1. Thrombotic disorders and anticoagulation therapy
Dr. Mohammad Harith Al-Saaty

2. Introduction
the balance of multiple procoagulant anticoagulant factors , including coagulation proteins , platelets , leucocytes , erythrocytes & component of vascular wall , prevent thrombosis development . Procoagulant activity necessary for hemostasis is modulated by the natural anticoagulant system ( protein C , protein S & antithrombin) thrombosis occur when this balance is disturbed .

3. - There is what is called ( virchow triad ) which contribute to the pathophysiology of thrombosis : 1. Stasis of blood 2. Blood hypercoagulability ( thrombophilia) . 3. Vascular wall abnormailties .

4. Aetiology
It is usually multifactorial : 1. Patient factors : a. Age b.Obesity c. Varicose veins d. Previous DVT e. Family hx. f. Pregnancy /puerperium g.Contraceptive pills ( specially estrogen containing pills ) h. Immobility e.g. long travel i. IV drug users ( specially femoral v.)

5. 2. Surgical conditions: a. Major surgery b
2. Surgical conditions: a. Major surgery b. Abdominal & pelvic surgery ( specially for CA ) c. Major lower limb orthopedic surgery . 3. Medical conditions : a. MI /HF b. Inflammatory bowel disease c. Malignancy d. Nephrotic syndrome e. Stroke , Guillian -Barre syndrome ( immobility).

6. 4. Blood diseases : a. Polycythemia rubra vera b
4. Blood diseases : a. Polycythemia rubra vera b. Essential thrombocythemia c. Myelofibrosis d. PNH e. Inherited thrombophilia ( protein C & S deficiency , antithrombin deficiency , favtor V leiden ….).

7. 5. Antiphospholipid syndrome : ( recurrent venous thrombosis , arterial thromboembolism , recurrent abortion & fetal death ) Usually associated with : -lupus anticoagulant : more strongly associated with thrombosis than anticardiolipin Ab . - Anticardiolipin antibody .

8. Inherited thrombophilic conditions
Indications for thrombophilia testing : 1. Venous thrombosis below 45 years ( specially if unprovoked) 2. Recurrent venous thrombosis . 3. Family hx. Of recurrent thrombosis / unprovoked thrombosis . 4. Combined arterial & venous thrombosis . 5. Venous thrombosis at unusual sites ! : ( cerebral venous thrombosis, budd chiari syndrome , mesenteric vein ..) .

9. Investigations of possible thrombophilia : 1. Antithrombin 2
Investigations of possible thrombophilia : 1. Antithrombin 2. Protein C 3.Protein S 4. Antiphospholipid Ab , lupus anticoagulant & anticardiolipin . 5. Factor V leiden 6. JAK2 mutation 7. Prothrombin G20210A 8. Flow cytometry e.g in PNH there is deficiency of CD 55 & CD 59 .

10. Deep venous thrombosis ( DVT)
-lower limb DVT is far more common than upper limb DVT . - Aetiology : mentioned in the previous slide . - Lower limb DVT usually start in the distal veins , causing pain , swelling , increase in temprature & dilatation of the superficial veins , it is typically unilateral , but can be bilateral & the clot may extend proximally into the inferior vena cava .

11. - Bilateral DVT is more commonly seen with underlying malignancy or anomalies of the IVC. You should differentiate DVT from other causes of unilateral swelling : *cellulitis ( marked erythema, well demarkated area , source of entry of infection , fever ….) * Traumatic musle tear or hematoma * Rupture baker cyst * Lymphadema .

12. Proximal DVT ( above knee ) is more significant than distal one because there is higher chance of pulmonary embolism with the proximal DVT . Always assess the patient for signs & symptoms of Pulmonary embolism .

15. Wells score for DVT

16. Investigations
The approach to patient with suspected DVT depend on the pretest probability ( according to wells score , ≤ 1 means low probability , 1-2 moderate probability , ≥ 2 means high probability ) . In patient with low probability : measuring D Dimer should be done , if it is normal further investigation of DVT is unnecessary ! ( bec. D-Dimer has high negative predictive value in low pretest probability patients .)

17. If the pretest probability is moderate to high , further tests should be done to confirm DVT . Compression ultrasound or doppler us is the imaging modality of choice . Contrast venography is rarely used now . Pelvic us is also useful when there is suspecion of pelvic mass . Other investigations for thrombophilia should be sent when the condition is recurrent .

