History Of Abnormal Bleeding Research Articles

Low-coverage whole-genome sequencing for the effective diagnosis of early endometrial cancer: A pilot study

BackgroundEndometrial carcinoma (EC) is a disease that predominantly affects peri- and post-menopausal women and its incidence has continued to rise over recent years. Since the gold standard for EC diagnosis—hysteroscopic biopsy—is invasive, expensive, and unsuitable for wide use, there is an urgent need for a non-invasive method that exhibits both high sensitivity and high specificity. We therefore investigated the efficacy of UterCAD (the uterine exfoliated cell chromosomal aneuploidy detector) using tampon-collected specimens for the early detection of EC. MethodsWe prospectively recruited 51 patients with a history of abnormal bleeding and who planned to undergo hysteroscopic examination or hysterectomy between March 2020 and January 2021. Before executing an invasive procedure, a tampon was inserted into the patient's vagina for 6 h to collect exfoliated cells from the uterine cavity. Total DNA was extracted and low-coverage whole-genome sequencing was performed on an Illumina HiSeq X10, and we analyzed the differences in chromosomal status between women with EC and those bearing benign lesions using UterCAD. ResultsThirty EC patients—including 26 with endometrioid carcinoma (EEC) and four with uterine serous carcinoma (USC), as well as 14 benign cases—were enrolled in our final analysis. Copy-number variations (CNVs) were detected in tampon specimens collected from 26 EC patients (83.3%), including 21 with EEC (80.7%) and four with USC (100%). In the benign group, only one woman with focal atypical hyperplasia presented with a 10q chromosomal gain (P < 0.001). In the EC group, the most common CNVs were copy gains of 8q (N = 14), 2q (N = 4), and 10q (N = 3); and copy losses of 2q (N = 3) and 17p (N = 2). When we stratified by FIGO stage, the CNV rates in stages IA, IB, and II/III were 83.3% (15/18), 85.7% (6/7), and 80.0% (4/5), respectively. At the optimal cutoff (|Z| ≥ 2.3), UterCAD discriminated 83.3% of EC cases from benign cases, with a specificity of 92.9%. ConclusionsWe initially reported that UterCAD could serve as a non-invasive method for the early detection of EC, especially in the rare and aggressive USC subtype. The use of UterCAD might thus avoid unnecessary invasive procedures and thereby reduce the treatment burden on patients.

High Prevalence of Congenital Factor VII (FVII) Deficiency in Adolescent Females with Heavy Menstrual Bleeding and Iron Deficiency Anemia

To examine the clinical characteristics and prevalence of congenital bleeding disorders (CBDs), with emphasis on congenital factor VII (FVII) deficiency and other rare bleeding disorders, in adolescent and young adult females referred to a hemophilia treatment center (HTC) for evaluation and management of heavy menstrual bleeding (HMB) and iron deficiency anemia (IDA) DESIGN: In this single-center retrospective study, we reviewed the clinical characteristics and prevalence of CBDs in postmenarchal females, younger than 22 years of age, referred to an HTC from 2015 to 2021 for evaluation of HMB with or without IDA. One hundred females, with a mean age of 15 years (range 9-20 years), met initial study criteria, and 95 were included in the final analysis. Forty-five (47%) females were ultimately diagnosed with a CBD. The most prevalent diagnoses were FVII deficiency and type 1 von Willebrand disease (VWD) (42.3%, n=19 each). Forty-two percent of patients with FVII deficiency had a low-for-age FVII activity level, 21.1% were only positive for the FVII R353Q variant associated with borderline FVII levels, whereas 36.8% had both a low-for-age FVII activity level and a positive R353Q variant. Eighty percent of patients with a CBD were found to have relatives with abnormal bleeding symptoms. Congenital FVII deficiency is prevalent among female adolescents experiencing HMB with or without IDA. In addition to VWD, evaluation for this specific factor deficiency should be considered as part of the initial CBD workup. Presence of abnormal bleeding history in the family could also help to predict presence of a CBD.

Massive single visit cervical pre-cancer and cancer screening in eastern Democratic Republic of Congo

BackgroundIn the Democratic Republic of Congo (DRC), practical and affordable strategies for cervical cancer screening are needed to detect and treat pre-cancerous and cancerous lesions in a timely fashion. This study presents the results of mass cervical cancer screenings in eastern DRC using a “screen and treat” approach.MethodsIn two mass cervical cancer screening campaigns, patients underwent a combination of visual inspection of the cervix with acetic acid, visual inspection of the cervix with Lugol iodine solution, and colposcopy with or without loop electrosurgical excision procedure. Cervical biopsy samples were taken for histology analysis. Marital status, age, history of abnormal bleeding, and number of pregnancies were recorded for each patient and association analyses were performed.ResultsOf the 644 women who received cervical pre-cancer and cancer screening, 48 had suspicious pre-cancer and cancer lesions that were biopsied (7.45%). On histology analysis cervical intraepithelial neoplasia (CIN) was identified in 15 (2.33%), squamous cell carcinoma (SCC) was identified in 6 (0.93%) and non-neoplastic cervicitis was identified in 11 (1.71%). Abnormal bleeding was significantly associated with CIN/SCC but no significant association was observed for prior pregnancy, patients’ home region, or age.ConclusionForty-eight women with suspicious pre-cancerous or cancerous lesions were successfully identified using the “screen and treat” approach in eastern DRC, suggesting that this approach is feasible for reducing cervical cancer morbidity and mortality. However, community awareness would be necessary, providers would have to be properly trained, referral and follow up mechanisms would have to be put in place, and equipment / supplies would have to be secured if the “screen and treat” approach is to be successful on a wider scale. There is ongoing need for HPV vaccination in DRC as a primary prevention strategy against cervical cancer.

