Deep Venous Thrombosis	46
Fahad S. Alasfar, Dwayne Badgett, and Anthony J. Comerota

A 67-year-old male had a history of a right calf deep venous thrombosis (DVT) following a flight from California to New York. He was treated on that occasion with anticoagulation with unfractionated heparin then Coumadin for 3 months. Recently, he was diagnosed with sigmoid cancer. He is now on postoperative day 3 from exploratory laparotomy, sigmoid colectomy and extensive lysis of adhesions. Although he was haemodynamically stable, he required a transfusion of three units of blood. DVT prophylaxis for the perioperative period included graded knee-high compressive stockings and intermittent pneumatic compression (IPC).

Question 1

What are the risk factors that predispose to DVT?

Question 2

What is the clinical presentation of a patient with anti-thrombin III (ATIII) deficiency?

Question 3

Regarding antiphospholipid antibody (APA) syndrome, which of the following is not correct?

A.  Procainamide has been associated with the development of APA syndrome.

B.  Thrombotic complications associated with APA syndrome are limited to the venous system.

C.  Long-term anticoagulation has been recommended in managing APA syndrome, maintaining the international normalized ratio (INR) at 3 or higher.

D.  Recurrent venous and arterial thrombosis is a major feature of the APA syndrome.

A.J. Comerota ( )

Department of Surgery, Temple University Hospital, Philadelphia, PA, USA

G. Geroulakos and B. Sumpio (eds.), Vascular Surgery,	483
DOI: 10.1007/978-1-84996-356-5_46, © Springer-Verlag London Limited 2011

484	F.S. Alasfar et al.

Question 4

Regarding Factor V Leiden gene mutation, which of the following is/are correct?

A.  Factor V Leiden mutation is an important risk factor for pulmonary embolism and DVT during pregnancy or use of oral contraceptives.

B.  Factor V Leiden mutation is associated with an increased risk of myocardial infarction and angina.

C.  Hyperhomocystinaemia increases the risk of Factor V Leiden carriers having any Venous Thromboembolic Episodes (VTE) from 2% to 10%.

D.  A single-point mutation in the gene coding for coagulation Factor V results in the formation of a Factor V molecule that is not inactivated properly by activated protein C (APC).

Question 5

Which of the following statements are true concerning prophylaxis for DVT?

A.  There are many prospective randomised studies supporting the efficacy of graded compression stockings in preventing DVT in patients with malignancy.

B.  IPC is as effective as low-dose unfractionated heparin (LDUH) in reducing the risk of DVT.

C.  LDUH and low-molecular-weight heparin (LMWH) are most effective in preventing DVT.

D.  Dextran is an excellent alternative to LDUH in preventing DVT.

On the fifth postoperative day, the patient began complaining of mild left calf pain and swelling. On physical examination, his lower extremities were warm with normal pulses. The left calf was mildly swollen with slight tenderness. A venous duplex of the lower extremity revealed thrombosis of the left popliteal, posterior tibial and peroneal veins.

Question 6

Which of the following statements regarding perioperative DVT is/are correct?

A.  In general surgery, the overall incidence of DVT as assessed by labelled fibrinogen uptake (FUT) is 25%.

B.  In surgical patients with malignant disease, the incidence of postoperative DVT is 60%.

C.  The incidence of postoperative DVT after total hip replacement is 45–55%. D.  Major trauma patients have a low risk for DVT.

E.  Patients undergoing elective neurosurgical procedures have a 20–25% incidence of DVT documented by radioisotopic scanning.

The patient was started on a therapeutic regimen of LMWH (enoxaparin) 1 mg/kg every 12 h and a daily dose of Coumadin.The patient’s baseline coagulation profile was normal

46  Deep Venous Thrombosis	485

and his platelet count was 190,000.On day 3 of anticoagulation, his INR was 2.2 and his platelet count dropped to 67,000.

Question 7

Regarding heparin-induced thrombocytopoenia (HIT), which of the following is/are correct?

A.  It is caused by IgM antibodies that recognise the complex of heparin and platelet factor 4.

B.  The peak incidence occurs 4–14 days after initiation of heparin.

C.  It occurs more commonly with unfractionated heparin than with LMWH. D.  It can be treated by reducing the dose of LMWH.

E.  Argatroban and hirudin are acceptable agents used for the treatment of HIT.

LMWH was discontinued and the patient started on Argatroban. On the tenth postoperative day, the patient started complaining of left flank pain and his haemoglobin level dropped to 6 g/dL. A computed tomography (CT) scan of his abdomen revealed a 6 × 7-cm retroperitoneal haematoma. Because of the haematoma, anticoagulation was discontinued and an inferior vena cava (IVC) filter inserted.

Question 8

Which of the following are acceptable indications for an IVC filter?

A.  Complication or contraindication to anticoagulation in a patient diagnosed with a pulmonary embolism

B.  Recurrent thromboembolism despite therapeutic anticoagulation C.  Acute iliofemoral DVT

D.  Recurrent pulmonary embolism with pulmonary hypertension

Question 9

Regarding thrombolysis for acute DVT, which of the following is/are correct?

