Risk Factors, Prevention, Management of DVT

Detailed presentation on the risk factors, clinical picture, prevention and management of Deep venous thrombosis with complications.

1. DEPARTMENT OF INTERNAL MEDICINE WDH DEEP VENOUS THROMBOSIS DR DIKKO YUSUF A.

2. OUTLINE INTRODUCTION EPIDEMIOLOGY PATHOPHYSIOLOGY ETIOLOGY AND RISK FACTORS CLINICAL PICTURE COMPLICATIONS INVESTIGATIONS MANAGEMENT

3. INTRODUCTION DEFINITION: Deep venous thrombosis is defined as the formation of a blood clot or thrombus in a deep vein, most commonly in the legs or pelvis. Thrombus; also called blood clot is the final product of a blood coagulation cascade in hemostasis; consists of platelets, RBCs and fibrin mesh. DVTs are commonly asymptomatic and resolve spontaneously. The most common life threatening concern with DVT is the potential for a clot to detach from the veins, travel as an embolus through the right side of the heart and become lodged in the pulmonary artery; commonly referred to as pulmonary embolism.

4. VENOUS DRAINAGE OF LOWER LIMB The leg veins are divided into superficial and deep veins with communicating veins and perforators. Venous system of the lower limb is characterized by presence of unidirectional bicuspid valves which allow blood to flow from below upwards and from the superficial to the deep veins. The superficial veins lie superficial to the deep fascia. They consist of long saphenous vein on the antero-medial aspect of the leg and thigh & Short saphenous vein on the postero-lateral aspect of the leg and their tributaries The deep veins are intra and inter muscular which accompany their named arteries within the musculofascial compartments of the lower extremity. Communicating veins perforate the deep fascia and connect the deep to the superficial veins. Perforating veins are veins which drain the lower part of the leg, they pierce the deep fascia and drain the skin directly into the deep venous system. There are about 3 perforators in the medial side of the leg and 1 in the lateral side.

5. Formation of a thrombus: Coagulation Cascade A thrombus occurs when the hemostatic process, which normally occurs in response to injury, becomes activated in an uninjured or slightly injured vessel. A thrombus in a large blood vessel will decrease blood flow through that vessel (termed a mural thrombus). In a small blood vessel, blood flow may be completely cut off (termed an occlusive thrombus), resulting in death of tissue supplied by that vessel. If a thrombus dislodges and becomes free-floating, it is considered an embolus. Platelet activation occurs through injuries that damage the endothelium of the blood vessels, exposing the enzyme called factor VII, a protein normally circulating within the vessels, to the tissue factor, which is a protein encoded by the F3 gene. The platelet activation can potentially cause a cascade, eventually leading to the formation of the thrombus. Fibrinolysis is the destruction of blood clot in the blood vessel. The process requires the the formation of a substance called Plasmin/Fibrinolysin.

6. Plasmin is. formed from inactivated glycoprotein called Plasminogen. Plasminogen is synthesized in the liver and it is incorporated with the other proteins in the blood clot. Plasminogen is converted into plasmin by tissue plasminogen activator. t-PA is inhibited by a substance called t-PA inhibitor and Factor V and Factor VIII.

7. Epidemiology Venous thromboembolism( VTE; DVT+PTE): It’s the 3rd leading & commonest cause of deaths amongst cardiovascular diseases, after ischemic heart dxs & CVA, with a very high mortality & morbidity rate, usually due to under diagnosis & or poorly treated PE.( Note that cardiovascular dxs is the leading cause of mortality world wide especially in low & middle income countries, with an estimate 17.5M deaths, with over ¾ of these death occurring in low & middle income countries like African countries Paucity of data in Africa; Nigeria in particular, as a result of poorly equipped hospitals & poorly trained health care personnel. However, A 5years autopsy report by A.A Awotedu published in Nov.1992 in Central Africa journal of medicine, on pulmonary embolism in Ibadan(UCH), spanning btw 1985-1989, PE occurred in 3.8% of all autopsied pts during this period. on autopsy findings & clinical features in 60 patients with fatal pulmonary embolism. 15.6% were diagnosed of having PE ante mortem, pulmonary infarction occurred in 13.3%, a male to female ratio of 1:4, mean age was 47years.

