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New In Coagulation

WHAT'S NEW IN COAGULATION: JULY 2009

Researchers Detect Blood-Clotting MechanismFinding could help those with potentially deadly conditions
A central aspect of this response to damage is the ability to bring bleeding to an end, a process known as hemostasis,Yet regulating hemostasis is a complex balancing act.If people have too much hemostatic activity, they can develop an excess of blood clots, resulting in thrombosis, which is a potentially deadly condition. On the other hand, if there is too little hemostatic activity, people could bleed to death, according to background information in the news release.
To achieve and maintain the right hemostatic balance, the body has a feedback system controlled by miniscule forces in the circulation system. The forces are applied to the highly-sensitive A2 domain of the blood-clotting protein called von Willebrand factor (VWF), which acts as a "force sensor," the researchers explained.
By manipulating single molecules, the researchers found that the tiniest force causes A2 molecules to unfold and lose much of their complex, three-dimensional organization. After the unfolding, the enzyme ADAMTS13 comes into play. The enzyme cuts the molecule, hence controlling the size of the blood clot, according to the study, in the June 5 issue of Science.To manipulate molecules, the researchers used "optical tweezers" developed in Wong's lab, which can apply miniscule forces to individual molecules while observing tiny changes in their length.
A better understanding of the mechanism of blot clotting could lead to new treatments for injuries or bleeding disorders, such as type 2A von Willebrand disease, the researchers noted.

Dipyridamole Plus Aspirin May Improve Hemodialysis Graft Patency
http://cme.medscape.com/viewarticle/703073?src=cmemp
Engl J Med. 2009;360:2191-2201, 2240-2242.
Clinical Context
Vascular access failure is common in patients with renal failure who are receiving hemodialysis with grafts. When grafts are used, stenosis can develop, leading to thrombosis. Costly procedures may be required to restore and maintain graft patency. A small study has suggested that dipyridamole with or without aspirin could inhibit thrombosis in newly created grafts.
This is a double-blind, randomized controlled trial to examine the effect of extended-release dipyridamole plus aspirin on stenosis and prolongs primary unassisted patency of newly created arteriovenous grafts in patients receiving hemodialysis.
Study Highlights
Included were patients older than 18 years from 13 US sites; these patients were undergoing long-term hemodialysis or expected to within 6 months and were scheduled for new arteriovenous grafts for hemodialysis.
Excluded were patients who were pregnant or breast-feeding, with a known bleeding disorder, peptic ulcer disease, low platelet count (< p =" .03)" p =" .02);" p =" .57)." p =" .005).">Benefits of Aspirin Therapy Outweigh Bleeding Risks in Hypertensive Patients With Chronic Kidney Disease
http://www.medscape.com/viewarticle/703642?sssdmh=dm1.479640&src=nldne

In a hypertensive population with chronic kidney disease (CKD), the benefit of aspirin therapy in reducing major cardiovascular events outweighs the risk for bleeding and, in fact, might be even greater than the benefit obtained by people with normal kidney function, according to an analysis of participants in the Hypertension Optimal Treatment (HOT) study, presented here at the World Congress of Nephrology, a Joint Meeting of the European Renal Association-European Dialysis and Transplant Association and the International Society of Nephrology.
The study involved 18,597 participants, aged 50 to 80 years, with diastolic blood pressure of 100 to 115 mm Hg and a baseline glomerular filtration rate (GFR) of 60 mL/min per 1.73 m2 or less, including 536 patients with values less than 45 mL/min per 1.73 m2. Subjects were randomized to daily acetylsalicylic acid (75 mg) or placebo. n the overall HOT population, the use of aspirin reduced major cardiovascular events by 15% (P = .03), reduced myocardial infarction by 36% (P = .02), and increased the risk for major bleeding by 80% (P < .001). The risk for major cardiovascular events was reduced by 66% (95% confidence interval [CI], 33% - 83%) in those with a baseline GFR of less than 45 mL/min per 1.73 m2, by 15% (95% CI, 17% - 39%) in those with a baseline GFR of 45 to 59 mL/min per 1.73 m2, and by 9% (95% CI, 9% - 24%) in those with a baseline GFR of 60 mL/min per 1.73 m2 or higher (P = .03) Mortality was reduced by 49% (95% CI, 6% - 73%) in those with a baseline GFR of less than 45 mL/min per 1.73 m2 and by 11% (95% CI, 31% - 40%) in those with a baseline GFR of 45 to 59 mL/min per 1.73 m2 (P = .04); there was no significant reduction in those with a baseline GFR of 60 mL/min per 1.73 m2 or higher. The risk for major bleeding events was increased with aspirin by: 291% (95% CI, 92% - 927%) for those with a baseline GFR of less than 45 mL/min per 1.73 m2 171% (95% CI, 74% - 391%) for those with a baseline GFR of 45 to 59 mL/min per 1.73 m2 153% (95% CI, 111% - 210%) for those with a baseline GFR of 60 mL/min per 1.73 m2 or higher. But the differences between these groups was not statistically significant (P = .27), World Congress of Nephrology 2009: A Joint Meeting of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the International Society of Nephrology (ISN): Abstract 766. Presented May 25, 2009. Multivessel Coronary Artery Thrombosis
http://www.medscape.com/viewarticle/589154?src=mp&spon=17&uac=123046FG

