Inherited Thrombophilias: Are They an Important Risk Factor in Bariatric and Post-Bariatric Surgery?

by Sean Lille, MD; and Robin Blackstone, MD

Introduction
Venous thrombotic events (VTE), including deep vein thrombosis (DVT) in the lower extremities and pulmonary embolism (PE), are potentially fatal events. Although the risk of DVT in bariatric surgery and post-bariatric surgery has been reported to be low, the onset of VTE is often dramatic and acute, with 10 percent of fatalities occurring within the first hour of occurrence.1 In addition, VTE is the leading cause of mortality after bariatric surgery.2-4 With the widespread adoption of laparoscopic and less invasive, more accessible procedures, the number of bariatric and post-bariatric surgeries will continue to increase. VTEs and their potential debilitating effects are a major concern.

Recent discoveries in the last decade with coagulation genetics have revealed that a segment of the population expresses a procoagulant genotype. The majority of those identified as carriers do not progress to clinical expression. However, if combined with or in the presence of other environmental risk factors seen frequently with bariatric and post-bariatric surgery patients, the danger of a VTE becomes more enhanced.5

Due to the paucity of available data regarding the association of VTE-susceptible genes in obese individuals, consensus involving optimal evaluation and prophylactic methods during weight loss surgery procedures is lacking. The aim of this article is to inform the bariatric and post-bariatric medical professionals about procoagulant genetic disorders or inherited thrombophilia in order to better understand the risk potential for VTE in these genetic carriers. The secondary aim is to suggest options for evaluation and prophylaxis in these high-risk patients.

VENOUS THROMBOSIS IN THE BARIATRIC PATIENT
The symptoms of lower extremity DVT include edema and/or tenderness in the hip, thigh or leg; calf pain on ankle dorseflection (Homan’s sign); and/or “palpable cords” (thrombosed veins) in the legs. The thrombotic clot can potentially dislodge and lead to a fatal pulmonary embolism (PE). DVT can also develop into a post-thrombotic syndrome, where conditions of chronic edema, pain, leg ulcers, and dermatitis can severely debilitate the patient and impair quality of life.6

Rates for postoperative DVT and PE have been reported as low as 0.36% to 6% and 0.2% to 3.0%, respectively, for gastric bypass.4,7,8 The overall VTE rate for post-bariatric contouring procedures is 2.9%.9 Earlier reports were plagued with the inherent design flaws of retrospective analysis, but Gonzalez et al prospectively evaluated 380 laparoscopic gastric bypass patients and reported a DVT rate of 0.26% without a case of PE.10 Similar findings were discovered by Levi et al, who reported a prospective VTE range from 0.8% for laparascopic bypass to 2% for open bypass.11

A prospective study, however, using duplex ultrasonography pre- and postoperatively found 12% of patients with thromboembolic disease.8 It is important to note that VTE symptoms can be mild or absent; therefore, clinical trials may under-report VTE occurrence. More importantly, approximately 50% of fatalities that do occur in gastric bypass procedures are the direct result of a PE.3,4,7,9-13,10-15

RISK FACTORS
Multiple risk factors have been found to have a relationship to the development of VTE (Figure 1).9,10,12,13,15,16 Risk factors frequently associated with bariatric and post-bariatric surgeries include advancing age, obesity, severe venous stasis disease, immobilization, abdominal surgery, and oral contraceptives. Although the surgical duration of laparoscopic gastric bypass procedures is usually within three hours, body contouring surgeries can often be greater than 4 to 5 hours in length. Nevertheless, laparoscopic gastric bypass surgeries have been demonstrated to have an increase in the hypercoaguable state that can last up to four weeks following surgery.10,14,17 In addition, a recent report demonstrated no difference in VTE rates between open and laparascopic Roux-en-Y gastric bypass procedures.18

Age is a well established independent risk factor for VTE. Most studies show a higher risk with patients in the sixth decade and beyond. Obesity as an independent risk factor has recently been challenged;7,8 however, several studies do show an association with VTE beginning with patients having a body mass index (BMI) greater than 35, with a precipitous increase associated with a BMI greater than 40.19,20 Numerous studies have confirmed the relationship between VTE and estrogen containing oral contraceptives and hormone replacement therapy.21

The important point to stress is that weight loss patients already present with risk factors of obesity and abdominal surgery. In a recent study that did not account for the presence of inherited thrombophilias, over 80% of bariatric patients had at least one other additional risk factor.18

