Management of DVT

Soheir Adam, MD, MSC, FRCPath Asst. Professor & Consultant Hematologist KAU

VTE
Incidence of VTE 2-3 per 1000
Incidence is higher in men than in

women ( above the age of 45). Overall adjusted incidence in men is 130 : 100,000 vs 110: 100,000 in women(1.2:1)

VTE
DVT and PE are a single clinical entity
Risk of early death in DVT + PE is 18 X higher

than in DVT alone of PE cases present with sudden death Other predictors of poor survival in DVT are older age, male gender, confinement to hospital, CHF, chronic lung disease, neurological disease and active malignancy.

3. Thrombus formation in the left auricle (computer graphics superimposed on in-body photograph) The irregular beating of the heart in atrial fibrillation creates ideal conditions for thrombus formation in the left auricle, especially in patients with mitral valve insufficiency.

5. Fragmentation of the thrombus (computer graphics superimposed on in-body photograph) As the size of the thrombotic mass increases, it becomes more of a threat. Especially if the heart rate is normalised, fragments of the thrombus may break away to be swept into the circulation.

PE
Predictors of poor survival in PE: Syncope Arterial hypotension Right sided HF ( clinically or by plasma markers levels or echocardiography) These should receive aggressive anticoagulation +/- thrombolytic therapy.

11. Diagnosis of pulmonary embolism (perfusion and ventilation scans) In another patient with pulmonary embolism, a perfusion scan shows that an embolus has stopped the blood flow to part of one lung. The ventilation scan shows that this area is ventilated normally.

Long Term Complications of VTE

Complications of VTE
1. Recurrence
Prandoni et al found the risk after

cessation of anticoagulation 24.8% at 5 years and 30.3% at 8

14. Ref: Schulman S et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group. N Engl J Med 1997;336:393-8
Short-term primary prevention of deep vein thrombosis/pulmonary embolism with anticoagulant therapy is today common practice for patients undergoing orthopaedic surgical procedures. Patients with confirmed deep vein thrombosis, irrespective of the underlying cause, typically receive anticoagulant treatment for 3 to 6 months, depending on the location of the thrombosis and on other risk factors that the patient may have. For pulmonary embolism the duration of treatment is often 6 months. However, the optimal length of therapy is the subject of debate. Patients are at increased risk of suffering from a new episode of venous thromboembolism once anticoagulant therapy is completed. The next embolus may well prove to be fatal. There is a marked difference in the cumulative probability of a new episode of venous thromboembolism between the patients receiving indefinite treatment and those in the 6-month group.

Complications of VTE
Risk of recurrence increased with Male gender Increased age Increased BMI Neurological disease Paresis Active malignancy Idiopathic VTE APS Prt C,S and AT deficiency Persistent residual DVT Consider prolonged 2ry prophylaxis in the above

Complications of VTE
Factors not predictive of recurrence: VTE in pregnancy, CCP and gynecological surgery Recent surgery, trauma or fracture. Recent immobilzation Hormonal therapy (Tamoxifen) Failed prophylaxis Distal DVT, deep muscular DVT Short term oral anticoagulation considered

Recurrent PE
Risk of 7 day case mortality is significantly higher

(34%) in recurrent PE, compared to recurrent DVT(4%) alone Consider prolonged anticoagulation, especially if compromised cardiopulmonary functions

Complications of DVT
2- Post- thrombotic syndrome Develops in 20- 30% of DVT Valvular damage or scarring leading to incompetence / residual venous obstruction due to incomplete clearance Systemic thrombolytic therapy wasnt found to reduce incidence of PTS. Catheter- directed thrombolysis may hold potential but not recommended routinely.

Complications of DVT
Risk factors for PTS Inadequate initial anticoagulation Recurrent DVT Higher BMI Distal vein thrombosis Recently, persistently elevated D- dimers Not impact for long term anticoagulation.