Simultaneous thrombosis of multiple epicardial coronary arteries is an uncommon clinical finding in ST-segment elevation myocardial infarction (STEMI). Most patients with acute multivessel thrombosis are critically ill, and the recognition of this condition is of paramount importance to enable prompt and appropriate management. We present a case and review all previously reported cases of multiple coronary thromboses.
Several possible underlying conditions for multiple coronary thromboses have been suggested, such as cocaine use, hypercoagulable state and essential thrombocytosis. Several case reports of patients with essential thrombocytosis resulting in multivessel coronary thrombosis have been published.[1,4,8,14] Although our patient had an increase in platelet count after the event, the bone marrow biopsy result was not consistent with essential thrombocytosis. Reactive thrombocytosis after acute MI has been reported to be a relatively common finding.[18]
Although multiple coronary thromboses are extremely rare in current clinical practice, pathological studies have shown that epicardial coronary thromboses were found in 10% of patients who died from acute MI.[19] Patients with multiple thromboses tend to be more critically ill, as 50% of the patients described in the literature, including our current case, presented with cardiogenic shock. These patients may presumably be the ones who develop out-of-hospital cardiac arrest and death, and hence, the possibility of this condition may be underestimated.
Acute multiple coronary thromboses may be associated with a systemic prothrombotic condition, hence the term "pancoronaritis".[20] Previous studies using angioscopy and IVUS showed that multiple plaque ruptures are frequent in acute coronary syndromes and can be detected in different coronary arteries.[21,22] Another possible mechanism is that the first event causing impairment of the flow of other vessels can lead to acute secondary thrombosis. In addition, the possibility of multiple coronary emboli due to aortic or mitral valve endocarditis[23] and paradoxical emboli through an intracardiac shunt must be considered in patients with no risk factors for coronary artery disease.
Multiple epicardial coronary thromboses occurring in a patient with STEMI is unusual. Despite the inherent tendency to contribute acute MI to a single culprit lesion, STEMI with multiple culprit arteries can occur, and it is crucial to recognize this condition to determine the appropriate treatment since most of these patients are critically ill.


