APS is an acquired hypercoagulable state which presents classically as recurrent arterial and/or venous thrombosis and is a major cause of late first- and second-trimester spontaneous fetal loss. In addition to thrombotic complications, diagnosis of APS requires the presence of ≥ 1 of the following antiphospholipid antibodies on 2 occasions ≥12 weeks apart: 1) anti-ß2-glycoprotein 1 antibodies; 2) anticardiolipin antibodies; and 3) lupus anticoagulant (LA)1.
An unexpected prolongation of aPTT may be a clue to the presence of APS and may be explained by the in vitro prevention of the assembly of the prothrombinase complex—which catalyzes the conversion of prothrombin to thrombin— by LA2,3.
Because the phospholipid component of the reagent used in aPTT tests determines its sensitivity to LA, aPTT results may vary, influenced by the type and concentration of phospholipids used in the assay. Other factors such as acute phase reaction associated with increased fibrinogen and factor VIII levels may also impact the results by shortening the aPTT and potentially masking a weak LA2.
- Giannakopoulos B, Passam F, Ioannou Y, Krilis SA. How we diagnose the antiphospholipid syndrome.Blood. 2009;113:985-94.
- 2. Abo SM, DeBari VA. Laboratory evaluation of the antiphospholipid syndrome. Ann Clin Lab Sci 2007;37:3-14.
- Smock KJ, Rodgers GM. Laboratory identification of lupus anticoagulants. Am J Hematol. 2009;84(7):440-2.
Contributed by Ricardo Ortiz, medical student, Harvard Medical School
Heparin is one of the most overlooked causes of hyperkalemia in hospitalized patients, occurring in 5-8% of treated patients, including those on thromboprophylaxis1.
The risk of heparin-induced hyperkalemia is increased in the elderly, those with preexisting diabetes mellitus or renal insufficiency, as well patients on concomitant use of certain drugs such as spironolactone, ACE inhibitors, NSAIDs, and trimethoprim2. Hyperkalemia is usually detected after at least 3-4 days of treatment with subcutaneous heparin, and usually resolves within a few days of discontinuation of therapy1,2. Fractionated heparin products such as enoxaparin may also be associated with hyperkalemia2 but the risk appears to be lower1.
The mechanism of heparin-induced hyperkalemia appears to be through suppression of aldosterone synthesis by inhibiting the function of the glomerulosa zone of the adrenal medulla2,3. Such inhibitory action is usually of no consequence when renal function is normal and potassium excretion is not otherwise impaired.
- Potti A, Danielson B, Badreddine R, et al. Potassium homeostasis in patients receiving prophylactic enoxaparin therapy. J Thromb Haemost 2004;2:1208-9.
- Thomas CM, Thomas J, Smeeton F, et al. Heparin-induced hyperkalemia. Diabetes Res Clin Pract 2008;80:e7-e8.
- 2. Liu AA, Bui T, Nguyen HV, et al. Subcutaneous unfractionated heparin-induced hyperkalemia in an elderly patient. Australas J Ageing 2009;28:97.
Since their relatively recent introduction, a major concern over NOAC use has been the lack of available reversal agents akin to vitamin K or fresh frozen plasma used to reverse anticoagulation effect of warfarin. Fortunately, there are currently three potential NOAC reversal agents on breakthrough or fast-track status at the FDA, facilitating their rapid approval based on phase III trials: (1) Idarucizumab, a humanized mouse antibody fragment, or Fab, targeted specifically for reversal of dabigatran; (2) Andexanet alfa, a class-specific antidote for reversal of direct factor Xa inhibitors (apixaban, rivaroxaban, edoxaban), as well as an indirect factor Xa inhibitor, enoxaparin; and (3) Ciraparantag (PER977), a synthetic water-soluble compound that reverses direct thrombin (dabigatran), direct factor Xa (apixaban, rivaroxaban, edoxaban), and indirect factor Xa inhibitors (enoxaparin) (1). So stay tuned…Help may be on the way!
1. Ansell JE. Universal, class-specific, and drug-specific reversal agents for the new oral anticoagulants. J Thromb Thrombolysis, published online 08 October 2015.
Contributed by William L. Hwang, MD.
