The clinical manifestation of AT deficiency is usually deep vein thrombosis (DVT), but it can also cause arterial thromboses on rare occasions. AT deficiency increases the risk of a first-time VTE event by 20-fold [8]. Since AT acts as a cofactor for heparin, patients with AT deficiency often require excessively high doses of heparin to achieve therapeutic anticoagulation. Resistance to anticoagulation with heparin raises the possibility of AT deficiency and should prompt further testing. Unfortunately, diagnosing AT deficiency at the time of the acute VTE event is usually impossible because AT levels normally decrease in the postoperative and postpartum periods and during anticoagulation with heparin and sometimes warfarin. Assessment for AT deficiency should therefore be pursued after the acute thrombotic event has resolved and the patient has stopped anticoagulation therapy. Subclassifications of AT deficiency describe the underlying pathophysiology and include reduced AT activity levels, reduced AT antigen and activity levels, and a defective heparin-binding site.

Patients with Protein C deficiency have a tenfold increased risk of VTE and frequently develop recurrent DVT [9]. As a vitamin K-dependent enzyme produced in the liver, protein C is affected by liver disease, disseminated intravascular coagulation (DIC), and warfarin therapy [10]. Warfarin decreases protein C levels more quickly than it inhibits procoagulant factors (Factors II, VII, IX, and X) making patients with protein C deficiency temporarily hypercoagulable and at risk for warfarin-induced skin necrosis. Preventing this complication is the rationale behind overlapping heparin and warfarin therapy during the initial stages of anticoagulation. Testing for protein C deficiency should occur after the VTE event has resolved and the patient has stopped taking oral anticoagulation. Antigen or activity levels can be used to detect protein C deficiency.

Protein S deficiency is associated with DVT which can occur in atypical locations [11, 12]. Protein S functions as a cofactor for protein C, and patients with protein S deficiency have a comparable thrombotic risk to those with protein C deficiency [9]. Like protein C, protein S is a vitamin K-dependent enzyme produced by the liver. Patients with protein S deficiency are therefore at risk for warfarin-induced skin necrosis if they are not appropriately transitioned from heparin to warfarin therapy. Although protein S deficiency is a hereditary disorder, functional deficiencies can occur during inflammatory states due to increased C4b-binding protein which lowers free protein S levels. Other conditions that can lower protein S levels include liver disease, DIC, pregnancy, estrogen hormonal therapy, and acute VTE. Tests for protein S deficiency usually measure total protein S activity or free activity levels and should be performed after cessation of anticoagulation therapy.

Factor V Leiden or activated protein C resistance is the most commonly identified hereditary disorder associated with VTE. The vast majority of thrombotic complications from this disorder involve DVT and pulmonary emboli (PE) [13]. Homozygotes for Factor V Leiden have a 50-fold increased risk of VTE and account for about 1.5 % of VTE events [14]. Factor V Leiden heterozygotes have a fourfold increased risk of VTE and account for 16 % of first-time VTE events and 7 % of all cases of VTE (initial and recurrent) [15–17]. Factor V Leiden predominantly affects Caucasians, with people of Scandinavian origin having the highest prevalence [18]. Some studies suggest that an acquired form of Factor V Leiden can also develop with estrogen use, pregnancy, and elevated levels of Factor VIII [19–22]. The risk of VTE associated with Factor V Leiden deficiency increases in the presence of other hypercoagulable states, including hyperhomocysteinemia, prothrombin gene mutation, protein C or S deficiency, and AT deficiency [23–27]. Prolonged airplane travel, immobility, and surgical interventions can also provoke thrombotic episodes. The laboratory diagnosis of Factor V Leiden involves a second-generation clotting assay which is 85 % specific and 100 % sensitive and usually requires PCR or genetic testing for confirmation [14, 28]. Diagnostic testing is not affected by the presence of an acute thromboembolic episode and may be performed at any time.

Patients with prothrombin gene mutation have a 2.5-fold increased risk for VTE [29]. Simioni and Ridker estimated a twofold increased risk of recurrent VTE similar to Factor V Leiden; however, other reports contradict this finding [30–33]. Patients with prothrombin gene mutation are also at increased risk for arterial complications associated with the coronary or cerebrovascular systems [34]. The disorder is essentially nonexistent in African American and Asian populations, and diagnostic testing is not affected by acute VTE [35].