A Unique Case of Type 3 Von Willebrand Disease

Background: Von Willebrand disease (vWD) is the most common inherited bleeding disorder worldwide. Genetic mutations in the von Willebrand gene may result in either quantitative (Types 1 and 3 vWD) or qualitative defects (Type 2 vWD) of von Willebrand Factor (vWF). Type 3 is the rarest and most severe form of vWD, resulting in a virtual absence of vWF. Type 3 vWD follows autosomal recessive inheritance and is most often reported in patients who are homozygous for the same gene mutation. We report a patient with type 3 vWD who inherited two different mutations, one from each parent, resulting in compound heterozygosity.Case:Our patient, now a 2 year old female, initially presented with prolonged bleeding lasting approximately 5 hours at the injection site of her 2 month immunizations. Labs on initial presentation showed a normal WBC count, hemoglobin, hematocrit, and platelet count, with normal levels of Factor IX, XI, and XII activity. PTT was prolonged at 59 (reference range 23.3-35.7) with a normal INR. Von Willebrand panel showed markedly decreased Factor VIII (2%), vWF antigen (6%), and vWF activity (8%). VWF multimers were absent, consistent with a diagnosis of type 3 vWD. VWF gene sequence analysis showed two pathologic variants, one on each allele: c2345delC in exon 18 and a deletion within exon 6. Her parents, both 27 years old and with no history of abnormal bleeding, are non-consanguineous. Analysis of parents for vWD revealed that mother is heterozygous for the c2345delC variant and the patient's father is heterozygous for the deletion within exon 6 of the VWF gene. The patient's older sibling who is now 4 years old developed unusual petechiae and bruising after an altercation at school, his testing was positive for only the maternal mutation, resulting in a diagnosis of Type 1 vWD, and a younger brother was negative for both mutations. Our patient has subsequently suffered recurrent episodes of bruising, gingival bleeding, and poor tissue healing and currently requires replacement therapy (prophylaxis) with Humate-P three times each week and additionally as needed.Discussion:Type 3 vWD is quite rare, with a prevalence ranging from 0.1-5.3 per million. Our case is especially interesting due to the unique inheritance pattern resulting in our patient's type 3 vWD phenotype. Type 3 vWD cases are often described in patients homozygous for a mutation in the VWF gene, frequently as a result of consanguinity. Our patient inherited a unique variant from each parent, resulting in heterozygous expression of two defective VWF alleles (compound heterozygosity). Our patient's maternally inherited defect c2435delC in exon 18 is the variant found in the original vWD family described by Dr. Erik von Willebrand in 1926. Less is understood about the paternally inherited defect of a deletion in exon 6 of VWF.In our patient's family, because each parent is heterozygous for a mutation in the VWF gene, future children have a 75% chance of inheriting at least one mutation, and a 25% chance of inheriting both mutations, leading to Type 3 vWD. Type 3 vWD patients have impaired endogenous synthesis of functional vWF, thus therapies such as desmopressin, used in other types of vWD to stimulate secretion of endogenous vWF, are ineffective. Instead, first-line treatment in Type 3 is replacement therapy with Humate-P as needed during bleeding episodes and/or as prophylaxis. Humate P is VWF/FVIII concentrate obtained from pooled human plasma from many carefully screened plasma donors and contains the clotting proteins VWF and FVIII. Humate-P has a VWF:FVIII ratio of approximately 2.4:1. Complications of therapy include the rare development of anti-vWF alloantibodies, which most often occurs in patients with partial or complete VWF gene deletions. Our patient has received aminocaproic acid for minimal bleeding episodes and due to her severe intensity of disease and age of increased risk of injuries had received plasma derived vWF/FVIII concentrates for multiple episodes of moderate bleeding. She has not developed antibodies yet, but is at high risk. The rWVF (recombinant von Willebrand factor) offers new perspective in treatment of vWD more so with type 3 disease. It is a homogenous protein synthesized by a genetically engineered Chinese hamster ovary (CHO) cell line, retains its intact multimer pattern because it is never exposed to proteases(ADAMTS13) which can degrade it. The rVWF is currently in phase 3 clinical trials DisclosuresNo relevant conflicts of interest to declare.