Coffee and Tea May Protect Against Stroke
http://cme.medscape.com/viewarticle/576548?sssdmh=dm1.480032&src=nldne
Stroke. 2008;39:1681-1687.
Clinical Context
Coffee and tea consumption may ameliorate the risk for stroke through multiple physiologic effects. Coffee contains antioxidants and can improve insulin sensitivity and reduce the risk for incident type 2 diabetes. Consumption of black tea reduces platelet activation and plasma levels of C-reactive protein, a marker of inflammation linked with an increased risk for ischemic stroke.
Despite these positive physiologic effects, there is conflicting evidence as to whether coffee and tea consumption can reduce the clinical risk for incident stroke. The current study addresses this issue in a large cohort of male smokers.
Study Highlights
Study subjects were drawn from the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. Participants were Finnish men between the ages of 50 and 69 years who smoked. The study was originally designed to determine whether supplements with alpha-tocopherol or beta-carotene could prevent cancer.
Men with a history of cancer were not permitted to participate in the study, and the current study excluded subjects with a history of a previous stroke.
All subjects underwent a history and physical examination, including laboratory evaluation, at baseline. A validated food frequency questionnaire captured data regarding coffee and tea consumption.
Incident stroke and intracranial hemorrhage were identified through national registries of hospital admissions and deaths. A review of these databases confirmed that the diagnosis was accurate in the vast majority of cases.
The main outcome of the study was the effect of quintile of coffee and tea consumption on the risk for incident stroke and intracranial hemorrhage. This result was adjusted for cardiovascular risk factors and randomized study treatment.
26,556 men provided data for study analysis. The mean age was 57 years, and the mean number of cigarettes smoked daily was 20.
2.5% of subjects reported never drinking coffee, whereas 64% did not drink tea. The authors note that most Finnish men drink black tea exclusively.
The mean daily coffee intake was 5.7 cups. Quintiles of daily coffee consumption were defined as less than 2 cups, 2 to 3 cups, 4 to 5 cups, 6 to 7 cups, and 8 or more cups.
Men who drank higher levels of coffee were younger, smoked more cigarettes, and were more likely to be physically active and free of diabetes and previous coronary heart disease. There was an inverse relationship between coffee and alcohol consumption.
There were 2702 cerebral infarctions, 383 intracerebral hemorrhages, 196 subarachnoid hemorrhages, and 84 unspecified strokes during a mean of 13.6 years of follow-up.
There was a progressively decreased risk for cerebral infarction associated with higher levels of coffee consumption, with a significantly reduced risk for infarction evident at 6 to 7 cups of coffee per day. The multivariate relative risk for cerebral infarction was 0.77 in men in the highest vs lowest quintiles of coffee consumption.
Coffee consumption did not affect the risks for intracerebral hemorrhage and subarachnoid hemorrhage.
Coffee consumption was effective in reducing the risk for cerebral infarction regardless of age, blood pressure levels, lipid levels, or the presence of diabetes or heart disease.
Both filtered and boiled coffees were effective in reducing the risk for cerebral infarction.
There was also an inverse relationship between overall caffeine intake and the risk for cerebral infarction.
Tea consumption also reduced the risk for cerebral infarction, with consumption of at least 2 cups per day associated with a relative risk of 0.79 vs no tea consumption.
Similar to coffee, tea consumption did not affect rates of intracranial hemorrhage.


Meta-Analysis Questions Use of Aspirin in Primary Prevention
http://www.medscape.com/viewarticle/703895?sssdmh=dm1.481051&src=nldne
The authors of a new meta-analysis of aspirin use in primary prevention say their results "do not seem to justify general guidelines advocating the routine use of aspirin in all healthy individuals above a moderate level of risk for coronary heart disease. The meta-analysis, published in the May 30, 2009 issue of the Lancet. Recommending aspirin for primary prevention in all people above a certain risk, are not supported by this new meta-analysis. Data suggest there is not good evidence of substantial benefit that outweighs risk enough to justify a public policy recommending routine use above a moderate CHD risk in primary prevention.The authors identify a benefit of aspirin in primary prevention on nonfatal ischemic events that is largely counterbalanced by an increase in bleeding events, including a small increase in hemorrhagic stroke, with no net effect on vascular mortality. That the risk factors for ischemic events were similar for bleeding events is an interesting observation on its own. The effects in men and women were more similar than dissimilar, which makes biological sense for antiplatelet therapy,"
Previous meta-analyses of aspirin primary-prevention trials were not based on individual participant data, so they could not reliably compare the benefits and risks of aspirin in prognostically important groups (such as older people and others at increased risk of coronary heart disease) and could not quantify reliably the extent to which people at increased risk of coronary heart disease might also be at increased risk of bleeding. Therefore, current guidelines largely ignore any differences in bleeding risk and recommend that aspirin be used widely for primary prevention in those at moderately raised risk of heart disease, and, as age is a major determinant of the risk of coronary heart disease, the guidelines recommend that daily aspirin should be started in all people above a specific age, they add.
Results from the six primary-prevention trials showed that serious vascular events occurred at a rate of 0.51% per year in people allocated to aspirin compared with 0.57% per year in controls. This absolute reduction of 0.07% per year represented a 12% proportional reduction. The risk of major bleeds was increased with aspirin from 0.07% to 0.10% per year, an absolute increase of 0.03%.
This proportional reduction in serious vascular events did not depend significantly on age, sex, smoking history, blood pressure, total cholesterol, body-mass index, history of diabetes, or predicted risk of coronary heart disease. The analysis suggests that the same factors that determine risk of heart disease also determine the risk of bleeding with aspirin, so that, even for people at moderately increased risk of coronary heart disease, the major absolute benefits and hazards of adding aspirin to a statin-based primary-prevention regimen could still be approximately evenly balanced.