8. 2017(August), Wiley Online library, summarized the epid. Of VTE in African population, using systematic review of all available journals on the continent, due to lack of available estimate at continental level, despite the increasing burden of CVD in African population: Prevalence of DVT following surgery in Africa : 2.4-9.6%, 2.4% in Nigeria by a study done by Adeleye et al, 5% in Uganda, 9.6% in Sudan. Mortality in Nigeria, study report by Adeleye et al; 60% in pts in a neurosurgical clinic. PE in pt. with medical illness varied btw 0.14% & 65%, with a mortality of PE In medical px btw 40-69.5%, whereas the case fatality rate after surgery was 60% in a single study In pregnant & postpartum women; btw 380-448 per100,000 birth per year. TB was associated with a 61.5% prevalence of dvt in a single study US Surgeon general est. that PTE causes btw 100-180,000 deaths in US alone & is the most preventable cause of in hospital death. Without prophylaxis the incidence of DVT is about 14% in gynecological surgeries 22% in neurosurgery 26% in abdominal surgery 45-60% in hip and knee surgeries 15-40% in urological surgeries. Epidemiology: cont

9. PATHOPHYSIOLOGY The process usually starts in the calf venous sinuses or in the iliac and femoral veins by adherence of platelets to the endothelial surface. More platelets then adhere. Fibrin and RBCs are deposited as layers in between the platelets giving a laminated appearance. When the vein is totally occluded, non adherent, jelly-like, propagating thrombus spreads up the vessel as far the next major tributary. The thrombus is loosely attached and can be easily detached leading to a pulmonary embolism. Later the thrombus becomes adherent to the vein wall. It then organizes and contracts producing destruction of the valves and luminal narrowing, which is responsible for the eventual development of Post phlebitic limb syndrome. Later on, the process of fibrinolysis and phagocytosis start and lead to recanalization of the vein, but the valves are permanently destroyed.

10. ETIOLOGY AND RISK FACTORS RISK FACTORS : PRESENCE OF AN ACUTE INFECTIOUS DISEASE AGE >75 YEARS CANCER HISTORY OF PRIOR DVT IV DRUG ABUSERS Over 100 years ago, Rudolf Virchow described a triad of factors that contribute to Thrombosis, known as Virchow’s triad; Circulatory stasis Hypercoagulability Endothelial injury

11. CIRCULATORY STASIS PROLONGED IMMOBILITY/PARALYSIS BURNS STROKE FRACTURE OF LOWER EXTREMITIES LONG PLANE OR CAR TRIPS (>4 HRS) ATRIAL FIBRILLATION LEFT VENTRICULAR DYSFUNCTION VENOUS INSUFFICIENCY/VARICOSE VEINS VENOUS OBSTRUCTION FROM TUMOR, PREGNANCY OR OBESITY.

12. ENDOTHELIAL INJURY TRAUMA OR SURGERY ATHEROSCLEROSIS VENEPUNCTURE CHEMICAL IRRITATION INJURY TO HEART VALVES/ REPLACEMENT INFLAMMATORY BOWEL DISEASES INDWELLING VENOUS CATHETER (SUBCLAVIAN OR INTERNAL JUGULAR LINES), RESPONSIBLE MOSTLY FOR UL DVTs

13. HYPERCOAGULABILITY SURGERY/TRAUMA MALIGNANCIES INCREASED ESTROGEN ORAL CONTRACEPTIVE PILLS INHERITED DISORDERS OF COAGULATION PROTEIN C DEFICIENCY PROTEIN S DEFICIENCY DEFICIENCY OF ANTITHROMBIN III FACTOR V LEIDEN MUTATION ACQUIRED DISORDERS OF COAGULATION NEPHROTIC SYNDROME SYSTEMIC LUPUS ERYTHEMATOSUS ANTIPHOSPHOLIPID SYNDROME INFLAMMATORY BOWEL DISEASE SICKLE CELL DISEASE.