Elevated levels of Factors VIII, IX, and XI can result in lower extremity DVT or PE [36]. Diagnosing these disorders can be challenging because common conditions such as bleeding and inflammation normally increase the levels of procoagulant factors. Laboratory tests to measure Factor VIII, IX, and XI levels should be performed in conjunction with an ESR or CRP to evaluate for concomitant inflammation [37, 38]. If the ESR or CRP levels are also elevated, the procoagulant factor levels must be considered nondiagnostic because of the potentially confounding presence of inflammation. Confirming that elevated levels of Factors VII, IX, and XI reflect a hypercoagulable state and not a temporary, acquired abnormality requires two tests at different time points demonstrating procoagulant factor elevations above the 90th percentile.

Hyperhomocysteinemia increases the risk of peripheral arterial disease, as well as arterial and venous thrombosis [39–42]. Several studies reported a 2–8-fold increased risk of stroke and myocardial infarction in patients with hyperhomocysteinemia [43, 44]. Although vitamin and folate replacement can reduce serum levels of homocysteine, normalizing the laboratory value of homocysteine does not affect clinical outcome or reduce cardiovascular risk. The only purpose of diagnosing hyperhomocysteinemia is to identify patients at higher risk for cardiovascular and thrombotic events. Patients with atypical arterial thromboses or premature atherosclerosis warrant an evaluation for hyperhomocysteinemia; however, measuring homocysteine levels in patients with VTE is not usually indicated.

Antiphospholipid antibody syndrome usually causes recurrent miscarriages in young women or lower extremity DVT; however, this syndrome also increases the risk of arterial thrombosis [45, 46]. The risk of recurrent VTE increases 4–7.7-fold after the initial episode, with the recurrence frequently localized to the site of the initial event [47–49]. Depending on the subtype of antiphospholipid antibody syndrome, the risk of initial DVT can be as high as 3.6-fold [50]. First-time VTE risk increases up to tenfold in patients who have antiphospholipid antibody syndrome and other concomitant hypercoagulable conditions [50]. Laboratory examination for antiphospholipid antibody syndrome involves two different assays: anticardiolipin antibody for IgG and IgM antibodies and anti-β2 glycoprotein 1 screening. Although ongoing infection and underlying malignancy can create erroneous test results, the presence of acute VTE does not affect test accuracy.

In 1865, Trousseau first recognized that cancer increased the risk of VTE. The most common thrombotic manifestations of cancer are DVT and PE, and the risk of VTE ranges from 7- to 20-fold for patients with metastatic disease on chemotherapy [51, 52]. Multiple factors influence the risk of thrombotic complications in patients with cancer including: the type and stage of cancer, surgical vs. chemotherapy, comorbid conditions, immobility, and presence of central venous catheters. Some cancers cause vascular complications by exerting extrinsic compression on adjacent blood vessels. The risk of arterial thrombosis and embolization also increases in cancer patients including cerebral, myocardial, and peripheral thromboembolic episodes.

Low-molecular-weight heparin (LMWH) is more effective than warfarin at preventing thrombotic recurrence or propagation in patients with cancer [53, 54]. Patients with VTE and active cancer should be therefore maintained on long-term LMWH. Although newer anticoagulants may be equally effective in patients with cancer, more supporting data is required before they can be recommended for widespread use. Anticoagulation therapy in patients with cancer must be carefully monitored as bleeding complications occur more frequently in this population [55].

No specific testing for hypercoagulable conditions is recommended for cancer patients.

Hypercoagulable disorders associated with pregnancy are the leading cause of maternal death in the United States with over half of the VTE episodes occurring postpartum [56–58]. Pregnancy creates a prothrombotic state by increasing fibrinogen and Factor VIII levels while decreasing fibrinolytic activity and the level of protein S. As the gravid uterus enlarges, it compresses the inferior vena cava and the left iliac vein which explains why the majority of DVTs during pregnancy occur in the left lower extremity [59–62]. Patients with any inherited coagulation disorder have a markedly increased risk of DVT during pregnancy and the postpartum period [63]. Hellgren et al. reported that 60 % of pregnant patients with VTE had Factor V Leiden deficiency [19]. Patients who develop VTE during pregnancy should be assessed for underlying hypercoagulable disorders to assess their overall thrombotic risk status and to determine the risk of recurrent VTE during future pregnancies.

