Abstract
Hypercoagulability is a well-documented and prominent risk factor for venous thromboembolism. The role of thrombophilia in arterial thrombotic events is less well defined. A 52-year-old male patient with multiple atherogenic risk factors was admitted for non-healing pedal ulcer and absent distal pulses. Based on the clinical presentation, Doppler ultrasound and angiography findings, the patient underwent elective in situ bypass arterial reconstruction. The saphenous vein graft was of satisfactory quality and the procedure went routinely. Acute graft thrombosis on postoperative day 0 was recognized immediately and prompted an emergent surgical revision. No technical errors or anatomical/mechanical causes for failed reconstruction were found and the graft was successfully thrombectomized using a Fogarty balloon-catheter. Graft rethrombosis, however, ensued after several hours. Considering the absence of threatening limb ischemia and the idiopathic recurrent thrombosis, raising suspicion of prothrombotic state, conservative treatment was pursued. Postoperative thrombophilia testing proved positive for activated protein C resistance, mandating introduction of chronic oral anticoagulation. Six months later, the operated extremity is viable. Inexplicable vascular graft thrombosis, particularly if early and recurrent, should raise suspicion of underlying thrombophilia. If confirmed by laboratory testing, long-term secondary antithrombotic prophylaxis may be required.
Keywords
Introduction
Thrombophilia (hypercoagulability, prothrombotic state) is defined as an inherited or acquired abnormality of hemostasis that affects a delicate balance between procoagulant and anticoagulant factors, predisposing to thrombosis. For instance, deficiencies in physiological inhibitors of coagulation like antithrombin III (AT III), protein S and C (Figure 1), promote thrombogenesis. A significant proportion of the general population has a detectable coagulation defect, but most of the affected persons only develop thrombosis in the presence of an additional ‘trigger’ risk factor (‘two-hit’ hypothesis). A thrombophilic condition can be identified in up to 50% of patients with an unprovoked (idiopathic) deep vein thrombosis (DVT). Resistance to activated protein C (APCR) is the commonest inherited coagulation disorder associated with DVT. In contrast, the role of thrombophilia in arterial thrombotic events, including arterial graft thrombosis, is less clear. In the pathogenesis of arterial thrombosis, hypercoagulability and stasis are considered less important, while the third element of the classic Virchow's triad, i.e. changes in the vessel wall, is believed to have a decisive influence.1–3
Schematic overview of the essential steps in the clotting cascades with outline of the protein C anticoagulant activity. The intrinsic pathway (clinically assessed by activated partial thromboplastin time, aPTT) has less in vivo significance and is initiated when contact is made between blood and exposed negatively charged surfaces. The extrinsic cascade is initiated upon vascular injury and is measured by prothrombin time, PT. At the site of injury, tissue factor (TF, factor III) is expressed and binds to FVIIa (the initiation phase), leading eventually to the conversion of prothrombin (FII) to thrombin (FIIa) by the prothrombinase complex (FXa and FVa). The two pathways converge at the activation of factor X to Xa (common pathway). The propagation phase amplifies the response through the FIXa–FVIIIa complex (‘intrinsic tenase’). Factor X activation by the intrinsic tenase complex is the rate-limiting step for thrombin generation in TF-dependent coagulation. Protein C (PC) is vitamin K-dependent plasma protein with anticoagulant and profibrinolytic activities. It is activated (PCa) by thrombin bound to thrombomodulin (Tm) on the surface of endothelial cells and requires protein S (PS) as an essential co-factor to inactivate FVIIIa and FVa (dotted lines). Activated protein C, thus, inhibits generation of FXa and thrombin (negative feedback loop) and ultimately blocks the conversion of fibrinogen (coagulation factor I) to fibrin
Case report
