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Habib Ur Rehman, MBBS, FACP, FRCPC Elevated APTT? Department of Medicine, Regina General Hospital, How best to follow up Saskatchewan, Canada [email protected]

This step-by-step guide will help you refine The author reported no potential conflict of interest your approach to an abnormal activated partial relevant to this article. thromboplastin time.

CASE u During an office visit, 23-year-old CASE u Mr. K’s physical examination is un- John K tells you that he recently experienced remarkable and his renal and liver panel— excessive bleeding after a dental extraction. including serum albumin—are within the He says that he has no personal or family his- normal range. As noted earlier, he had no tory of a bleeding disorder and is not taking history of bleeding before the tooth extrac- any medication that might have contributed tion; his family history is negative for excessive to the problem. bleeding, as well. His lab work shows a normal and international normalized ratio (INR). His activated partial thrombo- Consider an artifactual cause plastin time (APTT), however, is 67 seconds It’s important to rule out artifactual causes (normal=24-37 seconds). of an abnormal APTT before undertaking a How would you manage his care? more detailed investigation. Although not applicable in this case, unfractionated hepa- orrect interpretation of abnormal rin in a central venous or arterial catheter can APTT readings requires an under- prolong APTT. C standing of the clinical context in z A high value will give which the test is ordered and the test’s limita- falsely prolonged APTT. This is due to the tions. In cases like Mr. K’s, the top priorities increased concentration of citrate relative to are taking a careful history and performing a the small volume of plasma.1 The lab should thorough physical examination. be alerted if the hematocrit is high so that Specifically, you need to ask about any the volume of in the collec- personal or family history of spontaneous tion tube may be adjusted for more reliable mucosal bleeding, menorrhagia, hemostatic results. difficulties with previous surgeries or den- z Lipemic, hemolyzed, or icteric plasma tal extractions, medication use (including specimens interfere with the optical system ), and alcohol use. Find out of the instruments and may also give false whether there is a history of or results.2 malnutrition/malabsorption. Does the pa- z Delays and extreme temperatures tient bruise easily? can also alter results. The specimen should As you would expect, such signposts not be delayed for more than 4 hours as fac- warrant further investigations. And if the per- tor VIII is labile and longer time will result in sonal or family history does suggest a bleed- an artifactually prolonged APTT.3 (See “APTT: ing disorder, the patient should be referred to Understanding the test” on page E2.) In ad- a hematologist. dition, prolonged exposure to high tempera-

jfponline.com Vol 62, No 6 | JUne 2013 | The Journal of Family Practice E1 vascular , and deficien- cy due to malabsorption or malnutrition. APTT: Understanding z Is an inhibitor at work? The presence the test of an inhibitor is suggested if the mixing Activated partial thromboplastin time studies do not result in correction of the pro- (APTT) measures the integrity of the intrinsic longed APTT to normal range. and common pathways of the coagulation If factitious use of or cascade. Any deficiency or inhibitor of the inhibitors is suspected, (TT) clotting factors within the intrinsic or com- and reptilase time help determine if heparin mon pathways will result in a prolonged or direct thrombin inhibitor is present. TT is APTT. The factors involved in the intrinsic and common pathways are II (prothrombin), prolonged by both heparin and thrombin in- V, VIII, IX, X, XI, XII, and (factor I). hibitors, but reptilase time is not affected by either of the drugs. anticoagulant should be tested if there is no history of treatment with un- tures may enhance degradation of factors V fractionated heparin or direct thrombin in- and VIII, whereas prolonged exposure to cold hibitors such as lepirudin and argatroban. temperatures may activate factor VII.4 However, antiphospholipid are estimated to have a prevalence of 1.0% to Ask patients CASE u Because there is no physical evidence 5.6% in healthy populations.7 Moreover, lu- with an elevated of liver, renal, or connective tissue disease in pus anticoagulant is transient in most cases APTT about Mr. K’s case and artifactual causes are not at and is most often of no clinical significance. a personal or work, the next logical step is a mixing study. It is therefore important to interpret the lupus family history anticoagulant in the context of the illness. of spontaneous z If the inhibitor is still a mystery, you mucosal Does the mixing study will need to test for specific factor inhibitors bleeding, correct the prolonged APTT? like factor VIII inhibitor (acquired hemo- menorrhagia, A mixing study with normal plasma will dif- philia). Inhibitors are alloantibodies, which or hemostatic ferentiate between a coagulation factor de- develop, for example, in patients with hemo- difficulties ficiency and the presence of an inhibitor. philia who are treated with blood products with previous Correction of the prolonged APTT to the such as fresh frozen plasma (FFP), cryopre- surgeries or reference range after mixing a sample of the cipitate, or factor VIII concentrate. dental patient’s blood with normal plasma in a 1:1 extractions. ratio implies a deficiency of a clotting factor in the intrinsic or common final pathway of When an elevated number the coagulation cascade. The deficiency may doesn’t mean what you think involve one or more of the following: factors There are certain limitations of APTT in VIII, IX, XI, or XII; high-molecular-weight identifying the deficient factors because the kininogen (HMWK); and prekallikrein (PK). sensitivity of APTT to identify deficient com- A clotting factor assay will identify the defi- mon pathway factors is low.8 (There may be cient factor. deficiency of a common pathway factor but z Congenital or acquired? Assuming a normal APTT). Composition of the partial that a clotting factor deficiency exists, the thromboplastin reagent can result in marked next step is to determine the nature of the differences in the sensitivity of the test to co- deficiency in terms of congenital or acquired agulation factor deficiencies. defects. Congenital causes of factor VIII, IX, In addition, factor VIII levels may give and XI deficiency are hemophilia A, B, and C, false-negative results in and in re- respectively. Hemophilia affects one in 5000 sponse to physical stress and trauma, as fac- males born in the United States;5 about 9 out tor VIII rises markedly in both cases. Thus, it of 10 have hemophilia A.6 may mask a mild deficiency. Acquired causes of factor deficiencies are Deficiencies of factor XII, HMWK, or PK liver disease, use, disseminated intra- do not result in a bleeding disorder despite