Patients with HIT develop heparin-induced antibodies directed against platelet factor-4. The antibodies trigger the activation and aggregation of platelets which ultimately releases prothrombotic platelet particles into the circulation. The clinical manifestation of HIT can include either venous or arterial thrombosis despite low levels of platelets [64]. HIT typically occurs 3–5 days after exposure to unfractionated heparin; however, HIT can also occur following treatment with LMWH. In patients with prior heparin exposure, HIT can occur as early as 24 h after receiving heparin.

All patients being treated with any form of heparin should have platelet monitoring for at least 5 days. The diagnosis of HIT should be considered in patients who develop thrombocytopenia or have a significant decrease in the platelet count after exposure to heparin. Any thrombotic event that occurs after heparin initiation should also raise the possibility of HIT. If HIT is suspected on clinical grounds, all forms of heparin should be stopped immediately and anticoagulation should continue using a direct thrombin inhibitor (argatroban, lepirudin) or anti-Xa inhibitor (fondaparinux). If HIT is confirmed, anticoagulation should transition to warfarin only when the platelet count normalizes. Testing for HIT can include a serotonin release assay or enzyme-linked immunosorbent assay (ELISA) which has a diagnostic accuracy approaching 100 % when used in combination [65].

At least half of VTE events that occur in patients with hypercoagulable disorders are provoked by the clinical circumstances. This finding suggests that thromboprophylaxis could reduce the incidence of VTE for hypercoagulable patients who face clinical settings which are associated with an increased thrombotic risk such as surgery and immobility [9, 14, 66]. Multiple guidelines attempt to stratify the VTE risk of patients to determine the appropriate thromboprophylaxis for surgical procedures [67, 68]. Mechanical thromboprophylaxis includes early ambulation and intermittent compression stockings, while pharmacologic thromboprophylaxis typically involves unfractionated heparin, LMWH, or anti-Xa inhibitors. Current American College of Chest Physicians (ACCP) guidelines provide comprehensive recommendations for thromboprophylaxis based on the type of surgical intervention and risk stratification of the patient [69]. These consensus-based guidelines are updated every few years and should be familiar to all surgeons. Approximately one half of VTE events occurring in young patients are associated with inherited hypercoagulable states [70]. Estrogen replacement and hormonal methods of birth control add to the hypercoagulable state and should be avoided in this high-risk patient population [66].

The optimal duration of anticoagulation for patients with hereditary hypercoagulable disorders varies depending on the clinical scenario. The average risk of recurrent VTE is about 5 %, and recurrence seems to be lower for patients with a provoked vs. spontaneous VTE [70]. Patients with a provoked VTE due to transient thrombotic risk factors such as surgery should be treated with a finite period of anticoagulation of 3–6 months [67]. In contrast, current treatment recommendations for patients with a spontaneous VTE are less specific ranging from 2 years to lifelong anticoagulation [32, 67]. The risk of bleeding complications and the high cost of therapy make lifelong anticoagulation an unappealing treatment option [71, 72]. Warfarin has a 3 % risk of significant bleeding per year and a 0.6 % risk of a fatal hemorrhage [6]. Since patients with hypercoagulable disorders have a less than 3 % risk of primary VTE, the risk-benefit calculation usually comes out against lifelong anticoagulation. Based upon these assumptions, few patients have an absolute indication for lifelong anticoagulation.

Regardless of whether the thrombotic episode was provoked or spontaneous, the majority of patients with hypercoagulable disorders should be treated in a similar fashion to patients without clotting abnormalities. This universal treatment strategy is based on the hypothesis that most, if not all patients, who develop thrombotic complications have abnormalities in the clotting cascade and that most, if not all, episodes of VTE are provoked. The only difference in clinical scenarios may be the clinician’s ability to diagnose the hypercoagulable disorder or detect the often subtle instigating event [73].