A 52-year-old male patient with multiple atherogenic risk factors, including smoking (34-pack-year-history), diabetes mellitus type 1, obesity (body mass index 35.1), coronary artery disease (prior myocardial infarction) and longstanding arterial hypertension, was admitted because of a non-healing plantar ulcer of the right foot and an associated absence of popliteal and pedal pulses. Based upon the clinical presentation, Doppler sonography findings (ankle brachial index, ABI: 0.6; right saphenous vein intact structurally and functionally) and angiography imaging (Figure 2), right femoral to posterior tibial in situ bypass was planned. Routine preoperative laboratory work-up, including prothrombin time (PT), activated partial thromboplastin time (aPTT), platelet count and platelet function testing, showed no conspicuous abnormalities. Elective operation was performed under spinal anesthesia, with intraoperative systemic heparinization. The ipsilateral saphenous vein graft was found to be of satisfactory quality (non-varicose, 3.5–4.5 mm in transverse diameter) and the revascularization procedure went routinely. The proximal anastomosis of the bypass graft was constructed in such a manner as to correct the existing ostial stenosis of the profunda femoris artery. For valvulotomy, LeMaitre expandable valvulotome (LeMaitre Vascular, Sulzbach, Germany) was used; adequate pulsatile flow throughout the in situ graft was achieved without difficulties. Immediately after the operation, while observing the patient in the intensive care unit, physical and Doppler sonographic signs of acute graft thrombosis were detected, prompting an emergent revision of the arterial reconstruction. Surgical exploration confirmed complete saphenous graft thrombosis. No technical errors, anatomical or mechanical causes for failed reconstruction were found (i.e. adequate inflow, correct anastomoses, absence of graft angulation or torsion, no retained valves, and satisfactory outflow). The graft was successfully thrombectomized with a Fogarty balloon-catheter. After another several hours, however, graft rethrombosis ensued. Considering the absence of threatening limb ischemia and confronted with unexplainable, recurrent graft thrombosis – raising suspicion of the endogenous prothrombotic state – we opted to pursue with conservative treatment. Postoperatively, laboratory testing for thrombophilia was undertaken using the automated hemostasis analyzer available at our clinic's biochemical laboratory (BCS XP, Dade Behring, Deerfield, IL, USA). The investigated thrombophilia panel encompassed aPTT, PT, international normalized ratio (INR), fibrinogen, D-dimer, FII, FVII, FXII, von Willebrand factor, AT III, protein C, protein S, lupus anticoagulant and anticardiolipin antibodies, and assay for activated protein C resistance (ProC Ac R assay, Siemens Healthcare Diagnostics Products GmbH, Marburg, Germany). Results revealed, most notably, APCR (APCR ratio: 3.89). After consulting with the hematologist, genetic testing for factor V Leiden mutation was proposed to the patient, but due to the high cost it was not affordable to him (not covered by regular health insurance in Serbia). Chronic oral anticoagulation (warfarin) was introduced and control thrombophilia panel screening was scheduled in 12 months The patient was discharged on postoperative day 7 with an INR stabilized in the therapeutic range,2,3 unchanged ABI on the operated leg (0.6) and detailed information on the crucial importance of better control of atherogenic risk factors. With an adequate counseling and medicamentous support, he managed to stop smoking and reduce body weight. Six months later, the operated extremity is viable, with pedal ulcer almost healed.
Preoperative conventional contrast angiogram of the right lower limb (transfemoral access) demonstrating extensive infrainguinal and infragenicular atherosclerotic arterial occlusive disease with satisfactory iliac segment inflow, complete occlusion of the superficial femoral and popliteal arteries, richly developed perigenicular collateral network, ostial stenosis of the deep femoral artery (arrow), and single-vessel crural run-off (posterior tibial artery, arrowhead)
Discussion
The modern era of understanding the etiology of thrombosis began with the German pathologist Rudolf Virchow, who in 1856 postulated three major categories of factors contributing to thrombosis, still valid today and known as Virchow's triad: 4 (1) alterations in the blood flow (stasis), (2) changes in the constitution of blood (hypercoagulability) and (3) changes in the vessel wall (injury). It is well recognized that these classes of pathogenic factors do not have the same role in arterial and venous thrombosis. Arterial thrombosis is overwhelmingly dominated by atherosclerosis (vessel wall changes). Stasis does not play a prominent role in the etiology of arterial thrombosis because of high blood pressure and flow through the arterial system. Although hypercoagulability does affect the risk of arterial thrombosis, its role in arterial disease is much less pronounced than in venous thrombosis and relatively little is still known about coagulopathies that predispose to arterial thromboembolism or unexplained arterial reconstruction thrombosis.