Give Early Heparin Bolus to All STEMI Patients to Reduce Stent Thrombosis
http://cme.medscape.com/viewarticle/590334?sssdmh=dm1.482807&src=nldne

New data from the HORIZONS AMI trial suggest that inadequate very early antithrombin and antiplatelet therapy is one of the strongest drivers of early stent thrombosis in ST segment elevation myocardial infection (STEMI) patients undergoing primary percutaneous coronary intervention (PCI) with stenting, with the take-home message to give all patients a heparin bolus and 600 mg of clopidogrel as soon as possible - either in the ambulance or as soon as they arrive in the emergency department. Cigarette smoking was one of strongest drivers of late stent thrombosis. The HORIZONS AMI trial, the largest trial of primary PCI ever conducted, involved 3602 STEMI patients within 12 hours of symptom onset undergoing primary PCI who were randomized to treatment with heparin plus a GP IIb/IIIa inhibitor or to bivalirudin alone. The primary results showed that bivalirudin monotherapy resulted in less major bleeding, comparable rates of ischemia, and improved survival compared with heparin plus a GP IIb/IIIa inhibitor at 30 days and one year.
The most important factor influencing acute stent thrombosis appeared to be use of early nonrandomized heparin before patients had been randomized to the study drug. Patients who received such treatment had significantly lower rates of stent thrombosis within the first 24 hours regardless of which treatment group they were assigned
A 600-mg loading dose of clopidogrel also appeared to be important in reducing stent thrombosis, particularly subacute stent thrombosis in the bivalirudin group. Dangas commented: "Again, this simple intervention of 600-mg clopidogrel seemed to have an effect. Early upfront intense antiplatelet therapy is of prime importance in these patients." He added: "So we have a clear message from this data: Give potent antiplatelet therapy and a bolus of heparin as soon as possible to ST-elevation-MI patients. This is a practical and viable solution."
Other factors that affected acute and subacute stent thrombosis in HORIZONS AMI were vessel flow, lesion characteristics, and number and length of stents, while patient-related factors including cigarette smoking were predictors of late stent thrombosis. The type of stent implanted (drug eluting or bare metal) did not affect the risk of stent thrombosis during any time interval up to one year.
Inadequate very early antithrombin and antiplatelet therapy is one of the strongest drivers of early stent thrombosis, both acute and subacute, in STEMI patients undergoing primary PCI with stenting. Therefore, all patients should be given a heparin bolus and 600 mg of clopidogrel as soon as possible, either in the ambulance or immediately on arrival in the emergency department.
Other factors that predicted acute and subacute stent thrombosis were vessel flow, characteristics of the lesion, and number and length of stents. Cigarette smoking and other patient-related factors increased the likelihood of late stent thrombosis. Risk for stent thrombosis for up to 1 year was not affected by choice of stent type (drug eluting or bare metal).

