Deep Vein Thrombosis

Overview

A deep-vein thrombosis (DVT) is a blood clot that originates in the deep veins of the body, primarily in the legs, but also in the arms, mesenteric, and cerebral veins. Deep-vein thrombosis (DVT) is a common and serious condition. It's a symptom of venous thromboembolism, which is the third leading cause of death from cardiovascular illness after heart attacks and stroke. Recurrent thrombosis and "post-thrombotic syndrome" are a major cause of morbidity in people who do not develop pulmonary emboli.

Deep vein thrombosis (DVT) definition

A blood clot that forms in a vein deep within the body is known as deep vein thrombosis, or DVT. Deep vein clots most commonly develop in the lower leg or thigh. Thrombophlebitis is a condition in which a vein expands.

It's a symptom of venous thromboembolism, which is the third leading cause of death from cardiovascular illness after heart attacks and stroke. Recurrent thrombosis and "post-thrombotic syndrome" are a major cause of morbidity in people who do not develop pulmonary emboli. The most common cause of pulmonary embolism is deep vein thrombosis (DVT). Morbidity can only be decreased by early diagnosis and treatment.

Epidemiology

DVT is a serious and preventable cause of death all over the world. It affects about 0.1 percent of the population each year. The overall yearly incidence of venous thromboembolism (VTE) is 117 per 100,000, adjusted for age and gender (DVT, 48 per 100,000; PE, 69 per 100,000), with males having higher age-adjusted rates than females 

A first VTE affects both men and women equally, with men having a larger risk of recurrent thrombosis. DVT is mostly a disease of the elderly, with an increasing frequency as people become older.

According to a study by Keenan and White, African-American individuals have the highest likelihood of developing VTE for the first time. The risk of Hispanic patients is almost half that of Caucasians. Caucasians have a reduced chance of recurrence than African-Americans and Hispanics.

In children, the prevalence of VTE is modest. Caucasian studies have indicated annual rates of 0.07 to 0.14 per 10,000 children and 5.3 per 10,000 hospital admissions.

This low incidence could be attributed to vessel walls' higher antithrombin potential, greater capacity to create thrombin, and increased capacity of alpha-2-macroglobulin to block thrombin. The neonatal period is when the incidence is highest in children, followed by another increase in adolescence. Because of pregnancy and the use of oral contraceptives, the incidence rate is higher in adolescent girls.

VTE is substantially more common in pregnant women than in nonpregnant women of similar age, and the risk is larger after a cesarian section than after a vaginal delivery. The reported rate of DVT in an African community was 48 DVT per 100,000 births per year, according to a study. The postpartum period appears to be the time when the incidence is highest.

Following general surgery operations, the risk of DVT is estimated to be 15% to 40%. After hip or knee replacement surgery or hip fracture surgery, it practically doubles (40 percent to 60%). Without prophylaxis, fatal PE occurs in 0.2 to 0.9 %of patients having elective general surgery, 0.1 to 2% of those having elective hip replacement, and up to 2.5 percent to 7.5 percent of those having hip fracture surgery. Though most symptomatic VTE events and fatal PE occur in surgical patients, the majority of symptomatic VTE episodes and fatal PE occur in medical patients.

Etiology

Risk Factors

Following are the risk factors and are considered as causes of deep venous thrombosis:

• Reduced blood flow: Immobility (bed rest, general anesthesia, operations, stroke, long flights)
• Increased venous pressure: Reduced flow in the veins due to mechanical compression or functional impairment (neoplasm, pregnancy, stenosis, or congenital anomaly which increases outflow resistance)
• Mechanical injury to the vein: Trauma, surgery, peripherally inserted venous catheters, previous DVT, intravenous drug abuse.
• Increased blood viscosity: Polycythaemia rubra vera, thrombocytosis, dehydration
• Anatomic variations in venous anatomy can contribute to thrombosis.

Increased Risk of Coagulation

• Genetic deficiencies: Anticoagulation proteins C and S, antithrombin III deficiency, factor V Leiden mutation
• Acquired: Cancer, sepsis, myocardial infarction, heart failure, vasculitis, systemic lupus erythematosus and lupus anticoagulant, Inflammatory bowel disease, nephrotic syndrome, burns, oral estrogens, smoking, hypertension, diabetes

Constitutional Factors

Obesity, pregnancy, Increasing age, surgery, and cancer.

