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New In Coagulation

New Heparin Standards Reduce Potency of Drug 10%

Manufacturers of heparin will begin rolling out a product next week that is roughly 10% less potent than the heparin currently available, and the Food and Drug Administration is asking clinicians to be aware of the change, particularly in situations where the drug is administered as an intravenous bolus.The heparin reformulation is the result of manufacturing controls occurring in the wake of the 2007 and 2008 contaminations that were linked to deaths and allergic reactions and was proposed by the US Pharmacopeia (USP), a nonprofit standards-setting organization. The USP monograph change includes a modification in the reference standard for the drug's unit dose. The change in the heparin unit dose now matches the World Health Organization International Standard (IS) unit dose definition, one that is currently in use in Europe.
The USP manufacturing controls took effect October 1, 2009 for production, but the new product will not be shipped until October 8, 2009. The FDA points out there will be periods of overlap when both the old and new heparin is available. There are four companies that market heparin in the US: APP, the largest manufacturer, Hospira, Baxter, and B Braun. Three of the four companies will include the letter N on their product to identify the heparin with the new reference standard, while Hospira will identify the changed product with a numeric code.
In addition to the new reference standard, the change in the monograph includes a new test method, which, unlike the previous method, is able to detect impurities that may be present in heparin.


Personalized Medicine and Antiplatelet Therapy: Ready for Prime Time?

The concept of personalized medicine is receiving significant attention due to the greater awareness of the influence of genes to the drug effects. Single nucleotide polymorphisms (SNPs) in the DNA are the most frequent form of sequence variations in the human genome and appear to affect the efficacy and safety of many drugs. The term 'pharmacogenetics' was coined over 40 years ago with an ultimate goal of using the genetic makeup of an individual to predict drug response and efficacy.[1-3] We are just at the beginning of a new era in personalized cardiovascular therapies. However there is little doubt that, in the near future, pharmacogenetic testing will become a valuable tool for a drug and dose selection and thus result in a more desirable benefit/risk ratio for drugs prescribed to patients.
Over the past decades, the platelet has emerged as a major pathway involved in cardiovascular diseases. The platelet as a 'drug target' has spawned a variety of new drugs that have been shown in large-scale randomized trials to improve patient outcomes in acute coronary syndromes and following percutaneous revascularization procedures.[4-6] Until recently aspirin, centred on the tromboxane pathway, was the only antiplatelet agent considered to be the gold standard for effectiveness in both primary and secondary prevention of atherothrombotic diseases.[7] Although it continues to be used as the gold standard antiplatelet therapy, adenosine diphosphate (ADP) receptor antagonists and phosphodiesterase inhibitors in combination therapy appear to exert synergistic effects and provide added benefits among high-risk patients for cardiovascular disease.[7,8]
Nevertheless an important lesson that has emerged from number of trials is that antiplatelet potency per se does not necessarily guarantee enhanced clinical benefit or tolerability for a given patient.[8-11] This may in part be due to the substantial interindividual variation in platelet response to ADP.[9-11] The mechanism underlying such variation has recently become clearer (Figure 1). Specifically the wide inter-subject variabilities to antiplatelet agents such as clopidogrel, may be genetically mediated and arises from altered drug metabolism or transport.[12-15] In the current review, we will focus on the key molecular mechanisms involved in the pharmacological action of oral antiplatelet drugs, the environmental and genetic factors that may impact antiplatelet therapies. We will also provide an update on recent advances in personalized medicine of relevance to arterial thrombosis and antiplatelet drugs. Finally, we will provide our perspectives of pharmacogenetic testing for drugs used to treat cardiovascular diseases.


