1. PREVENTION AND TREATMENT OF
DEEP VEIN THROMBOSIS
DeShawndre Bridley
6th Year Doctorate of Pharmacy Candidate
Florida A&M University
2. OBJECTIVES
Case Presentation
Outline DVT
Pathophysiology
Epidemiology
Diagnosis
Complications
Discuss Pharmacological Management
Review Case Study
3. CASE PRESENTATION
M.H. is a 47 y/o, 268lb WF admitted to the ER on 10/22/07
CC: “My calf started to swell last week. Now the pain is so
bad that I’m having a hard time walking.”
HPI: Noticed swelling of the right calf approximately 4 days
ago. She reported to the ED of her local hospital 1 day after
the onset of calf pain and swelling. Venous Dopplers were
performed and the patient was told that she had a blood clot
in her right leg. According to the patient she was given a
prescription for an injection and instructed to follow-up with
her PCP within the next 1 to 2 days. She failed to have the
prescription filled because her pharmacy did not have the
drug in stock. Because of increasing pain and
discomfort, M.H. was seen by her physician this morning
who recommended hospitalization to initialize therapy for
her blood clot.
4. CASE PRESENTATION
PMH: Previous DVT at the age of 38;
treated with warfarin for 3 months
FH: Father died at 42 from MI; mother
alive at 71 with breast cancer diagnosed 5
years ago, s/p radiation/chemotherapy;
sister alive and well. No family history of
venous thromboembolic disease
reported.
5. CASE PRESENTATION
SH: Patient lives with her husband and 16
y/o son; works in a department store as a
cashier. 24 pack-year smoking history;
currently smokes ½ to 1 ppd. (-) EtOH or
IVDA
Meds: Raloxifene 60mg PO qd
Multivitamin 1 tab PO qd
Denies the use of herbal products
7. DEEP VEIN THROMBOSIS
Deep vein thrombosis (DVT) is the
development of thrombi in the deep veins
of the extremities or pelvis.
DVT
Deep venous thrombophlebitis
8. EPIDEMIOLOGY & DEMOGRAPHICS
Annual incidence in urban population is
1.6 cases/1000 persons.
The risk of recurrent thromboembolism is
higher among men than women
Annual incidence is 0.1% in white
population
9. ETIOLOGY
The etiology is often multifactorial (prolonged
stasis, coagulation abnormalities, vessel
wall trauma).
The following are risk factors for DVT:
• Prolonged immobilization (≥3 days)
• Postoperative state
• Trauma to pelvis and lower extremities
• Birth control pills, high-dose estrogen
therapy;
10. ETIOLOGY
Visceral cancer (lung, pancreas, alimentary
tract, GU tract)
Age >60 yr.
History of thromboembolic disease
Hematologic disorders (e.g., antithrombin III
deficiency, protein C deficiency, protein S
deficiency, heparin cofactor II deficiency, sticky
platelet syndrome, G20210A prothrombin
mutation, lupus
anticoagulant, dysfibrinogenemias, anticardiolipi
n antibody, hyperhomocysteinemia, concurrent
homocystinuria, high levels of factors VIII, XI, and
factor V Leiden mutation)
11. ETIOLOGY
Pregnancy and early puerperium
Obesity, CHF
Surgery requiring >30 min of anesthesia
Gynecologic surgery (particularly
gynecologic cancer surgery)
12. ETIOLOGY
Recent travel (within 2 wk, lasting >6 hr)
Smoking and abdominal obesity
Central venous catheter or pacemaker
insertion
Superficial vein thrombosis, varicose
veins
13. DIAGNOSIS
Symptoms: The patient may complain of
leg swelling, pain, or warmth.
Signs: The patient’s superficial veins
may be dilated, and a “palpable cord”
may be felt in the affected leg. The
patient may experience pain in the back of
the knee when the examiner dorsiflexes
the foot of the affected leg.
