1. Management of DVT Soheir Adam, MD, MSC, FRCPath
Asst. Professor & Consultant Hematologist KAU

2. 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)

3. 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.

4. 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. 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

6. 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.

7. 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.

8. Long Term Complications of VTE
Recurrence
PTS

9. Complications of VTE Recurrence
Prandoni et al found the risk after cessation of anticoagulation 24.8% at 5 years and 30.3% at 8

10. 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.

11. 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

12. 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

13. 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

14. Complications of DVT 2- Post- thrombotic syndrome
Develops in % 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.

15. 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.

16. 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

17. 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.

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

19. 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 %

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.

21. 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

22. 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)

23. 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

24. Indirect thrombin inhibition Heparin/antithrombin/thrombin complex

25. 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).

26. 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.

27. 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 …

28. 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

29. 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)

30. 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

31. 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

32. 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

33. Imberti et al, 2006
Journal of Thrombosis & Haemostasis

34. 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

35. 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

36. 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

37. 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

38. 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

39. Duration of Anticoagulation
Plan designed clearly for each patient individually at the start of anticoagulation

40. 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).

41. 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

42. BSH guidelines 2005

43. 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

44. 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

45. 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