To the Editor:—

I read with interest the report by Fanashawe et al.  1describing two cases in which deep hypothermic circulatory arrest (DHCA) with aminocaproic acid was complicated by massive thrombosis once heparin was reversed by protamine. Postmortem studies were conducted to search for occult hypercoagulable states, and one patient turned out to carry factor V Leiden (FVL). The authors assert that FVL was “almost certainly contributory” to the event and suggest consideration of preoperative testing for FVL to guide decision-making in cases in which DHCA is planned. 1 

While I find these cases very interesting, there is no evidence in the present literature to support that FVL “almost certainly” contributed to the thrombotic risk in one of these patients. Although this conclusion is physiologically plausible, FVL does not always carry risk in specific clinical settings. One example is the lack of association of FVL with venous thrombosis after orthopedic surgery. 2,3Also, most population studies have failed to show an association of FVL with coronary thrombosis and stroke, 4–7although FVL may increase arterial thrombotic risk in specific patient subgroups. 8,9A few studies have suggested (but not proven) that FVL may carry clinical significance in cardiac surgery, 10,11and it is possible that larger studies may characterize this significance in greater detail. However, it is currently pure speculation to suggest that risk of DHCA with aminocaproic acid is increased by the presence of FVL.

It is equally misguided to suggest preoperative screening for FVL and to base patient care decisions on anecdotal reports. No prospective, controlled studies exist to validate the use of preoperative testing for FVL, so it is very unclear how this information should be used. If my next patient is known to carry FVL, what do I do next? Is antifibrinolytic therapy unnecessary? Is it dangerous? Is DHCA safe with aprotinin? Do we need to cross-match fewer units of erythrocytes? Since these genetic studies are becoming widely available, it is concerning that a possible abuse of this test may follow the authors’ suggestions. If the authors themselves had tested their second patient for FVL preoperatively, they may have felt better justified in using aminocaproic acid, only to be dreadfully surprised when they observed a similar thrombotic event.

The risk of FVL in cardiac surgery is presently unclear. The risk of FVL in the presence of cardiac surgery, DHCA, and antifibrinolytic therapy is even less well understood. Fanashawe et al.  perform an important service by reporting a tragic complication of antifibrinolytic therapy and therefore highlight the need to carefully research the possible contributing factors. However, we must be exceedingly cautious not to draw conclusions about genetic risk factors or issue recommendations for patient care based on anecdotal reports. What is needed is a large-scale association study, examining gene-environment interactions, to characterize the role of FVL in cardiac surgery. Only then will we be justified in concluding that FVL is “contributory” toward a particular outcome or in proposing preoperative screening in an effort to reduce risk.

Fanashawe MP, Shore-Lesserson L, Reich DL: Two cases of fatal thrombosis after aminocaproic acid therapy and deep hypothermic circulatory arrest. A nesthesiology 2001; 95: 1525–7
Ryan DH, Crowther MA, Ginsberg JS, Francis CW: Relation of factor V Leiden genotype to risk for acute deep venous thrombosis after joint replacement surgery. Ann Intern Med 1998; 128: 270–6
Woolson ST, Zehnder JL, Maloney WJ: Factor V Leiden and the risk of proximal venous thrombosis after total hip arthroplasty. J Arthroplasty 1998; 13: 207–10
Cushman M, Rosendaal FR, Psaty BM, Cook EF, Valliere J, Kuller LH, Tracy RP: Factor V Leiden is not a risk factor for arterial vascular disease in the elderly: Results from the Cardiovascular Health Study. Thromb Haemost 1998; 79: 912–5
Longstreth WT Jr, Rosendaal FR, Siscovick DS, Vos HL, Schwartz SM, Psaty BM, Raghunathan TE, Koepsell TD, Reitsma PH: Risk of stroke in young women and two prothrombotic mutations: factor V Leiden and prothrombin gene variant (G20210A). Stroke 1998; 29: 577–80
Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP: Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men [see comments]. N Engl J Med 1995; 332: 912–7
Vargas M, Soto I, Pinto CR, Urgelles MF, Batalla A, Rodriguez-Reguero J, Cortina A, Alvarez V, Coto E: The prothrombin 20210A allele and the factor V Leiden are associated with venous thrombosis but not with early coronary artery disease [in process citation]. Blood Coagul Fibrinolysis 1999; 10: 39–41
Rintelen C, Mannhalter C, Ireland H, Lane DA, Knobl P, Lechner K, Pabinger I: Oral contraceptives enhance the risk of clinical manifestation of venous thrombosis at a young age in females homozygous for factor V Leiden. Br J Haematol 1996; 93: 487–90
Baranovskaya S, Kudinov S, Fomicheva E, Vasina V, Solovieva D, Khavinson V, Schwartz E: Age as a risk factor for myocardial infarction in Leiden mutation carriers. Mol Genet Metab 1998; 64: 155–7
Moor E, Silveira A, van't Hooft F, Tornvall P, Blomback M, Wiman B, Ryden L, Hamsten A: Coagulation factor V (Arg506->Gln) mutation and early saphenous vein graft occlusion after coronary artery bypass grafting. Thromb Haemost 1998; 80: 220–4
Sweeney JD, Blair AJ, Dupuis MP, King TC, Moulton AL: Aprotinin, cardiac surgery, and factor V Leiden. Transfusion 1997; 37: 1173–8