Superficial Vein Thrombosis Linked to Deep Vein Thrombosis

Superficial vein thrombosis (SVT) affecting the skin may be linked to deep vein thrombosis (DVT) in approximately one quarter of cases, according to the results of a prospective study.The goal of this study was to examine the association of DVT in patients with sonographically proven SVT. The study sample consisted of 46 consecutive patients with SVT enrolled from the outpatient department of the Department of Dermatology, Medical University of Graz. At the beginning of the study, every participant had color-coded duplex sonography of both lower extremities. A history of thromboembolic events, recent immobilization, active malignant disease, oral contraceptive use, and other potential risk factors for thromboembolic disease were documented.
DVT, which was mostly asymptomatic, was detected in 24% of participants, most often involving the calf muscle veins. Location of the DVT was in the leg affected by SVT in 73%, in both legs in 18%, and in the contralateral leg in 9%. All patients with DVT had SVT located on the lower leg and positive D-dimer findings.Limitations of this study include relatively small sample size and lack of a comparison group.
Arch Dermatol. 2009;145:753-757. Abstract
Study Highlights
- Patients who showed clinical signs of SVT between 2006 and 2007 were identified from a phlebology outpatient clinic.
- 46 consecutive patients (32 women and 14 men) were included.
- Patients were asked about history of venous thromboembolism, pulmonary embolism, immobility (Braden scale), malignant disease, oral contraceptive use, and use of compression stockings.
- All patients underwent color-coded duplex sonography and compression ultrasonography of all venous segments (from groin to ankle) of both lower limbs regardless of clinical symptoms of DVT, both to confirm SVT diagnosis and to detect or exclude DVT.
- Cases were categorized into SVT of the great and small saphenous veins and their branches and combinations and DVT of the thigh, the calf muscle veins, or perforating veins.
- Laboratory tests included blood cell count, liver and renal function tests, D-dimer assay, and analysis of thrombophilic disorders.
- Age range of patients was 19 to 91 years, with a median age of 65 years.
- Mean age of the women was 67 years and median body mass index (BMI) was 26.42 kg/m2.
- The mean age of the men was 53.9 years, and median BMI was 28.42 kg/m2.
- All patients showed venous insufficiency with varicose great saphenous veins or varicose small saphenous veins.
- None of the patients had been immobilized in previous weeks.
- 7% had malignant disease, and 4% were using oral contraceptives.
- The duration of SVT symptoms, defined as a tender, indurated cord along the superficial veins and redness and increased temperature of the affected area, was between 1 and 21 days.
- The great saphenous vein was affected in 10 patients, the small saphenous vein in 5, and the branches in 19.
- The D-dimer level was elevated in 11 of 46 patients.
- In 24% (11/46) of patients, concomitant asymptomatic DVT was found.
- 73% of DVTs were found in the same leg as the SVT, 9% in the contralateral leg, and 18% in both extremities.
- Only the calf veins were affected in 4 of 11 patients with DVT.
- Thrombosis of perforating veins was found in 45% and of the posterior tibial veins in 18%.
- The median age of patients with DVT was 73 years, 8 years older than those without DVT, but this difference was not statistically significant.
- In all patients with DVT, the SVT affected the lower leg, but in the group without DVT, one third of SVTs affected the thigh.
- Lower leg SVT was significantly associated with a higher frequency of DVT (P = .02).
- All patients with DVT had an elevated D-dimer level.
- Patients with normal D-dimer level were only found in the group without DVT.
- 6 of 11 patients with DVT reported wearing compression stockings regularly before the occurrence of SVT to minimize symptoms.
- Factors of BMI, Braden scale for immobility, oral contraceptive use, and a history of thrombophilic disorders were not significantly different between the 2 groups.
- The authors concluded that DVTs were associated with SVTs and that in patients with SVTs of the lower leg, deep veins should be assessed by color-coded duplex sonography to exclude DVT.
- They also suggested that evaluation of the contralateral leg for DVT be performed in those with lower leg SVT.
Clinical Implications
- Lower leg SVTs are associated with a higher incidence of ipsilateral and bilateral DVTs.
- Factors associated with DVT in patients with SVT include elevated D-dimer level and lower leg (vs thigh) SVT but not BMI, immobility, oral contraceptive use, or a history of thrombophilic disorders