In the last 50 years, the molecular basis of blood coagulation and the anticoagulant systems that control it have been elucidated (Figure 1). Under physiological conditions, these opposing but highly integrated systems are in the state of constant and complex interplay aiming to preserve the fluidity and flow of blood throughout the circulatory system. A myriad of hypercoagulable states can affect this delicate balance, tipping it toward thrombosis. Thrombophilic states can be inherited or acquired and related to either an increase of a procoagulant factor(s) or a reduction of an anticoagulant agent or lack of its activity. Most thrombotic episodes seem to occur with additive combination of acquired and inherited predisposing factors. To complicate the picture further, classic risk factors for atherosclerosis such as smoking, hypertension, hyperlipidemia, and diabetes mellitus also represent hypercoagulable states per se. Moreover, it is known that thrombophilia defects may be acquired after surgical intervention. Indeed, vascular surgery is an obvious exogenous procoagulant event responsible for arterial wall injury and tissue factor liberation. It has been reported that AT III, protein C and S deficiency, as well as platelet hyperactivity may manifest de novo in postoperative patients.1–3
The first major form of thrombophilia, AT deficiency, was identified in 1965, 5 while the most common abnormalities were described in the 1990s. Hereditary APCR was first described by Dahlbäck et al. in 1993 6 and was characterized as an autosomal dominant alteration in factor V that prevents the normal APC-FV anticoagulant mechanism. Factor V Leiden (FVL), named after the city Leiden in the Netherlands, where the genetic defect was first identified in 1994 by Bertina et al., 7 represents the most common hereditary hypercoagulability disorder. A mutation in the FV gene leading to the replacement of arginine at position 506 with glutamine, which renders the resultant molecule (FVL) more resistant to degradation by APC, is responsible for the great majority of APCR cases, the remainder of which is made up of acquired conditions such as antiphospholipid syndrome (APS). Resistance to APC is measured using a plasma assay and exogenous APC, and is indicated by a lowering of the APC ratio (normal range 2.2–2.6). This will identify the majority of patients with FVL, who may also be identified directly by using genetic testing by polymerase chain reaction, but not all mutations lead to lowering of the APC ratio. 8
The common forms of thrombophilia associated with increased risk of thrombotic complications of vascular surgery
F, (coagulation) factor; PAOD, peripheral arterial occlusive disease; APC, activated protein C; DVT, deep vein thrombosis; G, guanine; A, adenine
Vig et al. 11 screened a total of 150 patients with peripheral arterial occlusive disease (PAOD) (ABI < 0.8) for thrombophilia (protein C and protein S, AT, lupus anticoagulant, APCR, FVL, and prothrombin mutations) and also performed fasting homocysteine assays. Over a quarter of patients (27.3%) had evidence of thrombophilia and over a third (37.3%) had hyperhomocysteinemia. The commonest thrombophilia defect was protein S deficiency (11.3%), followed by FVL mutation (6.7%), protein C deficiency, lupus anticoagulant, and prothrombin mutation (4.0% each); one patient had an AT deficiency (0.7%). Only the presence of critical ischemia was associated with a positive thrombophilia screen on single variable analysis (P = 0.03). Similarly, Ray et al. 12 demonstrated a correlation between the level of coagulation activation and the severity and progression of PAOD (as determined by claudication distance, ABI, duplex sonography and angiography). They reported the prevalence of thrombophilia (protein C deficiency, protein S deficiency, AT deficiency and lupus anticoagulant) to be 11% in controls, 27% in stable claudicants and as much as 40% in patients who required revascularization.
Thrombophilic states may be important causes of failure of arterial interventions. The risk of thrombotic occlusion following arterial revascularization in patients with an identified thrombophilia defect appears to be considerably higher than in patients with no evidence of a thrombophilia defect.9,10 Collins et al. 13 reported that patients with markers of hypercoagulability were six times more likely to develop complications than controls (10/13 compared with 2/13). Flinn et al. 14 demonstrated that distal bypasses failed in 33% (5/15) of patients with AT deficiency compared with 13.4% (9/67) of controls. Eldrup-Jorgensen et al. 15 prospectively studied 20 young (<51 years old) PAOD patients undergoing aortoiliac or infrainguinal reconstructions. Four patients suffered early postoperative thrombotic complications (<30 days), all of whom had thrombophilia identified preoperatively. Patients with multiple coagulation abnormalities appeared to be at special risk. In a prospective study of 137 patients undergoing a mixture of peripheral arterial reconstructions, Donaldson et al. 16 identified 14 patients (10%) with a hypercoagulable state. Three of these patients (27%) suffered an early graft thrombosis, compared with only two of 123 patients with a normal thrombophilia screen (1.6%). Ray et al. 12 studied 124 patients undergoing arterial reconstruction and reported 75 graft occlusions after a mean follow-up of 44 months. Almost half (49%) of these were subsequently identified as having thrombophilia, compared with 27% of patent reconstructions. Abnormalities identified in the graft occlusion group were protein C deficiency (21% of occlusions), protein S deficiency (17%), lupus anticoagulant (25%), and multiple abnormalities (12%). In a subsequent prospective study, the same group 17 investigated the presence of thrombophilia prior to arterial reconstruction in 60 patients with one-year follow-up. A preoperative thrombophilia was identified in 65% of patients whose graft subsequently occluded within one year, compared with 20% of those with a patent graft (P < 0.05). The presence of thrombophilia was particularly significant in early graft failures, where 11 of the 12 occlusions within one month had a preoperative hypercoagulable abnormality. Lupus anticoagulant was seven times as common in patients who had occluded grafts than in those whose grafts remained patent. Taylor et al. 18 demonstrated that patients with evidence of APS were twice as likely to have had a previous failed lower limb vascular procedure. Mean graft patency for occluded lower limb procedures was 17 months in patients with APS and 50 months in those without. Nielsen et al. 19 reported the results of 80 patients undergoing infrainguinal vein bypass surgery. Nine percent of patients had evidence of anticardiolipin antibodies. Graft thrombosis within three months occurred in 57% of patients with an anticardiolipin antibody compared with 30% of those without. Primary graft patency at six months was 14% in those with anticardiolipin antibodies compared with 57% in those without (P = 0.03). In a study by Curi et al., 20 the five-year primary patency of infrainguinal reconstructions was poorer in those with hypercoagulability (28 versus 35%, P = 0.004), which also adversely affected secondary patency, limb salvage and survival.
