Study No

1 Prophylaxis of Thromboembolic Disease MUDr. Petr Dulíček, PhD2 Prof. MUDr. J. Martínková, CSc1 Prof. MUDr. L. Chrobák, CSc2 1. Department of Hematology, University Hospital, Hradec Králové Czech Republic Tel: 420 49 5832686, fax: 420 49 5832011 2. Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Králové, Šimkova 870, 500 01 Hradec Králové, Czech Republic Tel: 420 49 5816 233; Fax: 420 49 55 13 022; e-mail: martinkova@lfhk.cuni.cz Case information: A 58- year old married Caucasian woman, administrative worker. Family history: Father died of myocardial infarction at the age of 68, mother is healthy, but has already had two episodes of venous thromboembolism. The first event was following cholecystectomy, the second one occurred in puerperium. Personal history: Since childhood she has been treated for pain in her left hip joint. Otherwise she is healthy. She has had no surgery. She was admitted for a planned total hip replacement. Weight adjusted dosage of low molecular weight heparin (LMWH) – Fraxiparin 0.4 ml 12 hours before surgery was given as prophylaxis for venous thromboembolism. The same dosage of Fraxiparin was administered 12 hours following surgery and for 3 consecutive days after surgery. Then the dosage was increased to 0.6 ml daily until the tenth day after surgery and afterwards this therapy was withdrawn. Four days after discharge she felt pain in her left leg and she also noticed swelling of this leg with a short episode of dyspnea. Because of these symptoms, she consulted an orthopedic surgeon. Physical examination : Patient without any signs of dyspnea, cyanosis or fever, body weight 80 kg, blood pressure 120/80, physical examination was normal except for swelling of the left lower extremity under the knee with a positive plantar and Homan’s sign. The operation wound was healed, with no signs of the inflammation or bleeding. Question No. 1 Reading the patient´s history you realize that Fraxiparin (nadroparin) is: A. Convetional unfractionated heparin. B. One of low molecular weight heparins. C. A coumarin derivative. Answer No. 1 A. False. B. True C. False. Question No. 2 What is the main effect of Fraxiparin? A. It works by binding to antithrombin III, the naturally occuring inhibitor of thrombin and of the other serine proteases (factors IXa, Xa, XIa a XIIa) and enormously potentiating their inhibitory action. B. Inhibition of activated factor X (f. Xa). 2 Answer No. 2 A. False. This action belongs to heparin. B. True. LMWHs inhibit mainly f. Xa. On this factor intrinsic and extrinsic coagulation pathways converge. Activated factor X catalyzes the conversion of prothrombin (f. II) to thrombin (f. IIa) which is the most important enzyme of the coagulation cascade: first, it cleaves the small small peptides from the N-terminal region of fibrinogen dimers allowing them to polymerize to form strands of insoluble fibrin. Second, it also acts on receptors on thrombocyte surface membranes thereby causing thrombocyte activation. The thrombus consists of thrombocytes and other formed elements of the blood enmeshed within a fibrin network. That is why LMWHs elicit mainly antithrombotic effects and only slight anticoagulation action. Question No. 3 What is the usual route of LMWH administration? A. Orally. B. Subcutaneously. C. I.V. Answer No. 3 A. False. B. True. C. False. I.V. administration is rare. It is recommended for instance for patients on hemodialysis Question No. 4 Which of the following differential diagnosis should be considered ? A. Acute myocardial infarction. B. Deep venous thrombosis. C. Pulmonary embolism. D. Inflammation of the operation wound. Answer No. 4 A. False. Neither subjective complaints nor physical examination are indicative of myocardial infarction. B. True. C. True. If deep venous thrombosis is suspected the possibility of pulmonary embolism must be taken into consideration. D. False. Operative wound is without any signs of inflammation. Body temperature is normal. Question No. 5 May total hip replacement be a risk factor for thromboembolism? : A. No. B. Yes, it may my considered to be moderate risk for thromboembolism. C. Yes, there is a high risk of thromboembolism. 