Impact of PTS
In the US $ 200,000,000 annually to

treat PTS and 2 million work days lost In Sweden its 75% of cost of DVT ttt In developing world major morbidity Poorer QOL

16. Post-thrombotic syndrome; leg ulcer Considerable numbers of patients suffer from post-thrombotic syndromes with, in severe cases, leg ulcers. Venous thromboembolism is an underestimated disease with huge socio-economic implications.

Management of VTE
Aim of Management: Initially : to prevent propagation of thrombus Chronic anticoagulation to allow fibrinolysis and recanalization.

Management of VTE
Heparin immediately and for at least 5

days VKA started on the 1st day Failure to achieve optimum treatment early on leads to recurrence rates of 20 %

Haemostasis: generation of thrombin and clot formation

Management of VTE
UFH vs. LMWH Pros:

Similar efficacy &superior safety Monitoring Risk of bleeding (lower risk in LMWH 1.3% vs. 2.1%, odds ratio 0.60, meta-analysis of 14 studies) Lower overall mortality ( cancer pts.) Outpatient management Overall cost

Table 1 Recurrent symptomatic venous thromboembolism (VTE), major bleeding and mortality at 3 months summary of two meta-analyses in deep vein thrombosis and pulmonary embolism

Low molecular weight heparin (%) Deep vein thrombosis

Unfractionated heparin (%)

OR (95% CI)

Recurrent VTE
Major bleeding Mortality Pulmonary embolism Recurrent VTE Major bleeding Mortality

86/1998 (4.3)
30/2353 (1.3) 135/2108 (6.4) 30/988 (3.0) 14/1023 (1.4) 46/988 (4.7)

113/2021 (5.6)
51/2401 (2.1) 172/2137 (8.0) 39/895 (4.4) 21/928 (2.3) 55/895 (6.1)

0.75 (0.551.01)
0.60 (0.390.93) 0.78 (0.620.99) 0.68 (0.421.09) 0.67 (0.361.27) 0.77 (0.521.15)

Management of VTE
LMWH Cons

Reversal in bleeding patients: only the AT activity, not the Xa is neutralized Obese patients: adjusted vs. total body weight Renal failure

Indirect thrombin inhibition Heparin/antithrombin/thrombin complex

Thrombin Antithrombin

Heparin

Management of PE
UFH gradually replaced by LMWH
Similar efficacy and safety in sub-

massive PE No difference in mortality between altepase and LMWH compared to LMWH alone (NEJM 2002) Thrombolytic therapy essential in massive PE (better identification of patients needed).

Thrombolytic Therapy in PE
Table 2 Subgroup analysis of trials that included major (hemodynamically unstable) pulmonary embolism compared with those that excluded patients with major pulmonary embolism

Trials that included patients with major Trials that excluded patients with PE major PE Outcome Recurrent PE or death Recurrent PE Death Major bleeding Lysis, n/N (%) 12/128 (9.4) 5/128 (3.9) 8/128 (6.2) 28/128 (21.9) Heparin, n/N (%) 24/126 (19.0) 9/126 (7.1) 16/126 (12.7) 15/126 (11.9) OR (95% CI) 0.45 (0.22 0.92) 0.61 (0.23 1.62) 0.47 (0.20 1.10) 1.98 (1.00 3.92) Lysis, n/N (%) 13/246 (5.3) 5/246 (2.0) 8/246 (3.3) 6/246 (2.4) Heparin, n/N (%) 12/248 (4.8) 7/248 (2.8) 6/248 (2.4) 8/248 (3.2) OR (95% CI) 1.07 (0.50 2.30) 0.76 (0.28 2.08) 1.16 (0.44 3.05) 0.67 (0.24 1.86)

Wan et al, Circulation 2004.

