Laboratory Bulletin... Updates and Information from Rex Healthcare and Rex Outreach
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Laboratory Bulletin... Updates and Information from Rex Healthcare and Rex Outreach August 2000 Issue Number 49 Prothrombin G20210A and Introduction: Since the 1960s, several genetic disorders that contribute to venous thrombosis have been characterized. Protein S, Protein C and antithrombin deficiency Venous are rare autosomal dominant disorders, have a relatively high risk for thrombosis and Thrombosis are well know. In the 1990’s the link between hyperhomocysteinemia and thrombosis has been established. Recently, the two most common causes of familial thrombophilia, Factor V Leiden and Prothrombin G20210A, have become known. Prothrombin G20210A is prothrombin (factor II) with a single substitution of adenine for guanine at position 20210 that results in increased risk for thrombosis. Decreased levels of prothrombin are associated with increased risk for hemorrhage, whereas elevated prothrombin levels have been associated with increased risk for venous thrombosis. The mechanism whereby this genetic defect results in increased levels of prothrombin is unknown. Prevalence: Factor V Leiden occurs in 5% of the general population and in about 20% of patients with venous thrombosis. Prothrombin G20210A occurs in less than half as many people as factor V Leiden and is almost absent in nonwhites and Asians. About 32% of the causes of deep vein thrombosis can be attributed to known hereditary conditions (Table 1). The rest of the cases are due to acquired risk factors or undiscovered genetic disorders. Table 1. Prevalence of Inherited Risk Factors in Caucasians* Prevalence in Prevalence in general population patient with DVT Relative Risk factor (%) (%) risk Factor V Leiden 5 20 7 Prothrombin G20210A 2 6 3 Protein C deficiency 0.2 – 0.4 3 7 Protein S deficiency 0.7 2 10 Antithrombin deficiency 0.02 1 5 Hyperhomocystinemia 1:335,000 0.1 2.5 *DVT = deep vein thrombosis Clinical Importance: Many investigators believe that the G20210A genetic defect alone is usually not sufficient for the development of venous thrombosis. Although it is the second most common cause of inherited thrombophilia, it is only a mild risk factor for venous thrombosis. Additional risk factors such as smoking, surgery, oral contraceptive use, hormone replacement therapy, varicose veins, pregnancy, postpartum period, immobilization and other inherited thrombophilic conditions are necessary to cause thrombosis. Testing of asymptomatic individuals is not indicated. There are certain subgroups that benefit from testing. These include individuals with a history of venous thrombosis or a clear family history of thrombosis may benefit. Copyright© 2000 Rex Healthcare/Comprehensive Laboratory Services, Inc. 919/784-3040. All rights reserved. Acute management of patients with thrombosis in the setting of Prothrombin G20210A is similar to that for venous thrombosis due to other causes. Long term anticoagulant therapy should be considered for patients with recurrent deep vein thrombosis and both Factor V Leiden and Prothrombin G20210A defects. Currently, there is no consensus of opinion of who should be tested and who should be treated. Laboratory Testing: The analysis of Prothrombin G20210A is done by polymerase chain reaction at the Mayo Reference Lab. Two full yellow-top (ACD) tubes are required. Green top (heparin) tubes are not acceptable. The result is reported as positive or negative and has a 7 days turn-around time. The fee for the test is approximately $322.00. References: 1. Nguyen, MD Adrian, “Prothrombin G20210A Polymorphism and Thrombophilia,” Mayo Clinic Proceedings, 2000;75:595-604. 2. DeStephan, MD Valerio, et. Al., “The Risk of recurrent Deep Vein Thrombosis among heterozygous carriers of both Factor V Leiden and The G20210A Prothrombin Mutation,” New England Journal of Medicine, 1999;341:801-6. Stephen V. Chiavetta, MD Deleted: Monitoring Deleted: Low Molecular Low molecular weight heparins (LMWH) are prepared from unfractionated heparin that has been depolymerized. Several LMWH preparations have been approved by the Weight FDA for deep vein thrombosis (DVT) prophylaxis during orthopedic and abdominal Heparin surgery. One LMWH has recently been approved for use in the treatment of DVT. The advantages of LMWH include improved bioavailability and adequate plasma levels, which usually can be achieved by subcutaneous administration once or twice daily. Laboratory monitoring of LMWH is not usually necessary, but may be indicated in certain circumstances. LMWHs are cleared primarily by the kidneys; therefore, patients with renal insufficiency may benefit from periodic monitoring. Adult patients who are obese or who have low body weigh also may require intermittent monitoring because