7: 53-year-old man with leg swelling

Question 1

Smoking is the single greatest contributor to death in this country, causing approximately 450,000 deaths annually in the U.S.

Answer 1

During 2000-2004 approximately 443,000 people in the United States annually died prematurely from cigarette smoking or exposure to secondhand smoke.

This figure has grown from an average annual estimate of approximately 438,000 deaths during 1997-2001, but this increase is predominantly due to population growth. Although deaths from cigarette smoking have not increased significantly, they remain high. Among adults, 160,848 (41%) of deaths were attributed to cancer, 128,497 (32.7%) to cardiovascular diseases, and 103,338 (26.3%) to respiratory diseases.

The three leading specific causes of smoking-attributable death were lung cancer at 128,922, ischemic heart disease at 126,005, and chronic obstructive pulmonary disease (COPD) at 92,915. An estimated 49,400 lung cancer and heart disease deaths annually were attributable to exposure to secondhand smoke. Smoking resulted in an estimated annual average of 270,000 deaths among males and 174,000 among females in the United States. For females, smoking during pregnancy resulted in an estimated 776 infant deaths annually during 2000-2004. The average annual smoking-attributable mortality estimates also include 736 deaths from residential fires caused by smoking.

Question 2

Deaths caused by hypertension

Answer 2

Hypertension is the single largest risk factor for cardiovascular mortality in the US. Overall uncontrolled hypertension decreases life expectancy by 20 years. Most of these deaths are due to the increased risk that hypertension incurs for coronary artery disease, hypertensive cardiomyopathy, cerebrovascular disease and chronic renal disease.

Question 3

Deaths caused by diabetes

Answer 3

Deaths caused by diabetes in the US; 213,062. The majority of deaths from diabetes also results primarily from the increase in cardiovascular disease and chronic renal failure. Diabetics have twice the mortality of non-diabetics. The risk of cardiovascular disease in diabetics is so high that it is assumed that they have cardiovascular disease if they have diabetes.

Question 4

Deaths caused by obesity

Answer 4

Deaths caused by obesity in the US; 300,000. Obesity is rapidly gaining on smoking as the single greatest cause of mortality in our country. A body mass index (BMI) of over 32 kg/m2 has been associated with a doubled mortality rate among women over a 16-year periodand obesity is estimated to cause an excess 111,909 to 365,000 death per year in the United States. Obesity on average reduces life expectancy by six to seven years. A BMI of 30-35 reduces life expectancy by two to four years while severe obesity BMI > 40 reduces life expectancy by 20 years for men and 5 years for women.

Question 5

Prevention of Embolism

Answer 5

More than 95% of pulmonary emboli arise from thrombi in the deep venous system of the lower extremities. Ninety percent of deaths due to pulmonary embolism result within an hour or two – before diagnostic and therapeutic plans can be implemented. Therefore, prevention and prompt treatment of DVT is the most effective approach to prevention of, and death due to, embolism.

Question 6

Pharmacology and Management of the Vitamin K Antagonists

Answer 6

The half-life of warfarin is around 40 hours, that means it will take five to seven days for the steady state to be stable. When making a dose adjustment for a outpatient on warfarin, one should wait at least this long before rechecking an INR, as checking sooner can lead to overreactions and great swings in a patient’s INR.

Question 7

Ulcer Classification: The Wagner Grading System

Answer 7

1. Grade 1: Diabetic ulcer (superficial)
2. Grade 2: Ulcer extension (involving ligament, tendon, joint capsule or fascia)
3. Grade 3: Deep ulcer with abscess or osteomyelitis
4. Grade 4: Gangrene forefoot (partial)
5. Grade 5: Extensive gangrene of foot

Question 8

Ulcer Management

Answer 8

Grade 1-2 ulcer management generally can be done as outpatient and should include extensive debridement, local wound care, and relief of pressure. If there is significant erythema and or purulent exudate, then treatment for infection is warranted.

Grade 3 lesions require evaluation for possible osteomyelitis as well as peripheral arterial disease. Both of these conditions may need to be addressed prior to resolution of the ulcer. Typically at least a brief hospitalization is required to address these issues.

Grade 5 lesions require emergent hospitalization and surgical consultation, often resulting in amputation.

Question 9

Requirement for Treating DVT on Outpatient Basis

Answer 9

In order to treat DVT on an outpatient basis...
The patient must be:
Hemodynamically stable 
With good kidney function 
At low risk for bleeding

The home environment must be:
Stable and supportive
Capable of providing the patient with daily access to INR monitoring (if using warfarin as the anticoagulant)

Question 10

Goals of DVT Therapy

Answer 10

1. Immediate inhibition of the growth of thromboemboli
2. Promotion of thromboembolic resolution
3. Prevention of recurrence

Heparin achieves the first goal, it encourages the second by allowing fibrinolytic dissolution to be achieved unopposed. It is available in two forms: unfractionated heparin or low-molecular weight heparin (LMWH).