A 10% Prevalence of Silent Stroke Found in "Healthy" Adults
http://cme.medscape.com/viewarticle/576762?sssdmh=dm1.483220&src=nldne
Stroke. Published online June 26, 2008.
Clinical Context
A previous population-based study in the Netherlands found that nearly 1 in 4 adults between the ages of 60 and 90 years had evidence of a previous cerebral infarct on screening MRI. The vast majority of these infarcts were silent, in that subjects reported no history of symptoms consistent with stroke. This study by Vermeer and colleagues, which was published in the January 2002 issue of Stroke, demonstrated that the rate of silent and symptomatic cerebral infarcts increased at a rate of 8% per year of patient age, and women were more likely to have silent infarcts vs men. The presence of hypertension increased the risk for SCI, but a history of diabetes or smoking did not.
The current study evaluates a large cohort of adults for other factors that might promote SCI.
Study Highlights
The study sample was drawn from the Framingham Offspring Cohort. These individuals have received health examinations every 4 to 8 years since 1971. The current analysis excluded members of the cohort with contraindications to MRI, such as cardiac pacemakers, as well as participants with prevalent stroke or dementia.
2040 participants underwent brain MRI after their sixth study examination. SCI was defined by cerebral infarcts in subjects without a clinical history of stroke or transient ischemic attack.
The main outcome of the study was the prevalence of SCI and factors that promoted these infarctions. Analysis included echocardiography, ultrasound imaging examination of the carotid arteries, and plasma homocysteine levels. A multivariate analysis was performed to examine the independence of various risk factors for SCI.
The mean age at the time of MRI was 62 years.
53% of participants were women, and 37% had hypertension.
The prevalence of diabetes and AF was 8.7% and 2.2%, respectively.
The prevalence of SCI was 10.7%.
Participants with SCI were older and had a higher systolic blood pressure vs patients without SCI.
Most infarcts were located in the basal ganglia (52%), whereas infarcts were also found in other subcortical areas (35%) and cortical areas (11%).
On logistic regression analysis, neither age nor sex was predictive of SCI. Each increase of 1 SD in the FSRP score was associated with an odds ratio (OR) of infarct of 1.27.
Other independent predictors of SCI were stage I hypertension (OR, 1.56), elevation of plasma homocysteine levels in the highest quartile (OR, 2.23), and AF (OR, 2.16).
Carotid stenosis greater than 25% (OR, 1.62) and increased carotid intima-media thickness (OR, 1.65) also increased the risk for SCI.
Left ventricular mass, total cholesterol and high-density lipoprotein cholesterol levels, current cigarette smoking, and a history of cardiovascular disease did not significantly affect the risk for SCI.
Pearls for Practice
In a previous study, the risk for SCIs was increased with older age, female sex, and the presence of hypertension. A history of diabetes and smoking did not alter the risk for silent infarct.
The current study finds that the prevalence of SCI in a large community cohort is 10%. Most infarcts were located in the basal ganglia, and hypertension, AF, elevated plasma homocysteine levels, and carotid stenosis were associated with an increased risk for SCI.


Proinflammatory and Prothrombotic Markers Seen in Obese Kids With No Other Metabolic Syndrome Risk Factors
http://www.medscape.com/viewarticle/704463?sssdmh=dm1.486661&src=nldne

Obesity in children and adolescents is associated with marked increases in proinflammatory and prothrombotic markers, even in the absence of the metabolic syndrome and its composite risk factors, new research suggests obese children have significantly higher levels of IL-6, C-reactive protein (CRP), insulin, plasminogen activator inhibitor-1 (PAI-1), adiponectin, and fibrinogen than lean, age-matched controls.Given the dramatic rise in the proportion of obese kids--17% in 2006, -these findings add new weight to concerns that cardiovascular disease over the next few decades will be increasingly common even in young adults.
More than 300 children and adolescents were screened enrolling only those aged seven to 18 with a body-mass index (BMI) greater than the 95% for age, with no glucose, blood-pressure, or lipid abnormalities. In addition, 87 lean (BMI 10th-75th percentile), age-matched kids, with no family history of glucose, hypertension, or lipid abnormalities were enrolled as control subjects.
Blood tests from both groups showed that CRP and fibrinogen levels were significantly higher in the obese children, both those prepubescent and mid- or past puberty. The CRP results were striking--increased by 8% in the prepuberty group and by 12% in the kids already past puberty. Levels of IL-6, PAI-1, insulin, and adiponectin were also significantly elevated in the obese children, as compared with the lean controls. These data suggest that profound abnormalities in proinflammatory and prothrombin markers are already present in children with simple obesity, even in the absence of associated comorbidities of metabolic syndrome.