FDA Safety Changes: Arixtra, Sulfonylureas, Tobramycin

The US Food and Drug Administration (FDA) has approved safety labeling revisions to warn of factors that increase the risk of bleeding in patients receiving treatment with fondaparinux sodium, the risk for hemolytic anemia with use of sulfonylureas in patients with glucose-6-phosphate dehydrogenase deficiency, and the potential for the development of Clostridium difficile-associated diarrhea more than 2 months after completion of antimicrobial therapy.
Fondaparinux (Arixtra) Bleeding Risk Increased in Certain Settings
As with other anticoagulants, use of fondaparinux is linked to a risk for hemorrhage. Extreme caution is advised when treating patients with conditions that increase this risk, such as congenital or acquired bleeding disorders; active ulcerative and angiodysplastic gastrointestinal tract disease; hemorrhagic stroke; uncontrolled arterial hypertension; diabetic retinopathy; or shortly after brain, spinal, or ophthalmologic surgery.
Coadministration of other agents that increase the risk for hemorrhage should also be avoided, unless essential for management of the underlying condition (eg, vitamin K antagonists in venous thromboembolism). Patients receiving combination therapy should be carefully observed for signs and symptoms of bleeding. Isolated cases of elevated activated partial thromboplastin time temporally associated with bleeding events have been reported after administration of fondaparinux with or without concomitant use of other anticoagulants, the FDA noted.
Use of fondaparinux earlier than 6 hours after surgery has also been linked to an increased risk of bleeding; at least 6 to 8 hours should elapse before treatment is initiated.
Because of the increased risk of bleeding in low-weight patients, presurgical use of fondaparinux for deep vein thrombosis (DVT) prophylaxis should be avoided in those weighing less than 50 kg. Use of fondaparinux for the treatment of DVT and pulmonary embolism (PE) should be approached with caution in low-weight patients.
Fondaparinux is also linked to an increased risk of bleeding in patients with impaired renal function because of decreased clearance. Caution and periodic assessment of renal function are advised when treating patients with creatinine clearance ranging from 30 mL/minute to 50 mL/minute; treatment should be discontinued for severe renal impairment (creatinine clearance < 30 mL/minute). The FDA notes that the anticoagulant effect of fondaparinux persists for 2 to 4 days after discontinuation of therapy in patients with normal renal function, a period that may be extended in those with renal impairment.
Fondaparinux is a factor Xa inhibitor (anticoagulant) indicated for the prevention of DVT in patients undergoing hip fracture surgery, hip replacement surgery, knee replacement surgery, or abdominal surgery. It also may be used for the treatment of DVT or acute PE when administered in conjunction with warfarin.


New Review Confirms Homocysteine Lowering Does Not Prevent CVD Events


A new meta-analysis has found no benefit of lowering homocysteine with vitamin-B supplementation for either primary or secondary prevention of cardiovascular disease
The new research provides "scientific proof . . . that folic acid, vitamin B12, and vitamin B6 do not work to prevent cardiovascular disease," he said, adding that his message to people would be: "Save your money." Doctors should advise their patients of this message and instead encourage them to quit smoking, exercise more, and monitor blood pressure, glucose, and lipids to reduce the risk of cardiovascular events, he stressed.
Remarkably Consistent Data
The new review includes data from eight randomized clinical trials--CHAOS, FOLARDA, GOES, HOPE-2, NORVIT, VISP, WAFACS, and WENBIT--assessing the effects of homocysteine lowering for preventing cardiovascular events with a follow-up period of one year or longer, in a total of 24 210 participants. MI and stroke were the primary outcomes.Homocysteine lowering did not reduce the risk of nonfatal or fatal MI (pooled relative risk 1.03), stroke (RR 0.89; 95% CI 0.72-1.09), or death from any cause (RR 1.00).