Diagnosing hereditary hypercoagulable disorders may be more important for the family and progeny of the affected individual. Knowledge of an increased VTE risk can help determine the need for thromboprophylaxis in patients who face high-thrombotic-risk situations such as pregnancy, hormone use, surgery, and prolonged air travel. Testing for hereditary hypercoagulable disorders should be considered in several scenarios listed in Table 22.4. Prophylactic anticoagulation is not recommended for asymptomatic individuals found to have hypercoagulable states.

Popliteal artery entrapment syndrome (PAES) encompasses a group of anatomic anomalies that cause compression of the popliteal artery and occasionally the popliteal vein. The hemodynamically significant stenosis that occurs in PAES usually manifests as claudication but can cause progressive ischemia and limb loss if not diagnosed and appropriately treated. Stuart first described the anatomy of popliteal artery entrapment in 1879, but the associated clinical manifestations of PAES were not recognized until 1958 [74, 75]. Although the incidence remains unclear, PAES appears to be the most common cause of claudication symptoms in young people. Bouhoutsos et al. reported a 0.165 % prevalence of PAES in young men entering the Greek military while Turnipseed et al. reported that PAES caused atypical claudication in 0.15–4 % of young patients, and Gibson et al. reported a 3.5 % prevalence of PAES in postmortem specimens [76–79].

During embryologic growth, the popliteal artery normally develops after the medial head of the gastrocnemius muscle has migrated to the medial femoral condyle. Derangements in the timing and sequence of these events lead to the various types of PAES. Abnormally, early development of the popliteal artery or delayed migration of the medial head of the gastrocnemius causes compression and medial displacement of the artery by the gastrocnemius muscle (Type I). In Type II PAES, early development of the popliteal artery interferes with the normal migration of the medial head of the gastrocnemius muscle causing abnormal muscle insertion into the femur. If mesodermal remnants of the medial head of the gastrocnemius fail to involute, they form abnormal fibrous bands or muscle slips that compress the popliteal artery (Type III). These bands can attach to the femoral condyles or the intercondylar space. The rarest form of PAES, Type IV, involves persistence of the primitive axial artery which is compressed by the popliteus muscle. Compression of the vein and artery by any mechanism is classified as Type V.

Type VI PAES can be a catch all term for other anatomic variants or it can designate functional popliteal artery entrapment. The term functional PAES is usually applied when none of the anatomic abnormalities are present, but arterial compression is documented by radiologic imaging during positions of stress or activity. The etiology, incidence, natural history, and treatment of functional PAES remain controversial. Leading theories regarding the pathophysiology of functional entrapment speculate that compression results from muscular hypertrophy or the soleal sling [80]. Pillai et al. reviewed MRI findings and found that patients with functional PAES had more extensive attachment of the medial head of the gastrocnemius muscle to the midline of the bone and the intercondylar notch as well as greater muscle bulk adjacent to the neurovascular bundle [81]. Other imaging studies have questioned the clinical relevance of functional PAES by showing that some form of compression occurs in up to 80 % of healthy adults during forced plantar flexion of the foot [80, 82, 83].

Regardless of the mechanism or PAES type, external compression of the popliteal artery gradually damages the vessel leading to fibrotic occlusion in advanced stages. As the popliteal artery slowly narrows, some patients form a poststenotic aneurysm with thrombus formation and distal embolization. Tibial nerve involvement has also been reported.

PAES should be considered in patients younger than 50 who present with claudication or exertional calf muscle pain. The majority of patients with PAES present before 30 years of age and the male-to-female ratio is about 2:1 [84]. Roche-Nagle et al. found that young athletes participating in basketball, football, rugby, or martial arts were most commonly affected by PAES and 25 % of patients had bilateral involvement [85, 86].

All forms of PAES cause repetitive trauma to the artery which can potentially lead to aneurysmal degeneration, thrombosis, or distal embolization. The clinical signs and symptoms depend on the stage at which the patient seeks medical attention. A delayed presentation of PAES frequently occurs when young patients dismiss muscle cramps as a sign of being “out of shape” and primary care physicians overlook early signs and symptoms of arterial insufficiency. If weakness, paresthesias, and edema are also present, PAES may involve simultaneous nerve and or vein compression. In some patients, the discomfort caused by walking paradoxically improves with more vigorous exercise. These atypical claudication symptoms can create a confusing clinical picture causing further delays in the diagnosis of PAES.