15. DIAGNOSIS
Laboratory Tests
Serum Concentrations of D-dimer, a by-
product of thrombin generation, usually are
elevated.
The patient may have an elevated erythrocyte
sedimentation rate (ESR) and White Blood
Cell (WBC) count.
16.
17. NONPHARMACOLOGIC THERAPY
Initial bed rest for 1-4 days followed by
gradual resumption of normal activity
Patient education on anticoagulant
therapy and associated risks
18. ACUTE GENERAL PHARMACAOTHERAPY
Traditional treatment consists of IV
unfractionated heparin for 4 to 7 days
followed by warfarin therapy.
Low–molecular-weight heparin enoxaparin
(Lovenox) is also effective for initial
management of DVT and allows outpatient
treatment.
Recommended dose is 1 mg/kg q12h SC and
continued for a minimum of 5 days and until
a therapeutic INR (2-3) has been achieved
with warfarin
19. DOSAGES FOR LMWH AND UFH
Enoxaparin (Lovenox) 1mg/kg every 12
hours or 1.5mg/kg every 24 hours
Dalteparin (Fragmin) 100units/kg every 12
hours or 200units/kg every 24 hours
Tinzaparin (Innohep) 175units/kg every 24
hours
UFH: Loading dose of 80 to 100units/kg
(max. 10,000units) followed by a continuous
IV infusion at an initial rate of 17 to 20
units/kg/h (max. 2300 units/h)
20. ADVANTAGES OF LOW MOLECULAR WEIGHT
HEPARIN OVER UNFRACTIONATED HEPARIN
More reliable dose-response relation
No need for laboratory monitoring with the activated partial
thromboplastin time (although can be monitored with anti-Xa
activity)
No need for dose adjustments
Lower incidence of thrombocytopenia
No excess bleeding
Can be administered by the patient at home
Economically advantageous
21. ACUTE GENERAL PHARMACOTHERAPY
Once-daily fondaparinux (Arixtra), a
synthetic analog of heparin, is also as
effective and safe as twice daily
enoxaparin in the initial treatment of
patients with symptomatic DVT.
Selective inhibitor of factor Xa
Dose: 7.5mg SC daily
22. ACUTE GENERAL PHARMACOTHERAPY
Warfarin therapy should be initiated when
appropriate (usually within 72 hr of
initiation of heparin).
Interferes with vitamin K dependent
factors (II, VII, IX, X)
Interactions: Ethanol, Vitamin E,
Cranberry juice
Pregnancy category X
23. ACUTE GENERAL PHARMACOTHERAPY
Low–molecular-weight heparin, when
used, should be overlapped with warfarin
for at least 5 days and until the INR has
exceeded 2 for 2 consecutive days.
24. ACUTE GENERAL PHARMACOTHERAPY
Exclusions from outpatient treatment of
DVT include patients with potential high
complication risk (e.g., Hemoglobin
<7, platelet count <75,000, guaiac-positive
stool, recent CVA or noncutaneous
surgery, noncompliance).
25. ACUTE GENERAL PHARMACOTHERAPY
Insertion of an inferior vena cava filter to
prevent pulmonary embolism is
recommended in patients with
contraindications to anticoagulation
26.
27. ACUTE GENERAL PHARMACOTHERAPY
Thrombolytic therapy (streptokinase) can
be used in rare cases (unless
contraindicated) in patients with
extensive iliofemoral venous thrombosis
and a low risk of bleeding
Not generally used unless there is a
massive thrombus or limb salvage is
necessary (due to gangrene)
Has not been shown to decrease
morbidity or mortality in PE
28. CHRONIC PHARMACOTHERAPY
Conventional-intensity warfarin therapy is
more effective than low-intensity warfarin
therapy for the long term prevention of
recurrent DVT.
The low-intensity warfarin regimen does
not reduce the risk of clinically important
bleeding.