14. Hypercoagulable state of malignancies Up to 15% of cancer patients present with DVT The highest incidence is found in mucin producing adenocarcinomas, pancreas and GIT malignancies Prevalence is seen as Pancreas -28% Lung - 27% Stomach - 13% Colon - 13% Breast(premenopausal) - 1-2% Breast (postmenopausal) - 3-8% Prostate - 2%

15. UPPER EXTREMITY DVT Upper extremity deep vein thrombosis (UEDVT) accounts for approximately 5 to 10 percent of all cases of DVT with incidence increasing due to higher frequency of intravenous catheter use. Veins considered to be "deep" classically have a corresponding named artery. In the upper extremity the deep veins include the paired radial veins, paired ulnar veins, paired brachial veins, axillary vein, and subclavian vein. The most common site of UEDVT involves the axillary and subclavian veins; however, the more distal brachial vein may also be involved. Additionally, many also consider the internal jugular veins to be included in the deep veins given their proximity to the central venous system. UEDVT can occur in primary and secondary forms with the symptom severity and treatment options varying between the two types. Primary UEDVT is less common than secondary UEDVT and most typically is effort-induced, known as Paget-Schroetter syndrome (PSS ). PSS is a venous form of thoracic outlet syndrome (vTOS) which classically occurs in the dominant arm of young athletes. The pathophysiology involves compression of the neurovascular bundle exiting the thoracic outlet. Compression is caused by repetitive motion of the upper extremity which, in the setting of anatomic abnormalities, such as hypertrophied scalene muscles, congenital presence of cervical ribs, and subclavius ligaments, place these individuals at a higher risk of UEDVT. Secondary UEDVT occurs due to thrombosis as a result of indwelling devices such as a central venous catheters (CVC), pacemaker or defibrillator leads, and tunneled central access lines. Catheter-associated UEDVT is the most common etiology comprising 93% of all UEDVT

16. CLINICAL PICTURE ASYMPTOMATIC GROUP CLASSICAL GROUP COMPLICATIONS GROUP

17. CLASSICAL GROUP Usually presents with a triad of Pain, Swelling and Tenderness. Pain: Usually an aching discomfort and tightness in the involved calf or thigh or upper arms. Swelling: This is the most reliable physical sign. It is evidenced by measuring the circumference in both limbs. In calf thrombosis, the swelling is limited to foot and ankle, in femoral thrombosis, the swelling involves the calf and lower part of the thigh, while ilio-femoral thrombosis, there is massive swelling involving the whole lower limb Tenderness: is present on grasping the affected calf or thigh or on compressing the muscle against bone.

18. COMPLICATION GROUP Phlegmasia alba dolens: Also called milk leg or white leg. It occurs due to total occlusion of deep venous system. The leg then must rely on the superficial venous system for drainage. The superficial system is not adequate to handle large volume being delivered to the leg via the arterial system. The result is edema, pain and white appearance(alba) of the leg.

19. Phlegmasia cerulea dolens : Further progression of PAD will result in occlusion of the superficial venous system thereby preventing all outflow from the leg. The leg becomes more swollen, increasingly painful. furthermore, edema and loss of venous outflow impedes arterial inflow producing Ischemia with possible progression to gangrene. Complication group: contd

20. Post-thrombotic syndrome It is a chronic complication of DVT that manifests months to years after initial event. Symptoms range from mild erythema and localized induration to massive extremity swelling and ulceration, usually exacerbated by by standing and relieved by elevation of the extremity. It is usually managed by Sub-fascial endoscopic perforator surgery (SEPS)

21. Complications cont Pulmonary Embolism : Pulmonary emboli may originate from thrombi in venous circulation.Fragments of these thrombi are dislodged and float to the right side of the heart which pumps them into the pulmonary artery where it gets impacted in the artery or in one of its branches Clinical presentation depends on the size and number of emboli Maybe asymptomatic or may present with Shortness of breath Tachypnea Pleuritic chest pain Decreased oxygen saturation Sinus tachycardia Hemoptysis Cardiac arrest with pulseless electrical activity PE accounts for 2-3% of all hospital mortalities wholly or in part