of possible idiosyncratic pharmacokinetics. Other patients who may benefit from monitoring include outpatients on long-term therapy for malignancy (Trousseau’s syndrome) or for patients with thrombosis refractory to oral anticoagulants, or patients who cannot take oral anticoagulants (pregnant patients or those with drug allergies). Monitoring of pediatric patients is recommended because infants and small children may require larger doses then adults, and studies have not yet confirmed the safety and efficacy of LMWH in this population. LMWH cannot be monitored with common coagulation tests, such as the prothrombin time and the activated partial thromboplastin time. Instead, plasma concentration of LMWH is usually monitored by measuring its ability to inhibit exogenous factor Xa in an anti-Xa activity assay. The therapeutic range for LMWH has not been rigorously defined; however, in the treatment of DVT (with twice daily dosing), an acceptable peak level range is 0.5 to 1.1 anti-Xa U/ml. When administrated subcutaneously, peak plasma levels should be tested on specimens collected 4 hours after injection. LMWH can cause heparin-induced thrombocytopenia, although this is much less common than with unfractionated heparin. A platelet count prior to treatment can be Copyright© 2000 Rex Healthcare/Comprehensive Laboratory Services, Inc. 919/784-3040. All rights reserved. useful if complications occur and subsequent thrombocytopenia is found. Bleeding complications from LMWH therapy can be managed by withholding the drug or by transfusion of packed red blood cells and volume expanders if necessary. However, fresh frozen plasma will not be useful because of the inhibitory activity of the drug. If necessary, treatment with protamine sulfate to neutralize the heparin should be considered. LMWH THERAPY Prophylaxis Therapeutic No Monitoring Child or Weight < 50kg or > 100 kg Continue therapy No Overdose (?) Monitor Yes or Renal insufficiency Yes or Pregnancy Withold No Significant Bleeding Dose No Monitoring Adjust Dose Yes No No Withhold dose Bleeding (?) Yes Protamine SO4 References: Fairweather RB. When should low-molecular-weight heparin be monitored? College of American Pathologists Today. July 1999. Stephen V. Chiavetta, MD OIG: Discount Proposal On November 30, 1999 the Office of the Inspector General (the OIG) issued Advisory Opinion 99-13, which addresses discounted account billing in doctor’s offices for Would Violate pathology and laboratory services. Advisory Opinion 99-13 explains that pathology Anti-Kickback and laboratory providers risk violating the fraud and abuse laws by providing steep Laws discounts to referring physicians and at the same time billing Medicare/Medicaid substantially more. The opinion related to a case in which a pathology group was placed in the position where, to match prices of its competitor, the group proposed offering "account billing customers" significant discounts. Services provided to Medicare and other federally insured patients would be billed to those programs at the group's regular price. "If the group used the discounting scheme, its profit margin for the non-federal health care program business would be less than the profit margin on the services billed to the federal program. Even though the discounts would not be conditioned upon the referring physicians sending the pathology group Medicare and other federally program business – often a safe harbor – the proposed arrangement would not pass muster, the OIG said. The advisory opinion noted that an established discount safe harbor does not protect price reductions offered to one payer but not Copyright© 2000 Rex Healthcare/Comprehensive Laboratory Services, Inc. 919/784-3040. All rights reserved. offered to Medicare or Medicaid. The proposed arrangement poses a significant risk of improper swapping of business, especially in light of the pathology group's statement that many of its competitors are agreeing to such discounts, the OIG said. These competitor discount arrangements might similarly run afoul of Medicare's anti-kickback statute, the OIG warned." () What does this mean to your office practice business? The issue of the OIG ruling is complex and may generate serious legal implications for not only laboratories providing services but also for physician office practices receiving these services. The Anti-Kickback Statute prohibits the payment, receipt, offering or solicitation of remuneration to induce a referral. The providing laboratory benefits by billing the federal (Medicare) allowable charge and the physician office benefits by marking up the discounted charge to non federal insurance programs. Thus, improper Deleted: arrangements could result in criminal and/or civil penalties being assessed against both a laboratory offering an improper discount and the physician or physician