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WHAT'S NEW IN COAGULATION: September 2008

WHAT'S NEW IN COAGULATION
FEIBA VH (Anti-Inhibitor Coagulant Complex, Vapor Heated)Background
According to the FDA-approved prescribing information (PI), FEIBA VH is a freeze-dried sterile human plasma fraction with Factor VIII inhibitor bypassing activity and is indicated for the control of spontaneous bleeding episodes or to cover surgical interventions in hemophilia A and hemophilia B patients with inhibitors. FEIBA VH is contraindicated in patients who are known to have normal coagulation mechanism.
FDA reported the following claim filed by the manufacturer Baxter is misleading and the email notification sent by the company be removed.:
"Controlled 78% of bleeds with 3 or fewer infusions-60% of which were controlled with 1 infusion within 12 hours"
The claim is misleading because it overstates the efficacy of FEIBA and the claimed efficacy rate of 60% with one infusion is inconsistent with the PI. According to the PI, "In 130 (78%) of the episodes, hemostasis was achieved with one or more infusions. of these, 36 % were controlled with one infusion within 12 hours" (Clinical Pharmacology). Additionally, the above claim is false or misleading because it only presents that FEIBA "controlled 78% of bleeds with 3 or fewer infusions," but omits important contextual information that the bleeds were controlled "within 36 hours." By omitting this information, the overall presentation of the claim misleadingly suggest that 60% of the bleeds were controlled within 12 hours, which is false.
"FEIBA is well tolerated in 96%-100% of infusions with a low thrombotic event incidence (0.008%)"
The safety claim that FEIBA is "well tolerated" in 96-100% of infusions and has a low incidence of thrombotic events (0.008%) is misleading because it minimizes the fact that serious thrombotic events can occur with FEIBA particularly following the administration of high doses and/or in patients with thrombotic risk factors," and "patients .must be monitored for the development of DIC [disseminated intravascular coagulation] and/or symptoms of acute coronary ischemia". Moreover, the following adverse events, but not limited to, that are reported in the referenced studies1-5 to support the safety claim are inconsistent with the term "well-tolerated":

Antihemophilic Factor, Human (RECALL)REASON:
CSL Behring L.L.C. is initiating a Voluntary Recall of four lots of Monoclate-P®, Antihemophilic Factor, Human. These lots are being withdrawn because they do not meet the potency specification when stored for three months at 5°C. CSL Behring is requesting that the use of these lots be immediately discontinued and the products be returned to the company. No adverse events or product complaints have been reported or associated with the use of this lot.
http://www.fda.gov/cber/recalls/anticsl081808.htm


