (mestranol 0.1 mg and norethisterone 2 mg) for 20 days every cycle, serum AT3 activity had markedly decreased after completion of the 1st series. In successive series, no significant difference was observed between the values before and after treatment. AT3 activity was almost equal to that of control values in the 3rd-5th series of treatments and then displayed a tendency to decrease. Changes in plasma AT3 activity was almost the same as those in the serum. 2) A marked decrease in serum and plasma AT3 activity was also observed for women taking low dosage combined OCs (mestranol 0.05 mg and norethisterone 1 mg). It seemed ineffective to reduce the estrogen component of the OCs for purposes of preventing the decrease in AT3 activity. 3) Use of norethisterone alone, 5 mg/day for 20 days, did not induce remarkable changes in both serum and plasma AT3 activity, although it is considered 1 of the estrogenic gestagens. 4) AT3 activity in Japanese women was considerably higher than that reported in Western women. This perhaps could explain the low incidence of thromboembolic disease in Japanese women. 5) Serum alpha1 AT had significantly increased after the initial cycle and kept high concentrations for the succeeding 24 series. 6) OCs had no influence on the concentrations of alpha2 M and FDP in serum. (author's modified)     

Antithrombin III activity in normal and toxemic pregnancies.

From August 1989 to October 1990, 83 pregnant Chinese women were the subjects for measuring the levels of plasma functional antithrombin III (AT III) activity. The correlations of AT III activity with perinatal outcome and the changes in maternal hepatorenal function were analyzed. The population was divided into four groups: Group I (n = 30), normal pregnancies; Group II (n = 23), mild pre-eclampsia; Group III (n = 26), severe pre-eclampsia; and Group IV (n = 4), eclampsia. The results demonstrated that: 1) AT III activity decreased with the severity of toxemia (p < 0.001), 2) AT III activity correlated with the degree of perinatal outcome and maternal morbidity, and 3) reduction of AT III activity correlated with impairment of maternal hepatorenal function. In conclusion, plasma AT III activity is a valuable parameter in the evaluation of toxemia.     

Prophylaxis of thrombosis in antithrombin III-deficient women during pregnancy and delivery

Prophylactic treatment of two asymptomatic antithrombin III (AT III) -deficient women with oral anticoagulants and heparin during pregnancy and after delivery appeared to be feasible. Oral anticoagulants caused no change in plasma AT III levels in either woman. A high dose of heparin intravenously in one of them caused a strong reduction in the AT III level which was corrected by infusion of AT III concentrate during delivery. A low dose of heparin subcutaneously in the other caused no significant change in plasma AT III levels. There is probably no need for AT III substitution during an uncomplicated pregnancy.     

Plasma Antithrombin III Levels in Pre-Eclampsia

In a prospective study plasma AT III was determined in 2423 samples obtained from 653 women during pregnancy and post partum. The women were allocated to groups, according to the highest diastolic blood pressure, in the third trimester. AT III levels were normal throughout pregnancy, during labour and after vaginal delivery, except in 57 women with pregnancy induced or aggravated hypertension. We present evidence that AT III depression in pre-eclampsia is caused by increased consumption. AT III levels correlate with maternal morbidity as revealed by hepatorenal damage. A weak but significant correlation of AT III and platelets with placental infarction was demonstrated. Proteinuria was the best predictor of fetal outcome. AT III plasma levels increased the number of correct predictions. Following vaginal delivery AT III plasma levels rapidly returned to normal values.     

The treatment of 48 patients affected by ovarian carcinoma at stages III and IV F.I.G.O

The Authors analyzed the treatment of 28 patients in stage III (FIGO) and 20 patients in stage IV affected by epithelial ovarian cancer. In these cases, surgery was based on the criterion of cytoreduction and, where possible, maximum radicality. Within a month from surgery, all patients underwent a program of combined chemotherapy (VCR + 5 FU + CTX) envisaging successive cycles, every four weeks. Minimal side effects were generally observed. 13/28 (46.4%) responses were recorded in stage III and 4/14 (28.6%) in stage IV. The highest percentage of responses, 80%, was obtained in patients with a residual tumor less than 2 cm, all belonging to stage III. Stage III and stage IV patients with a residual tumor greater than 2 cm responded in 45% and 33% of the cases respectively. Patients who underwent explorative laparotomy showed negligible responses. There was a statistically significant difference survival between stage III and stage IV patients (p less than 0.001), among patients with a similar residual tumor greater than 2 cm, but in different stages (p less than 0.05), and among stage III patients who responded or not to chemotherapy (p less than 0.001).     

The prognostic significance of surgical staging for carcinoma of the endometrium.