Genotyping Info Now in US Clopidogrel Label
http://www.medscape.com/viewarticle/704510?sssdmh=dm1.486899&src=nldne

The US labeling for clopidogrel (Plavix, Sanofi-Aventis/Bristol-Myers Squibb) has been updated to include additional information on factors affecting patients' responses to the drug [1]. This includes a large new section on pharmacogenetics and new advice that concomitant use of drugs that inhibit the CYP2C19 enzyme, such as omeprazole, should be discouraged.
The information on pharmacogenetics explains that several polymorphic CYP450 enzymes convert clopidogrel to its active metabolite, and the patient's genotype for one of these enzymes--CYP2C19--can affect the antiplatelet activity of the drug. It notes: The CYP2C19*1 allele corresponds to fully functional metabolism, while the CYP2C19*2 and CYP2C19*3 alleles correspond to reduced metabolism. The CYP2C19*2 and CYP2C19*3 alleles account for 85% of reduced-function alleles in whites and 99% in Asians. Other alleles associated with reduced metabolism include CYP2C19*4, *5, *6, *7, and *8, but these are less frequent in the general population.
The prescribing information includes a table illustrating the frequencies for the common CYP2C19 phenotypes and genotypes in different populations.
CYP2C19 Phenotype and Genotype Frequency in Different Populations
Population
White (%)
Black (%)
Asian (%)
Extensive metabolism: CYP2C19*1/*1
74
66
38
Intermediate metabolism: CYP2C19*1/*2 or *1/*3
26
29
50
Poor metabolism: CYP2C19*2/*2, *2/*3, or *3/*3
2
4
14
The labeling states that pharmacogenetic testing can identify genotypes associated with variability in CYP2C19 activity and that there may be genetic variants of other CYP450 enzymes with effects on the ability to form clopidogrel's active metabolite. But it also adds that the optimal dose regimen for poor metabolizers has yet to be determined.
Genotype results do not tell the whole story and that probably both gene and platelet-function tests would be used together in future. Platelet-function tests are a good way of guiding therapy in patients already taking one of these drugs, but patients need to be on an antiplatelet drug to measure how much the platelets have been inhibited, and genotyping would therefore be more useful when selecting the initial drug to start treatment with

1. Bristol-Myers Squibb. Plavix labeling information. Available at: http://packageinserts.bms.com/pi/pi_plavix.pdf.


Uncertainty Remains as to Whether Genetic Testing for VTE Improves Outcomes
http://www.medscape.com/viewarticle/704650?sssdmh=dm1.488649&src=nldne

There is insufficient evidence to conclude that genetic testing for two prothrombotic mutations improves outcomes for patients with venous thromboembolism (VTE) or for family members of people who carry the mutations, a new review has found Clinicians test for genetic mutations in factor V Leiden and prothrombin G20210A--the two most common inherited risk factors for VTE--when treating patients who have had or are at risk of VTE, and such tests are widely offered in the US, with the FDA having approved the first tests for these mutations in 2003
Segal said that in the absence of studies directly addressing the issue of whether genetic testing improved patient care, her team instead examined whether "the tests actually predict that there will be recurrent disease in these people or in their relatives, and whether treating patients with these mutations improves their outcomes. Those were the results we were able to report."
They included 46 articles in their review. They found that testing for factor V Leiden mutations "does predict recurrence, a little bit, although the odds ratios are not very high," she said, and "the prothrombin mutation appears to minimally predict recurrent disease, with the odds ratios being a little bit higher for family members than they were for those with incident disease."
In addition, she notes, "We also saw that there were studies demonstrating that treating patients with the mutations with anticoagulation does improve their outcomes, it does reduce the risk of recurrence, but probably to about the same extent as treating anybody who has had a VTE."
She said her team did not specifically address the issue of cost. "We would have reported on cost outcomes had we seen any, but we didn't. We did review some cost-effectiveness studies, but it's a little hard to know what to do with cost-effectiveness data if the test itself isn't remarkably effective."
"There is no direct evidence that testing for these mutations and the resultant management reduce VTE-related outcomes in individuals who have had VTE or in the probands' family members who have been tested," the researchers say. "We conclude that the incremental value of testing individuals with VTE for these mutations is uncertain