Implications of deranged activated partial thromboplastin time for anaesthesia and surgery.

Bleeding during and after surgery ranges from trivial to fatal. Bleeding is in part determined by the patient's coagulation status. The UK National Institute for Health and Care Excellence recommends a pre-operative clotting test for patients with a history of abnormal bleeding. Anaesthetists are familiar with the prothrombin time assay, used to monitor warfarin effect, but anaesthetists may be less familiar with the activated partial thromboplastin time (APTT), which tests the function of the 'intrinsic' clotting pathway. The activated partial thromboplastin time may be prolonged due to contamination, anticoagulant therapy, clotting factor deficiencies, lupus anticoagulant or acquired inhibitors of specific clotting factors. A prolonged activated partial thromboplastin time should lead to: further testing to exclude heparin contamination or therapy, mixing studies to identify factor deficiencies and if necessary dynamic studies, such as the dilute Russell's viper venom time and the Actin FS-activated partial thromboplastin time, to identify direct factor inhibitors. These tests identify abnormalities and their implications for bleeding, helping anaesthetists and haematologists to manage haemostasis for individual patients.

Abstract 2203: A prospective study of endometrial cancer detection in women presenting for evaluation of abnormal peri- and postmenopausal bleeding

Abstract Background: Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries and the incidence and mortality of EC continue to rise in the US. When detected early, EC is highly curable, suggesting that early detection strategies could reduce EC mortality. Women who develop EC often have a prolonged history of abnormal bleeding, offering a window for identifying many at-risk women prior to the development of advanced cancer. To evaluate risk prediction, novel sampling and early detection strategies in women at increased risk of EC, we established a prospective cohort of women with abnormal bleeding that is followed for endometrial hyperplasia and cancer endpoints. Methods: We consecutively enrolled women ≥45 years old presenting to the Mayo Clinic for evaluation of abnormal uterine bleeding (AUB), postmenopausal bleeding (PMB), thickened endometrial stripe (ES) on imaging, or Lynch Syndrome (LS). From all women, an intravaginal tampon and an endometrial brushing via Tao brush were collected before endometrial biopsy. Epidemiological EC risk factor data, clinical data, and endometrial biopsy histology results were abstracted from medical records. Absolute risk of endometrial hyperplasia and EC were calculated overall and in strata based on clinical symptoms and risk factors. Results: Among the first 1,000 women enrolled into the study, 712 (71%) were overweight or obese, 534 (53%) were postmenopausal, and 214 (22%) were current hormone replacement therapy (HRT) users. Endometrial biopsy and, if indicated, subsequent hysterectomy, detected 39 ECs, 16 atypical hyperplasias, and 28 hyperplasias without atypia at baseline evaluation. Among 534 postmenopausal women, 453 (85%) reported any type of bleeding, with spotting (39%) and light bleeding (27%) being more common than heavy bleeding (14%). Among perimenopausal women with AUB (n=452), the absolute risk of EC at baseline was 0.9% and among women with PMB, the absolute risk of EC at baseline was 7.5%. Among women with PMB, EC risk was modified by HRT use (risk of 2.6% in women on HRT and 8.2% in women not on HRT, respectively), obesity (risk of 5.3%, 8.1% and 9.5% for women with normal, overweight, and obese BMI, respectively), and type of bleeding (risk of 9.7%, 4.9%, and 8.2% in women with spotting, light or heavy bleeding, respectively). Discussion: While risk of endometrial cancer in perimenopausal women with AUB is low, approximately 8% of women presenting for clinical work up of PMB have underlying EC. Clinical presentation and risk factors modify the absolute risk of EC and may inform clinical management. Additional recruitment and prospective follow-up is underway to improve estimates of short- and long-term EC risk in women with PMB. With its collection of tampon and Tao brush samples, the study will provide a unique resource to evaluate molecular markers of EC and EC risk in elevated-risk women. Citation Format: Nicolas A. Wentzensen, Megan Clarke, Viji Shridhar, Maureen Lemens, Matthew Hopkins, Lisa Ahlberg, Shannon Laughlin-Tommaso, Karl Podratz, Mark Sherman, Jamie Bakkum-Gamez. A prospective study of endometrial cancer detection in women presenting for evaluation of abnormal peri- and postmenopausal bleeding [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2203.

Haemostatic Disorder in Women with Unexplained Menorrhagia: A Tertiary Care Centre Experience from Northern India.