http://www.medscape.com/viewarticle/561169_print
Guidelines Updated for Prevention of DVT and PE Linked With Gynecologic Surgery News Author: Laurie Barclay, MD
Désirée Lie, MD, MSEd
August 9, 2007 - The American College of Obstetrics and Gynecology (ACOG) has updated its guidelines for prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) associated with gynecologic surgery. The evidence-based clinical management guidelines, which are published in the ACOG Practice Bulletin in the August issue of Obstetrics and Gynecology, are intended to update and replace those from the October 2000 Practice Bulletin.
- The most common mutations predisposing to VTE are factor V Leiden, and mutation G20210A is carried mainly in white patients; screening should be conducted in all white patients with a history of DVT.
- Elevated levels of homocysteine levels increase the risk for VTE and may be genetic or acquired.
- Antiphospholipid antibodies are acquired and should be considered in systemic lupus erythematosus, recurrent fetal loss, severe preeclampsia, or intrauterine growth restriction.
- Risk for VTE is classified as low, moderate, high, and very high.
- Risk stratification is based on type and duration of procedure, and predisposing factors such as previous history, cancer, immobility, genetic mutations, comorbidities, medications, and age.
- Options for prophylaxis are classified as "mechanical" and "pharmacologic."
- Mechanical devices reduce venous stasis and promote endogenous fibrinolysis.
- Pharmacologic methods prevent formation of clots and affect the clotting cascade but have an adverse effect of bleeding.
- 50% of VTEs occur within 24 hours of surgery and 75% within 72 hours of surgery; in high-risk patients, the risk may persist beyond 21 days.
- Low-risk patients undergoing gynecologic surgery do not require specific thromboprophylaxis other than early ambulation.
- Moderate-risk patients may receive the following alternative measures: graduated compression stockings (knee or thigh equally effective) or pneumatic compression devices placed before surgery and continued until fully ambulatory, 5000 U of UFH 2 hours before and every 12 hours after surgery until discharge, or LMWH subcutaneously 12 hours before surgery and once a day postoperatively until discharge.
- For high-risk patients, alternatives include pneumatic compression devices placed before surgery and continued until full ambulation, UFH 5000 U administered subcutaneously 2 hours before surgery and every 8 hours postoperatively until discharge, or LMWH subcutaneously 12 hours before surgery and once daily postoperatively until discharge.
- For highest-risk patients, combination prophylaxis with pneumatic compression devices and either low-dose UFH or LMWH should be considered.
- Use of outpatient prophylaxis with LMWH for up to 28 days should be considered in the highest-risk patients.
- If LMWH cannot be administered 12 hours before surgery, postoperative dosing should begin within 6 to 12 hours.
- Patients undergoing laparoscopic surgery should be stratified by risk similarly to those undergoing laparotomy.
- Pneumatic compression devices are as effective as low-dose heparin and LMWH for DVT prophylaxis and reduce VTE 3-fold in gynecologic patients with cancer.
- Risk for VTE is 4 times higher in patients who use oral contraceptives, but current recommendations do not include discontinuation of combination oral contraceptives before laparoscopic tubal ligation or other brief surgical procedures.
- Regional anesthesia is associated with a 50% decrease in risk for DVT vs general anesthesia, but use of pharmacologic thromboprophylaxis is linked with increased risk for hematoma.
- Anticoagulation should be delayed after a hemorrhagic aspirate and for 2 hours after removal of a spinal or epidural catheter.
- 20% of American women report some use of herbs within 12 months of surgery, and subtherapeutic levels of anticoagulation may result from herb-drug interactions.
- Herbs that may interfere with therapy include ginseng, St. John's Wort, gingko, ginger, and glucosamine-chondroitin.
- Risk of VTE after gynecologic surgery is 15% to 40%, and thromboprophylaxis according to risk stratification is effective in reducing risk.
- Single treatment alternatives for VTE prophylaxis should be offered to patients at moderate and
- high risk and combination prophylaxis to those at highest risk.



Danger Giving Topical Thrombin IntravascularlyThe Institute for Safe Medication Practices (ISMP) recently warned about the dangers of accidentally giving topical thrombin intravascularly. Thrombin applied topically can help stop oozing blood and minor bleeding from capillaries and small veins. Some thrombin products are produced as a frozen solution.

Because of its clotting action, topical thrombin should only be applied to the surface of bleeding tissue. It should never be injected systemically, because that can lead to extensive intravascular clotting and death. ISMP points out that topical thrombin has been mistaken for parenteral medication and administered intravascularly, despite labeling on the thrombin vials that warns against injecting the product. The confusion may arise because the vial-and-syringe packaging of some topical thrombin products makes them look like parenterals.
http://www.ismp.org/Newsletters/acutecare/archives/NL_20070208.pdf