29. CHRONIC PHARMACOTHERAPY
The optimal duration of anticoagulant therapy
varies with the cause of DVT and the patient's risk
factors:
1. Therapy for 3-6 mo. is generally satisfactory in
patients with reversible risk factors (low-risk
group).
2. Anticoagulation for at least 6 mo. is
recommended for patients with idiopathic venous
thrombosis or medical risk factors for DVT
(intermediate-risk group).
3. Indefinite anticoagulation is necessary in
patients with DVT associated with active cancer;
long-term anticoagulation is also indicated in
patients with inherited thrombophilia (e.g., deficiency
of protein C or S antibody), antiphospholipid, and
those with recurrent episodes of idiopathic DVT
(high-risk group).
30. CHRONIC PHARMACOTHERAPY
Measurement of d-dimer after withdrawal
of oral anticoagulation may be useful to
estimate the risk of recurrence. Patients
with a first spontaneous DVT and a d-
dimer level <250 μg/mL after withdrawal
of oral anticoagulation have a low risk of
DVT recurrence.
31. PEARLS AND CONSIDERATIONS
When using heparin, there is a risk of
heparin-induced thrombocytopenia (with
unfractionated more so than with LMWH).
Platelet count should be obtained initially
and repeated every 3 days while on
heparin.
32. PEARLS AND CONSIDERATIONS
Approximately 20%-50% of patients with
DVT develop postthrombotic syndrome
characterized by leg edema, pain, venous
ectasia, skin induration, and ulceration.
33. PEARLS AND CONSIDERATIONS
Exercise following DVT is reasonable
because it improves flexibility of the
affected leg and does not increase
symptoms in patients with
postthrombotic syndrome
34. PREVENTION IS BETTER THAN TREATMENT
Mechanical Methods
Earlymobilization as soon as possible after
surgery
Graded compression stocking
Pharmacological Methods
UFH
LMWH
Fondaparinux
Warfarin
35. PEARLS AND CONSIDERATIONS
Prophylaxis of DVT is recommended in all
patients at risk (e.g., low–molecular-
weight heparin [enoxaparin 30 mg SC bid]
after major trauma, post surgery of hip
and knee; enoxaparin 40 mg SC qd post–
abdominal surgery in patients with
moderate to high DVT risk; gradient
elastic stockings alone or in combination
with intermittent pneumatic compression
[IPC] boots following neurosurgery).
36. PEARLS AND CONSIDERATIONS
Fondaparinux (Arixtra), a synthetic analog
of heparin, can also be used for
prevention of DVT after hip fracture
surgery, hip replacement, or knee
replacement. Initial dose is 2.5 mg SC
given 6 to 8 hr postoperatively and
continued daily. Its bleeding risk is similar
to enoxaparin; however, it is more
effective in preventing DVT
37. CASE PRESENTATION
Subjective:
Calf pain and swelling
Risk Factors: Smoking, SERM use, Previous DVT
Objective:
(+) Homan’s sign in right calf with no palpable cord
Factor V Leiden Mutation – positive
Venous compression Ultrasonography- RLE shows
non compressibility of the right posterior tibial vein
with no color flow. Normal compressibility and flow
demonstrated within the right common femoral and
iliac veins. LLE shows normal compression of the
deep venous system from the level of the common
femoral vein to the popliteal vein
38. CASE PRESENTATION
Assessment:
AcuteDeep vein thrombosis of the right
posterior tibial vein requiring initiation of
anticoagulation. Venogram not necessary
due to positive ultrasound results
39. DVTs in and/or around the politeal vein are termed proximal
41. CASE PRESENTATION
Plan
Day 6
Discontinue LMWH
Patientis to continue on warfarin therapy for at
least one year due to prior DVT
42. REFERENCES
1. Anderson F.A. , Jr, Spencer F.A., Risk factors for venous
thromboembolism. Circulation (2003) 107 : pp 9-16
2. White R.H., The epidemiology of venous thromboembolism. Circulation
(2003) 107 : pp I4-I8.