E2 The Journal of Family Practice | JUne 2013 | Vol 62, No 6 ELEVATED APTT

prolonging the APTT markedly. This is im- of choice for bleeding episodes. Prophylactic portant since factor XII deficiency has been treatment is given before surgical procedures found to be among the most common causes or activities that carry a high risk of provoking of unexpected prolongation of APTT.9 a bleed. Factor VIII infusion 3 times a week to pre- CASE u You exclude an acquired bleeding dis- vent hemarthrosis in severely affected patients order based on Mr. K’s history, physical exam, is gaining acceptance. Desmopressin acetate and normal results on his liver panel and a (DDAVP) is the drug of choice for treatment complete blood count. However, a repeat APTT of patients with mild hemophilia (factor VIII is prolonged and a mixing study with normal activity >5%).10 Antifibrinolytic agents like plasma corrects the APTT. Further testing dem- e-aminocaproic acid and tranexamic acid can onstrates normal factors IX and XI, but his lev- be used for mucosal oral or dental bleeds. You el of factor VIII is only 10% of the reference also make sure Mr. K obtains a medical alert range, confirming a diagnosis of hemophiliaA . bracelet. JFP You advise Mr. K to get vaccinated Correspondence against hepatitis A and B. You also discuss Habib Ur Rehman, MBBS, Department of Medicine, Regina available treatment options and their indica- Qu’Appelle Health Region, Regina General Hospital, 1440 – 14th Avenue, Regina, SK, S4P 0W5, Canada; tions. Recombinant factor VIII is the treatment [email protected]

A mixing study References with normal 1. Adcock DM, Kressin DC, Marlar RA. Minimum specimen 6. National Heart, Lung, and Blood Institute. What is hemophilia? plasma will volume requirements for routine : depen- July 1, 2011. Available at: http://www.nhlbi.nih.gov/health/ dence on citrate concentration. Am J Clin Pathol. 1998;109: health-topics/topics/hemophilia/. Accessed May 28, 2013. differentiate 595-599. 7. Petri M. Epidemiology of the antiphospholipid syn- between a 2. Laga AC, Cheves TA, Sweeney JD. The effect of specimen - he drome. J Autoimmun. 2000;15:145-151. molysis on coagulation best results. Am J Clin Pathol. 2006;126: 8. Hillman C, Lusher JM. Tests of blood coagulation technical points coagulation 748-755. of clinical relevance. In: Lusher JM, Barhart MI, eds. Acquired factor deficiency 3. Kamal A, Tefferi A, Pruthi RK. How to interpret and pursue an Bleeding Disorders in Children. Vol 2. New York, NY: Masson; abnormal , activated partial thromboplas- 1981:107. and the presence tin time, and in adults. Mayo Clin Proc. 2007;82: 9. Halbmayer WM, Haushofer A, Schön R, et al. The prevalence of of an inhibitor. 864-873. moderate and severe FXII (Hageman factor) deficiency among 4. McCraw A, Hillarp A, Echenagucia M. Considerations in the labo- the normal population: evaluation of the incidence of FXII de- ratory assessment of haemostatsis. . 2010;16(suppl ficiency among 300 healthy blood donors. Thromb Haemost. 5):74-78. 1994;71:68-72. 5. Centers for Disease Control and Prevention. Hemophilia. Data 10. Hemophilia and von Willebrand’s disease: 2. Management. & Statistics. Updated May 7, 2013. Available at: http://www.cdc. Association of Hemophilia Clinic Directors of Canada. CMAJ. gov/ncbddd/hemophilia/data.html. Accessed May 28, 2013. 1995;153:147-157.

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