The Frequency of Menorrhagia and Bleeding Disorders in University Students

Study Objective: Menorrhagia is an important health problem in women of reproductive age. The aims of this study were to assess the prevalence of menorrhagia and hemostatic abnormalities associated with menorrhagia in university students. Methods: The pictorial blood assessment chart (PBAC) was used to identify students with menorrhagia. Those with a PBAC score > 100 were examined by pelvic ultrasound and laboratory tests including complete blood count, levels of clotting factors, von Willebrand factor antigen, and ristocetin cofactor activity and Platelet Function Analyser-100 (PFA-100). Platelet aggregation was studied in students with prolonged PFA-100 closure time. Results: Menorrhagia was identified in 82 (21.8%) of 376 students. Six of 82 students who had pelvic pathologies were excluded. Eleven (14.5%) of the remaining 76 students were found to have bleeding disorders, including von Willebrand disease in five (6.5%), platelet function disorder in four (5.2%), and clotting factor deficiencies in two (2.6%). Conclusions: Menorrhagia is a common but mostly unrecognized and untreated problem among university students. Underlying bleeding disorders are not rare and require comprehensive hemostatic evaluation for identification.     

Clinical practice

Mucocutaneous bleeding is common in childhood and may be the result of primary hemostatic disorders such as vascular abnormalities, von Willebrand disease, thrombocytopenia, and platelet dysfunction. A detailed bleeding history and physical examination are essential to distinguish between normal and abnormal bleeding and to decide whether it is necessary to perform further laboratory evaluation. Initial laboratory tests include complete blood count, peripheral blood smear, mean platelet volume, von Willebrand factor (VWF) antigen assay, VWF ristocetin cofactor activity, and factor VIII activity. Once thrombocytopenia and von Willebrand disease have been excluded, platelet function should be tested by platelet aggregation. Additional specific diagnostic tests, such as platelet secretion tests and flow cytometry for the detection of platelet surface glycoprotein expression, are needed to confirm the raised hypothesis.     

Clinical and laboratory features of 178 children with recurrent epistaxis

PURPOSE: To determine the clinical and laboratory features of 178 children referred for the evaluation of recurrent epistaxis to an outpatient hematology clinic in a university medical center. PATIENTS AND METHODS: Medical records of 3681 outpatient pediatric hematology referrals were retrospectively review, and 178 children with recurrent epistaxis from 1985 to 1999 were identified. Historic (other bleeding symptoms: gingival bleeding, easy bruising, menorrhagia, and gross blood in the urine or stool: duration and severity of the epistaxis episodes; and family history of bleeding) and laboratory (complete blood count and coagulation tests) data were analyzed. RESULTS: There were 103 boys and 75 girls with a median age of 84 months (range 15-219 months). Sixty-seven percent (n = 119) did not have a coagulopathy diagnosed and 33% (n = 59) did. The diagnoses included von Willebrand disease in 33, platelet aggregation disorders in 10, thrombocytopenia in seven, mild factor VIII deficiency in three, Bernard-Soulier syndrome in two, factor VII deficiency in one, factor IX deficiency in one, and factor XI deficiency in one, and coagulation inhibitor in one. Of the historic data, only a family history of bleeding was predictive of diagnosing a coagulopathy (P = 0.023). The duration and severity of the epistaxis and the presence of other bleeding symptoms had no predictive value. Children with a coagulopathy diagnosed had a longer median partial thromboplastin time (PTT) (33.1 vs. 30.5 seconds; P = 0.012). CONCLUSIONS: One-third of children presenting with recurrent epistaxis have a diagnosable coagulopathy. A positive family history and a prolonged PPT are useful predictive data.     