Question 11

DVT Therapy: Advantages of Low-Molecular Weight Heparin (LMWH) over Unfractionated Heparin

Answer 11

LMWH has several advantages over unfractionated heparin:

• -Longer biologic half-life so it can be administered subcutaneously once or twice daily
• -Laboratory monitoring is not required
• -Thrombocytopenia is less likely although periodic monitoring of platelets may be needed
• -Dosing is fixed
• -Bleeding complications are less common

LMWH may be used in the outpatient setting; whereas unfractionated heparin requires hospitalization as it is administered intravenously with the dosage based on body weight and titrated based on the activated partial thromboplastin time. One advantage to unfractionated heparin is that it can be immediately shut off and reversed in the case of bleeding due to its very short half-life. In a patient with a significant bleeding risk (e.g. recent admission for gastrointestinal bleeding), it is advisable to choose unfractionated heparin over low molecular weight heparin, which has a much longer half-life once injected.

Question 12

Warfarin

Answer 12

Prothrombopenic drugs like warfarin are not suitable for initial therapy in thromboembolism because their onset of action is too slow. Their only role is in maintaining anticoagulant protection for prolonged periods.

Monitor warfarin dose by measuring the INR and titrate the warfarin dose every three to seven days to an INR of 2.0-3.0. The advantages of warfarin include its minimal cost and familiarity among medical providers. Its disadvantages include its highly variable dosing range, its requirement of frequent laboratory monitoring, and its high rate of interactions with other medications.

Question 13

Factor Xa inhibitors

Answer 13

This relatively new class of drugs has the advantage of not requiring weekly lab monitoring of INR and thus makes adherence an easier process. Fondaparinux is the parental form of the drug and could be used instead of LMWH. Rivaroxaban and apixaban are oral factor Xa inhibitors which may be used in place of warfarin. Although these drugs have been found to be as effective as and generally safer (i.e. fewer bleeding complications) than warfarin and LMWH, the negatives of this class of medications includes high cost and difficulty in reversing the anticoagulation in the face of a bleed.

Question 14

Direct thrombin inhibitors

Answer 14

Dabigatran i s the only direct thrombin inhibitor available on the US market currently. Like the factor Xa inhibitors, dabigatran may be taken orally and does not require laboratory monitoring. It also has been demonstrated in meta- analyses to lead to fewer bleeding complications compared to warfarin. One potential advantage to dabigatran over the factor Xa inhibitors is that a reversal agent (idarucizumab) was recently approved by the FDA, which may be useful in the case of serious bleeding. Neither direct thrombin inhibitors or factor Xa inhibitors may be used in pregnant patients (unlike heparin, they cross the blood-placenta barrier) or in patient with significant renal disease.

Question 15

Treatment of Thrombotic Disease with Inherited Thrombophilia

Answer 15

Patients with inherited coagulation disorders typically are anticoagulated indefinitely after an episode of thrombotic disease.

Question 16

Criteria for Recommended Screening for Inherited Thrombophilia

Answer 16

Although there are no absolute indications for screening for inherited thrombophilias, expert opinion on which patients are likely to benefit from such investigations includes patients with one of the following:

• -Initial thrombosis occurring prior to age 50 without an immediately identified risk factor (e.g., idiopathic or unprovoked venous thrombosis).
• -A family history of venous thromboembolism.
• -Recurrent venous thrombosis.
• -Thrombosis occurring in unusual vascular beds such as portal, hepatic, mesenteric, or cerebral veins.

There is currently no evidence to support any change in outcome when using such a strategy.

Question 17

Recommended Action When Goal INR is Overshot

Answer 17

If the goal INR is substantially overshot, it increases the risk of bleeding complications significantly.

Warfarin should be held, and an oral dose of Vitamin K should be given to reduce INR.

• -Omitting a dose of warfarin is an insufficient response to a potentially dangerous situation.
• -Probably the second best answer is to discontinue the warfarin and repeat the INR in 24 hours, and this would be appropriate if the INR was greater than five and less than nine.
• -It is inappropriate to continue warfarin at the current dose because of risk of bleeding.
• -Finally, discontinuing warfarin, giving 5 mg Vitamin K IV, and repeating until INR less than 4.0 is an overreaction to a supratherapeutic INR in a non-bleeding patient.

Question 18

Complete blood count

Answer 18

Elevated white blood cell count might make you consider cellulitis. However, a normal white count would not rule it out, nor is a leukocytosis specific enough to give you the diagnosis.

Question 19

Culture and sensitivity

Answer 19

Would not tell you whether cellulitis is present, and is usually not useful in evaluating chronic ulcers.

Question 20

D-dimer

Answer 20

Is a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is a relatively sensitive, but poorly specific test for the presence of DVT. While a negative result (low D- dimer concentration in the blood) practically rules out thrombosis, a positive result can indicate thrombosis, but does not rule out other potential causes, such as infection. Its main use, therefore, is to exclude thromboembolic disease where the probability is low.

Question 21

MRI

Answer 21

Could identify the presence of thrombus. Expensive compared to venous doppler.

Question 22

Lymphedema

Answer 22

Lymphedema is generally painless, but patients may experience a chronic dull, heavy sensation in the leg. In the early stages of lymphedema, the edema is soft and pits easily with pressure. In the chronic stages, the limb has a woody texture and the tissues become indurated and fibrotic.