Menorrhagia is a common gynaecological problem and its cause remains unexplained in a significant proportion of females. The present study was done to diagnose a wide range of haemostatic disorders which can give rise to menorrhagia in women of adolescent, postadolescent and perimenopausal age group. A total of 1100 women presenting to gynaecological emergency with complaints of menorrhagia underwent comprehensive evaluation. After excluding local pelvic pathology and hormonal disorders as a cause of menorrhagia 104 women were included in this study. Screening investigations including bleeding time, prothrombin time, activated partial thromboplastin time, platelet count and morphology were done. The following diagnostic investigations were carried out as and when required. Platelet aggregation tests using adenosine diphosphate and ristocetin, platelets function tests, specific factor analysis as and when required. Age of patients ranged from 13 years to 46 years. Eighteen patients had menorrhagia since menarche. Seven patients had family history of abnormal bleeding. Twenty three patients were found to have systemic haemostatic disorder (10 patients of Von Willebrand Disease (vWD), seven of Glanzmann-Thrombasthenia, one of Bernard- Soulier syndrome and five of immune thrombocytopenic purpura). From this study it is concluded that systemic haemostatic disorders are found in substantial number of women presenting with menorrhagia. Hence, after excluding organic/hormonal cause, haemostatic disorders should be considered before taking patient for invasive surgical procedures.

Platelet Function Testing Is Commonly Performed in Patients with Known Confounding Factors

Introduction: Commonly used platelet function tests include Platelet Function Analyzer -100 Closure Time (PFA-100), used as a screening test, and platelet aggregation testing by Light Transmission Aggregometry (LTA), which can help differentiate between various types of platelet function defects and guide further testing. In this study, we assessed the indications for platelet aggregation testing at our center, and the effect of factors that may interfere with the outcomes of testing.Methods: This was a retrospective electronic medical records based study in which we included all patients in our healthcare network who had platelet aggregation testing done using LTA between August 2008 and August 2013. Routine descriptive measures were used for frequencies and proportions. McNemar test was used for comparison of paired nominal variables and Wilcoxon signed-rank test was used for comparison of paired continuous variables. P value < 0.05 was considered significant.Results: Four hundred ninety seven patients had platelet aggregation testing performed during the 5-yr study period. Among these, 315 (63%) patients had antecedent screening with PFA-100 with 157 (31%) showing at least one abnormality. Two hundred forty nine (50%) patients underwent some form of further testing after LTA, including VWF analysis (42%), platelet flow cytometry (19%) and/or electron microscopy (1%). Two hundred fifty six (51%) patients had at least one factor previously known or suspected to interfere with platelet aggregation testing (platelet count <100,000, hematocrit <25% or medications), and 205 (80%) of these patients had abnormal results in response to one or more agonists. Eighty three of these patients had repeat aggregation testing performed - 26 were re-tested after correction of 1 or more suspected factor (s), while 57 were re-tested without correction. The former group showed a significant improvement with subsequent testing, both in the average number of abnormalities in the LTA panel (P = 0.01) and in the number of patients with abnormal aggregation to ≥2 agonists (P = 0.02), while the outcomes of platelet function testing in the latter group did not significantly change on subsequent testing (P = 0.15 and 0.21 respectively for the above two parameters). Three hundred forty five (69%) patients had a current or past history of abnormal bleeding. Of these, 81% had history of spontaneous bleeding while 29% had surgical or procedure-related bleeding. The most common sites of spontaneous bleeding were skin (47%) and mucosa (45%). Eight percent of patients had a history of spontaneous bleeding in deeper sites. Fourteen percent had a family history of abnormal bleeding. The most common indication for testing was documented abnormal bleeding (62%) - recent or past. Twenty five percent underwent testing for peri-operative prediction of bleeding risk and 13% to monitor efficacy of anti-platelet therapy.Conclusions: A majority of the patients in our study did not have abnormalities in PFA-100 testing despite abnormal results on subsequent platelet aggregometry. Fifty one percent of patients who underwent aggregometry were on medications that may affect platelet function or had other factors known or suspected to interfere with aggregation testing. Eighty percent of these patients had abnormal results. Repeat testing after correction of the known factor(s) led to a significant improvements in the results of LTA. The most common indication for platelet aggregation testing was a current or past history of abnormal spontaneous bleeding and the most common sites of bleeding in these patients were the skin and mucosal surfaces. DisclosuresMcCrae:Momenta: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Syntimmune: Consultancy; Halozyme: Membership on an entity's Board of Directors or advisory committees.

A History of Abnormal Bleeding Correlates with Platelet Dysfunction in Aggregation Studies but Not PFA-100 Analyses