Bleeding Disorders May Cause Menorrhagia and Postpartum Hemorrhage

http://cme.medscape.com/viewarticle/704655?sssdmh=dm1.489121&src=nldne

Although menorrhagia or postpartum hemorrhage may result in considerable, clinically significant blood loss, congenital bleeding disorders exacerbating these conditions historically tend to be underdiagnosed, presumably because of lower awareness among obstetricians and gynecologists vs hematologists.
Clues suggesting the possibility of an underlying bleeding disorder include a family or personal history of bleeding events. Recognizing these clues should improve collaboration among obstetrician-gynecologists and hematologists, reduce diagnosis of "idiopathic" menorrhagia, and result in better management of reproductive tract bleeding events. Women who have these conditions should thereby have improved quality of life and school and work performance indicators.
Questions and Answers Addressed
The 6 central questions addressed by the conference, and some specific consensus answers to these questions, were as follows:



1. What is menorrhagia?
Although menorrhagia is typically defined as more than 80 mL of blood loss per menstrual cycle, other indicative features are soaking through a pad or tampon within 1 hour, soaking through bed clothes, below normal ferritin levels, anemia, and pictorial blood assessment chart score of more than 100.
2. When should a gynecologist or obstetrician suspect a bleeding disorder and pursue a diagnosis?
Indicators suggesting an underlying bleeding disorder include menorrhagia since menarche, a family history of a bleeding disorder, or failed response to conventional management of menorrhagia.
Other indicators are a personal history of 1 or more of the following: epistaxis; notable bruising without injury; minor wound bleeding; bleeding of oral cavity or gastrointestinal tract without an obvious anatomic lesion; prolonged or excessive bleeding after dental extraction; unexpected postsurgical bleeding; hemorrhage from ovarian cysts or corpus luteum; hemorrhage requiring blood transfusion; and PPH, especially delayed PPH.
Even in the presence of gynecologic disease such as uterine fibroids, a bleeding disorder may contribute to menorrhagia.
3. What hematologic evaluations should be ordered, and when should they be repeated?
Platelet number and function and specific coagulation factor profile should be evaluated in consultation with a hematologist. Other tests should include complete blood cell count, activated partial thromboplastin time, prothrombin time, VW factor (VWF) measured with ristocetin cofactor activity and antigen, coagulation factor VIII, and fibrinogen.
If results of these tests are normal, women should undergo testing of platelet aggregation and platelet release. Although testing should not be delayed to coincide with menstruation, subsequent testing during menses should be considered if the first set of VWF levels is at the lower limit of normal.
Hormonal contraception should not be interrupted to permit testing.
4. How should menorrhagia be managed in women with bleeding disorders?
Tranexamic acid (1 - 1.5 g, 3 - 4 times/day) may be given before hematologic testing, although management is optimally started once the diagnosis is made. Nonsteroidal anti-inflammatory drugs should be avoided. Further management strategies differ based on whether future fertility and/or becoming pregnant soon are desired. A combination of therapies is often needed, and consultation with a hematologist is essential. Hemostatic treatment should start on the first or second day of menses.