Smoking Influences Antiplatelet Response to Clopidogrel
Clopidogrel is a prodrug that is metabolized in the liver in 2 steps to its active metabolite. The active metabolite binds irreversibly to platelet receptors to inhibit platelet aggregation. However, patients with highly reactive platelet receptors have been demonstrated to have higher rates of ischemic events after PCI.
Cigarette smoking induces one of the CYP450 enzymes that metabolize clopidogrel into its active metabolite, and there is some evidence that smokers have better cardiovascular outcomes with clopidogrel treatment vs nonsmokers. The current study compares platelet inhibition with clopidogrel therapy in smokers and nonsmokers..
Current smokers have increased platelet inhibition and lower platelet aggregation on clopidogrel than nonsmokers, a new study has shown [1]. The authors say that the mechanism of this smoking effect deserves further study and may be an important cause of response variability to clopidogrel therapy.(August 12, 2008, issue of the Journal of the American College of Cardiology ) In a previous study we conducted in 96 patients treated with 300 mg of clopidogrel for elective coronary artery stenting showed that 28% of the responders to clopidogrel were smokers, compared with 13% of the nonresponders. And another study by Matetzky et al has reported that smokers were less often clopidogrel resistant."
http://www.medscape.com/viewarticle/578585?sssdmh=dm1.374461&src=nldne



Excess Body Weight Linked to Risk for Recurrent Venous Thromboembolism
Excess body weight is a risk factor for recurrent venous thromboembolism, according to the results of a study reported in the August 11/25 issue of the Archives of Internal Medicine. The study cohort consisted of 1107 patients observed for an average of 46 months after a first unprovoked venous thromboembolism and withdrawal of anticoagulant therapy. Exclusion criteria were pregnancy, need for long-term antithrombotic treatment, a history of previous or secondary thrombosis, natural coagulation inhibitor deficiency, lupus anticoagulant, or cancer. The primary outcome measure was symptomatic recurrent venous thromboembolism. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared.
Recurrent venous thromboembolism occurred in 168 patients. Patients with recurrence had higher mean BMI vs those without recurrence (28.5 ± 6.0 vs 26.9 ± 5.0; P = .01). There was a linear relationship between excess body weight and recurrence, with the adjusted hazard ratio (HR) for each 1-point increase in BMI being 1.044 (95% confidence interval [CI], 1.013 - 1.076; P < .001). The probability of recurrence 4 years after discontinuation of anticoagulant therapy was 9.3% (95% CI, 6.0% - 12.7%) in patients of normal weight, 16.7% (95% CI, 11.0% - 22.3%) in overweight patients, and 17.5% (95% CI, 13.0% - 22.0%) in obese patients. Patients of normal weight who have had a thrombosis should be told that weight gain might increase their future risk of venous thrombosis."http://www.medscape.com/viewarticle/579186 Acute STEMI Gains with Prehospital Triple Antiplatelet Therapy

August 15, 2008 (London, UK) - The addition of "high-bolus-dose" tirofiban (Aggrastat, Merck) to dual antiplatelet therapy in the prehospital setting significantly improved ST-segment resolution both before and after primary PCI in patients with acute ST-elevation MI (STEMI), in the placebo-controlled second Ongoing Tirofiban in Myocardial Evaluation (ON-TIME 2) trial [1]. Such triple antiplatelet therapy, given with unfractionated heparin before PCI, didn't seem to increase the risk of major bleeding.
There was a statistically significant reduction in a composite clinical end point with added tirofiban, but the trial wasn't powered for clinical outcomes, according to ON-TIME 2 investigators; ST-segment resolution is an indirect marker for myocardial reperfusion.The routine administration of glycoprotein [GP] IIb/IIIa blockers in patients with STEMI is a class 2a indication according to [US and European guidelines]," observe the authors, yet "large registry studies show that in real-world practice, GP IIb/IIIa blockers are given to only 25% to 30% of patients with STEMI, often for bailout situations." The current trial, they write, suggests that the drugs "should not be restricted to patients with complications after PCI, even in a setting in which high-dose clopidogrel is given well in advance of PCI."
Studies of prehospital GP IIb/IIIa inhibition in STEMI, usually with abciximab (ReoPro, Centocor/Eli Lilly), have been conducted primarily in Europe, where ambulances are often staffed by physicians. In ON-TIME 2, van't Hof et al write, "patients were diagnosed and immediately treated in the ambulance by either a physician or a dedicated well-trained paramedic. Diagnosis was correct in 94% of patients with computerized ECG algorithms only, without the need for transmission of the ECG to the hospital."

Donna Castellone

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Donna Castellone,
MS, MT(ASCP)SH
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