Introduction:In this retrospective medical records-based study we analyzed the association between abnormal spontaneous or procedure-related bleeding and patterns of abnormality in tests of platelet function. Commonly used platelet function tests include Platelet Function Analyzer -100 Closure Times (PFA-100 CT), platelet aggregation testing using Light Transmission Aggregometry (LTA), and platelet dense granule release assay (by lumi-aggregometry). Other related tests include Von Willebrand factor (VWF) analysis, platelet flow-cytometry for cell surface glycoprotein expression, and electron microscopy. LTA in our center uses five different agonists - ADP, arachidonic acid, collagen, epinephrine and ristocetin, while lumi-aggregometry is performed using four agonists - ADP, arachidonic acid, collagen and epinephrine.Methods:This study included 497 patients who had platelet aggregation testing done using LTA between August 2008 and August 2013. Sixty-nine percent (n = 354) of these patients had a history of abnormal bleeding. Since the data were not normally distributed, Wilcoxon rank-sum test (for continuous variables) and Fisher's exact test (for categorical variables) were used wherever appropriate. P value of < 0.05 was considered as significant.Results:Of the patients with a history of abnormal bleeding, 81% had spontaneous bleeding, 29% had surgery/procedure-related bleeding, and 13% had history of both types of abnormal bleeding. Three hundred nine of these patients had a recent (< 4 weeks) bleeding event. Abnormal bleeding, recent or historical, was found to associate significantly with impaired platelet aggregation, as well as platelet release in response to ADP, arachidonic acid, collagen or epinephrine (P<0.001 for all). Abnormal aggregation and release in response to ≥2 different agonists was also significantly associated with abnormal bleeding, as was the total number of abnormalities on the aggregation and release panel (P<0.001).A history of a recent bleeding event (<4 weeks) was found to be associated with reduced aggregation in response to arachidonic acid (P = 0.001), impaired aggregation and release in response to collagen (P =0.04 and <0.001 respectively), and reduced platelet release in response to epinephrine (P = 0.005). Recent bleeding also correlated with the total number of abnormalities in the aggregation (P = 0.002) and release panels (p =0.03).No significant association was found between a history of abnormal bleeding (either recent or historical) and prolonged PFA-100 closure times (collagen/ADP or collagen/epinephrine), or any abnormality in VWF analyses or platelet flow-cytometry studies.Conclusions:While PFA-100 closure times, VWF analyses and platelet flow-cytometry panel failed to show an association with abnormal bleeding (historical or recent), impaired platelet aggregation or release in response to several agonists was found to correlate with abnormal spontaneous and/or procedure-related bleeding, recent as well as historical, suggesting that platelet aggregation and release assays may be useful in diagnosis of a bleeding diathesis in patients with an appropriate clinical history DisclosuresMcCrae:Halozyme: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Syntimmune: Consultancy; Momenta: Consultancy.

A Rare Case of Bleeding - Acquired Factor Inhibitors with Normal Coagulation Tests

Introduction: Acquired Factor XIII deficiency due to an antibody inhibitor (AIFXIII) is a rare but life-threatening bleeding disorder. Factor XIII is a fibrin stabilizing enzyme that crosslinks fibrin monomers. Deficiency of Factor XIII results in destabilization of formed clots within 24-48 hours, resulting in delayed hemorrhage. Because the standard coagulation tests are normal, the diagnosis of this disease requires a high degree of suspicion and specialized testing. We report a case of an 88-year-old female presenting with severe hemorrhage of unknown origin.Goal: We aim to heighten the awareness amongst clinicians of the possibility of acquired FXIII deficiency when a patient presents with bleeding symptoms and normal routine coagulation tests.Case: An 88-year-old female with a recent diagnosis of autoimmune hemolytic anemia (AIHA) on oral Prednisone developed left arm swelling, pain, and ecchymosis. She denied anticoagulation and history of abnormal bleeding. CT scan of the arm showed a biceps muscle hematoma measuring 17cm in length. On day 4, she developed hematoma on the contralateral forearm, which prompted bilateral fasciotomies and evacuation. Patient continued to have bleeding from her right forearm hematoma, requiring further exploration and evacuation of multiple clots.Laboratory Tests: Her Hg dropped from 9.2 g/dl to 6.6 g/dl requiring RBC transfusions. Peripheral blood smear revealed features of chronic hemolysis. She had a normal coagulation profile including PT (11.1 sec), INR (1.05), PTT (24.4 sec), fibrinogen (295mg/dL) and normal platelet function assay. Her D-dimer was elevated at 371 ng/ml. She had a normal CRP (3.3mg/L), ANA antibody (<1:40) and ESR (23 mm/hr). SPEP showed hypoproteinemia without monoclonal bands. The patient's FVIII (307%), VWF ag (307%), VWF activity (369%), VWF collagen binding assay (412%) and alpha-2-antiplasmin (101%) were normal. Patient's Factor XIII levels were measured at 8%. We suspected this to be a case of AIFXIII. Testing for inhibitor with serial dilutions showed an antibody titer of 1:40.Results: She was started on 100 mg/d of Cyclophosphamide and continued on 20mg of Prednisone. No further hematomas developed. Patient was discharged on day 29 with a close follow up. On day 66, patient had AIHA flare (Hg: 6.6g/dL) and was treated with PRBCs, Rituximab 375mg/m^2 for 4 infusions and prednisone 40mg daily. Her Factor XIII activity on day 68 was 12% and inhibitor titer 1:10. On day 98, patient developed large ecchymoses on the right knee, thigh and buttock. Her Factor XIII activity dropped to < 10% again and inhibitor titer went up to 1:20 on serial dilution. She was transfused with PRBCs and was started on IVIG at 1000 mg/kg X 5. Cyclophosphamide was stopped and Prednisone was decreased to 10mg daily. Her Factor XIII is still <10% but inhibitor titer is down to 1:10. Patient is not actively bleeding.Discussion: There are less than 60 reported cases of AIFXIII in the literature. This is the first reported case presenting with warm antibody hemolytic anemia. Various treatments have been employed in the past for AIFXIII. It involves two strategies: hemostasis to treat acute bleeding symptoms and inhibitor eradication. Use of steroids and immunosuppressants such as Cyclophosphamide, Rituximab, and Cyclosporine has been prevalent in most of the cases to obtain inhibitor eradication. It is hard to define what combination of therapy works because most of the cases involve use of combination of these strategies and spontaneous remissions have also been seen. In this case, we suspect that patient presented with higher than expected factor XIII activity (8%) at the onset because she was already on immunosuppression for her AIHA for 2 months prior. She was refractory to first-line therapy with Rituximab and Cyclophosphamide in combination with steroids for complete inhibitor eradication. Second line therapy with IVIG was recently given and we are hopeful of a response.Conclusion: AIFXIII is a rare but life-threatening bleeding disorder that should be suspected especially when elderly patients present with hemorrhage of unknown origin and normal screening coagulation studies. Characterization of the factor XIII activity and detection of antibodies should be undertaken promptly in order to provide the best anti-hemorrhagic and inhibitor eradication treatment. DisclosuresNo relevant conflicts of interest to declare.