3 Answer No. 5 A. False. B. False. C. True. Total hip replacement is a surgery with the highest risk of VTE. Without prophylaxis prevalence of venous thromboembolism is 40% - 80%, proximal deep venous thrombosis 10% - 30% and fatal pulmonary embolism 1% -10%. Choose the examinations needed for further decision: A. ECG. B. X – ray examination of the lungs and the heart. C. Blood gas. D. Venous ultrasound of veins. E. Perfusion lung scanning. F. Prothrombin time expressed as INR (International Normalized Ratio). G. APTT – activated partial thromboplastin time. H. D- fibrinogen dimers. Results of laboratory workup needed for further decision revealed : A. ECG: sinus rhythm – heart rate 80/min. B. X- ray examination of the lungs and the heart showed no abnormality. C. pH = 7.41, p02 = 9.8 kPa, pC02 = 3.6 kPa. D. Ileofemoral thrombosis of her leg was detected. E. Her perfusion lung scanning was normal. F. INR = 1.1. G. APTT patient plasma = 33.6 s., control plasma = 32.1 s. H. D-fibrinogen dimers = 1500 μg/ml. Question No. 6 Was the diagnosis of pulmonary embolism confirmed? A. Yes. B. No. Answer No. 6 A. False. The perfusion lung scanning revealed no abnormality, but venous ultrasound showed ileofemoral thrombosis of the left leg (VTE). B. True. Question No. 7 The most probable cause of VTE was: A. Insufficient dosage of LMWH. B. LMWH was administered only for 10 days. C. The patient was discharged without anticoagulation treatment. D. LMWH was given without laboratory monitoring. 4 Answer No. 7 A. False. A correct dosage of LMWH based on a weight – adjusted regimen was administered (Leyvraz and Bachmann 1990 – European Ortopedic Fraxiparine Study). B. False. The regimen mentioned above (answer no 4A) recommends 10 days of administration. C. True. Prolonged prophylaxis of venous thromboembolism is recommended in patients with positive family history of venous thromboembolism. In this case either LMWH or warfarin can be given for 10 – 12 weeks after this surgery. D. False. Question No. 8 Was the INR (1.1) within the normal range A. No, it is out of normal range (decreased) and confirms venous thromboembolism. B. The INR is within the normal range. Answer No. 8 A. False. The therapeutic range for most indications is 2-3. B. True. Question No. 9 Why is INR within normal range? A. Because the action of LMWHs is rather short and after 4-day discontinuation of therapy ended. B. Because the INR is not influenced by LMWHs. Answer No. 9 A. False. The INR is not influenced by LMWHs. B. True. Question No. 10 How do you consider the APTT? A. Within normal range. B. This value is prolonged and characterizes LMWH action. Answer No. 10 A. True. B. False. Prolongation by 10 seconds at least if compared with the control is out of normal range. Moreover, LMWHs preferentially inhibit factor Xa (see also Answer 2B). Therefore, they do not prolong the APTT. Question No. 11 Which test should be chosen to control LMWHs? A. There is no need to check LMWHs. B. The Duke or Ivy tests. Answer No. 11 A. True. Monitoring is not needed in routine practice. The only exceptions are: LMWHs in childhood and in patients with impairment of renal function (because of decreased excretion 5 and possible drug accumulation in body). Then f. Xa should be monitored. The test may not be routinely available in each laboratory. B. False. The values of these tests are prolonged (normal range 3-5 minutes) in patients with thrombocytopenia, thrombocytopathia, von Willebrand disease, and after drugs inhibiting platelets aggregation (such as Aspirin) Question No. 12 How do you consider the examination of D-fibrinogen dimers? This value is: A. High. B. Within normal range. Answer No. 12 A. True. Fibrinogen dimers are important for thrombus formation (see also Answer No 2B). Checking the activity of this process we can exclude with 99% probability of the occurence of VET in case of D-fibrinogen dimers < 250 μg/ml. B. False. Question No. 13 Is thrombophilia examination indicated in this case ? A. No. B. Yes. Answer No. 13 A. False. A