3. Antithrombotic Therapy for Venous Thromboembolic Disease The
Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy
Chest - Volume 126, Issue 3 (September 2004)
4. Barrit DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary
embolism: a controlled trial. Lancet 1960; 1:1309–1312
5. Crowther MA, Ginsberg JB, Kearon C, et al. A randomized trial comparing
5-mg and 10-mg warfarin loading doses. Arch Intern Med 1999; 159:46–
48
6. Kernohan RJ, Todd C. Heparin therapy in thromboembolic disease.
Lancet 1966; 1:621–623
7. Harrison L, Johnston M, Massicotte MP, et al. Comparison of 5-mg and
10-mg loading doses in initiation of warfarin therapy. Ann Intern Med
1997; 126:133–136
Most important disease affecting the peripheral veins. Most pulmonary emboli arise from DVTs in the legs.
Usually originates in one of the distal or calf veinsWhen compared to the caucasian population, studies have shown that Hispanics seem to be protected against DVT, AA have a higher risk of DVT, and Asians and pacific islanders have a decreased risk of DVT
-Virchow’s Triad (venous stasis-slowed blood flow in the deep veins, due to increase blood viscosity, obstruction, prolonged periods of immobility; hypercoagulability due to malgnancy; vessel wall trauma due to orthopedic surgery-conjugated equine estrogen but not esterified estrogen is associated with increased risk of DVT; estrogen plus progestin is associated with doubling the risk of venous thrombosis . Estrogens appear to increase serum clotting factor concentration
The patient in the case was positive for factor V Leiden mutation.Inherited disorder which results from a single point mutation, amino acid substitution of arginine for glutamine at Arg-506, affects factor V’s activated protein C binding site. Protein C is responsible for inactivating factor V and decreasing clots. With this disorder protein C is unable to inactivate factor V.
Early puerperium- right after giving birth
Symptoms are nonspecific, and objective testing must be performed to establish the diagnosisPain on dorsiflexion is a positive Homan’s sign. Dorsiflexion is movement of the foot upward.
Duplex ultrasonography is the most commonly used test to diagnose DVT. It is noninvasive and can measure the rate and direction of blood flow and visualize clot formation in proximal veins of the legs. I cannot reliably detect small blood clots in distal veins. Coupled with a careful clinical assessment, it can rule out or in the diagnosis in the majority of cases. It uses sound waves to visualize the arteries and veins.Venography is an invasive test that involves injection of radiopaque contrast dye into a foot vein. It is expensive and can cause anaphylaxis and nephrotoxicity.
Blood testssuch as for fibrin d-dimer, a fibrin degradation product, addto the diagnostic accuracy of the non-invasive tests. d-dimerlevels are > 500 ng/ml in nearly all patients with venousthromboembolism. Alone, they are insufficient to establish thediagnosis as such levels are non-specific and often can be foundin patients admitted to hospital and in those with malignancyor after recent surgery. Thus, a low or normal d-dimer levelwith a low pretest probability makes a diagnosis of deep veinthrombosis (or pulmonary embolism) unlikely.
The use of low molecular weight heparin in deep vein thrombosisand pulmonary embolism is now firmly established. Many trialsand meta-analyses have confirmed their superior efficacy, saferprofile, and cost effectiveness over unfractionated heparin.This is partly due to more targeted action: unfractionated heparinacts on both thrombin and factor Xa about equally, whereas lowmolecular weight heparin is more active against factor Xa. Thelow molecular weight heparins are, however, different, and trialsfor one cannot be extrapolated to another. The introductionof low molecular weight heparin has advanced antithrombotictherapy by providing effective anticoagulation without the needfor routine monitoring or adjustments, although it can be monitoredthrough an anti-Xa effect. It also allows patients with uncomplicateddeep vein thrombosis to be treated in the community, thus savingan average of 4 or 5 days of admission per patient. Low molecularweight heparin has been shown to be more effective than vitaminK antagonists (almost all being warfarin) in preventing deepvein thrombosis after major orthopaedic surgery, with no significantdifference in rates of bleeding.