A.  Studies show no difference in lysis capability between anticoagulation and lytic therapy.

B.  Randomised studies support lytic therapy for all lower-extremity DVT.

C.  Patients with iliofemoral DVT treated with catheter-directed thrombolysis have a better quality of life than patients treated with anticoagulation alone.

D.  Lytic agents are more effective when delivered by catheter-directed intrathrom-bus infusion rather than systemic intravenous infusion.

486	F.S. Alasfar et al.

46.1  Commentary

The natural history of DVT has been described well in the literature. Complications of venous thromboembolism continue to be a major cause of death and morbidity each year. In the USA, there are approximately 50,000–200,000 deaths each year secondary to pulmonary embolism. Fifty-two percent of patients with DVT develop pulmonary embolism,1 most of which occur from the proximal venous segments of the lower extremities.

Patients with proximal DVT had a pulmonary embolism incidence of 66%, whereas tibial thrombi had a 33% incidence.1 Multiple studies have shown a 50% reduction in fatal pulmonary embolism when prophylaxis with LDUH is used.2 Moreover, natural history studies have shown that the long-term morbidity of post-thrombotic syndrome (PTS) is significant following DVT. PTS has been reported in 33–79% of patients following proximal DVT and 2–29% of patients with calf DVT. Masuda et al.3 reported valve reflux in 30% of individuals with calf DVT followed for 3 years. Furthermore, they reported that 23% of patients with calf DVT have ongoing pain and swelling of the affected extremity.

Thus, proper prophylaxis, early diagnosis and appropriate therapy are of paramount importance in preventing the shortand long-term complications of DVT.

An understanding of the risk factors for DVT is helpful for appropriate DVT prophylaxis. These risk factors include prior DVT/pulmonary embolism, prolonged immobilisation or paralysis,malignancy,majorsurgery(especiallyabdominal,hipandlower-extremitysurgery), age over 40 years, and severe heart disease. There are also hypercoagulable states that predisposetothrombosis.HaematologicalabnormalitiesincludeproteinCandproteinSdeficiency, Factor V mutation, disorders of plasminogen activation and antiphospholipid antibodies.

Lupus anticoagulant and HIT are also associated with DVT. Proteins C and S are part of the naturally occurring balance of coagulation that prevents thrombosis by inactivating Factors Va and VIIIa. Deficiency of these factors leads to an increased risk of thrombosis. Proteins C and S, like Factors II, VII, IX and X, depend on vitamin K. Because of the shorter half-life of protein C, a transient hypercoagulable state can be induced early in the course of treating patients with a warfarin compound due to the acute reduction in protein C level. A search for an underlying hypercoagulable disorder should be undertaken in patients with recurrent DVT or unexplained arterial or graft occlusion.

Chronic warfarin therapy may reduce the level of proteins C and S by 30–50%; therefore, these levels should be measured after the patient has discontinued warfarin. Indefinite oral anticoagulation is indicated in patients with confirmed deficiency. [Q1]

ATIII is an important naturally occurring anticoagulant that inhibits the enzymatic activation of thrombin and other naturally occurring clotting factors. The heterozygous form of ATIII deficiency is asymptomatic and may affect 1 in 2,000 people. A chronic deficiency ofATIIIcan occur withprotein loss in nephroticsyndrome, liver disease, sepsis and Disseminated Intravascular Coagulation (DIC). When complications occur, heparin followed by Coumadin is the treatment of choice. [Q2]

APA is a heterogeneous group of circulating autoantibodies directed primarily against negatively charged phospholipid compounds. These antibodies interfere with the thromboplastin reaction against the activated platelet. Recurrent venous and arterial thrombosis is a

46  Deep Venous Thrombosis	487

major feature of APA syndrome. Thrombosis associated with APA syndrome has occurred in diverse anatomic locations, causing a wide spectrum of clinical manifestations. DVT and pulmonary embolism are common complications of APA.4 Similarly, arterial thrombosis involving carotid,5 hepatic, splenic, mesenteric and retinal arteries causing infarction has occurred. APA syndrome should be suspected in young patients with stroke or arterial occlusion.

APA syndrome has been associated with multiple medications. However, procainamide has been implicated more commonly than other drugs.6

The diagnosis should be suspected based on the clinical presentation or the unexplained prolonged PTT. Diagnostic tests for APA syndrome include serology testing for APA and clotting assays. The primary treatment remains anticoagulation, maintaining an INR at or above 3.0.7,8 [Q3: B]

Protein C is one of the key regulatory proteins for coagulation cascade. APC cleaves and inactivates Factors Va and VIIIa. A single-point mutation in the gene coding for Factor V results in the formation of a Factor V molecule that is not inactivated properly by APC.9 Factor V Leiden mutation is an important risk factor for pulmonary embolism and DVT, especially during pregnancy or oral contraceptive use.10

Hyperhomocystinaemia increases the relative risk of a Factor V leiden carrier having any VTE.11 There is no increased risk of myocardial infarction or angina in patients with Factor V Leiden mutation.12 [Q4: A, C, D]