22. CLINICAL EXAMINATION Palpate distal pulses and evaluate capillary refill to assess perfusion Elicit for color change, temperature changes Move and palpate all joints to detect acute arthritis or other joint pathology Examine signs suggestive of underlying predisposing factors. Neurologic examination may detect nerve root irritation; motor, sensory and reflex deficits should be noted

23. Signs Homan’s sign : pain in the posterior calf or knee with forced dorsiflexion of the foot. It is not a specific sign. Moses sign : Also called Bancroft’s sign, pain is elicited when the calf muscle is compressed forward against the tibia but not when the calf muscle is compressed from side to side. It is positive in DVT involving Posterior tibial veins. Lowenberg’s sign : pain is elicited rapidly when a blood pressure cuff is placed around the calf and inflated to 80mmHg. Neuhof’s sign : Thickening and deep tenderness elicited while palpating deep calf muscles. Linton’s sign : After applying a tourniquet at the saphenofemoral junction, patient is made to walk, then limb is elevated in supine position, prominent superficial veins will be observed.

24. Differential Diagnoses of DVT Cellulitis Arthritis Muscle injury or tear Neuropathy Lymphedema Ruptured baker’s cyst

25. WELL’S CLINICAL PREDICTION GUIDELINE The Wells CPG quantifies the pretest probability of DVT The model enables physicians to reliably stratify patients into high, moderate and low risk categories. It incorporates risk factors, clinical signs and the presence or absence of alternative diagnoses. Scores can stratified in either 2 or 3 risk groups. In the 3 risk group, patients with 0 or less are classified low risk, 1-2 moderate risk, 3 or greater high risk. In the 2 risk group, patients with <2 are classified DVT unlikely, >2 DVT likely.

26. LIMITATION OF WELLS SCORE It is useful in secondary and tertiary care centers but has not been validated for use in primary care centers. The accuracy of the Wells rule in primary care has been questioned. A validation study showed an unacceptable failure rate, even when the results of the d-dimer assay were applied. This led to the development and validation of a primary care–specific decision rule, that included elements of patient medical history, physical examination, and d-dimer assay, but, unlike the Wells rule, it does not include the estimated probability of an alternative diagnosis. 

27. Investigations Clinical examination alone is able to confirm only 20-30% of cases of DVT May be Blood test or Imaging Imaging may be Non invasive or Invasive

28. Blood tests: D- dimer D-dimer is a specific degradation product of cross-linked fibrin. Because concurrent production and breakdown of clot characterize thrombosis, patients with thromboembolic have Elevated levels of D-Dimer Measuring D-dimer can be done using ELISA, Latex agglutination or blood agglutination test False positive D-dimers may be seen in patients with Recent (within 10 days) surgery or trauma Recent myocardial infarction or stroke, acute infection Disseminated intravascular coagulation Pregnancy or recent delivery Active collagen vascular disease or metastatic cancer It should be noted that D-dimer assays present a low specificity for DVT. The value of this test should be limited to ruling out rather than confirming the diagnosis of DVT.

29. Imaging: Venography It is an X-ray examination that uses injection of contrast material to show how blood flows through veins. It can conclude and exclude the diagnosis of DVT when other objective testings are not conclusive It has the disadvantage of being invasive and expensive and can primarily cause DVT in 3% of patients who undergo the procedure.

30. Nuclear Imaging Studies The radioactive isotope incorporates into the growing thrombus, this test can distinguish a new clot from an old clot. Nuclear medicine studies are done with I-125 labelled fibrinogen. It is more commonly used for research purposes.

31. Magnetic resonance venography Magnetic resonance imaging: It detects leg, pelvis and pulmonary thrombi. It is 97% sensitive and 95% specific for DVT. May be contrast or non contrast. It also distinguishes a mature from an immature clot. MRI is safe in all stages of pregnancy It may not be appropriate for patients with pacemakers or other metallic implants, it can be an effective diagnostic option for some patients.

32. Imaging Plethysmography : It measures the change in lower extremity volume in response to certain stimuli. Ultrasonography : Color flow duplex scanning is the imaging test of choice for patients with suspected DVT. It can also distinguish other causes of leg swelling such as tumor, popliteal cyst, abscess or hematoma.