Comparison of PFA-100 and bleeding time testing in pediatric patients with suspected hemorrhagic problems

BACKGROUND: The bleeding time test is difficult to perform, standardize, and interpret in children. In this study the authors evaluated the sensitivity, specificity, and efficiency of the bleeding time test and the PFA-100 in a series of children referred for possible bleeding problems. PATIENTS AND METHODS: Between February 2000 and August 2001 patients aged more than 6 months and less than 18 years of age who were referred to the authors' institution for a hemostatic evaluation were included in the study if residual blood was available for testing on the PFA-100 instrument. Fifty-two children had platelet count, prothrombin time, partial thromboplastin time, bleeding time, and PFA-100 testing performed as well as an evaluation by a hematologist. For PFA-100 testing, 52 patients had Col/Epi measurements; adequate sample remained for Col/ADP testing on 32. Additional testing for diagnostic purposes was at the discretion of the treating physician. RESULTS: Use of the Col/Epi cartridge in the PFA-100 instrument offered 100% sensitivity and 97% specificity for detection of qualitative platelet abnormalities, compared with 37% and 88%, respectively, for bleeding time testing. For pediatric patients with von Willebrand disease, the sensitivity was 100% using the Col/Epi cartridge, compared with 17% for the bleeding time test. The sensitivities for combined qualitative platelet defects and von Willebrand disease using the Col/Epi or Col/ADP cartridges were 100% and 87%, respectively, compared with 37% for the bleeding time test. CONCLUSIONS: The PFA-100 is a more efficient test; it can replace the bleeding time test as a component of the laboratory evaluation of children with a potential bleeding problem.     

The prevalence of bleeding disorders among healthy pediatric patients with abnormal preprocedural coagulation studies

BACKGROUND: We evaluated the prevalence of hemostatic disorders among pediatric patients with abnormal screening coagulation tests. PROCEDURE: We analyzed 48 consecutive referrals for abnormal prothrombin times, partial thromboplastin times, or closure times obtained as preprocedural screens. Patients were evaluated by uniform diagnostic testing. RESULTS: Seventeen patients (35%) had an isolated nonspecific inhibitor (NSI). Six patients (12.5%) presented with mildly low factor activity with a concomitant NSI. These deficiencies were of unclear clinical significance. One patient (2%) had a lupus anticoagulant. Only 9 patients (19%) had a possible or true mild bleeding disorder: 5 patients (10%) had isolated low von Willebrand factor levels, 2 patients (4%) had possible type I von Willebrand disease, and 2 (4%) had platelet aggregation disorders. In all patients, personal and family bleeding history had a positive predictive value of 45% for hemostatic disorders. CONCLUSIONS: The most common diagnosis among the patients referred to us for abnormal preoperative coagulation tests was a NSI, which is not associated with an increased risk of operative bleeding complications. Less than 20% had a possible or true mild bleeding disorder. Although certain bleeding disorders can be occult in children and are associated with perioperative bleeding risks, our study demonstrates the inherent limitations in making a laboratory diagnosis of a bleeding disorder in pediatric patients preoperatively. Our findings contribute to existing doubt about the usefulness of prothrombin times, partial thromboplastin times, and closure times to identify occult bleeding disorders in this population.     

Thrombocytopenia in children with severe iron deficiency

PURPOSE: Thrombocytopenia has been reported in some children with severe iron deficiency anemia, but the validity of the association and the mechanism of the thrombocytopenia are not well established. Six children with severe iron deficiency and thrombocytopenia are described, and the literature is reviewed. PATIENTS AND METHODS: Clinical, hematologic, and morphologic data were collected and analyzed for six patients referred for evaluation of severe microcytic anemia and thrombocytopenia. RESULTS: The children ranged in age from 14 months to 17 years (median age 27 months) and were otherwise healthy. The iron deficiency was nutritional in four patients younger than 3 years of age and resulted from menstrual blood loss in two teenage girls. The mean initial hemoglobin was 2.5 g/dL (range 1.6-4.7) and the mean initial platelet count was 64 x 109/L (range 11-102). Bone marrow examinations were performed in three patients and showed increased numbers of megakaryocytes. After treatment with therapeutic doses of oral iron, all the patients showed rapid increases in their platelet counts. CONCLUSIONS: These observations validate and extend previous reports of an association between severe iron deficiency and thrombocytopenia. The increased numbers of megakaryocytes and the extremely rapid increase in platelet counts after initiation of iron therapy suggest an essential role for iron in a late stage of thrombopoiesis.     