Lupus Anticoagulant a Major Risk Factor for Stroke and MI in Young Women

A new study shows that lupus anticoagulant, a subtype of antiphospholipid antibodies, dramatically increases the risk for ischemic stroke and, to a lesser degree, myocardial infarction (MI) in young women.The presence of lupus anticoagulant was associated with a more than 40-fold increase in the risk for stroke and with a 5-fold increase in MI. The presence of other cardiovascular risk factors, such as smoking and the use of contraceptives, dramatically compound this already high risk.
Anti-β2-glycoprotein I antibodies were associated with an increased risk for stroke but not MI, and no increase in the risk for stroke or MI was seen with anticardiolipin or antiprothrombin antibodies.
Antiphospholipid Syndrome
Antiphospholipid syndrome is an acquired risk factor for arterial thrombosis. The syndrome has been found to be more prevalent in women younger than 50 years than in the general population, the authors write. It is characterized by vascular thrombosis or complications during pregnancy, followed by a repeated positive test for antiphospholipid antibodies at least 12 weeks apart.
A number of different subpopulations of autoantibodies can be measured, including lupus anticoagulant, anticardiolipin antibodies, anti-β2-glycoprotein I antibodies, and antiphospholipid antibodies. "There's always a long debate on 2 things," Dr. de Groot said: "How important are these antibodies for the risk of thrombosis, and which of these assays is the best."
To look further at these questions, the researchers used data from the Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) study, a large multicenter population-based case-control study looking at risk factors associated with arterial thrombosis, including MI, ischemic stroke, and peripheral vascular disease.
They enrolled women younger than 50 years who were admitted to the hospital at 16 centers with a first ischemic stroke or MI between January 1990 and October 1995. Another 59 women who presented with an ischemic stroke at their institution between 1996 and 2001 were also included. Information was collected on cardiovascular risk factors and, during the second phase, between 1998 and 2002, blood samples were taken to measure antiphospholipid antibody profiles and determine genetic prothrombotic risk factors.
In all, the population consisted of 175 patients with ischemic stroke, 203 with MI, and 628 healthy controls matched for age, residence area, and index year.
Lupus anticoagulant was found in 30 (17%) of the women with ischemic stroke, 6 (3%) of those with MI, and only 4 (0.7%) of those in the control group. The presence of lupus anticoagulant was associated with a high risk for both MI and stroke, a risk greatly compounded by the use of oral contraceptives or smoking.
Lancet Neurol. Published online September 25, 2009. Abstract
Study Highlights
- Included were women aged 18 to 49 years from 16 academic centers and 8 nonacademic centers with ischemic stroke or MI enrolled between 1990 and 1995, with 59 additional women who were enrolled between 1996 and 2001.
- Excluded were those with transient ischemic attack, hemorrhagic stroke, carotid dissection, and a history of cardiovascular disease.
- Control subjects matched for age, residence, and index date of event were recruited by random digit dialing.
- In the first phase of the study, diagnoses were confirmed, and participants completed a questionnaire asking about oral contraceptive use, smoking, alcohol, lifestyle, and other information.
- In the second phase (1998-2002), participants had blood and buccal swabs taken for antiphospholipid antibodies and other risk factors.
- All antiphospholipid antibody tests were done at a central laboratory.
- In the first phase, 248 women with MI, 203 with ischemic stroke, and 925 control subjects were enrolled; 628 control subjects had blood samples drawn.
- 203 women with MI and 127 with ischemic stroke had blood drawn.
- Mean age was 41 years, 95% were of European origin, 2% to 5% had diabetes, 3% to 10% had hyperlipidemia, 33% to 53% used oral contraceptives, and 42% to 82% were current smokers.
- Hypertension was more prevalent in those with MI (26%) and ischemic stroke (28%) vs the control subjects (6%).
- Lupus anticoagulant was found in 3% of women with MI, 17% of women with ischemic stroke, and 0.6% of control subjects.
- The adjusted odds ratio [OR] for MI was 4.6 and for ischemic stroke was 45.7 in women with vs those without lupus anticoagulant.
- The presence of anticardiolipin and antiprothrombin antibodies did not affect the risk for MI or ischemic stroke.
- The risk for ischemic stroke, but not MI, was increased in women with elevated anti-β2-glycoprotein I antibodies (OR, 2.3).
- Adjustment for hypertension, diabetes, and hyperlipidemia did not change the association of MI and ischemic stroke with a positive lupus anticoagulant result.
- In women without lupus anticoagulant, the risk for MI was 2.3 in oral contraceptive users and 6.4 in smokers.
- In women with lupus anticoagulant, the OR for MI was 21.6 for those who used oral contraceptives and 33.7 for those who smoked.
- In women without lupus anticoagulant, the risk for ischemic stroke was 2.9 for those who used oral contraceptives, 2.2 in smokers, and 8.8 in those with the factor XIII 204Phe variant.
- In women with lupus anticoagulant, the OR for ischemic stroke was 201.0 in users of oral contraceptives, 87.0 for smokers, and 81.4 in those with the factor XIII 204Phe variant.
- The population-attributable risk for ischemic stroke because of lupus anticoagulant was 20.1%.
- The authors concluded that the presence of lupus anticoagulant increased the risk for ischemic stroke and, to a lesser degree, MI, in women younger than 50, and these risks were further increased by use of oral contraceptives or smoking.
- They suggested that screening for lupus anticoagulant may be indicated for women with ischemic stroke because treatment with anticoagulants vs antiplatelet drugs is indicated in these patients.
Clinical Implications
- The presence of lupus anticoagulant increases the risk for MI and ischemic stroke among women younger than 50 years.
- The risk for MI and ischemic stroke associated with lupus anticoagulant is increased by use of oral contraceptives and by smoking in women younger than 50 years.