33. Management General therapeutic measures Specific treatment Anticoagulation Thrombolytic therapy Surgical measures Filters

34. General measures: Bed rest and Elevation of limb Patient should be confined to a bed with the feet elevated 15-20 degrees above the level of the heart. Elevation reduces edema and pain and increases venous return thus reduces further thrombosis. Application of elastic stocking will also help venous return. Thrombi usually take 7-10 days to become adherent to the vein wall, the patient should be kept in bed in this period. Usually the swelling, pain and tenderness would have resolved by this time. Gradual ambulation with elastic support is then allowed but standing and sitting with the legs dependent are forbidden because the accompanying rise in venous pressure aggravates edema and discomfort. These measures are continued for 3-6 months until recanalization and collateralization develop.

35. Anticoagulation Anticoagulation remains the mainstay of medical therapy for deep venous thrombosis because it is not invasive, it treats most patients with no immediate demonstrable sequelae to DVT. It has low risk complications. First line therapy for non high risk venous thromboembolism consists of Direct Oral Anticoagulants (Dabigatran, rivaroxaban, apixaban or edoxaban). Vitamin K antagonists are also recommended over Low molecular weight heparin unless DVT is associated with malignancies in which LMWH is preferred. Barring any contraindication to aspirin, aspirin is recommended to prevent recurrent DVT following anticoagulant cessation

36. HEPARIN USE IN DVT Heparin is a heterogeneous mixture of polysaccharide fragments with varying molecular weights but with similar biological activity. The larger fragments exert their anticoagulant effect by interacting with antithrombin III (ATIII) to inhibit thrombin . ATIII, the body’s primary anticoagulant, inactivates thrombin and inhibits the activity of activated factor X in the coagulation process. The low-molecular-weight fragments exert their anticoagulant effect by inhibiting the activity of activated factor X. The hemorrhagic complications attributed to heparin are thought to arise from the larger higher-molecular-weight fragments. UFH is given via IV route. It is given at an initial bolus of 80U/kg, then initiate a constant maintenance infusion of 18U/kg. Monitor the aPTT or heparin activity level, hematocrit and platelet count every 24hrs LMWH example enoxaparin, dalteparin,tinzaparin are given via SC route. Has a longer half life, doesn’t require frequent monitoring or dose adjustment except in markedly obese and CKD pts. Enoxaparin is given as 1mg/kg12hrly. In pregnant women with DVT, LMWH has clear advantages over UFH including lower incidence of HIT, better bioavailability and reduced monitoring requirements.

37. HEPARIN INDUCED THROMBOCYTOPENIA (HIT) Heparin-induced thrombocytopenia (HIT) is a complication of heparin therapy. There are two types of HIT. Type 1 HIT presents within the first 2 days after exposure to heparin, and the platelet count normalizes with continued heparin therapy. Type 1 HIT is a non-immune disorder that results from the direct effect of heparin on platelet activation. Type 2 HIT is an immune-mediated disorder that typically occurs 4-10 days after exposure to heparin and has life- and limb-threatening thrombotic complications. In general medical practice, the term HIT refers to type 2 HIT. HIT must be suspected when a patient who is receiving heparin has a decrease in the platelet count, particularly if the fall is over 50% of the baseline count, even if the platelet count nadir remains above 150 × 109/L. Clinically, HIT may manifest as skin lesions at heparin injection sites or by acute systemic reactions (eg, chills, fever, dyspnea, chest pain) after administration of an intravenous bolus of heparin. If heparin-induced thrombocytopenia (HIT) is suspected, the first step is to discontinue all heparin products immediately and avoid any further exposure.