The clinical course of immune thrombocytopenic purpura in children who did not receive intravenous immunoglobulins or sustained prednisone treatment

OBJECTIVE: To demonstrate the result of watchful waiting without specific therapy in unselected children with acute immune thrombocytopenic purpura (ITP). STUDY DESIGN: Between May 1992 and October 1999, 55 consecutive children (aged 2 months to 16 years; 28 boys and 27 girls) with acute ITP did not receive intravenously administered immune globulin G (IVIG) or sustained prednisone treatment. Patients with extensive mucosal bleeding were given prednisone, 2 mg/kg/d, for 3 days. RESULTS: In 37 of 55 patients the initial platelet count was <10,000/microL. Ten of these patients had active mucosal bleeding. Five additional patients with bleeding had platelet counts between 10,000 and 20,000/microL. Four patients were given a 3-day course of prednisone. Chronic ITP occurred in 7 (13%) of the patients; 29 patients achieved remission within 6 weeks, and 19 patients, between 6 weeks and 6 months. No life-threatening bleeding occurred, and no patient died. CONCLUSION: Most children with severe thrombocytopenia do not have active mucosal bleeding. This management approach, which did not administer specific therapy, avoided side effects, reduced cost, and was effective.     

Hemostatic changes in idiopathic venous thrombosis in childhood and adolescence]

The prevalence of inherited thrombotic syndrome in the general population appears to be higher than that of inherited bleeding disorders. The most important candidates for screening are patients with unexplained venous thromboembolism at ages of less than 40 years: In 18 children and adolescents suffering from "idiopathic" vein thrombosis laboratory screening has been performed: PT, PTT, TT, platelet count, spontaneous platelet aggregation, von Willebrand factor, fibrinogen, plasminogen, antithrombin III, protein C, C1-inactivator, alpha-1-antitrypsin, alpha-1-antichymotrypsin, alpha-2-antiplasmin and alpha-2-macroglobulin. Compared to an age matched healthy control group in children with idiopathic vein thrombosis we could demonstrate in vitro platelet activation with significant enhanced platelet aggregation and elevated levels of von Willebrand factor in the onset of the disease. Antithrombin III, protein C, alpha-2-antiplasmin and alpha-2-macroglobulin were significantly decreased. These changes turned to be normal in the following 6 to 9 months. PT, PTT, TT, platelet count, plasminogen, alpha-1-antitrypsin, alpha-1-antichymotrypsin and c1-inactivator showed no alterations compared to the control. Platelet activation and alteration of platelet function in vivo and in vitro is established to initiate thrombosis. The von Willebrand's VIII molecule is involved in this step. The decreased inhibitors of the hemostatic system antithrombin III and protein C in the onset period of thrombotic diseases are discussed to be an increased turnover, whereas the decreased levels of alpha-2-antiplasmin and alpha-2-macroglobulin might be a counter-regulation to the thrombotic event, showing an "activated" fibrinolytic system.     

Interaction of iron deficiency and lead and the hematologic findings in children with severe lead poisoning

Microcytic anemia, long considered an effect of lead poisoning, may in fact result from coexisting iron deficiency. In this study, how RBC size, hemoglobin, and zinc protoporphyrin vary as a function of iron status in a group of children with high lead levels was examined. Charts of all children (N = 51) admitted to Cook County Hospital for treatment of lead poisoning in 1981 to 1983 were reviewed for data on age, blood lead level, hemoglobin concentration, MCV, transferrin saturation and zinc protoporphyrin level. The mean lead level was 86 micrograms/dL and the range was 63 to 190 micrograms/dL. Children with transferrin saturation values less than 7% had a mean MCV of 56 microL, hemoglobin of 8.9 g/dL, and zinc protoporphyrin of 693 micrograms/dL; for those with saturations of 7% to 16%, the values were 61 microL, 10.1 g/dL, and 581 micrograms/dL, respectively; the children with saturations greater than 16% had normal mean MCVs and hemoglobin concentrations (74 microL and 11.4 g/dL) and a mean zinc protoporphyrin value of 240 micrograms/dL (P less than .0005). Multiple linear regression was used to correct for effect of age, and transferrin saturation remained the most important predictor of MCV, hemoglobin, and zinc protoporphyrin levels; the addition of lead did not improve the models. Results of this study suggest that iron deficiency is strongly associated with some of the observed toxicities of lead. Also, lead poisoning can exist without producing microcytosis or anemia, and zinc protoporphyrin concentration may not be a sensitive indicator of lead level in the absence of iron deficiency.     