This study is based on a retrospective review of 156 patients with endometrial carcinoma from 1978 through 1984 who underwent primary surgical evaluation. All cases were retrospectively restaged using the newly adopted FIGO surgical staging. The preoperative FIGO clinical stage distribution for this study was as follows: 121 (77.6%) Stage I, 22 (14.1%) Stage II, 5 (3.2%) Stage III, 2 (1.3%) Stage IV, and 6 (3.8%) unstaged patients. Most patients had TAH-BSO with a collection of peritoneal washings and retroperitoneal lymph node sampling. Surgical staging revealed 122 (78.2%) Stage I, 9 (5.8%) Stage II, 12 (7.7%) Stage III, and 13 (8.3%) Stage IV patients. Surgery upstaged 12.4% of clinical Stage I. In clinical stage II, 59.0% were downstaged while 27.3% were upstaged. For clinical Stage III, 60.6% were upstaged, but no downstaging occurred. No change in stage occurred for clinical Stage IV patients. Ninety-seven surgically staged patients received no adjuvant therapy. The remaining 59 patients had adjunctive treatment which consisted of radiotherapy (59.3%), hormonal therapy (25.4%), chemotherapy (5.1%), or combined modality treatment (10.2%). All patients were followed until death or a minimum of 5 years (60-139 months; median, 82 months) with the exception of 13 patients who were lost to follow-up (2-58 months; median, 34 months). Five-year survival by clinical staging was as follows: 86.2% for Stage I, 85.9% for Stage II, and 0% for Stage III and IV. Five-year survival by surgical staging was 90.6% for Stage I, 85.7% for Stage II, 58.3% for Stage III, and 0% for Stage IV. The 13 patients who were lost to follow-up were censored in all survival analyses at the time of last contact. Stepwise regression analysis using a parametric proportional hazards model identified surgical stage as the most significant prognostic factor (P = 0.02). Univariate analysis showed that patients with surgical Stage IC had significantly worse prognosis (75.0%, 5 years) than those in surgical Stage IA (93.8% 5 YS) or IB (95.4% 5 years). In summary, this study demonstrates that surgical staging as recommended by FIGO is indicated to accurately determine the initial extent of disease in endometrial carcinoma. In addition, surgical staging is the strongest predictor of survival. Deep myometrial invasion appears to be a significant independent prognostic factor within surgical Stage I. The role of adjunctive radiotherapy in Stage I disease awaits the results from an ongoing multi-institutional, prospectively randomized trial.     

Continuous subcutaneous infusion of GnRH agonist: effective dosage in the treatment of endometriosis and its influence on the ovarian response to human menopausal gonadotropin

This study was designed to compare the clinical and hormonal efficacy of the treatment for endometriosis using continuous infusion of three different doses of GnRH agonist (A). In addition, we examined the ovarian responsiveness to human menopausal gonadotropin (hMG) administration during GnRH-A treatment. Thirteen endometriosis patients were divided into 3 groups and given different doses. GnRH-A (Buserelin) was infused continuously through the subcutaneous route at rates of 200 micrograms (Group I; n = 5), 100 micrograms (Group II, n = 4) and 10 micrograms (Group III; n = 4) per day for 24 weeks. After the start of treatment, serum estradiol (E2) was suppressed to the menopausal range within 2 weeks and thereafter maintained this range until 24 weeks in each group. The LH and FSH response to a GnRH Challenge test was completely abolished within 2 weeks in 3 groups. Although serum FSH decreased to below the pretreatment value within a week, the FSH level was significantly lower in groups I and II than in group III until 8 weeks. No difference in the LH level during the treatment was seen among the 3 groups. After completion of the 24 weeks' treatment, FSH increased rapidly, and ovulation returned within 4 to 6 weeks in each group. Pregnancy was achieved in two patients in group I, one patient in group II and one patient in group III during cycles 2 and 5. Serum E2 increased to 200-300 pg/ml in 3 out of 7 patients treated with hMG during GnRH-A infusion, whereas no increase in E2 was seen in the remaining 4 patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

中药红藤方对大鼠的异位子宫内膜芳香化酶表达的影响

目的:探讨中药红藤方对异位子宫内膜的抑制作用。方法:用手术自体移植法成功建立的子宫内膜异位症大鼠模型,随机分成5组:红藤方高剂量组(80g生药/kg,A组)、低剂量组(20g生药/kg,B组)、达那唑组(60mg/kg,C组)、去势组(D组)和模型组(E组),连续给药21d后,检测各组的血清E2水平及异位内膜和卵巢的芳香化酶的变化;另测定异位内膜的体积。结果:A组、C组和D组的异位内膜生长均明显受到抑制,且3组间无统计学差异(P>0.05),与E组比有统计学差异(P<0.05);组织学观察可见,异位内膜呈退化趋势,A、C和D组间大鼠血清中的E2水平无统计学差异(P>0.05),与E组相比有统计学差异(P<0.05);A组、C组及D组异位内膜、卵巢组织的芳香化酶P450低表达,A组与E组间有统计学差异(P<0.05)。结论:红藤方可通过抑制异位内膜、卵巢的芳香化酶活性表达,降低局部雌激素含量,抑制异位内膜的生长,使异位内膜萎缩。     

Hodgkin's disease in children: a review of 21 cases.