INHERITED THROMBOPHILIA
Inherited thrombophilia is inherited in a dominant pattern with a 50% transmission rate in primary relatives (parent, children, siblings).22,23 The more distant the relative (grandparents, aunts, uncles, nieces, nephews—25% risk of inheritance; cousins—12.5% risk of inheritance), the lower the risk.22,23 These genetic mutations, which represent an array of polymorphic variance in coagulation and fibrinolysis genes, induce changes in the activities or quantity of their corresponding gene products or phenotypes. Although these changes cause minimal hemostatic disruptions in the large percentage of the affected population, when combined with other environmental risk factors, the thrombotic risk can be significantly enhanced. Hence, patients presenting for bariatric and/or post-bariatric surgeries are already predisposed to perioperative thrombosis. These additional risk factors can serve as a trigger for the clinical manifestation of inherited thrombophilias.

The exact clinical data elucidating the association of inherited thrombophilias with VTE in bariatric and post-bariatric surgery is minimal; therefore, its role is not completely understood. Inherited thrombophilias present with a predominance of venous thrombosis. They include deficiencies in coagulant proteins seen with antithrombin (AT) III, protein C and S, along with gene mutations in Factor V and prothrombin G20210A.22-25 Many of these gene alterations that increase the susceptibility of the patient to VTE are so diverse in the general population that the impact from a clinical standpoint can range from a negligible effect to a clinical measurable risk. Although it affects 19 million people in the US, many are not aware of their carrier state.22,23

What we do seem to find is that, although the genotype expression can have a role in determining clinical impact, environmental interactions appear to have a significant effect.23 As we know from the risk factors described previously, the weight loss patient is unique in that several or more associated risks for VTE are already present. If that patient possesses a genotype for a procoagulant state, interactions with additional inherent risk factors could lead to a clinical expression manifested as a VTE. Healthcare professionals who provide care for bariatric and post-bariatric surgeries must, therefore, be highly aware in determining the risk for a VTE occurrence or reoccurrence.

Factor V Leiden is the most common inherited thrombophilia and is almost exclusively found in the Caucasian population of Northern European ancestry, with a prevalence of 5% to 7% occurrence in the general population.22,24 It is identified in 18% of patients of all ages with first time VTE, and 40% of patients with VTE who are younger than 50 years. The risk of VTE in this group is 3.4-fold compared to the general population. It is rare in Hispanics and African Americans with a 2% occurrence, and is usually not found in Asians.22–24

Discovered in the last decade, prothrombin gene mutation G20210A is the second most common inherited cause of VTE.22-24 It occurs in 2% to 3% of healthy individuals and in 7% of patients with a first time VTE.22-24 The VTE risk of those with this gene mutation is 3.1-fold compared to the general population.22-24 The Factor V and prothrombin gene mutation G20210A are commonly associated with venous thrombosis; however, when combined with additional concurrent risk factors such as smoking or hyperhomocystenemia, arterial thrombosis manifested as a stroke or mild myocardial infractions may occur.

Protein C deficiency, first described over 25 years ago, occurs in 0.2% to 0.3% of the general population, with a relative risk to be 10- to 15-fold.26 The incidence of Protein S deficiency in general population, although not firmly established, is thought to be approximately 0.3% to 0.13%.27 Homozygous Protein C and S traits are associated with neonatal thrombosis, whereas heterozygous deficiency has an increased risk of VTE occurrence later in life. Antithrombin III protein deficiency occurs in approximately 0.02% of the general population and is seen in less than 5% of patients with a first time VTE occurrence. This protein deficiency, however, is a more severe disorder compared to Protein C or S and increases the VTE risk 25- to 50-fold.28

Inherited hyperhomocystenemia, which is an inborn error in metabolism that can either can be acquired or inherited, can occur in anywhere from 13% to 25% of the population.29 Unlike other inherited thrombophilias, it can be associated with arterial thrombosis. Hyperhomocystenemia is a prime example of a gene-environment interaction where the thrombotic risk can develop in the condition of low dietary levels of B12, B6, and folate, along with renal failure, hypothyroidism, increasing age, and tobacco ingestion.30

Most patients with thrombophilia possess only one copy of an altered gene, which is called a heterozygote. Although clinical expression is variable, the lifetime risk compared to the general population for VTE development for heterozygote gene mutations is higher in the rare protein deficiencies of AT III and protein C and S (9%–50%, 3%–7%, and 2%–20%, respectively). It is, however, lower in the more common heterozygote genetic thrombophilia’s of Factor V Leiden and prothrombin G20210A (4%–7%, 2.8% lifetime risk, respectively).22–24,30,31