Among the available methods of DVT prophylaxis, LDUH and LMWH are the most effective in reducing DVT as assessed by FUT.13 LDUH was the first anti-thrombotic agent evaluated in early randomised studies. LDUH, dextran, IPC and graded elastic stockings also significantly reduce the incidence of postoperative DVT.13

LDUH given subcutaneously (5,000 U) every 8 or 12 h started preoperatively and continued postoperatively for 7 days has been shown to decrease the incidence of DVT from 25% to 8%.14 Moreover, these studies have shown a 50% reduction of fatal pulmonary embolism when patients are treated with LDUH. LMWH and LDUH have been shown to be equally effective in preventing DVT in general surgery patients.14

Advantages of LMWH include improved bioavailability, once-daily dosing, and a lower incidence of HIT.15

IPC is an attractive method of DVT prophylaxis since there are no observed complications. This device provides intermittent compression lasting 10 s/min with insufflation pressures of 35–40 mmHg. In a trial comparing IPC with LDUH, both agents were effective in reducing lower-extremity DVT in high-risk patients.16

Graded compression stockings decrease the risk of DVT, but data are limited regarding the effect on the prevention of DVT and pulmonary embolism. There are no randomised trials on the use of these stockings alone in high-risk patients, although current recommendations suggest the use of more effective methods. Fifteen to 20% of patients will not receive benefit from elastic stockings because of their leg shape or size. Dextran has not been shown to be as effective as either LMWH or LDUH in preventing DVT; however, it may reduce the incidence of pulmonary embolism. Disadvantages of dextran include its high price, risk of anaphylaxis, potential for volume overload, and need for intravenous access. It is also contraindicated in patients with impaired renal and cardiac function. [Q5: B, C]

488	F.S. Alasfar et al.

The incidence of DVT in general surgery patients has been well established. Overall, the incidence of DVT was 25% in general surgery patients not receiving prophylaxis. In patients with other risk factors, i.e., malignancy, the risk of DVT is 29%. Overall, the risk of pulmonary embolism is 1.6% while the risk of fatal pulmonary embolism is 0.8%.13 Patients undergoing major orthopaedic surgery of the lower extremity are at high risk of postoperative DVT, despite improved techniques and early mobilisation. The incidence of postoperative DVT after total hip replacement is 45–57%, with the risk of proximal DVT being 23–36%.17 The incidence of pulmonary embolism in this group is 6–30% and that of fatal pulmonary embolism is 3–6%. Because many pulmonary embolisms are asymptomatic, and because of the high incidence of DVT in the postoperative period,

proper prophylaxis is mandatory.18

DVT and pulmonary embolism are considered common complications after major trauma. A recent study using a venographic endpoint demonstrated that major trauma patients (injury severity score >9) have an exceptionally high risk of venous thromboembolism (58%). This study also revealed that there is a greater than 50% incidence of DVT in the major trauma subset.19

Pulmonary embolism is the most frequent reason for death following spinal cord injury. Clinically recognised DVT and pulmonary embolism occur in only 15% and 5% of cases, respectively.20 However, the incidence of DVT in patients with acute spinal cord injury by venography has been reported to be between 18% and 100%, with an average of 40%. The incidence of fatal pulmonary embolism is 4.6%, with the greatest risk occurring in the first 2–3 months after spinal-cord injury.21 [Q6: A, C, E]

Approximately 2–5% of patients exposed to heparin will develop HIT. This is caused by IgG antibodies that recognise complexes of heparin and platelet factor 4, leading to platelet activation via platelet Fc gamma IIa receptors. Formation of a procoagulant, plate- let-derived microparticles generates thrombin and makes patients especially vulnerable to venous thromboembolism.22,23

When examined directly, the clot appears white due to the concentration of fibrin and platelets. HIT should be suspected if a patient develops DVT or pulmonary embolism while receiving heparin, especially if the platelet count drops below 35%. HIT usually develops between the 4th and 14th days after initiation of heparin, although a rapid fall in platelet count can occur in response to heparin if the patient has had recent heparin exposure.

HIT occurs much more commonly with unfractionated heparin than with LMWH.15 Upon recognition of HIT, heparin should be discontinued; however, appropriate anticoagulationshouldbecontinuedtoavoidathromboticcomplication,whichhasbeenobserved in up to 50% of patients within 30 days of the diagnosis of HIT.15

Current treatment options include lepirudin,24 argatroban and danaparoid. Lepirudin is recombinant hirudin (r-hirudin) and is approved for the treatment of patients with HIT. It is a potent direct thrombin inhibitor and is given in a bolus dose of 0.4 mg/kg/min followed by an infusion of 0.2 mg/kg/h, but the dosage should be adjusted in patient with renal dysfunction. Argatroban is a synthetic peptide that binds to and inhibits thrombin. It is given in doses of 0.5–4 mg/kg/min and has the advantage of normal excretion (hepatic) in patients with impaired renal function. Danaparoid is a mixture of heparan sulphate and dermatan sulphate, which inhibits thrombin generation indirectly via inhibition of Factor