Pathophysiology

Thrombus development preferentially begins in the valve pockets of the calf veins and spreads outward. This is particularly true of those that occur after surgery. Though most thrombi develop after surgery, some develop days, weeks, or months later.

A recent notion of enhanced expression of endothelial protein C receptor (EPCR) and thrombomodulin (TM) and lower expression of Von Willebrand factor (vWF) in valve sinus endothelium compared to vein luminal endothelium lends support to the origin of thrombus in valve pockets. The valvular sinus endothelium's anticoagulant (EPCR, TM) characteristics are upregulated, whereas procoagulant (vWF) capabilities are downregulated.

Fibrin and red cells make up the majority of thrombus (red or static thrombus). At autopsy, a venous thrombus must be distinguished from a postmortem clot. Gelatinous postmortem clots with a dark red dependent section (formed by red cells that have settled by gravity and a yellow chicken fat supernatant resembling melted and clotted chicken fat).

The majority of the time, they are not attached to the underlying wall. The venous thrombi, on the other hand, are more solid. Transsection reveals hazy strands of pale gray fibrin. They almost always have a point of attachment to the wall.

When the popliteal vein or thigh veins are implicated, DVT is defined as proximal, and when the calf veins are involved, it is characterized as distal. In terms of clinical significance, proximal vein thrombosis is more common and is linked to major chronic conditions like active malignancy, congestive heart failure, respiratory insufficiency, or age over 75, whereas distal thrombosis is linked to risk factors including recent surgery and immobility.

Proximal DVT is considerably more likely to cause fatal PE. In 17 percent to 50% of patients, post-thrombotic syndrome, a chronic, potentially disabling illness marked by limb edema, discomfort, venous ectasia, and skin induration, is diagnosed one year after DVT.

Forms of acute large venous thrombosis with blockage of venous drainage to the extremity are uncommon VTE presentations. Phlegmasia alba dolens, phlegmasia cerulea dolens, and venous gangrene are among them. The thrombosis in phlegmasia alba dolens affects mainly the primary deep venous channels of the extremity, leaving collateral veins unaffected. The thrombosis in phlegmasia cerulea dolens, on the other hand, extends to the collateral vein, causing severe fluid sequestration and increased edema.

Clinical features of DVT

DVT can't be diagnosed just on a patient's medical history or a physical examination. DVT in the lower extremities can be either symptomatic or asymptomatic. Erythema, pain, warmth, swelling, or tenderness are not always evident in patients with lower extremity DVT. Lower extremity pain, calf tenderness, and lower extremity swelling are common symptoms in patients with proximal DVT.

In DVT, Homans' sign may be visible. Because most of these characteristics lack specificity, clinical examination usually signals the need for additional testing. In both pregnancy and acute major venous thrombosis, the left leg is the most common site for venous thrombosis. This could be caused by the right iliac artery compressing the left iliac vein 

Phlegmasia alba dolens is distinguished by edema, discomfort, and blanching in the absence of cyanosis, whereas phlegmasia cerulea dolens is distinguished by cyanosis that proceeds from distal to proximal areas with bleb/bulla development.

Clinical prediction rules

The use of a clinical model that standardizes the clinical assessment (combining risk factors, signs, and symptoms) and then stratifies patients suspected of DVT is a widely accepted evidence-based approach to diagnosis of VTE.

Despite the fact that this methodology has been utilized in both primary and secondary care settings, there is little question that it does not ensure accurate risk estimation in primary care patients with suspected DVT.

The model established by Wells and colleagues is the most widely recommended. An early model was established based on clinical presentation and risk factors to classify individuals into low-, moderate-, and high-probability categories.

DVT is an 85 percent risk in the high-probability group, a 33 percent risk in the moderate-probability group, and a 5% risk in the low-probability group. However, in a later study, Wells and colleagues simplified the diagnosis process even further by categorizing patients into two risk groups: "DVT improbable" if the clinical score is less than one, and "DVT likely" if the clinical score is greater than one.

Pretest probability assessment (Wells score)

Notes: DVT unlikely: ≤1; DVT likely: ≥2

Diagnosis

As per the NICE guidelines following investigations are done:

• D-dimers (very sensitive but not very specific) 
• Coagulation profile
• Proximal leg vein ultrasound, which when positive, indicates that the patient should be treated as having a DVT

Deciding how to investigate is determined by the risk of DVT. The first step is to assess the clinical probability of a DVT using the Wells scoring system.