Claudication symptoms due to PAES may not occur until the patient has walked for miles. The onset of exertional leg pain depends on the extent of arterial compression and the physical conditioning of the patient. Due to their young age, long walking distance, and lack of atherosclerotic risk factors, many patients with PAES are initially referred to orthopedic or sports medicine physicians, and a vascular etiology for their symptoms is not considered until late in the course of disease. The sudden onset of severe claudication usually signifies acute occlusion of the popliteal artery. Although critical limb ischemia (CLI) can result from popliteal artery occlusion or emboli to the tibial vessels, only 20 % of patients with PAES present with symptoms of CLI [87, 88]. In most patients, the entrapped popliteal artery undergoes gradual injury allowing time for collateral formation, similar to that seen in atherosclerotic occlusive disease.

The differential diagnosis of PAES should include compartment syndrome and popliteal adventitial cystic disease. Eliminating adventitial cystic disease from the differential diagnosis is usually straightforward since it does not have a predisposition to athletes and usually occurs in less active young patients. Several studies reported that PAES was the cause of symptomatic claudication in up to 60 % of young athletes [87, 89]. In contrast, Turnipseed et al. found that functional entrapment accounted for only 4 % of cases of claudication in young patients with chronic compartment syndrome causing the majority of symptoms [79]. Different referral patterns may explain the contradictory conclusions reached by these studies. Other non-atherosclerotic vascular complications in young, otherwise, healthy athletes can include exercise-induced fibrosis of the external iliac artery most often described in avid cyclists and arterial thoracic outlet syndrome that can occur in baseball pitchers and other athletes engaged in repetitive overhead arm motion.

Patients with PAES typically have palpable pedal pulses at rest which decrease or disappear with active plantar flexion of the foot. Any patient with suspected PAES should undergo exercise testing in the noninvasive vascular lab. Unless the patient is presenting with an advanced stage of entrapment, the popliteal and tibial arteries should have normal triphasic waveforms when the leg is in the neutral position. Active knee extension and forced plantar flexion of the foot occlude the popliteal artery in most patients with PAES. Likewise, a normal ABI at rest (greater than 1.0) should fall to less than 0.9 with exercise in patients with PAES. Well-conditioned athletes with PAES may need to perform more vigorous exercise than the standard vascular lab protocol to induce changes in ABI. Similarly, patients with functional entrapment frequently are usually athletes who develop symptoms at distances measured in miles, not blocks.

MRA or CTA imaging studies can confirm the diagnosis of PAES, identify specific muscular or tendinous abnormalities, and detect the presence of aneurysmal degeneration which warrants repair of the artery. Assessment of the contralateral limb should also be performed as the prevalence of bilateral PAES ranges from 30 to 67 % [90–93]. Angiography usually helps determine whether an arterial bypass is necessary by assessing the extent of intimal damage and identifying distal runoff vessels. All diagnostic modalities should attempt to reproduce the popliteal artery compression that occurs during exercise. Unless the popliteal artery is already occluded or anatomic abnormalities for PAES identified, images of the leg in neutral position should be compared to images obtained with forced active dorsiflexion of the foot against resistance with the knee fully extended. Failure to perform these maneuvers may lead to a false-negative result. Eliminating compartment syndrome from the differential diagnosis may involve taking pressure measurements in the muscle compartments of the lower leg. Left untreated, PAES can acutely occlude the popliteal artery which causes severe, short-distance claudication. DiMarzo et al. and Levien also found a higher rate of distal embolization in patients who had delayed diagnosis and treatment of PAES [87, 94].