A much smaller percentage of the population contains two copies of the altered genes and are called homozygotes. Factor V Leiden and prothrombin gene G20210A mutation, the two most common recurring inherited thrombophilias, can exist together and are referred to as double heterozygotes. Possessing more than one inherited procoagulant gene mutation significantly increases the formation of a clot.22-24,30,31 For example, a Factor V Leiden homozygote alteration increases a patient’s risk, making it 50 to 80 times higher, and a double heterozygote has a lifetime risk of 20 times greater than non-carrier patients. Similar enhanced risk potential is also seen in prothrombin homozygotes, although the exact numerical data does not yet exist.22-24,30,31

Evaluation of a patient’s personal or family history can also reveal an enhanced potential risk factor. For instance, a family history of VTE in the presence of an inherited thrombophilia can potentially increase the risk of VTE to be almost eight times higher compared to carriers without a positive family history.32 In patients who have a previous occurrence of VTE, the risk of a recurrent VTE can be as high as 30% in those that suffered a spontaneous event, and lower in those patients who have had a circumstantial event in association with trauma or surgery.32

TESTING RECOMMENDATIONS
VTE is a complex, multifactorial disease resulting from gene-gene and gene-environment interactions. Because clinical penetrance of inherited thrombophilia is so variable, the utility of widespread screening of weight loss patients seeking surgery is not practical. In addition, individuals found to be carriers by random screening could suffer insurance scrutiny or undo anxiety, yet receive no real preventative benefit. Since there is no evidence or knowledge to clearly predict an initial or recurrent VTE, there exists a confusion and a lack of uniformity among physicians regarding the management of individual carriers. Anywhere from 10% to 20% of the general population possesses one or more of the VTE-susceptible genes.30,37 However, because the clinical onset of the disease is modulated not only by genes, but additional additive or multiplicative effects of other environmental risk factors present with bariatric and post-bariatric patients, extreme vigilance of genetic thrombophilias must be conducted; and if discovered, additional prophylactic administration is recommended.

Factor V Leiden and prothrombin G mutation G20210A gene mutations along with protein C and S, antithrombin III deficiencies, and elevated homosysteine screening tests should be considered according to the American Academy of Molecular Genetics and the College of American Pathologists for patients younger than age 50 experiencing an MI, recurrent VTE, spontaneous VTE, family history of VTE, VTE in unusual sites (renal, portal, or mesentary system), or in women with a significant history of recurrent pregnancy loss or unexplained severe eclampsia.20-22 In addition, it may be of utility to test for anti-cardio lipin antibodies and lupus anticoagulant assays in patients with VTE in the absence of any family history of VTE or in the presence of autoimmune disease.

PROPHYLAXIS
Preoperative Methods
Patients must be medically optimized prior to any surgeries, which includes cessation of tobacco three months before any surgery. The patient must demonstrate a strong will to continue cessation and be prepared to discontinue three months following the surgery to allow optimal tissue healing. Clearly it would be optimal if the patient could stop smoking permanently. Discontinuing hormone replacement therapy and oral contraceptives for four weeks prior to surgery is also required.

Procoagulant effects of estrogen containing compounds have known to have an effect as long as one month following the cessation of treatment. Optimizing dietary intake with supplements of folate, B12, and B6 is critical in either acquired or congenital hypohomocystemenia.30 In addition, patients with inflammatory bowl disease, or hypothyroidism, which are known to trigger VTE in acquired hyperhomocystenemia, must be stabilized prior to surgery.

PERIOPERATIVE METHODS
Non-pharmacological Techniques
Pneumatic compression devices are an effective measure against VTE and have been demonstrated in studies to be as effective as low dose heparin in the general population.33 In addition, foot compression devices, often used with obese patients, appear to have similar benefit in increasing lower extremity blood flow and promoting fibrinolysis as calf pneumatic devices.34 Compression devices should be placed 30 minutes prior to the procedure, to optimize fibrinolitic activity prior to surgery.35 There is no data for bariatric and post-bariatric patients to support the use of pneumatic compression devices on only one extremity or on the upper extremities.