Dosages for heparin can be found by using a nomograph based upon wt and activated partial thromplastin timeaPTT should be measure no sooner than 6 hours after beginning the infusion or any dosage change. The therapeutic range is 1.5 to 2 times the mean normal control valueBleeding is the major SE of heparin therapy, more so with unfractionated heparin. HIT thrombocytopenia is common and is a platelet count less than 150,000/ml. Platelets typically begin to fall within 5 days of therapy and should be monitored every 1-2 days Protamine sulfate given via slow IV infusion over 10 min (1mg/100U of UFH infused during the previous 4 hours; max. 50mg)Antifactor Xa is used to monitor LMWH. Acceptable target range is 0.5-1unit/ml and should be drawn approximately 4 hours after SC administration. Particulary in renally insufficient, pregnant,elderly, patients weighing less than 50kg, patients that require therapy for more than 14days etc.Protamine sulfate dose is 1mg/1mg of enoxaparin or 1mg/100 antifactor Xa units of dalteparin or tinzaparin administered the previous 8 hours. If in the previous 8-12 hours the dose is 0.5mg/100 antifactor Xa units. Not recommended for doses given greater than 12 hours prior
Fondaparinux is a precisely engineered pentasaccharide, whichbinds antithrombin and enhances its activity towards factorXa but is devoid of activity against thrombin. This brings severaladvantages, such as a more predictable profile, a long halflife (17 hours), and no activity towards platelets. It is atleast as effective as unfractionated heparin in treating pulmonaryembolism,323 at least as effective as a low molecular weightheparin in treating deep vein thrombosis,24 with a benefit overa low molecular weight heparin in risk reduction of venous thromboembolismafter orthopaedic surgery.25 In one UK health economics study,fondaparinux was more effective and reduced costs to the healthcaresystem when compared with a low molecular weight heparin.26An example of recommended uses of this and other agents in adefined group (mostly after surgery) is shown on bmj.com, althoughothers recommend a different approach in medical patients.27
A 5 mg loading dose of warfarin is recommended in inpatients because it produces less excess anticoagulation than does a 10 mg dose; the smaller dose also avoids the development of a potential hypercoagulable state caused by precipitous decreases in levels of protein C during the first 36 hr of warfarin therapy. In the outpatient setting, a warfarin nomogram using 10 mg loading doses may be more effective in reaching a therapeutic INR
An inferior cava filter (IVC filter) is a device place in the inferior vena cava to prevent PE. It is used in patients that have failed or had complications with oral anticoagulant therapyMost filters are placed for the following reasons. Failure of anticoagulation; eg development of deep vein thrombosis (DVT) or pulmonary emboli (PE) despite adequate anticoagulation. Contraindications to anticoagulation; eg a patient at risk of PE who has another condition that puts them at risk of bleeding, such as a recent bleed into the brain, or apatient about to undergo major surgery Large clots in the vena cava or iliac veins Patients at high risk of having a PE
An inferior cava filter (IVC filter) is a device place in the inferior vena cava to prevent PE. It is used in patients that have failed or had complications with oral anticoagulant therapyMost filters are placed for the following reasons. Failure of anticoagulation; eg development of deep vein thrombosis (DVT) or pulmonary emboli (PE) despite adequate anticoagulation. Contraindications to anticoagulation; eg a patient at risk of PE who has another condition that puts them at risk of bleeding, such as a recent bleed into the brain, or apatient about to undergo major surgery Large clots in the vena cava or iliac veins Patients at high risk of having a PE
Unlike heparins and warfarin, which prevent extension and recurrenceof thrombosis, the thrombolytic agents (for example, streptokinase,urokinase and tissue-plasminogen activator) lyse the thrombi.Indications for this therapy are, however, unclear. Recent guidelines18do not recommend thrombolysis or thrombectomy for deep veinthrombosis unless for limb salvage.In cases of massive embolism, thrombolytic therapy with agents such as streptokinase, urokinase or tissue-plasminogen-activator (tPA) may be used to dissolve the PE and so relieve the obstruction. Treatment with thrombolytic agents is expensive and associated with an increased risk of hemorrhage, including hemorrhagic stroke. Therefore, such treatment should be limited to patients who have major PE or underlying cardio-respiratory disease and in whom early lysis is judged to be life-saving.