Hematologic toxicity of sodium valproate

PURPOSE: Sodium valproate is a commonly used anticonvulsant in the management of childhood refractory epilepsy with good response rates and acceptable toxicity. Hepatotoxicity is the most widely recognized toxicity. With the use of higher drug levels to achieve adequate seizure control, hematologic toxicity is being increasingly encountered, and the pediatric hematologist is consulted for these problems in the pre- or perioperative setting. The purpose of this article is to characterize the various hematologic toxicities encountered in a clinical setting and to provide guidelines to assist in the management of these patients. METHODS: A literature review was undertaken to identify the hematologic toxicities of valproate used as monotherapy or polytherapy. Key words used in the search were valproate, hematology, and bleeding. RESULTS: Valproate can cause direct bone marrow suppression leading to aplastic anemia or peripheral cytopenia affecting one or more cell lines. Occasional fatal bone marrow failure, myelodysplasia, and a clinical picture resembling acute promyelocytic leukemia have also been seen. Thrombocytopenia, macrocytosis, neutropenia, and pure red cell aplasia can occur but are not reported to be life-threatening. A bleeding diathesis associated with valproate use may include thrombocytopenia, abnormal platelet function, and acquired von Willebrand disease type I. CONCLUSIONS: Hematologic toxicities of valproate are common, vary in onset and severity, are recurrent, transient, or persistent, and usually occur with a serum valproate level greater than 100 microg/mL. In most situations, even when highly clinically significant, they can be reversed with dosage reduction; drug discontinuation is rarely required. Potential adverse effects such as thrombocytopenia and leukopenia are easily detected by laboratory monitoring, which should be continued indefinitely at least on a quarterly basis. Caution for elective surgery is advised; preoperative coagulation studies should be done, including platelet function studies and von Willebrand factor levels. Perioperative use of DDAVP to increase von Willebrand factor levels and improve platelet function is appropriate in some cases.     

Decreased clearance of von Willebrand factor in a patient with type 2B von Willebrand disease following development of immune thrombocytopenia

We report a case of concurrent type 2B von Willebrand disease (VWD) and immune thrombocytopenia (ITP). The patient had characteristic loss of von Willebrand factor (VWF) high molecular weight multimers (HMWM) but a normal platelet count in the initial 8 years after diagnosis of type 2B VWD. When he developed severe thrombocytopenia, however, both his VWD indices and VWF HMWM normalized. As his platelet count increased, he again lost the HMWM and his VWD indices decreased. These results suggest that the severe thrombocytopenia led to decreased clearance of VWF, especially the HMWM.     

Coombs Positive Thrombotic Thrombocytopenic Purpura in a Male Pediatric Patient: An Urgent Diagnostic Challenge

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy often caused by deficiency of von Willebrand (vW) factor cleaving protease, ADAMTS‐13, leading to large vW multimers and intravascular platelet aggregation. Hemolysis in TTP is mechanical and nonimmune mediated, thus Coombs testing is usually negative. We report a case of an adolescent with thrombocytopenia and Coombs positive anemia, diagnosed with Evans syndrome, but ultimately found to have TTP. TTP should be considered in children with thrombocytopenia and Coombs positive anemia who are refractory to steroids or develop signs of microangiopathy.  Recognition of this presentation can lead to life‐saving treatment with plasma exchange.     

Analysis of von Willebrand factor in platelets of patients with various forms of von Willebrand disease: Is there a clinical relevance?

Besides the investigation of coagulation factor VIII:c and von Willebrand factor in plasma, vWF antigen and vWF collagen-binding activity in platelets of 24 patients with various forms of von Willebrand disease were analysed. No platelet vWF:Ag or vWF:CBA was detectable in type 3 patients (n = 4). In contrast 6 out of 7 patients with type 2 vWD had normal or increased vWF levels. Two type 1 patients (out of n = 13) with low von Willebrand factor in platelets had no increased bleeding tendency. In two other individuals with normal amounts of von Willebrand factor in platelets and low plasmatic vWF and factor VIII:c, more frequent bleeding episodes reflecting the low plasmatic levels were observed in a long-term follow-up. Conclusion In our patients, bleeding history corresponded to plasmatic levels of FVIII:c and vWF.     