Although warfarin has long been the standard treatment for venous thromboembolism (VTE) and thomboprophylaxis in atrial fibrillation (AF), the need for its frequent monitoring, potential drug interactions, and narrow therapeutic window made it far from ideal. Since 2009, NOACs have become viable alternative agents owing to their more predictable and safer pharmacological profiles. NOACs include several direct factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) and a direct thrombin inhibitor (dabigatran). Approved indications include: (1) thromboprophylaxis in nonvalvular AF; (2) treatment of deep venous thrombosis or pulmonary embolism; and (3) primary prevention of postoperative VTE.
Compared to warfarin, NOACs are associated with a reduced risk of intracranial hemorrhage, and in the case of apixaban, lower risk of gastrointestinal bleeding; rivaroxaban and edoxaban have been associated with a higher risk of gastrointestinal bleeding. Apixaban is also the only NOAC whose dose can be safely reduced in chronic kidney disease, including those on hemodialysis.
1. Baber U, Mastoris I, and Mehran R. Balancing ischaemia and bleeding risks with novel oral anticoagulants. Nat Rev Cardiol 2015;12:66.
2. Ansell JE. Universal, class-specific, and drug-specific reversal agents for the new oral anticoagulants. J Thromb Thrombolysis 2015. Published online October 2015.
Contributed by William L. Hwang, MD.
The short answer is “yes” when deep veins, such as brachial, axillary or subclavian are involved; cephalic and basilic veins are superficial. Although some have suggested that isolated brachial vein thrombosis may be considered at low risk of complication, this assumption has not been corroborated by objective research (1).
There are no randomized trials of AC therapy in patients with upper extremity deep vein thrombosis (UEDVT). However, the American College of Chest Physicians has recommended a 3-month course of AC therapy similar to that of leg DVT for several reasons (1,2): 1. UEDVT has generally been reported to have complications and consequences comparable to that of leg DVT; 2. Several small cohort studies suggest lower rates of recurrent DVT, PE, and bleeding when treated similarly to leg DVT; and 3. The demonstrated benefit of AC therapy in leg DVT. In addition, post-thrombotic syndrome is relatively common (about 1 in 5) among patients with UEDVT (2).
1. Hingorani A, Ascher E, Marks N, et al. Morbidity and mortality associated with brachial vein thrombosis. Ann Vasc Surg 2006; 20:297-299.
2. Kearon C, Akl EA, Comerato AJ, et al. Antithrombotic therapy for VTE disease: American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(suppl):419S-494S.
2. Maynard G. Upper extremity deep vein thrombosis:A call to arms.JAMA Intern Med 2014;696-698.
Until recently, there were no randomized-controlled trials (RCTs) available to help guide our decision. A recent RCT, however, demonstrated that foregoing bridging anticoagulation was not inferior to bridging with low-molecular-weight heparin in patients with chronic or paroxysmal AF for the prevention of arterial thromboembolism and decreased the risk of major bleeding (1). Ineligibility criteria included mechanical valve; stroke, systemic embolism, or transient ischemic attack within the previous 12 weeks; major bleeding within the previous 6 weeks; creatinine clearance < 30 ml/min; platelet count < 100K/ cubic ml; or planned cardiac, intracranial, or intraspinal surgery. A caveat is that the study included relatively few patients (<5%) with CHADS2 score >4.
Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med 2015 (published June 22 at NEJM.org).
Not really! Many of the commonly used antibiotics have the potential for increasing the risk of major bleeding through disruption of intestinal flora that synthesize vitamin K-2 with or without interference with the metabolism of warfarin through cytochrome p450 isozymes inhibition. Although there may be some inconsistencies in the reports, generally quinolones (e.g. ciprofloxacin, levofloxacin), sulonamides (e.g. trimethoprim-sulfamethoxazole), macrolides (e.g. azithromycin), and azole antifungals (e.g. fluconazole) are thought to carry the highest risk of warfarin toxicity, while amoxacillin and cephalexin may be associated with a more modest risk (1,2). Metronidazole can also be a culprit (2).
1. Baillargeon J, Holmes HM, Lin Y, et al. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med. 2012 February ; 125(2): 183–189.
2. Juurlink DN. Drug interactions with warfarin: what every physician should know. CMAJ, 2007;177: 369-371.