Oral anticoagulants can be used in two ways: Commence with a low dose (3 mg) 10 to 14 days before surgery with the aim of adjusting the INR to 1.3 to 1.5 at the time of surgery and then gradually increase the dose to obtain an INR of 2.0 to 2.5 at 3 to 4 days postoperatively. This approach is relatively safe but impractical because it requires many days of careful monitoring. Commence with a dose of 5 mg on the evening of the operation or the first postoperative day, aiming for an INR from 2.0 to 3.0 on the 4th or 5th postoperative day. This approach is more practical and has been shown to be effective and relatively safe but still requires careful laboratory monitoring.
Compression stockings and pneumatic compression have been usedas prophylactic measures against deep vein thrombosis. Inferiorvena cava filters may be used when anticoagulation is contraindicatedin patients at high risk of proximal deep vein thrombosis extensionor embolisation. The filter is normally inserted through theinternal jugular or femoral vein. This approach should be consideredin those patients with recurrent symptomatic pulmonary embolismand as primary prophylaxis of thromboembolism in patients athigh risk of bleeding. Other mechanical and surgical treatments(for example, embolectomy) are usually reserved for massivepulmonary embolism where drug treatments have failed or arecontraindicated.
Post-thrombotic syndrome is caused by damage to the one-way valves in the veins, which leads to high blood pressure in these blood vessels. Post-thrombotic syndrome is the name used to describe the long-lasting swelling, redness, pain and, in severe cases, ulceration that can sometimes occur after an episode of DVT. Some patients who have venous thrombosis can develop post-thrombotic syndrome. The pain is relieved by rest and raising the affected limb. The swelling may never disappear, or it may return a few years later. Post-thrombotic syndrome is sometimes difficult to diagnose because it looks like DVT. If you are likely to have post-thrombotic syndrome, it usually develops within 2 years of your DVT. Patients who have had DVT are normally given advice about how to prevent the development of post-thrombotic syndrome.
Mobilization stimulates calf muscles and put pressure on the calf and leg veins, thus discouraging stasis and venous pooling of blood in the lower extremities. Compression stockings should be fitted properly in order to provide the appropriate grade of compression. Most compression in the ankle with compression decreasing as the stocking goes up the leg to just below the knee.
This is the dosing for prophylaxis. Acute treatment is higher.
RLE- right lower extremityLLE- Left lower extremity
A venogram is an X-ray test that takes pictures of the blood flow through the veins in a certain area of the body. During a venogram, a dye is put into your veins so they can be seen clearly on an X-ray picture. A venogram looks at the condition of your veins and the valves with your veins.
This patient will be on warfarin therapy for at least a year and maybe indefinitelyOver time, the body will usually dissolve some, but not all, of the clot. The remainder of the clot embeds in the vessel wall and becomes scar tissue. According to a study in the annals of internal medicine, A 5-mg loading dose of warfarin produces less excess anticoagulation than does a 10-mg loading dose; the smaller dose also avoids the development of a potential hypercoagulable state caused by precipitous decreases in levels of protein C during the first 36 hours of warfarin therapy.Another study in the archives of internal medicine showed that A 10-mg loading dose of warfarin is unlikely to be more effective than a 5-mg loading dose in achieving an INR of 2.0 to 3.0 by day 4 or 5 of therapy.