English

BACKGROUND: An association has been reported with presence of endometrial cells on cervical smears and clinically significant uterine lesions. Hence for early detection of endometrial pathology, the 2001 Bethesda system has suggested the mandatory reporting of presence of any atypical endometrial cells regardless of age and menstrual status and out of phase normal looking endometrial cells in women aged 40 years or more. OBJECTIVES: To assess the association between atypical glandular cells of endometrial origin in cervical cytology and histopathological findings in abnormal uterine bleeding cases. SETTINGS AND DESIGN: The study was conducted at JSS hospital, Mysore in the department of pathology. This was a descriptive type of study. The sample was collected from patients attending the gynecology OPD with the complaints of abnormal uterine bleeding in JSS hospital. MATERIALS AND METHODS: Smears for cervical cytology are collected using either pap smear or manual liquid based smear from 82 patients in the age group of 20-75 years with complaints of abnormal bleeding history. The results of cervical cytology were compared and confirmed with the endometrial pathology. RESULTS: Out of 82 abnormal uterine bleeding cases 14 showed atypical endometrial cells. On follow up of these cases, the results indicated an association between atypical endometrial cells in cervical cytology with endometrial carcinoma in 8 cases (60%), 1 case with complex hyperplasia with atypia (10%). CONCLUSION: Presence of atypical endometrial cells in all women with abnormal uterine bleeding has considerable clinical implications & further

Identification of a new dysfunctional platelet P2Y12 receptor variant associated with bleeding diathesis

AbstractDefects of the platelet P2Y12 receptor (P2Y12R) for adenosine diphosphate (ADP) are associated with increased bleeding risk. The study of molecular abnormalities associated with inherited qualitative defects of the P2Y12R protein is useful to unravel structure-function relationships of the receptor. We describe the case of 2 brothers, sons of first cousins, with lifelong history of abnormal bleeding, associated with dysfunctional P2Y12R and a previously undescribed missense mutation in the encoding gene. ADP (4-20 µM)–induced aggregation of patients’ platelets was markedly reduced and rapidly reversible. Other agonists induced borderline-normal aggregation. Inhibition of vasodilator-stimulated phosphoprotein phosphorylation and prostaglandin E1–induced increase in cyclic adenosine monophosphate (cAMP) by ADP was impaired, whereas inhibition of cAMP increase by epinephrine was normal. [3H]PSB-0413, a selective P2Y12R antagonist, bound to a normal number of binding sites; however, its affinity, and that of the agonists ADP and 2-methylthio-adenosine-5′-diphosphate, was reduced. Patients’ DNA showed a homozygous c.847T>A substitution that changed the codon for His-187 to Gln (p.His187Gln). Crystallographic data and molecular modeling studies indicated that His187 in transmembrane 5 is important for agonist and nucleotide antagonist binding and located in a region undergoing conformational changes. These studies delineate a region of P2Y12R required for normal function after ADP binding.

A Case of Acquired Transient Vitamin K Deficiency in a Teenage Girl

A 13-year old girl visited emergency medical center presenting with nasal bleeding and gross hematuria. She had no growth retardation, nor history of abnormal bleeding. Her initial blood test results showed normal platelet counts, normal liver enzyme level but prolonged prothrombin time and activated partial thromboplastin time. On admission, she showed massive but intermittent bleeding until the 15 hospital day. Evaluation including coagulation factor assay was done and the results were compatible with vitamin K deficiency. She was treated with vitamin K intramuscular injection 7 times and intermittent transfusion of red blood cells, platelets and fresh frozen plasma. After that, all of her blood test results returned to normal levels including coagulation tests concomitent with resolving symptoms. In that there were no proof of underlying diseases that can cause vitamin K deficiency, she was diagnosed as idiopathic transient vitamin K deficiency. pISSN 2233-5250 / eISSN 2233-4580 http://dx.doi.org/10.15264/cpho.2014.21.1.33 Clin Pediatr Hematol Oncol 2014;21:33∼36

Coagulation.