Platelet aggregation in iron deficiency anemia

In-vitro platelet aggregation with ADP, adrenaline and collagen was studied in pediatric patients with iron deficiency before and after iron therapy, and in normal controls. Hyporeactivity of platelets to all agonists was seen in the untreated patients. This returned to normal following correction of anemia by iron therapy. There was a significant correlation between hemoglobin or serum iron and transferrin saturation on the one hand, and parameters of platelet aggregation on the other (P<0.001). Results of zero order correlation coefficient however, showed that platelet reactivity was actually dependent on the hemoglobin levels rather than the iron parameters per se. This may explain the prolonged bleeding time in patients with iron deficiency, particularly those associated with thrombocytopenia. Anemic individuals may be protected against thrombotic disorders due to this reduced platelet reactivity.     

Anemia and undernutrition among preschool children in Uttar Pradesh, India

This study was conducted to assess the prevalence of anemia among preschool children (3-5 years) and its association with malnutrition in rural Barabanki district of Uttar Pradesh, India. Three out of 18 sub-centers in Nindura block, Barabanki, each with six villages, were randomly selected for this survey and 654 boys and 546 girls were included. Mean hemoglobin level in g/dL among boys and girls was 10.1 (SD: 1.66) and 9.9 (SD: 1.67) (P <0.06) respectively. The proportion of anemic children (Hb <11 g/dL) was 70%. Boys were heavier and taller as compared to girls. Among the 67.3% underweight children the mean hemoglobin level was 9.85 (SD: 1.67) as compared to 10.39 (SD: 1.62) in those without malnutrition (P <0.0001). Likewise, stunted children (87.6%) had statistically significantly lower mean hemoglobin levels than those not stunted. The odds ratio of an underweight and stunted child having moderate to severe anemia was 1.66. While more than half caretakers knew about the term "anemia " and associated physical weakness with it, only very few (2.5%) knew that iron intake will improve it. They relied on "doctors" (86.7%) for anemia prevention.     

Single dose of anti-D immune globulin at 75 microg/kg is as effective as intravenous immune globulin at rapidly raising the platelet count in newly diagnosed immune thrombocytopenic purpura in children

OBJECTIVE: To conduct a randomized prospective trial of immune globulin treatment for 105 Rh+ children with newly-diagnosed immune thrombocytopenic purpura and a platelet count<20,000/microL, to determine whether anti-D immune globulin (anti-D) is as effective as intravenous immune globulin (IVIg). STUDY DESIGN: Eligible patients received either a single intravenous dose of 50 microg/kg anti-D (anti-D50), 75 microg/kg anti-D, (anti-D75), or 0.8 g/kg IVIg, (IVIg). Patients were monitored for response to treatment and adverse events. RESULTS: By 24 hours after treatment 50%, 72%, and 77% of patients in the anti-D50, anti-D75, and IVIg groups, respectively, had achieved a platelet count>20,000/microL (P=.03). By day 7, hemoglobin concentrations decreased by 1.6 g/dL, 2 g/dL, and 0.3 g/dL in the anti-D50, anti-D75, and IVIg groups, respectively. Headache, fever, or chills occurred least often in the anti-D50 group. CONCLUSIONS: A single 75 microg/kg dose of Anti-D raised the platelet count in children with newly diagnosed immune thrombocytopenic purpura more rapidly than standard-dose anti-D and as effectively as IVIg, with an acceptable safety profile.     

Oral contraceptives and DDAVP nasal spray: patterns of use in managing vWD-associated menorrhagia: a single-institution study