• For patients with a score of 0 to 1, the clinical probability is low, but for those with 2 or above, the clinical probability is high.
• If a patient scores 2 or higher, either a proximal leg vein ultrasound scan or a D-dimer test should be performed within 4 hours if the result is negative. A D-dimer test should be performed if imaging is not possible within 4 hours, and an interim 24-hour dosage of a parenteral anticoagulant should be administered. Within 24 hours of receiving a request, a proximal leg vein ultrasound scan should be performed.
• All patients who have a positive D-dimer test but a negative proximal leg vein ultrasound scan should have the proximal leg vein ultrasound scan redone 6 to 8 days later.
• If the patient's DVT Wells score is less than 2, but the D-dimer test is positive, the patient should have a proximal leg vein ultrasound scan within four hours, or if that is not possible, a 24-hour dosage of a parenteral anticoagulant. After that, a proximal leg vein ultrasound scan should be performed within 24 hours of the request.
• Treat all patients diagnosed with DVT as if a proximal leg vein ultrasound scan is positive.

D-dimer assay

D-dimer is a cross-linked fibrin degradation product that forms when thrombin-generated fibrin clots are destroyed by plasmin. It indicates that blood coagulation and fibrinolysis have been activated all over the body. It is the most widely used biomarker for determining the severity of suspected VTE. In more than 25% of patients presenting with symptoms indicative of VTE, a combination of clinical risk stratification and a D-dimer test can rule out VTE without the need for further testing.

Even in individuals with a clinical suspicion of recurring DVT, this combination (clinical examination and D-dimer) has been shown to be effective in excluding DVT, particularly in patients in the lower clinical pretest likelihood group.

Levels of D-dimer can be popularly measured using three types of assay:

• Enzyme linked immunosorbent assay (ELISA).
• Latex agglutination assay.
• Red blood cell whole blood agglutination assay 

Venous ultrasonography

In patients who have been classified as having a high risk of DVT, venous ultrasonography is the examination of choice. It is noninvasive, safe, readily available, and reasonably priced. Compression ultrasound (B-mode imaging only), duplex ultrasound (B-mode imaging with Doppler waveform analysis), and color Doppler imaging alone are the three methods of venous ultrasonography. Blood flow in normal veins is spontaneous, phasic with respiration, and can be enhanced by physical pressure in duplex ultrasonography.

The pulsed Doppler signal is utilized to create images in color flow sonography. The proximal deep veins, specifically the common femoral, femoral, and popliteal veins, are usually investigated with compression ultrasound, whereas the calf and iliac veins are usually investigated with a mix of duplex ultrasound and color duplex.

Failure to compress the vein lumen under mild probe pressure is the most important ultrasonographic criterion for identifying venous thrombosis. Other ultrasonographic criteria for venous thrombosis diagnosis include the absence of spectral or color Doppler signals from the vein lumen, loss of phasic pattern in which flow is defined as continuous, response to valsava or augmentation (Duplex ultrasound), and complete absence of phasic pattern in which flow is defined as continuous.

Other benefits of venous ultrasound include its ability to diagnose other pathologies (Baker's cysts, superficial or intramuscular hematomas, lymphadenopathy, femoral aneurysm, superficial thrombophlebitis, and abscess), as well as the fact that there is no risk of irradiation, while its main disadvantage is its limited ability to diagnose distal thrombus.

Contrast venography

Venography is the final diagnostic test for DVT, however it is rarely used in acute DVT episodes since noninvasive procedures (D-dimer and venous ultrasound) are more appropriate and accurate. It entails cannulating a pedal vein and injecting a contrast material into it.

A consistent intraluminal filling defect visible in two or more images is the most reliable cardinal indication for diagnosing phlebothrombosis using venogram. An abrupt cutoff of a deep vein, a challenging symptom to interpret in patients with past DVT, is another valid criterion. It is both sensitive and specific, especially when determining the position, extent, and attachment of a clot.

Management

The goal of DVT treatment is to avoid pulmonary embolism, reduce morbidity, and lower the chance of developing post-thrombotic syndrome.