The haemostatic system comprises four compartments: the vasculature, platelets, coagulation factors, and the fibrinolytic system. There is presently no laboratory or near-patient test capable of reproducing the complex regulated interaction between these four compartments. The prothrombin time (PT) and activated partial thromboplastin time (APTT) only test the coagulation protein compartment of the system and results have to be carefully interpreted in the context of the clinical presentation and assay limitations. This article will give a general overview of the limitations of PT and APTT and discuss specific issues that need to be considered when the tests are requested, in the context of anticoagulant monitoring, bleeding symptoms, and routine preoperative screening. Of these indications, routine preoperative screening is the most controversial and is generally not warranted in the absence of an abnormal bleeding history.

Perioperative Management of Acquired Hemophilia A: A Case Report and Review of Literature

Introduction:Acquired hemophilia A is a rare bleeding disorder with a high mortality rate. Diagnosis and treatment of this disorder can be very challenging to anesthesiologists because of lack of a personal or familial abnormal bleeding history.Case presentation:We report a 60-year-old woman who presented to the operating room for an urgent fasciotomy. She was initially diagnosed to have compartment syndrome of her left upper extremity secondary to an expanding hematoma after multiple unsuccessful venipuncture attempts. After surgical intervention, she developed recurrent intramuscular hematomas, became severely anemic, and required surgical re-exploration and multiple blood product transfusions. Ultimately, she was found to have an elevated activated partial thromboplastin time (aPTT), very low FVIII activity, and high FVIII inhibitor titers consistent with the diagnosis of acquired hemophilia A.Conclusions:Treatment strategies in acquired hemophilia are based on two major objectives. During the acute stage, effective control of bleeding is critical. The ultimate therapeutic goal during the subacute phase is the elimination of the inhibitors targeting factor VIII. Here, we present this case and will review current literature regarding therapeutic approaches to this rare condition in the operating room setting and postoperative course.

Hypogranular Platelets in a 78-Year-Old Man

Patient: 78-year-old white man Chief Complaint : Abdominal aortic aneurysm with thrombocytopenia History of Present Illness: The patient has had a mildly decreased platelet count since 2004, which had become progressively lower. He had started taking a new oral hypoglycemic agent, sitagliptin phosphate (Januvia; Merck and Co, Inc, Whitehouse Station, NJ), in 2006 for his type-2 diabetes; there was speculation at the time that the decrease in platelets (Table 1) was related to the addition of this new medication to his regimen. No increased mucocutaneous bleeding was noted. No serious hemostatic challenges such as major surgery were recorded. Medical History: The patient has multiple comorbidities, including hypertension, hyperlipidemia, chronic renal insufficiency, coronary artery disease, post-myocardial infarction, atrial fibrillation, diabetes mellitus, congestive heart failure, erosive gastritis, and duodenal adenomas. Medications: The patient takes multiple medications, including warfarin sodium (Coumadin; Bristol-Myers Squibb Company, New York, NY), furosemide (Lasix; Sanofi-Aventis LLC, Paris, France), simvastatin (Zocor; Merck and Co, Inc), sitagliptin phosphate (Januvia), glimepiride (Amaryl; Sanofi-Aventis LLC), pioglitazone (Actos; Takeda Pharmaceutical Co Ltd, Osaka, Japan), lisinopril, colesevelam (Welchol; Daiichi Sankyo Co Ltd, Tokyo, Japan), and cholestyramine. Family History: No family history of abnormal bleeding or clotting is noted. Physical Examination: The patient was alert and oriented to person, place, and time without acute distress. No purpura, petechiae, or ecchymoses were observed. No lymphadenopathy, hepatomegaly, or splenomegaly was present. The patient reported no fevers, night sweats, or unexplained weight loss. The review of systems revealed no other pertinent hematologic findings. Laboratory Findings: The bone marrow was slightly to moderately hypercellular, and all 3 cell lineages were present. The bone marrow contained an adequate number of megakaryocytes with normal morphology and without clusters or dysplastic features. The immunohistochemical stain for factor VIII–related antigen helped to enhance visualization of megakaryocytes, platelets, and endothelial cells. Granulopoiesis was increased …