In 1985, Rignault described functional popliteal artery entrapment syndrome (FPAES) in symptomatic young military recruits who had no anatomic abnormality [80]. Lower extremity MRI demonstrated compression of the popliteal artery in positions of stress which appeared to result from hypertrophy of the muscles in the popliteal fossa. Other studies confirmed the two levels of compression described by Rignault: one between plantaris and medial head of the gastrocnemius and the other between the popliteus and plantaris muscles. Turnipseed further defined FPAES by identifying hypertrophy of the gastrocnemius as the primary etiology [83, 90, 95]. Although partial resection of the medial head of gastrocnemius muscle provides symptomatic relief for patients with FPAES, Deshpande found that decreasing activity alone obviated the need for surgical intervention in patients willing to abstain from extreme athletics [96].

Treatment for PAES should be performed by experienced surgeons with a detailed understanding and experience operating in this area. Surgery is the only effective treatment for anatomic PAES (Types I through V). Percutaneous, catheter-directed thrombolysis has a limited role in the treatment of PAES which involves restoring patency to an acutely occluded popliteal artery in anticipation of definitive surgical repair. Unlike arteries affected by atherosclerotic disease, the popliteal artery in patients with PAES is fibrotic and usually resists dilation with balloon angioplasty and stent placement. Endoluminal interventions are also destined to fail because they do not relieve the underlying problem of extrinsic compression.

All symptomatic patients with confirmed PAES should have surgery to resect the offending muscle or band. Surgery usually involves resection of the gastrocnemius medial head which can be guided by intraoperative duplex assessment of the vessel to confirm successful decompression. This procedure alone may provide definitive treatment for patients with early-stage PAES in whom the artery has not degenerated. Surgery for early-stage PAES can be performed with a posterior popliteal approach using a lazy “S” incision. An adequate length of artery should be exposed to evaluate for other fibrous compressive bands. If the medial head of the gastrocnemius muscle is causing compression of the popliteal artery or vein, it should be divided from its insertion on the medial femoral condyle. Techniques for excising the plantaris muscle, soleal sling, and popliteus muscle have also been described.

Advanced-stage PAES which causes occlusion or aneurismal dilation of the popliteal artery mandates treatment with an intersegmental arterial bypass, generally using the small saphenous or great saphenous veins as a bypass conduit. Some patients have chronic occlusion of the popliteal artery without symptoms of vein or nerve compression. These patients do not require division of the muscle bands and can be treated from a medial approach with the vein bypass tunneled subcutaneously, not anatomically.

Prophylactic intervention for patients with contralateral PAES should be performed electively if imaging studies confirm early-stage compression of the popliteal artery without vessel injury. Early surgical decompression can avoid the need for vascular repair or bypass. Surgical intervention usually allows young patients with PAES to resume their sports and athletic endeavors.

Follow-up information is somewhat limited to relatively small series. Kim et al. followed 22 bypasses in 18 patients with PAES dividing the patients into those with short-segment occlusions and those with occlusion extending beyond the popliteal artery [97]. Both posterior and medial surgical approaches were used in this series. Overall graft patency was 75 % at 3 and 5 years. Patients who had a bypass originating from the distal superficial femoral artery had a significantly lower patency compared to patients with a bypass originating from the above-knee popliteal artery (30 % vs. 86 % at 5 years).

A recent meta-analysis by Sinha et al. attempted to describe the clinical presentation, natural history, and treatment outcome of patients with PAES. Claudication was the most common symptom of PAES with 38 % of patients having bilateral disease, 23 % exhibiting functional entrapment, and only 11 % of patients presenting with critical limb ischemia [84]. At the time of presentation, 24 % of the popliteal arteries were occluded and 13.5 % had aneurismal degeneration. The median duration of symptoms prior to diagnosis was 12 months; however, there was no association between duration of symptoms and presence of significant arterial damage. Three studies in the meta-analysis reported outcomes on a handful of patients treated nonoperatively for PAES: 1 patient required amputation, 1 patient reoccluded 2 months after thrombolysis requiring bypass, 1 patient had persistent symptoms, and 1 patient with functional entrapment had symptom resolution. Although surgery had an overall success rate of 77 %, surgical complications included amputation, wound infection, hematoma, seroma, and deep vein thrombosis. Fewer reports exist for popliteal vein entrapment, and clinical outcomes may differ from PAES due to the predominantly female patient cohort [93, 98, 99].