CDC finds lax compliance with federal regulations led to heparin contamination


Lax compliance with federal regulations resulted in bacterial bloodstream infections from contaminated heparin syringes in several states, according to a new Centers for Disease Control and Prevention report," published Oct. 12 in the Archives of Internal Medicine, and which "has raised concerns about drug safety in an increasingly complex pharmaceutical industry." CDC investigators "traced the infections to syringes of the blood thinner heparin produced by a single company," which remained unnamed in the report. David Blossom, of the CDC, and colleagues wrote, "In the course of the investigation, we also identified several challenges to medical product tracking that should be addressed promptly so that disease outbreaks caused by exposure to contaminated medications can be dealt with more efficiently in the future."
How Can We Lower Risk for Clot in Patients With Antiphospholipid Antibodies?
Antiphospholipid antibodies (aPLs) are associated with hypercoagulability and clotting, with various mechanistic studies suggesting a direct role of aPLs in the generation of clots; however, clinically apparent clots do not develop in all patients with aPLs.[1] As such, there is a "2-hit hypothesis" to explain clots in patients with aPLs in whom aPLs predispose to clot, but some other factor may be present before a clinically apparent clot can develop.[2]
These authors sought to identify factors that may be associated with clotting in 1 of 3 clinical scenarios: primary antiphospholipid antibody syndrome; antiphospholipid antibody syndrome associated with systemic lupus erythematosus (SLE); or aPLs and SLE, but no history of clotting or pregnancy loss. The authors performed a cross-sectional chart review of 122 patients (84% female) followed at the Hopkins Lupus Center and determined the association of various factors with clotting using as a control group the patients with aPL/SLE, but no clots. They found that the prevalence of clotting and pregnancy loss was highest in those with antiphospholipid antibody syndrome and SLE. Venous thromboses were associated with elevated triglycerides (level of triglycerides considered elevated not reported), hereditary thrombophilia (including protein C and S deficiency, antithrombin III, and factor V Leiden mutations), anticardiolipin antibody immunoglobulin G > 40 IU (enzyme-linked immunosorbent assay; INOVA Diagnostics), and the presence of lupus anticoagulant (modified dilute Russell's viper venom time). Arterial clots were associated with hypertension and elevated homocysteine. No significant associations were found for pregnancy loss.
Viewpoint
This is a small but fascinating study seeking to identify factors that may be associated with clotting and pregnancy loss in patients with aPLs. Patients with antiphospholipid antibody syndrome with or without SLE can be difficult to treat, and anticoagulation alone may not prevent all clots, so it would be clinically useful to identify other factors that may be altered to decrease the risk for clotting or pregnancy loss in patients with aPLs. This study and others like it should help set the stage for prospective interventional trials with the goal to prove that modification of risk factors such as elevated triglycerides, lowering of aPL levels (perhaps through B-cell depletion), or treatment of hypertension leads to improved outcomes.
In the meantime, should we be treating elevated triglycerides and hypertension in patients with aPLs to decrease the risk for clotting? A proven answer to this question is not yet known, but given the established benefit of treating these conditions for prevention of cardiovascular disease in the general population, it may be worthwhile to consider treatment while awaiting conclusive studies.
Abstract
References
1. Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med. 2002;346:752-763. Abstract
2. Bordin G, Boldorini R, Meroni PL. The two hit hypothesis in the antiphospholipid syndrome: acute ischaemic heart involvement after valvular replacement despite anticoagulation in a patient with secondary APS. Lupus. 2003;12:851-853. Abstract
Primary Stroke Centers Use More Thrombolytic Therapy Than Other Hospitals, but Overall Numbers Still Low
Thrombolysis is administered at profoundly low rates; overall, at the rate of 2% to 3% in the United States across the board. Thrombolytic therapy is the only therapy approved by the US Food and Drug Administration for acute ischemic stroke. When the therapies were developed in the 1990s, the hope was that they would become widely used.Many hospitals simply do not have the infrastructure and staff to provide thrombolysis as an option.. The major problem probably is the limited time window for the therapy.
The recommendation has been that treatment must be administered within 3 hours of the onset of stroke symptoms, although a recent American Heart Association/American Stroke Association Science Advisory now states that tPA can be safely given out to 4.5 hours in selected patients, based on results of the third European Cooperative Acute Stroke Study.
Such prompt response, though, means the community must have an emergency network that can transport patients to a stroke center quickly. In addition, a hospital must have 24-hour physicians on call who are trained and licensed to provide thrombolytics, as well as 24-hour imaging to detect whether a patient is having a hemorrhagic or an ischemic stroke. The hospital also must have neuro-intensive care backup in case of hemorrhagic conversion of an ischemic stroke.