Anticoagulation is the cornerstone of treatment. Only those with proximal DVT (not distal) and pulmonary emboli should be treated, according to NICE guidelines. The hazards of anticoagulation must be evaluated against the benefits in each patient.

Anticoagulation

1. Low-molecular-weight heparin or fondaparinux for five days or until INR is greater than 2 for 24 hours
2. Vitamin K analogs for three months
3. In patients with cancer, consider anticoagulation for six months with low-molecular-weight heparin
4. In patients with unprovoked DVT consider vitamin K analogs beyond three months
5. Rivaroxaban is an oral factor Xa inhibitor which has recently been approved by the FDA and NICE and is attractive because there is no need for regular INR monitoring

Thrombolysis: The indications for the use of thrombolytics include:

1. Symptomatic iliofemoral DVT
2. Symptoms of less than 14 days duration   
3. Good functional status
4. A life expectancy of 1 year or more 
5. Low risk of bleeding

Because thrombolytic therapy can cause an intracranial hemorrhage, it's critical to pick the right patients. Endovascular procedures such as catheter-directed extraction, stenting, and mechanical thrombectomy have recently been tried with mixed results.

• Compression hosiery: Below-knee graduated compression stockings with an ankle pressure greater than 23 mm Hg for two years if there are no contraindications
• Inferior vena cava filters: If anticoagulation is contraindicated or if emboli are occurring despite adequate anticoagulation

Vena cava filters

Vena cava filters are only recommended in a few cases. Absolute anticoagulation contraindications, life-threatening bleeding while on anticoagulation, and inadequate anticoagulation are among them. Central nervous system (CNS) hemorrhage, overt gastrointestinal bleeding, retroperitoneal hemorrhage, extensive hemoptysis, cerebral metastases, massive cerebrovascular accident, CNS trauma, and substantial thrombocytopenia (50,000/L) are all absolute contraindications to anticoagulation. They can be retrievable or nonretrievable, with retrievability being the case for the majority of newly produced ones.

Short-term studies on the effectiveness of filters found a considerable reduction in the number of people suffering from PE, but no meaningful influence on PE in the long run. In the long run, there was a greater rate of recurring DVT. Hematoma over the insertion site, DVT at the insertion site, filter migration, filter erosion through the inferior vena cava wall, filter embolization, and inferior vena cava thrombosis/obstruction are all complications with inferior vena cava filters.

Prognosis

• Many DVTs will go away without causing any problems.
• Two years after a DVT, 43% of people develop post-thrombotic syndrome (30 % mild, 10 percent moderate, and severe in 3 %)
• DVT has a high risk of recurrence (up to 25 %)
• Within one month after diagnosis, roughly 6% of DVT cases and 12% of pulmonary embolism cases die.
• The presence of pulmonary embolism, advanced age, malignancy, and underlying cardiovascular disease are all substantially linked to early mortality after venous thromboembolism.

Conclusion 

DVT is a potentially severe clinical condition that can result in morbidity and mortality that could have been avoided. A more reliable technique of identifying DVT is to use a diagnostic route that includes pretest probability, D-dimer testing, and venous ultrasonography.

Many hospitalized patients have DVTs, and a pulmonary embolus is one of the most dangerous consequences. DVTs can occur in a variety of contexts and in practically every medical profession; failure to recognize DVT can end in a catastrophic pulmonary embolus. DVTs also necessitate a longer stay in the hospital and a pharmacological treatment regimen that can last anywhere from 3 to 9 months, all of which raises healthcare costs. As a result, it is best diagnosed and managed by a multidisciplinary team.

The emphasis is on DVT prevention. Nurses and pharmacists, in addition to physicians, are critical in educating patients about DVT prevention. Nurses are the first personnel to interact with patients who are admitted to the hospital, and it is at this point that DVT prevention begins.

Nurses must educate patients on the need of ambulation, using compression stockings, and taking anticoagulant drugs as indicated. Nurses have an important role in alerting physicians of the necessity for DVT prevention in both the operating room and after surgery. All healthcare personnel should follow the DVT prophylaxis and treatment guidelines that each institution has in place.

The pharmacist should be aware with the current anticoagulants and their indications if a DVT has formed. In addition, the pharmacist must educate patients on the need of treatment adherence as well as the requirement for regular testing to ensure that the INR is therapeutic.