The clinical data of 21 children with Hodgkin's disease were retrospectively analyzed to identify their characteristics. Our patients were exclusively boys, ranging in age from 2 years and 9 months to 13 years and 9 months (median 7 years and 10 months). A diagnosis could not be made until after the 2nd to 4th biopsy attempt in 9 patients, with a median time lapse of 5 months from initial biopsy. The primary manifestation was generally nodal enlargement, but also included idiopathic cholestasis and Coombs' positive hemolytic anemia. The disease stages of the patients at diagnosis were 2 stage I; 5 stage II; 10 stage III; 1 stage IV; and 3 not determined. The histologic subtypes were 12 nodular sclerosis, 5 mixed cellularity and 4 lymphocyte predominance. Nine patients had "B" symptoms. Seventy-one percent were associated with anemia and the majority were microcytic. There was a high prevalence of advanced disease (61%). The therapy plan was affected by treatment philosophy at the time, availability of anticancer drugs and the family's attitude toward primary treatment. The patients were initially treated with either radiotherapy alone, chemotherapy alone or combined modality regimens. Five patients were lost within 3 months of diagnosis. The remaining 16 patients were followed, with the longest duration being 9.5 years. Two patients died: 4 were lost after 5-12 months of follow-up, (2 with disease, 2 with no evidence of disease); and the remaining 10 were still being followed (from 2 months to 9 1/2 years). Among those still being followed, 6 of them had discontinued their therapy 8 months to 4 years 5 months earlier and none of them had evidence of tumor recurrence.     

"Optimal" cytoreduction for advanced epithelial ovarian cancer: a commentary

OBJECTIVE: To derive the most appropriate threshold to classify primary cytoreductive operations as "optimal" and address the clinical significance of this issue. METHODS: Criteria used to classify primary cytoreductive outcomes are reviewed. Survival outcomes are analyzed to address relative influences of the completeness of cytoreduction and "biological aggressiveness", as manifested by the extent of intra-abdominal metastases. RESULTS: Most cohorts analyzing relative influences of metastatic tumor burden and the dimension of residual disease on survival report completeness of cytoreduction to influence the prognosis more significantly than tumor burden, with necessity to perform various procedures having minimal or no influence. Equivalent survival is reported for completely cytoreduced patients with stage III disease whether substages IIIa/b (smaller tumor burden) are excluded or included. However, some stage IIIc series report more favorable median and 5-year survivals for small fractions of completely cytoreduced patients than series with a large visibly disease-free fraction. Increasing fractions of complete cytoreduction are reported in recent cohorts, without increase in morbidity. CONCLUSIONS: Complete primary cytoreduction improves the prognosis for survival significantly more than a small dimension of residual disease. Although prospective randomized trials addressing surgical issues have not been undertaken and numerous variables may reflect "biological aggressiveness" by influencing the prognosis, available data justify elimination of macroscopic disease to be the most appropriate objective of primary cytoreductive surgery. Stratification of survival by dimensions of residual disease in an investigational setting should include a visibly disease-free subgroup and if used, the term "optimal" should be applied to patients undergoing complete cytoreduction.     

A study of the mean concentration of plasma antithrombin III in arterial hypertension in pregnancy

Plasma antithrombin III (AT III) level was examined in 30 pregnant women with hypertension and 44 without hypertension. AT III level is significatively lower in the group of hypertension. The degree of reduction in plasma AT III level seems to be correlated with hyper uricemia but not with count of platelets or fibrinogen.     

Long-term survival in stage III and IV ovarian cancer

Summary A total of 104 unselected, previously untreated patients with invasive stage III or IV ovarian cancer were operated on between 1977 and 1984. Nine patients were lost in follow-up, three died from non-malignant disease. Thirteen of the 92 eligible patients (15%) were observed to survive 5 years or longer. In the 13 long-term survivors, 4 had stage IV disease, 7 positive peritoneal cytology, 3 bowel resection, and 12 residual disease <2 cm after primary surgery. Retroperitoneal lymph nodes were involved in 6/9 cases. The majority of 5-year survivors (69%) received cis-platin-containing combination chemotherapy. 5/7 long-term survivors had positive second-look. At 5 years, life-quality in 9/13 patients who were free of disease, was high. It can be concluded that only patients with optimally resected stage III or IV ovarian cancer have a realistic chance of long-term survival. It is expected that increasing radicality in surgery for ovarian cancer together with platinum-based chemotherapy regimens may improve long-term survival in the future. In addition, further studies of new chemotherapeutic approaches are needed.     