In several studies, early graft occlusion has been associated with APCR. Most notably, Ouriel et al. 21 prospectively monitored 76 patients who underwent infrainguinal reconstruction for a mean of 47 months. They reported that 11.6% of patients had evidence of APCR. Sixty percent (6/10) of patients with APCR had failed grafts compared with 24% (16/66) of those without APCR (P < 0.02). Graft patency was 48 ± 12% at 12 months and 33 ± 18% at five years in patients with APCR compared with 88 ± 8% at 12 months and 71 ± 13% at five years (P = 0.04) in patients with no defect. The authors emphasized that patients who were positive and occluded did so secondary to thrombosis whereas patients who were APCR negative often had a demonstrable anatomical lesion explaining the occlusion. They also noted differing prevalence of APCR within different subcategories of vascular disease (the most prevalent being in patients with symptomatic infrainguinal occlusive disease) and documented a family history of venous thrombotic events in a significant proportion of patients with APCR. A similar finding was seen in a study by Sampram et al. 22 in which 32% of those with FVL and 49% of those with APCR suffered graft occlusion (P < 0.001). They found the prevalence of FVL and APCR to be higher (26.4%) in 359 patients with PAOD than in 278 controls (12.2%). A smaller study by Foley et al. 23 in patients who had undergone lower limb arterial bypass surgery reported a 17.8% prevalence of FVL, compared with a local population prevalence of 3.5%. This study reported no association between FVL and graft occlusion, but excluded patients whose graft occluded within six weeks of surgery, a time period considered most important in graft occlusion associated with thrombophilia. In contrast, Sampram and Lindblat 24 suggested that an FVL mutation was associated with a doubled rate of failure for infrainguinal procedures both at one month and one year (37 versus 22% and 46 versus 27%). In contrast, Evans et al. 25 only reported one APC resistant patient in 116 claudicants, while Aleksić et al. 26 showed neither an increased prevalence of APCR in patients with PAOD nor a firm association between the presence of APCR and previous bypass occlusion or postoperative failure of the vascular reconstruction. Variations in reported figures and even opposing findings of various studies may be explained by the preferential use of DNA analysis or APC ratio to define FVL; variations in the lower value of the normal range for defining the normal APC ratio; and the severity of the presenting PAOD.
In summary, from the published data available, considerable number of patients presenting with PAOD will have thrombophilia and they are at risk of interventional failure. The studies suggest that the rate of arterial reconstruction occlusion maybe 2–12.5 times higher in patients with a thrombophilia defect. This is particularly marked when considering patients with multiple thrombophilias and early intervention failures. The indications for preoperative screening and the best management of detected thrombophilias in patients with PAOD, however, are still unclear and call for an evaluation by randomized trials. Indiscriminate testing for heritable thrombophilias in unselected patients with arterial thrombosis is not indicated. Selective thrombophilia screening, targeted to high-risk groups is more cost-effective than routine screening. It is reasonable to undertake an assessment for hypercoagulability before any revascularization procedure in patients with a personal or family history of thrombotic events, or with early onset of disease (younger than 45 years), or in the absence of the usual risk factors for PAOD.1,27,28 The high cost of screening may be offset against the reduced risk of failure of vascular intervention, which is typically associated with prolonged hospital stay, repeated intervention or amputation, all with significant costs. Hyperhomocysteinemia, antiphospholipid antibodies, and APCR are the commonest abnormalities, and should form the basis of a thrombophilia screen. The advent of automated testing of individual defects has made thrombophilia screening more available and decreased the time for a full thrombophilia test to be reported. There is no specific treatment for most thrombophilias, but recurrent episodes of thrombosis may be an indication for long-term oral anticoagulation.
Conclusion
Resistance to APC appears to represent a hypercoagulable state associated with an increased risk of arterial thrombotic events in addition to the well-described association with venous thromboembolism. Patients with APCR undergoing lower extremity bypass may be at an extraordinarily high risk of graft failure, and antithrombotic therapy is appropriate when revascularization becomes necessary. The preoperative identification of APCR provides the opportunity to restore the normal balance of thrombosis and improve long-term prospects for vascular reconstruction.