5. How can PPH be prevented in women with bleeding disorders?
Hematology consultation and collaborative care are recommended. VWF levels should be determined. If the coagulation factor profile is not in the normal range by the third trimester, delivery should take place at a specialized center. If third-trimester VWF levels are 50 IU/dL or more, epidural analgesia/anesthesia may be considered safe for delivery; otherwise, appropriate hemostatic cover is required. Adequate venous access is needed during labor, and the third stage of labor should be actively managed.
6. What do we know about menorrhagia and RBDs?
Tranexamic acid and aminocaproic acid or desmopressin (DDAVP) is useful for the treatment of menorrhagia in combined factor V or factor VIII deficiency, but additional research is needed to determine its role in other RBDs. Patients should be treated with antifibrinolytic treatment and appropriate factor replacement when available.
"An awareness of bleeding disorders (such as VWD, RBDs, and platelet disorders) is an important asset for obstetricians and gynecologists," the consensus authors write. "These disorders remain underdiagnosed in women with menorrhagia and potentially in other cases of abnormal bleeding (such as PPH)....The authors of this consensus believe that these recommendations will aid obstetricians and gynecologists to better anticipate, prepare for, and manage cases of abnormal reproductive tract bleeding in women with bleeding disorders."
Financial support for the meeting leading to this consensus statement was provided by CSL Behring, Marburg, Germany.
Am J Obstet Gynecol. Published online June 2, 2009.
Clinical Context
RBDs are inherited autosomally, with prevalence ranging from 1 in 2 million for factor II and factor XIII deficiencies to 1 in 500,000 for factor XI and factor VII deficiencies. The number affected by RBDs around the world has reached approximately 7000, with the most common being factor XI deficiency. VWD affects menstruation and childbirth and may lead to unacceptable blood loss. Because of menses and childbirth, VWD is more likely to present in women vs men, although the prevalence is similar between the sexes.
This is a consensus panel review constructed by obstetricians and gynecologists with hematologists based on a 2007 meeting of the literature on VWD in women focusing on presentation, diagnosis, and treatment strategies.
Study Highlights
The international panel of experts in women's health and hematology met at a meeting that consisted of a series of presentations on bleeding disorders including VWD and reproductive tract bleeding.
6 questions were addressed, and evidence was reviewed for the guidelines and used to grade recommendations.
Patients with VWD are at increased risk for mucocutaneous bleeding that includes epistaxis, bruising, prolonged bleeding after cuts and dental procedures, and other bleeding episodes.
Menorrhagia is defined as more than 80 mL of blood loss per menstrual cycle or soaking through a pad or tampon within 1 hour, soaking through bed clothes, below normal ferritin levels, anemia, and pictorial blood assessment chart score of more than 100.
The prevalence of menorrhagia in women with VWD is 74% to 92% and increases with higher prevalence of type 3 VWD vs type 1 or 2 VWD.
Type 3 VWD results from absence or near absence of VWF, may be associated with deep tissue bleeding, and is rare and severe.
In adult women with menorrhagia, VWD has a prevalence of 5% to 24%, with an average of 13% vs 1% on the general population.
In adolescents with menorrhagia, up to 33% have been found to have VWD.
Unlike menorrhagia, there are limited documented data on the prevalence of PPH in women with VWD.
The rate of PPH in women with VWD is estimated at 6% vs 4% for the general population, and PPH is often delayed beyond 24 hours after delivery, with the average day of examination at approximately 15 days.
A bleeding disorder should be suspected in women with the following risk factors: menorrhagia since menarche, a family history of bleeding disorder, epistaxis, bruising without injury, oral cavity and gastrointestinal tract bleeding without anatomic lesion, excessive bleeding after dental extraction, hemorrhage that required blood transfusion, or hemorrhage from ovarian cysts or corpus luteum.
Hematologic evaluation is indicated when an RBD is suspected and should not be delayed to coincide with menstruation.
Tests should be repeated if results are at the lower end of normal, and studies of platelet aggregation and release should be considered because these abnormalities may be associated with menorrhagia.
Identification of blood group is not essential to the hematologic workup.
Collaboration and referral to a hematologist is required, and the role of instruments is limited.
Initial management includes use of tranexamic acid 1 to 1.5 g, 3 to 4 times a day and avoidance of nonsteroidal anti-inflammatory drugs because they adversely affect platelet function.
There is no consensus on use of cyclooxygenase-2 inhibitors because of lack of data.
If fertility is desired, medical management is indicated including nonhormonal hemostatic agents (such as tranexamic acid and DDAVP).
In severe VWD unresponsive to DDAVP, coagulation replacement may be indicated.
If pregnancy is delayed, combined hormonal contraception, the levonorgestrel intrauterine system, and injectable medroxyprogesterone acetate are viable options.
For women who do not desire future fertility, more invasive strategies may be offered, including endometrial ablation and hysterectomy, but these should be avoided in adolescents.
In pregnant women, PPH should be avoided with use of the following strategies: third-trimester VWF levels of 50 IU/dL or higher, delivery at an experienced center with a blood bank, and active management of third stage of labor.

Donna Castellone

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Donna Castellone,
MS, MT(ASCP)SH
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