A 3-Year-Old Girl with Frequent Nose Bleeds

A 3-year-old girl presented with petechial hemorrhages and repeated nosebleeds. Two weeks earlier she had been admitted to a local hospital with nosebleeds accompanied by 2 episodes of vomiting dark red blood. Results of the laboratory evaluation included: white blood cell count, 8.2 × 109/L [reference interval (RI),3 4 × 109/L to 10 × 109/L]; hemoglobin, 10.7 g/dL (RI, 11–15 g/dL); platelet count, 142 × 109/L (RI, 100 × 109/L to 300 × 109/L), prothrombin time, 11.5 s (RI, 9–13 s); activated partial thromboplastin time, 31.2 s (RI, 26–39 s); and fibrinogen, 2.5 g/L (RI, 2.0–4.0 g/L). The patient was discharged in good condition after insertion of nasal packs. One day before the current admission, the patient had nose bleeds once again, this time accompanied by 4 episodes of hematemesis and tarry stool. At presentation, she had no fever and no diarrhea. She was not on any medications. The patient had a history of easy bruising, repeated gum bleeding, but not hemarthrosis. There was no family history of abnormal bleeding. On examination, she appeared pale, with normal vital signs. Her skin had scattered petechiae. The physical examination was otherwise unremarkable. At presentation, laboratory findings included the following: hemoglobin, 6.2 g/dL (RI, 11–15 g/dL); reticulocyte count, 6.8% (RI, 0.5%–1.5%). Other laboratory results are shown in Table 1. View this table: Table 1. Patient's laboratory results. In vitro testing showed that the patient's platelets did not aggregate in response to ADP, epinephrine, arachidonic acid, or collagen, but platelets had relatively normal ristocetin-induced aggregation. These findings were confirmed on repeat testing. A smear of peripheral blood showed no clusters of normal platelets. A flow cytometry evaluation revealed marked reduction in glycoprotein IIb/IIIa (GPIIb/IIIa). ### QUESTIONS TO CONSIDER 1. What disorders should be considered in the workup of children with repeated nose bleeds? …

Editor’s Choice

Editor’s Choice

Utility of Preoperative Hematologic Screening for Pediatric Adenotonsillectomy

We conducted a 3-year retrospective study to examine the results of preoperative hematologic screening, the incidence of postoperative bleeding, and the possible relationship between the two factors in patients who had undergone tonsillectomy with or without adenoidectomy. Our study population was made up of 875 patients--441 boys and 434 girls, aged 2 to 18 years (mean: 7.52 ± 4.25)--who had been treated at our institution from January 2004 through December 2006. In addition to demographic data, we compiled information on each patient's medical and surgical history, personal and family history of abnormal bleeding, indication for tonsillectomy, and preoperative hematologic screening results. The latter included determinations of the prothrombin time, activated partial thromboplastin time, international normalized ratio (INR), and platelet count. A total of 748 patients (85.5%) had normal findings on preoperative hematologic screening, and 127 (14.5%) had at least one abnormality. Postoperatively, hemorrhagic complications occurred in 31 children (3.5%)--in 22 of the 748 patients with normal screening results (2.9%) and in 9 of the 127 with a screening abnormality (7.1%); the difference between the two groups was statistically significant (p = 0.041). The abnormalities in the latter group consisted of an elevated INR but no otherwise identifiable coagulopathy. Another 14 patients with an abnormal screening result (11.0%) were found to have at least one coagulopathy that was newly diagnosed during our preoperative evaluation; they were treated perioperatively, and none bled postoperatively. Of 21 patients who had a personal or family history of abnormal bleeding, 5 (23.8%) were found to have a coagulopathy, but none bled following surgery. In conclusion, we found that preoperative hematologic screening identified patients with undiagnosed coagulopathies, and with appropriate treatment our surgeons were able to prevent some bleeding events in these patients. Our finding that patients with a mildly elevated INR had a higher incidence of postoperative hemorrhage warrants further study.

Identification and Functional Analysis of a Novel von Willebrand Factor Mutation in a Family with Type 2A von Willebrand Disease

von Willebrand factor (VWF) is essential for normal hemostasis. VWF gene mutations cause the hemorrhagic von Willebrand disease (VWD). In this study, a 9-year-old boy was diagnosed as type 2A VWD, based on a history of abnormal bleeding, low plasma VWF antigen and activity, low plasma factor VIII activity, and lack of plasma high-molecular-weight (HMW) VWF multimers. Sequencing analysis detected a 6-bp deletion in exon 28 of his VWF gene, which created a mutant lacking D1529V1530 residues in VWF A2 domain. This mutation also existed in his family members with abnormal bleedings but not in >60 normal controls. In transfected HEK293 cells, recombinant VWF ΔD1529V1530 protein had markedly reduced levels in the conditioned medium (42±4% of wild-type (WT) VWF, p<0.01). The mutant VWF in the medium had less HMW multimers. In contrast, the intracellular levels of the mutant VWF in the transfected cells were significantly higher than that of WT (174±29%, p<0.05), indicating intracellular retention of the mutant VWF. In co-transfection experiments, the mutant reduced WT VWF secretion from the cells. By immunofluorescence staining, the retention of the mutant VWF was identified within the endoplasmic reticulum (ER). Together, we identified a unique VWF mutation responsible for the bleeding phenotype in a patient family with type 2A VWD. The mutation impaired VWF trafficking through the ER, thereby preventing VWF secretion from the cells. Our results illustrate the diversity of VWF gene mutations, which contributes to the wide spectrum of VWD.