Pharmacist review may boost VTE prophylaxis among at-risk patients


Pharmacists can improve thromboprophylaxis awareness among physicians treating hospitalized patients, suggest results from a clinical trial." Researchers said "their person-to-person method could be an effective alternative to computer alert systems in hospitals without suitable equipment." However, in the trial, thromboprophylaxis "was ordered for 61 percent of 80 patients at moderate-to-high risk for VTE who received usual care compared with 73 percent of 60 patients in the pharmacist-review group." The researchers wrote, "Although our study did not find a statistically significant difference between the intervention and control groups, the trend we observed is consistent with the hypothesis that a pharmacist-driven system can increase VTE prophylaxis use among at-risk individuals."

Few Trauma Patients With Pulmonary Embolism Have Pelvic or Leg Deep Venous Thrombosis


Few trauma patients with pulmonary embolism (PE) have pelvic or leg deep venous thrombosis (DVT), suggesting that PE may occur de novo in the lungs, according to the results of a retrospective medical record review reported in the October issue of the Archives of Surgery.
At an academic level 1 trauma center, 247 patients were identified who underwent computed tomographic pulmonary angiography with computed tomographic venography (CTV) of the pelvic and proximal lower extremity veins from January 1, 2004, to December 31, 2006. Primary study endpoints were PE and DVT, and the investigators also excerpted data on demographic factors, injury type and severity, imaging results, duration of hospitalization, and mortality.
Of these 247 patients, 46 (19%) were diagnosed with PE and 18 (7%) with DVT. In two thirds of patients with PE, this was diagnosed within the first week of injury. Of the PEs, 18 were central, involving the main or lobar pulmonary arteries, and 28 were peripheral, involving the segmental or subsegmental branches.
DVT was present in only 7 patients with PE; of these, 4 were femoral, 2 popliteal, and 1 iliac. Of these 7 patients, 5 had central PE and 2 had peripheral PE. Patients with PE and DVT did not differ significantly from patients with PE without DVT in any of the studied variables.
Limitations of this study include the inability to determine the true incidence of PE among patients with proximal DVT and the lack of a diagnostic standard of reference for DVT.
Arch Surg. 2009;144:928-932.


Window for administering medications to limit damage from stroke may be wider, research suggests

Medications to limit damage from a stroke by dissolving blood clots must be given within three hours of the event, according to standard guidelines." Now, a new paper appearing in Lancet Neurology indicates "that the window of opportunity may extend to 4.5 hours."
Researchers in Germany reached that conclusion after conducting a secondary analysis of "data from the third European Cooperative Acute Stroke Study," in which the "use of recombinant tissue plasminogen activator (rt-PA, alteplase)" was evaluated among 821 patients, Medscape (10/20, Jeffrey) reported. "After those patients with evidence of brain hemorrhage or major infarction on computed tomography scan were excluded, the remaining patients were randomly assigned to receive treatment with intravenous tPA in the approved regimen of 0.9 mg/kg body weight (n = 418) or placebo (n = 403)."
According to HealthDay (10/20, Preidt), the "results showed a clear benefit from treatment with alteplase in all types of patients, including those younger and older than 65 years, men and women, and those with or without a history of diabetes, stroke, or high blood pressure." What's more, the work "supports the use of this thrombolytic drug in the extended period across a broad range of patient subgroups who meet the requirements of the European product label but miss the approved treatment window of zero to three hours," the authors concluded.
Swiss drug regulator sees no increased risk of blood clots from Bayer contraceptives.
Bayer AG said Switzerland's drug regulator Swissmedic sees no increased risk of deadly blood clots from its contraceptive pills containing the synthetic hormone drospirenone compared with similar products on the market." Bayer also said, however, that the "risk of such side effects is highest for all contraceptive pills in the first year of use."

