Question

Describe pathophysiology of deep vein thrombosis with an in depth discussion of underlying immunological mechanisms. How do these alter normal homeostatic processes? (550 words)

Answer 1

What is Deep Vein Thrombosis (DVT)?
Deep vein thrombosis, commonly referred to as “DVT,” occurs when a blood clot or thrombus, develops in the large veins
of the legs or pelvic area. Some DVTs may cause no pain, whereas others can be quite painful. With prompt diagnosis and treatment, the majority of DVT’s are not life threatening. How- ever, a blood clot that forms in the invisible “deep veins” can be life threatening. A clot that forms in the large, deep veins is more likely to break free and travel through the vein. It is then called an embolus. When an embolus travels from the legs or pelvic areas and lodges in a lung artery, the condition is known as a “pulmonary embolism,” or PE, a potentially fatal condition.

DVT is generally caused by a combination of two or three underlying conditions:
• Slow or sluggish blood flow through a deep vein
• Tendency for a person’s blood to clot quickly
• Irritation, inflammation or injury to the inner lining of the vein
There are a variety of settings in which this abnormal clotting process can occur. These include individuals on bed rest (such as during or after a surgical procedure or medical illness, such as heart attack or stroke) or those who are confined and unable to walk for prolonged periods of time (such as during pro- longed air or car travel). It can occur in certain families where there is a history of parents or siblings who have suffered from prior blood clots. It can also occur in individuals with active cancer or those undergoing cancer treatment which may pre- dispose the blood to clotting.Having a recent major surgical procedure, especially hip and knee orthopedic surgeries or one that requires pro- longed bed rest, predispose the blood to clotting. Irritation or inflammation occurs when a leg vein is injured by a major accident or medical procedure.
Also, there are specific medical conditions that may increase your risk of developing a DVT via these three mechanisms, such as congestive heart failure, severe obesity, chronic respiratory failure, a history of smoking, varicose veins, pregnancy and estrogen treatment. If you are concerned that you may be at risk, please consult with your health care provider.

Deep venous thrombosis usually arises in the lower extremities. Most DVTs form in the calf veins, particularly in the soleus sinusoids and cusps of the valves.

• Venous valves are avascular, which, in conjunction with reduced flow of oxygenated blood in veins, predisposes the endothelium to be hypoxemic. The endothelium around valves responds by expressing adhesion molecules that attract leukocytes. These cells transfer tissue factor to the endothelium, which can complex with activated factor VII to begin the coagulation cascade via the extrinsic pathway. The main component of these venous thrombi is fibrin (as product of coagulation cascade) and red blood cells, which get trapped in the clot. Platelets also contribute, but to a lesser extent.
• The skeletal muscle pump helps prevent DVT by moving blood past the valves (i.e. reducing venous stasis), which washes away activated clotting factors that can otherwise propagate the initial thrombus.
• If a clot forms and does not resolve (see below), it will extend proximally into the popliteal and femoral veins (“proximal veins”). 25% of calf DVTs will extend proximally within 7 days. While calf DVTs are usually asymptomatic and do not give rise to significant PEs, proximal DVTs are more likely symptomatic and can embolize to form dangerous PEs.

Antibodies against phospholipids
Antibodies against phospholipids, such as the lupus anticoagulant or antibodies directed against cardiolipin or ?2 glycoprotein I, interact with phospholipids or plasma proteins bound to an anionic surface. The prevalence of antibodies against phospholipids in unselected patients with deep vein thrombosis is about 5%.Whereas the lupus anticoagulant confers a tenfold increased risk for  first thrombosis and is a risk factor for recurrence the association between anticardiolipins and deep vein thrombosis is weak. Only high titres of the G isotype are thrombogenic.The relevance of raised amounts of antibodies directed against ?2 glycoprotein I is uncertain.
Thrombophilia
Several distinct abnormalities in the coagulation system are associated with increased risk for deep vein thrombosis (panel 2). These defects are generally inherited and can be detected in about 50% of patients with first spontaneous thrombosis. Many patients have more than one risk factor, and combined defects further enhance the risk. Risk for deep vein thrombosis can increase when patients with thrombophilia are exposed to temporal risk conditions such as surgery or trauma. Aspects on thrombophilia and women’s health issues, such as pregnancy or oral contraception, are addressed later in this Seminar.
Factor V Leiden
Factor V Leiden results from a point mutation in the factor V gene, which renders the protein resistant to degradation by activated protein C.The prevalence of heterozygous factor V Leiden in white populations is 5–8%.Factor V Leiden is reported in 12–30% of patients with spontaneous deep vein thrombosis,and it confers a sevenfold risk for thrombosis in heterozygotes and an 80-fold risk in homozygotes.Factor V Leiden is not a risk factor for recurrent deep vein thrombosis
Factor II
A transition at nucleotide 20210 in the 3? untranslated region of the prothrombin gene increases risk for deep vein thrombosis by unknown mechanisms. Carriers of the mutation have higher prothrombin concentrations than do non-carriers.In white populations, prevalence of the nucleotide transition is 0·7–4·0%.37 The mutation is reported in 7–18% of patients with spontaneous deep vein thrombosis, and it confers a 2·8-fold risk for the disorder in heterozygotes.Heterozygous carriers have a moderately enhanced risk for recurrent deep vein thrombosis.
Natural inhibitor deficiencies
Antithrombin is a potent inhibitor of several coagulation proteases. The frequency of antithrombin deficiency is rare in the general population (1 per 250–500 individuals) and is less than 1% in unselected patients with venous thromboembolism. Antithrombin deficiency confers a more than eightfold risk for deep vein thrombosis in an individual’s lifetime and enhances risk for thrombosis during temporary risk conditions (such as surgery)
Protein C is a vitamin K-dependent glycoprotein that circulates as a proenzyme and, on activation by thrombomodulin, inhibits factors V and VIII. Protein C deficiency arises in 1 per 200–500 people in the general population and in 3·2% of unselected patients with venous thrombolembolism.Heterozygous protein C deficiency confers a sevenfold increased risk for deep vein thrombosis.
Protein S is a vitamin K-dependent glycoprotein and a cofactor for protein C. The estimated prevalence of familial protein S deficiency is between 0·03% and 0·13% in the general population.This deficiency was reported in 7·3% of unselected patients with deep vein thrombosis, and it confers a more than eightfold lifetime risk for thrombosis.