The purpose of this study was to examine patterns of use for oral contraceptive and desmopressin acetate nasal spray, both used in managing menorrhagia in adolescents with von Willebrand disease (vWD). Hospital records of adolescents with documented vWD and menorrhagia were reviewed retrospectively. Subjects with vWD type 1 (n = 36) administered either oral contraceptives (OC) or intranasal desmopressin acetate (DDAVP) and followed from 6 months to 4 years were selected for inclusion. Treatment outcomes were examined with respect to effectiveness and safety. Assessing menstrual blood loss using PBAC scores from pretreatment and treatment periods determined effectiveness. Safety was evaluated by monitoring reported adverse events. No significant differences were identified in treatment effectiveness for controlling menorrhagia in vWD adolescents in the OC and intranasal DDAVP group comparisons: 86% versus 77% (P > 0.05), respectively. When combining both treatment groups, the majority of vWD adolescents, 81% (P > 0.05), experienced alleviation of menorrhagia symptoms. Treatment failures were attributed to either the inability of a regimen to control bleeding or to adverse events, including severe headaches and flushing with DDAVP. Safety outcomes were not significantly greater in vWD patients with menorrhagia when OC were compared with intranasal DDAVP. Both medical approaches, OC and DDAVP nasal spray, used in managing menorrhagia in adolescents with documented type I vWD were well tolerated and showed equivalent effectiveness, and no serious adverse events were reported.     

The prevalence of anemia in adolescents: a study from Turkey

A cross-sectional method was used to study a group of 400 high school students in Kocaeli, Turkey, aged 14 to 16 years, identified among 17,812 high school students. Students from 10 high schools were selected using a random sampling method. Whole blood counts were performed as a screening test for anemia. Serum ferritin levels and, when necessary, hemoglobin electrophoresis were determined for anemic students. Iron medication was prescribed for iron deficiency and genetic counseling was given to adolescents with thalassemia trait. Out of 338 participating students (mean age, 14.72+/-0.71 y), anemia (hemoglobin <12 g/dL for girls and <13 g/dL for boys) was detected in 17/174 girls (9.7%) and 6/164 boys (3.6%). Iron deficiency anemia was detected in 20/23 (86.9%) of anemic children [15/17 (88.2%) girls and 4/6 (66.6%) boys]. Of 23 students with anemia 2 had beta-thalassemia trait and 2 had both iron deficiency, and beta-thalassemia trait. Etiology of anemia could not be defined in 1 student. The prevalence of adolescent anemia in Kocaeli is almost equal to that in developed countries.     

Advances in the genetics and treatment of von Willebrand disease

von Willebrand disease (VWD) is a bleeding disorder caused by quantitative (type 1 and 3) or qualitative (type 2) defects of von Willebrand factor (VWF). The mechanisms of most inherited VWD types have been recently elucidated by genetic and molecular diagnosis, but the phenotypic tests based on measurements of plasma and platelet VWF, the ability of VWF to interact with its platelet receptor, and the analysis of the multimeric composition of VWF are always essential to identify patients with different VWD subtypes. The aim of treatment is to correct the dual defects of hemostasis, ie, abnormal coagulation expressed by low levels of factor VIII (FVIII) and abnormal platelet adhesion expressed by prolonged bleeding time (BT). Desmopressin is the treatment of choice in most patients with type 1 and type 2 VWD, who account for 60 to 70% of cases. In type 3 and in some severe forms of type 1 and type 2 VWD, desmopressin is not effective, and it is necessary to resort to plasma concentrates containing FVIII and VWF. Treated with virucidal methods, these concentrates are effective and currently safe, but they do not always correct the BT defect. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of the BT after concentrates is associated with continued bleeding.     

Rhabdomyolysis in diabetic ketoacidosis

Rhabdomyolysis is a potentially lethal disorder, characterized by elevated serum concentrations of creatine kinase (CK) due to skeletal muscle injury. In this paper a patient with diabetic ketoacidosis (DKA) is reported who developed rhabdomyolysis (maximum CK level, 37,700 U/L; normal, < 170 U/L), anemia (6.2 g/dL) and thrombocytopenia (16,000/microL). This combination of rhabdomyolysis with anemia and thrombocytopenia has not yet been reported in DKA. The pathogenic mechanism leading to rhabdomyolysis in DKA remains unsettled. From the literature it seems that those patients who develop rhabdomyolysis have very high glucose levels and a high osmolality on admission. Low phosphate levels can play a role as well. The etiology of anemia and thrombocytopenia in our patient remains obscure. Intravascular hemolysis could not be demonstrated but intramedullar hemolysis, due to osmolar shift or hypophosphatemia, cannot be excluded. A review of the literature data revealed that rhabdomyolysis is not so uncommon in DKA. However, to obtain incidence data in children, prospective studies are necessary.