Response and toxicity to topotecan in sensitive ovarian cancer cases with small residual disease after first-line treatment with carboplatinum and paclitaxel

OBJECTIVE: The objective of this open uncontrolled study was to evaluate the toxicity and efficacy of topotecan in ovarian cancer cases with microscopic small residual disease to a first-line treatment, given as sequential treatment, including carboplatinum and paclitaxel. METHODS: Inclusion criteria were laparotomically or laparoscopically documented microscopic or macroscopic (<2 cm) residual disease after first-line chemotherapy including carboplatinum plus paclitaxel in patients with histologically documented epithelial ovarian cancer FIGO stage III or IV at first diagnosis. All patients had a response >50% after first-line treatment. Eligible patients received 1.25 mg/m(2)/day of topotecan intravenously as a 30-min infusion for 5 consecutive days every 21 days for four cycles. A total of 38 women entered the study. Surgical "third-look" laparotomy or laparoscopy was performed in patients without clinical/instrumental evidence of progressive disease within 1 month from the last topotecan administration. RESULTS: A complete response was observed in 10 cases (28.6%, 95% confidence interval, based on the Poisson's approximation, 15.6-59. 5), a partial response in 1 (2.5%), progressive disease in 11 (31. 4%) and no change/stable disease in 13. The median duration of response was 8 months (range 5-20). The overall 1-year survival after treatment was 82.8% (SE 6.4). CONCLUSION: This study indicates that sequential therapy with carboplatin plus paclitaxel followed by topotecan, all given at standard doses, is feasible and provides favorable response rates.     

P53 mutations in tissue from Danish ovarian cancer patients: from the Danish "MALOVA" ovarian cancer study

OBJECTIVES: The p53 gene, a tumor suppressor gene located on the short arm of chromosome 17 (17p13), has been found mutated in 30-80% of epithelial ovarian cancers (OC), with the most frequently detected mutations in the conserved regions of the gene. A small number of studies investigated the survival of patients with p53 mutations in OC, but their conclusions are not in agreement. METHODS: We analyzed the frequency of p53 mutations in 124 Danish women with OC, using Single-Stranded Conformation Polymorphism analysis in addition with DNA sequencing and evaluated if mutations correlated with clinicopathological parameters and with patient survival. RESULTS: Thirty-five (28%) ovarian tumors were found to contain one or more p53 variations, two of which were considered polymorphisms. Twenty-seven (82%) mutations were single nucleotide substitutions of which 23 (85%) were missense mutations and therefore led to amino acid substitutions. Significantly shorter survival was found for stage III/IV patients with a p53 missense mutation compared to stage III/IV OC patients with wild type p53 (P = 0.0018). Multivariate Cox regression analysis restricted to 107 OC patients with a p53 missense mutation or p53 wild type in the tumor tissue and with information on radicality of primary surgery showed that missense p53 mutation (HR = 2.5, 95% CI: 1.21-4.98), radicality after primary surgery (HR = 1.7, 95% CI: 1.04-2.88), tetranectin (mg/l: HR = 0.78, 95% CI: 0.67-0.91) and stage (I vs. III: HR = 0.30, 95% CI: 0.10-0.92, II vs. III: HR = 0.24, 95% CI: 0.05-1.05, IV vs. III: HR = 2.70, 95% CI: 1.22-5.98) were independent prognostic factors. CONCLUSION: Missense mutations in the conserved regions of p53 may be of prognostic value in Danish OC patients.     

Clinical evaluation of antithrombin III concentrate (BI 6.013) for disseminated intravascular coagulation in obstetrics. Well-controlled multicenter trial

Antithrombin III (AT III) is known to be the most important inhibitor of serine protease in the coagulation system. In the presence of heparin, AT III is converted from its progressive activity state to an immediate activity state. In disseminated intravascular coagulation (DIC) in the field of obstetrics, the treatment has to be initiated very early. Heparin treatment, on the other hand, is critical since frequently postpartal or postoperative wound bleeding is present. We, therefore, established diagnostic criteria for the early diagnosis of DIC and investigated the clinical efficacy of a therapy with AT III in a well-controlled comparative study versus the injectable synthetic protease inhibitor FOY. The results of the trial showed that the AT III group (92%; n = 24) was significantly (p less than 0.001) superior in clinical efficacy to the FOY group (60%; n = 15). No side effects whatsoever were observed after treatment with AT III concentrate (Behring Institute). From these results, it could be concluded that a single therapy with AT III concentrate can sufficiently control the symptoms of DIC in the field of obstetrics without the risk of increased bleeding.