Outpatient Management of DVT

Pressure on hospital beds

Exclusion Criteria
Co- existent serious medical pathology
Severe acute venous obstruction Patients in significant pain Renal impairment creatinine > 200 mol/l Liver disease Communication problems Poor social background

Limited mobility
Active bleeding

Exclusion Criteria
High risk of bleeding Active peptic ulcer Uncontrolled hypertension ( diastolic> 110mmHg,

systolic >200mmHg) Angiodysplasia Recent CNS or eye surgery Recent hemorrhagic stroke Thrombocytopenia ( plts < 100 X109/ L)

Clinical Assessment for DVT Suitable for Outpatient Management

Yes
DVT confirmed

No

Yes Patient analgesia Support stocking Medical assessment

No

Need for medical follow- up

Outpatient Diagnosis
No undue delay
Validated clinical probability scores and

3rd generation D- dimer assays If indicated then radiological investigations will follow ( vacant slots for A/E ) Diagnosis usually responsibility of medical team, A/E team

Clinical Prediction Rule

Entire leg tenderness along deep veins Collateral superficial veins Entire leg swelling Calf swelling >3 cm difference Dilated superficial veins Pitting edema Recent bed ridden >3 days Major surgery within last 3 ms. Active cancer within last 6 mo. Plaster Paralysis Presence of alternative Diagnosis

Imberti et al, 2006 Journal of Thrombosis & Haemostasis

Outpatient Management
Under auspices of Hematology

Department One of several scenarios

Daily OPD attendance District nurse or outreach hemostasis nurse LMWH administered by GP Administered by patient or relative

Lines of Accountability in Outpatient Management of DVT

Lines of Accountability in Outpatient Management of DVT

Vitamin K Antagonists
> reduction of risk of recurrence
Bleeding risk is 1.4% per year of major

bleeds 0.25% of fatal bleeds per year

Vitamin K Antagonists
Inhibits Vitamin K dependent

carboxylase activity Prevents reduction of Vitamin K Humans secrete des--carboxyglutamic acid, an inactive protein Does not affect proteins already synthesized Monitoring Multiple interactions with other drugs

Duration of Anticoagulation
Plan designed clearly for each patient

individually at the start of anticoagulation

Long-term treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)*
Patient categories First episode of DVT or PE secondary to a transient (reversible) risk factor First episode of idiopathic DVT or PE First episode of DVT or PE and cancer First episode of DVT or PE with a documented thrombophilic abnormality Dru Duration g (months) VK A VK A LM WH VK A 3 Comments Recommendation applies to both proximal and calf vein thrombosis Continuation of anticoagulant therapy after 612 months may be considered Continuation of LMWH is recommended indefinitely or until the cancer is resolved Continuation of anticoagulant therapy after 612 months may be considered

612

36

612

First episode of DVT or PE with documented antiphospholipid antibodies or two or more thrombophilic abnormalities

VK A

12

Continuation of anticoagulant therapy after 12 months may be considered

VKA, vitamin K antagonist; LMWH, low molecular weight heparin. *Based on the Seventh ACCP Conference document (13).

Duration of Thromboprophylaxis
Indefinite anticoagulation recommended :
Two or more spontaneous thromboses One spontaneous thrombosis in case of AT deficiency or

the APS One life- threatening thrombosis One spontaneous thrombosis at an unusual site One spontaneous thrombosis in the presence of multiple genetic thrombophilia defects

BSH guidelines 2005

Prevention of Recurrent Venous Thromboembolism (PREVENT)

rate of recurrence by 60% compared to placebo No increase in major bleeding complications

Management of Thrombophilia
AT deficiency
Some patients are resistant to Heparin AT conc hasnt been studied in a controlled trial

as an alternative to Heparin AT conc. can be used safely and effectively in AT deficiency and

Acute severe VTE Difficulty to achieve adequate anticoagulation Recurrent thrombosis despite adequate anticoagulation

Protein C Deficiency
Oral anticoagulation started under cover of

Heparin Dose of OAC should be gradually increased from 2mg for 3/7 until desired INR is reached WISN is an uncommon complication due to a transient hypercoagulable status Protein C conc. Can be used for prophylaxis against recurrent skin necrosis