18. Doppler us in DVT

19. Management
The mainstay treatment of DVT is anticoagulation with heparin ( specially low molecular wt. heparin ) followed by warfarin or other oral anticoagulants like ( rivaroxaban ) which is oral Xa inhibitor , has rapid onset of action & can be used immediately without the need for LMWH .! Treatment with LMWH should be continued for at least 5 days , in the 3rd day when warfarin introduced , heparin should be continued until the INR has been in the target range ( 2-3) .

20. The duration of anticoagulation varies from pt to pt , DVT that occur after a temporary risk factor & then this factor has been removed should be treated for at least 3 months . Unprovoked DVT should be treated for at least 6 months . Recurrent DVT should be treated with anticoagulation for life.

21. Other lines of treatment including - Elevation of the leg - Analgesics - In limb threatening DVT , thrombolysis sould be considered . - Inferior vena cava filter ! : this is indicated in the following conditions : a. When there is strong contraindication to anticoagulation . b. Recurrent thrombosis despite adequate anticoagulation .

22. DVT in pregnancy ! Dvt is common in pregnancy , because of the hypercoagulability & the pressure of the gravid uterus on the lower limbs . Treatment of DVT in pregnancy should be done by LMWH throughout the whole pregnancy ( because warfarin is teratogenic , although there are studies suggest that warfarin can be used in the 2nd trimester ! ) . After delivery the pt. can be given warfarin .

23. Pulmonary embolism
The majority of pulmonary emboli arise from the propagation of lower limb DVT , other causes include : septic emboli ( from endocarditis affecting right sided valves ) , fat embolism , amniotic fluid embolism …. Causes : ( the same applied for other thromboembolic diseases ).

24. Clinical features
Clinical presentation varies , depending on number , size & distribution of emboli & on the underlying cardiorespiratory reserve . **Always ask about the possible risk factors ! Which may be present in majority of cases . ** always exclude other causes .

25. Acute pulmonary embolism : Symptomes: 1. Dyspnoea 2
* Acute pulmonary embolism : Symptomes: 1. Dyspnoea 2. Pleuritic chest pain 3. Hemoptysis ( specially with pulmonary infarction ) 4. Palpitation 5. Faintness or collapse ( with massive PE) .

26. Signs: 1. Tachypnoea 2. Tachycardia 3
Signs: 1. Tachypnoea 2. Tachycardia 3. Evidence of DVT ( not necessarily present) 4.Signs of pleural effusion ( which could be bloody in case of infarction ) 5. Pleural rub 6. In massive PE : cyanosis , hypotension , confusion , elevated JVP , arrythmia … 7. Sometimes normal chest examination !

28. Investigations : 1. ECG : Important to exclude other causes of chest pain a. Sinus tachycardia ( most common finding) b. RBBB C. T wave inversion d. AF e. S1Q3T3 ( not always present , usually with large emboli) .

29. 2. CXR : * Useful in excluding other causes of acute dyspnoea like , pneumothorax , pneumonia … * Could be normal , in fact normal CXR in acutely breathless & hypoxemic pt. should rise the suspecion of PE. * Other CXR findings in PE : a. Oligemia of the lung field ( westermark sign ) b. Wedge shape infarction ( triangular shape with the apex toward the hilum, Hampton hump sign) c. Paranchymal opacity d. Elevated hemidiaphragm e. Pleural effusion f. Enlarged pulmonary artery

30. 3. Arterial blood gas analysis : Typically show reduced pao2 with normal or low paco2 & respiratory alkalosis . In massive PE there is metabolic acidosis . 4. D-dimer: has high negative predictive value in low risk pts. i.e normal Ddimer in the setting of low risk PE can exclude PE. Measuring Ddimer in moderate – high probability PE is of little significanse , bec. Even if it is normal the pt. still has to be evaluated ( in high risk pt.) . D dimer is elevated in other conditions : a. Myocardial infarction b. Pneumonia c. Sepsis d. After surgery

31. 5. CT pulmonary angiography Is the first line diagnostic test , it has the advantage of visualizing the extent & distribution of the emboli & excluding other dx. , before sending the pt. to the test RFT should be normal bec. The contrast is nephrotoxic ,& ask about any previous allergy to the contrast . 6. Ventilation perfusion scanning: used when CT angio is not available or there is contraindications to the contrast . 7. Doppler us of the legs ( to exclude DVT) 8. Echocardiography :is useful in the differential dx. , there may be acute dilatation of the right heart in massive embolism , & thrombus may be visible .