38. Oral anticoagulants: Warfarin Blocks the synthesis of at least 4 vitamin k dependent clotting factors (prothrombin, factors VII, IX and X). Oral anticoagulants inhibit the synthesis of protein c and protein s which have an anticoagulant effect and so there is a period of relative hypercoagulability during the first few days of Warfarin therapy. This period should be covered by continuing heparin together with warfarin for the first 3 days. An initial dose of 10mg warfarin is followed by 5mg daily dose D/C Heparin after first 3 days of overlap therapy Basal level of prothrombin time and concentration are estimated prior to beginning of warfarin therapy Warfarin should be given for 3-6 months which is the time needed for recanalization and collateralization. Complications include Bleeding and it is managed by giving 10-20mg vitamin k intravenously. In case of severe bleeding, FFP is given.

39. Challenges with Warfarin: The need to overlap heparin with warfarin, is usually inconvenient, in most px it is started on the same day with heparin/fondaparinux Requires frequent periodic monitoring with INR & dose adjustments So many drug-drug interaction Drug- food interaction Affected by aging & systemic illness

40. Factor Xa and Direct Thrombin Inhibitors Fondaparinux, Rivaroxaban and Apixaban have been approved for the management of DVTs. Pharmacokinetic studies of Fondaparinux have shown that only a single daily SC dose may be required to manage DVTs. In August 2014, the AMPLIFY study (Apixaban for the Initial Management of Pulmonary Embolism and Deep Venous Thrombosis as First Line Therapy) compared use of Apixaban with Enoxaparin and Warfarin. The study revealed that Apixaban therapy resulted in 16% reduction in the risk of composite endpoint that included recurrent symptomatic DVT and associated complications. Data from the study also showed extended anticoagulation (12 months) with apixaban shortened hospital stays, with reduced associated incidence of major hemorrhage. Dabigatran inhibits free and clot bound thrombin snd thrombin induced platelet aggregation.

41. Contraindication to anti-coagulation

42. Thrombolytic therapy Patients with severe DVT including those with PAD and PCD are better managed with thrombolytic therapy. Thrombolysis may be either Pharmacolgical or Endovascular intervention Endovascular intervention may include Catheter directed thrombolysis, mechanical thrombectomy, angioplasty and/or stenting. Fibrinolytic activators dissolve fresh thrombi and produce rapid clearance of the occluded veins and may preserve competence and function of venous valves better than anticoagulant therapy. Eg Streptokinase (250,000IU bolus), Urokinase and tPA(0.5-1mg/hr) Complications: streptokinase may lead to allergic reactions and they may all lead to severe bleeding. Contraindication: Old age, hypertension, PUD, Hx of hemorrhagic diathesis, DIC, CVA.

43. SURGERY Surgical removal of DVT does not have a proven role. Some suggest that venous thrombectomy should only be considered in patients with impending venous gangrene despite optimal anticoagulation and all of the following: catheter-directed thrombolysis not available, iliofemoral DVT, symptoms for less than 7 days, good functional status, life expectancy greater than one year, and availability of appropriate resources and expertise

44. IVC Filters Indicated in case of progressive thrombosis or recurrent pulmonary embolism despite anticoagulant therapy. Also in case of contraindication to anticoagulant therapy. Done under Local anesthesia and radiographic guidance, the filter is placed by the percutaneous or open exposure method through the jugular vein. Complications may include hemorrhage, injury of IVC, perforation of the aorta, and migration.

45. PREVENTION Post operative DVTs are reduced by measures such as; Early ambulation after operations and active leg exercises while in bed. Adequate pre and post operative hydration. Elastic stocking support especially in the elderly Intraoperative and postoperative intermittent pneumatic compression of the lower limbs. Prophylactic anticoagulation : used in high risk cases for development of DVT History of DVT or PE Major surgery, particularly cancer operations Females on contraceptive pills Elderly patients Obesity Method: Low dose heparin 5000iu subcutaneously 2 hours before surgery and then every 12 hours until the patient is ambulant (5-7days) proved very effective in lowering the incidence of DVT by 50%.

46. –Rudolf Virchow “ All pathological formations are either degenerations, transformations or repetitions of typical physiologic structures ”

47. References Kasr-el-ainy textbook of Surgery teachmeanatomy.info Bailey and Loves Short Practice of Surgery Deep Venous Thrombosis by Dr Shashank www.medscape.com Textbook of Internal Medicine, Cairo University.

48. “Thank you.”