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 ¼ 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. Atrial Fibrillation

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 Recurrence PTS

Complications of VTE 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 wasn’t 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 The clotting mechanism involves a cascade of proteolytic reactions in which inactive enzymes activate one another. Each reaction exposes an active component on the enzyme that is capable of activating subsequent factors. A pivotal reaction is the cleavage of prothrombin to form thrombin (highlighted blue structures), a factor that not only increases clot development through the formation of fibrin, but also greatly enhances its own production by positive feedback activation of factors V and VIII.

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

Low molecular weight heparin (%) Unfractionated heparin (%) 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 (%) Unfractionated heparin (%) OR (95% CI) Deep vein thrombosis   Recurrent VTE 86/1998 (4.3) 113/2021 (5.6) 0.75 (0.55–1.01)   Major bleeding 30/2353 (1.3) 51/2401 (2.1) 0.60 (0.39–0.93)   Mortality 135/2108 (6.4) 172/2137 (8.0) 0.78 (0.62–0.99) Pulmonary embolism 30/988 (3.0) 39/895 (4.4) 0.68 (0.42–1.09) 14/1023 (1.4) 21/928 (2.3) 0.67 (0.36–1.27) 46/988 (4.7) 55/895 (6.1) 0.77 (0.52–1.15)

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

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 Outcome Trials that included patients with major PE Trials that excluded patients with major PE Lysis, n/N (%) Heparin, n/N (%) OR (95% CI) Recurrent PE or death 12/128 (9.4) 24/126 (19.0) 0.45 (0.22–0.92) 13/246 (5.3) 12/248 (4.8) 1.07 (0.50–2.30) Recurrent PE 5/128 (3.9) 9/126 (7.1) 0.61 (0.23–1.62) 5/246 (2.0) 7/248 (2.8) 0.76 (0.28–2.08) Death 8/128 (6.2) 16/126 (12.7) 0.47 (0.20–1.10) 8/246 (3.3) 6/248 (2.4) 1.16 (0.44–3.05) Major bleeding 28/128 (21.9) 15/126 (11.9) 1.98 (1.00–3.92) 6/246 (2.4) 8/248 (3.2) 0.67 (0.24–1.86) Wan et al, Circulation 2004.

Outpatient Management of DVT Hospital admissions Reduce the length of waiting time in A/E Pressure on hospital beds Cost issues Outpatient DVT is a current trend that has changed the face of management of this disorder, the need for it has arisen from the pressure for hospital beds …

Exclusion Criteria Co- existent serious medical pathology Severe acute venous obstruction Patients in significant pain Renal impairment creatinine > 200 µmol/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 No DVT confirmed Yes No Patient analgesia Support stocking Medical assessment Need for medical follow- up Refer to hemostasis nurse Anticoagulant treatment Liaise with general practitioner

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 Diagnosis shouldn’t be unduly delayed, the availability of validated clinical…., has helped screen those patients while they\rein A/E

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 Diagnostic team Investigation of initial DVT/ PE Investigation of recurrent DVT/PE Patient analgesia Assessment for ambulatory care Formal medical assessment Medical follow- up Liaison with GP

Lines of Accountability in Outpatient Management of DVT Treatment team Administration of outpatient care program Support stockings Patient education Thrombophilia testing Anticoagulant therapy Liaison with GP

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-γ-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 Drug Duration (months) Comments First episode of DVT or PE secondary to a transient (reversible) risk factor VKA 3 Recommendation applies to both proximal and calf vein thrombosis First episode of idiopathic DVT or PE 6–12 Continuation of anticoagulant therapy after 6–12 months may be considered First episode of DVT or PE and cancer LMWH 3–6 Continuation of LMWH is recommended indefinitely or until the cancer is resolved First episode of DVT or PE with a documented thrombophilic abnormality First episode of DVT or PE with documented antiphospholipid antibodies or two or more thrombophilic abnormalities 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) Closed in December 2002 Low – intensity Warfarin reduced the 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 hasn’t 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