Operative position can also assist in VTE prevention. Having the knees slightly flexed and elevated with a pillow placed below the knees during surgery is also helpful. Returning to early ambulation is also critical in preventing VTE. Compression stockings, on the other hand, are an inferior method since they do not create enough pressure to prevent stasis in a deep leg vein.36

Pharmacological Techniques
Unfractionated heparin (UH) or low dose unfractionated heparin (enoxaprin) have been extensively studied as a preventative medical method.37,38 A dose of 5,000 units of unfractionated heparin given subcutaneously two hours before an operation and then every eight hours has been found to reduce the risk of VTE.39 The subcutaneous route compared to the intravenous method has been found to be equally effective with less hematological monitoring and a decreased risk for major bleeding. Low molecular weight heparin (LMWH) has gained increased popularity recently as a drug of choice for chemoprophylaxis. The benefit of this class of anticoagulants is a decreased dosing schedule, which optimizes patient compliance and a decreased risk of heparin-induced thrombocytopenia.15 Low molecular weight heparin has been shown to decrease the incidence of DVT at prophylactic doses when compared with no treatment.40 Combination therapy of

LMWH or UH with pneumatic compression devices appears to decrease the risk of VTE even further compared to single therapy alone.41, 42
Initiation of prophylaxis with LMWH has not been established. Although there may be a concern for an increased risk of postoperative bleeding complications with preoperative administration of LMWH, in the author’s experience with 38 post-bariatric surgeries, LMWH treatment commencing 24 hours before and 12 hours after surgery has been successful without occurrence of bleeding problems. Until further data emerges, however, the authors prefer initiating LMWH 12 hours after surgery.

The dose and frequency of LMWH can either be fixed or weight-based. The merits of weight-adjusted dosing in gastric bypass patients appears to be gaining more acceptance. Schotlen et al found in gastric bypass patients that 40mg of enoxaparin given every 12 hours is more effective in preventing DVTs compared to the same frequency of 30mg of enoxaparin.38 These findings are consistent with the American College of Chest Physicians (ACCP) guidelines, which advise increasing the prophylactic dose of enoxaparin to 40mg from 30mg every 12 hours in the morbidly obese.43 The ACCP also suggests measuring anti-factor Xa activity (AFXa) after the third dose for patients weighing more than 150kg.42 Although the ACCP encourages measuring AFXa activity levels in the therapeutic context to ensure therapeutic anticoagulation of LMWH, we believe evaluating the pharmacokinetics of LMWH in significantly obese patients (BMI>60kg/m2) is critical to confirm that exoxaparin is within prophylactic parameters (0.2–0.5IU/mL, +10%).43 In post-bariatric weight loss patients who do not have the comorbidity of obesity, a daily frequency of 40mg of enoxaparin is acceptable (Figure 2).

The duration of postoperative treatment remains unclear. Extended treatment for patients with high risk has been shown to be effective in the orthopedic literature. The practice of extended treatment duration warrants serious consideration in high-risk obesity patients, especially those with associated comorbidities such as the presence of VTE genes, chronic immobility, severe venous stasis disease, and supermorbid obesity (BMI>60kg/m2).44 In patients without inherited thrombophilias, treatment should last until consistent ambulation is established, potentially up to 10 days following the surgery. When procoagulant VTE genes are present, however, four weeks should be recommended, since the procoagulant state of the vascular system following surgery can persist up to four weeks.3,15 Consultation with a hematologist is helpful in determining appropriate treatment strategies in these cases.

In patients that possess homozygous gene mutations of Factor V or combined Factor V and prothrombin gene mutations, or any inherited thrombophilia with a previous history of DVT should be considered for inferior venal cava filter (IVC) placement for bariatric surgery. With respect to post-bariatric cosmetic procedures, in these high-risk patients, the decision to proceed to surgery must be approached with the highest degree of caution. The author’s preferred option, until more data is available, is to avoid surgery. If surgery is chosen, then operative duration should be kept within two hours and the possibility of temporary IVC filter placement discussed.

CONCLUSION
The absolute incidence of DVTs in carriers with inherited thrombophilia is low. When combined with additional risk factors commonly appearing with bariatric and post-bariatric patients, however, the clinical expression of inherited thrombophilia can be potentiated.

Vigilance beginning with detailed personal and family medical history must be conducted. In cases where suspicions arise, screening tests should be performed and, if positive, appropriate chemoprophylatic management be conducted with the help of a hematologist. In patients with higher-risk, VTE-susceptible genes such as homozygous or double heterozygous traits, or in combination with a previous history of a spontaneous VTE, IVC filter should be considered. As weight loss surgery continues to increase, the role of thrombophilias in patient safety will have greater significance. Further studies are warranted to accurately predict the thrombotic risk factor in each individual patient, and to help determine optimal dosing, frequency, and duration of chemoprophylaxis in these high-risk patients.

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Category: Past Articles, Review