35. Differential Diagnosis of pulmonary embolism : 1
Differential Diagnosis of pulmonary embolism : 1. Myocardial infarction 2. Pneumonia 3. Pericardial tamponade 4. Aortic dissection 5. Pneumothorax 6. Acute pulmonary odema 7. In case of COPD : acute exacerbation of COPD .

36. Management of PE
1. General measures : Oxygen should be given to all hypoxemic pts.to maintain oxygen saturation above 90%. Circulatory shock should be treated with iv fluid or plasma expanders . Pain relieve is also important . 2. Anticoagulation : Should be started immediately in pt. with intermediate to high probability PE , the treatment is started with heparin which reduce the propagation of the clot & reduce the risk of further emboli .

37. LMWH like enoxaparin can be given subcutaneously in a dose of 1mg /kg every 12 hours Or using unfractionated heparin ( iv ) first as bolus dose 80 u /kg direct iv , then continuous iv infusion 18 u /kg /hour . Treatment should be continued for at least 5 days , warfarin should be introduced within hr. Heparin should not be stopped untill the INR at least 2 , then after at least 5 days & the INR reached 2-3 , heparin can be stopped & warfarin continued . Duartion of therapy ( as for DVT ) .

38. 3. Thrombolytic therapy & surgery : Thrombolysis is indicated in massive PE accompanied by cardiogenic shock & hemodynamic instability , contraindications to thrombolytics should be identified before starting therapy bec. There is risk of bleeding specially intracranial bleeding . Surgical embolectomy may be considered in resistant cases . 4. Caval filter : indicated in cases of strong C/I to anticoagulation , or pt. develop hemorrhage on anticoagulations & in recurrent thrombosis despite adequate treatment .

39. Anticoagulation therapy
HEPARIN : Unfractionated heparin :Act by activating anti thrombin III LMWH : act by inhibition of factor Xa. *Indication for heparin: 1.Prevention & treatment of VTE. 2. Acute coronary syndrome. 3. PCI ( percutaneous coronary intervention) 4.Acute peripheral arterial occlusion 5. Cardiopulmonary bypass 6. Hemodialysis

40. LMWH has several advantages over UFH : 1
LMWH has several advantages over UFH : 1.Nearly 100% bioavailable & therefore produce reliable dose dependent anticoagulation . 2.Generally do not require monitoring of its anticoagulant effect. 3. Longer half life than UFH , allowing once or twice daily dose sc. Rather than continuous iv route . 4. Incidence of heparin induced thrombocytopenia ( HIT) & osteoporosis is less with LMWH . Disadvantage of LMWH : 1. Difficult to be antagonize when there is bleeding due its half life. ( therefore , when there is conditions of high risk of bleeding , UFH is preferred) . 2. Not preferred when there is renal impairement .

41. Heparin induced thrombocytopenia (HIT)
Is a rare complication of heparin therapy , caused by induction of anti heparin / PF4 antibody which bind & inactivate platelets. This result in platelet activation & prothrombotic state with paradoxical thrombocytopenia . It is more common with unfractionated heparin & in high doses.

42. Features: usually start in about 5-14 days after starting heparin therapy , with a fall in platelet count with more than 30 % from baseline . The pt. may develop venous or arterial thrombosis with skin necrosis . Other causes of thrombocytopenia should be excluded . Treatment: once HIT is suspected , heparin should be stopped immediately . But alternative anticoagulant should be used such as direct thrombin inhibitors like argotraban , lepirudin & danaparoid .

43. New oral anticoagulants
New oral anticoagulants are now available as alternatives to warfarin. These include dabigatran, which targets thrombin, and rivaroxaban, apixaban, and edoxaban, which target factor Xa. All of these drugs have a rapid onset and offset of action and have half-lives that permit once- or twice-daily administration The new oral anticoagulants have been compared with warfarin for stroke prevention in patients with nonvalvular atrial fibrillation.

44. - They usually do not need monitoring
- They usually do not need monitoring . - Less intracranial bleeding than warfarin , but increased risk of GIT bleeding ( specially dabigatran) .

45. Antiphospholipid syndrome

46. Livido reticularis