Lymphedema initially involves the foot and gradually progresses up the leg so that the entire limb becomes edematous.

Question 23

Cellulitis

Answer 23

Cellulitis is an acute inflammatory condition of the skin characterized by localized pain erythema, swelling, and heat.

Small breaks of skin are associated with streptococcal infection, whereas staphylococcal cellulitis is commonly associated with larger wounds, ulcers, or abscesses.

Patients with diabetes are more susceptible to infections like cellulitis. Diabetic neuropathy causes an unawareness of abnormal pressure distribution, ill-fitting shoes, and cuts or punctures which then develop ulcers.

Vascular disease with diminished blood supply contributes to the development of the lesion, and infection is common.

Question 24

DVT

Answer 24

Classic symptoms of DVT include swelling, pain, and discoloration in the affected extremity.

Physical examination may reveal the palpable cord of a thrombosed vein, unilateral edema, warmth, and superficial venous dilation.

Classic signs of DVT, including Homan’s sign (pain on passive dorsiflexion of the foot), edema, tenderness, and warmth, are difficult to ignore, but they are of low predictive value and can occur in other conditions such as musculoskeletal injury, cellulitis, and venous insufficiency.

Chronic venous insufficiency may result from DVT and/or valvular incompetence. Following DVT, the valve leaflets become thickened and contracted so that they are incapable of preventing retrograde flow of blood; the vein becomes rigid and thick-walled. Although most veins recanalize after an episode of thrombosis, some may remain occluded. Secondary incompetence develops in distal valves because high pressures distend the vein and separate the leaflets.

Primary deep venous thrombosis can also occur without previous thrombosis. Patients with venous thrombosis often complain of a dull ache in the leg that worsens with prolonged standing and resolves with leg elevation. Examination reveals increased leg circumference, edema, and superficial varicose veins.

The presence of a thrombus in a vein may be accompanied by an inflammatory response in the vessel which may be minimal or may be characterized by granulocyte infiltration, loss of endothelium, and edema. This inflammatory process may also result in a low grade fever.

Smoking and obesity, are the most robust risk factors in the development of DVT and are independent of other risk factors. Diabetes, sedentary lifestyle, hypertension, hyperlipidemia, increasing age, prolonged immobility, surgery, trauma, malignancy, pregnancy, estrogenic medications (e.g., oral contraceptive pills, hormone therapy, tamoxifen (Nolvadex)), congestive heart failure, hyperhomocystinemia, diseases that alter blood viscosity (e.g., polycythemia, sickle cell disease, multiple myeloma), and inherited thrombophilias are other potential risk factors in the development of DVT.

Question 25

Venous Insufficiency

Answer 25

The edema of venous insufficiency can be differentiated from chronic lymphedema as venous insufficiency edema is softer, and there is often erythema, dermatitis, and hyperpigmentation along the distal aspect of the leg, and skin ulceration may occur near the medial and lateral malleoli.

Obesity is commonly associated with venous insufficiency.

Question 26

Peripheral arterial disease

Answer 26

Peripheral arterial disease (PAD) is the presence of systemic atherosclerosis in arteries distal to the arch of the aorta. As a result of the atherosclerotic process, patients with PAD develop narrowing of these arteries.

Patients with PAD have a history of claudication, which manifests as cramp-like muscle pain occurring with exercise and subsiding rapidly with rest. In addition, later in the course of the disease, patients may present with night pain, nonhealing ulcers, and skin color changes.

An ankle-brachial index (ABI) can be done to determine the presence of PVD. An ABI of <0.9 is consistent with the disease.

Classic risk factors for PAD are smoking, diabetes mellitus, hypertension, and hyperlipidemia. Obesity (body mass index (BMI) >30) increases risk for PAD as well. Recent trials have added chronic renal insufficiency, elevated C-reactive protein levels, and hyperhomocysteinemia to the list of risk factors.

The greatest modifiable risk factor for the development and progression of peripheral arterial disease (PAD) is cigarette smoking. Cigarette smoking increases the odds for PAD by 1.4 for every ten cigarettes smoked per day.

Arterial insufficiency is four times more prevalent in patients with diabetes than in those without diabetes. Nearly half of patients who’ve had diabetes for 20 years or more have peripheral arterial disease (PAD), usually below the knees.

Question 27

Wells criteria for the diagnosis of DVT: Low probability 0 or less, moderate probability 1-2, high probability 3 or more.

Answer 27

Active cancer (treatment ongoing or within previous 6 months or palliative)
1

Paralysis, paresis, or recent plaster immobilization of the legs
1

Recently bedridden for more than 3 days or major surgery within 4 weeks
1

Localized tenderness along the distribution of the deep venous system
1

Entire leg swollen
1

Calf swelling by more than 3 cm compared with the asymptomatic leg (measured 10 cm below the tibial tuberosity)
1

Pitting edema (greater in the symptomatic leg)
1

Collateral superficial veins (non-varicose)
1

Alternative diagnosis as likely or more likely than that of deep vein thrombosis
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