Oral Contraceptives and the Risk for Venous Thromboembolism
van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJ, Rosendaal FR
BMJ. 2009;339:b2921


Background
Oral contraceptive pills (OCP) are among the most common forms of contraception and are used by approximately one fourth of women of reproductive age.[1] Combination pills contain estrogen and progestogen. They work by suppressing follicle-stimulating hormone and luteinizing hormone production, altering tubal motility, and inducing unfavorable cervical mucous and endometrial changes. When used properly, failure rates are below 1%. In addition to providing effective contraception, their use is accompanied by numerous noncontraceptive health benefits (eg, reduced menstrual blood loss, less dysmenorrhea, less acne/ hirsutism, fewer ovarian cysts, fewer premenstrual symptoms, and fewer cases of ovarian and endometrial cancer). However, combination pills also cause undesirable side effects. Soon after their introduction, an increased risk for thromboembolic events and cardiovascular risk was observed (mainly among older women who smoked). In an effort to reduce this risk, newer formulations with lower estrogen dose and new progestogen components were introduced.
Estrogen influences hemostasis by increasing the levels of clotting factors (VII, VIII, X, fibrinogen) and plasminogen, lowering antithrombin III and protein S levels, and altering activated protein C (APC) resistance. APC induces decreased factor V activity. With increased APC resistance, this inhibition is not in effect and the coagulation cascade proceeds. The net effect of combination pills is a procoagulant effect. The overall hemostatic effect is partly caused by estrogen (found in all pills but at different doses) and partly caused by the type of progestogen. Various progestogens induce various changes. Third generation pills that contain desogestrel were found to induce a greater increase in factor II and VII levels.[2] Tans and colleagues[3] reported increased APC resistance with desogestrel-containing pills, and others have confirmed this finding.[4]
In addition to differences among the pills, other factors may also be responsible for venous thromboembolism (VTE) risk. Several known risk factors associated with VTE are age, weight, family history, and smoking. Not all studies control for the known risk factors, and unknown factors may remain unbalanced between cases and controls. In general, one would associate newer preparations with an improved risk profile; therefore, new users and higher-risk patients are more likely to be prescribed the new third-generation pills. This also would influence the number of VTE events.
This study confirms findings of previous studies that also reported an increased risk for VTE with third-generation OCPs compared with second-generation pills. The overall risk for VTE is 1 in 10,000 in the general population. The risk is elevated to 4-6 in 10,000 with OCP use, whereas with pregnancy, the risk is 8-10 in 10,000. These data also show that the risk for VTE is lower with any type of pill when compared with the risk during pregnancy. This is an important comparison because the pill is primarily used to prevent pregnancy. Various pills may be associated with various VTE risk profiles, but other benefits (contraceptive and noncontraceptive) must be considered as well to get an overall picture. Not all pills are tolerated well by all patients, and pills are associated with different bleeding/side effect profiles. Certain pills have a more pronounced effect on premenstrual symptoms or androgen complaints (drospirenone-containing pills).[5] Obviously one should use the pill with the best safety parameters, but the decision has to be based on an overall profile. If the patient discontinues the pill because of side effects (or lack of beneficial effects) and becomes pregnant, her risk for VTE increases or she is exposed to a different set of risks if the pregnancy is terminated. Although VTE risk does need to be considered when a pill is prescribed, the overall response to the pill and satisfaction with the pill is important as well, because we want the patient to comply with contraceptive use.

Donna Castellone

About the Author

Donna Castellone,
MS, MT(ASCP)SH
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