thrombophilia examination is indicated in this case due to the positive family history of VTE . B. True. Question No. 14 Which kinds of tests are included into thrombophilia examination? A. Antithrombin III activity (ATIII). B. Protein C activity. C. Protein S activity. D. Resistance to protein C. Answer No. 14 A. True. Deficiency of this factor is risky for VTE. Normal activity is within the range 80120%. B. True. Normal activity is within 70-110%. C. True. Normal activity is within 70-110%. D. True. Normal value 2-5?. Commentary: The thrombophilic examination did not detect any pathologic values of the above tests. Now, you should consider further pharmacotherapy. Question No. 15 What kind of therapy do you recommend after patient´s recent admission to hospital? A. Fibrinolytic therapy. B. Anticoagulant treatment with heparin. 6 C. Inhibition of platelet aggregation. D. Anticoagulant treatment with warfarin. Answer No. 15 A. False. This therapy is indicated only in specific cases such as in young patients with a venous gangrene etc. B. True. Heparin is “ the treatment of choice “ for deep venous thrombosis. A prospective study of the relation between the degree of the APTT prolongation and recurrence of venous thromboembolism revealed that reccurence was rare if the APTT was prolonged 1.5 or more times at all times, and if this prolongation was achieved within 24 hours. C. False. Inhibition of platelet aggregation is indicated neither in the treatment nor in the prophylaxis of VTE. D. False. Warfarin should follow therapy with heparin because the onset of its effect is delayed. Question No. 16 Which form of heparin do you prefer? A. Conventional unfractionated heparin. B. One of LMWHs (low molecular weight heparins). Answer No. 16 A. False. B. True. Question No. 17 Why LMWHs are preferred to unfractionated heparin for treatment of venous thrombosis? A. They are more active against venous thrombosis. B. Therapy is safer (bleeding is less frequent). C. Their antithrombotic activity is easily predictable. They have longer t1/2 and higher bioavailability. D. Therapy with unfractionated heparin has to be monitored, while that with LMWHs need not. Answer No. 17 A. False. Their action is comparable and very similar. B. False. The frequency of side effects especially of bleeding complications is comparable as well. C. True. Moreover, (as mentioned above) subcutaneous administration is preferred to intravenous route by most of the patients. D.True (see also Answer No.12A). Question No. 18 The duration of anticoagulation therapy with warfarin will be : A. Life long. B. Long term – at least one year. C. 6 months. Answer No. 18 A. False. B. False. 7 C. True. It was the patient’s first thrombotic event which was associated with the risk factor and without pulmonary embolism and therefore warfarin is indicated only for 6 months. Question No. 19 The INR should be: A.  2.0. B. 2.0 – 3.0. C.  3.0. Answer No. 19 A. False. This value of INR is not sufficient for secondary prophylaxis of venous thrombosis. B. True. This range is optimal for that purpose. C. False. CONCLUSION LMWH -Fraxiparin was given according to a therapeutic weight adjusted regimen – 0.8 ml subcutaneously twice daily for 7 days which was followed by warfarin. When the INR was between 2.0 – 3.0 for two consecutive days the patient was discharged from the hospital. References : 1. Leyvraz PF, Bachmann F.: Prophylaxie thromboembolique sous – cutanée en chirurgie de la hanche (Héparine standard en doses adjustées versus Fraxiparin ) Schweiz Med Wschr 120, 404, 1990 2. Lopaciuk S, Meissner AJ, Filipecki S et al.: Subcutaneous low molecular weight heparin versus subcutaneous unfractioned heparin in the treatment of deep vein thrombosis: Polish Multicenter Trial. Thromb Haemost 68, 14, 1992 3. Dahlbäck B.: Inherited thrombophilia : resistance to activated protein C as a pathogenic factor of venous thromboembolism. Blood 85, 607 – 614, 1995 4. Anticoagulant and Antiplatelet Drugs. In: Textbook of Clinical Pharmacology, Third ed. Edited by J.M.Ritter, L.D.Lewis, and T. G. K. Mant , Edward Arnold, 1995, pp 322-335.