Deep Vein Thrombosis Mechanism Of Blood Coagulation Biology Essay

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Abstract

Deep vein thrombosis is a common disease which leads to formation of a blood clot in a deep vein of the lower limb. DVT might have serious complications and one of them - pulmonary embolism is one of the most common causes of sudden death.

Both genetic and environmental factors play role in development of the disease. Many gene defects have been implicated and associated with DVT, including fibrinogen gamma gene and prothrombin 20120 gene.

Environmental factors triggering disease include prolonged bed rest and the contraceptive pill. Association between long haul flights and development of DVT is an interesting finding that has made an impact on health and safety regulations during air travelling.

Introduction

Deep vein thrombosis is the formation of thrombus in a deep vein of the lower limb.

Deep vein thrombosis often has serious consequences, fast diagnosis and treatment of this disease is of vital importance. It is insidious and difficult to recognize clinically. The most severe complication is in the form of pulmonary embolism, which poses an immediate threat to life. DVT and pulmonary emboli complicate the course of hospitalized patients and also can affect healthy persons, contributing to substantial death rate.

DVT most often occurs in the veins of the legs - some 60% of cases and 30% - in the veins of the pelvis (Robins and Cotran, 2006)

DVT and its consequences constitute one of the major cause of death worldwide. In Western Europe the incidence of deep vein thrombosis is 160-180 cases per 100 000 per year. It is estimated that DVT affects to 1% of the population of the United States of America. In the U.S. there has been a yearly 630 000 incidents of pulmonary embolism associated with the disease, which killed 200 000 people (Mayo Clinic data)

These data clearly suggest the necessity of implementation of early diagnosis and effective treatment of DVT.

Causes

Deep vein thrombosis is caused by stasis of blood in the deep veins which leads to the activation of blood coagulation and clot formation at a site where normally it should not appear.

Increased risk of deep venous thrombosis is associated with:

Advanced age

Bed rest and immobilization which decrease the milking action o musle of lower leg and slow venous return

Physical over activity ( Journal of Vascular Surgery 2001)

Trauma, surgery, burns result in reduced physical activity, injury to blood vessels and release of procoagulant substances

Hypercoagulable states

Acute DVT - left leg

http://www.stoptheclot.org/learn_more/learn_thrombosis.htm

Hypercoagubility and genetic risks of venous thrombosis

Hypercoaguable states are associated with increased risk of venous thrombosis. They might be inherited, acquired or both. Acquired states include medication (estrogen, birth control pills), post-op period, pregnancy, cancer.

Inherited states might be caused by protein deficiencies (protein C, protein S, factor V Leiden, antithrombin III)

Protein C - is one of the proteins that inhibit the process of blood clotting . It belongs to vitamin K-dependant protein family. Biochemically its classified as serine protease which degrades the active factor V (with the participation of heparin ) and factor VIII (with the help of protein S). Leiden mutation leads to the formation of aberrant factor V protein which is resistant to protein C action.

The plasma protein C occurs predominantly in an inactive form. Activation of protein C occurs on the cell surface of endothelial vessels by the interaction of thrombin and thrombomodulin .

Congenital protein C deficiency causes a tendency to vascular thrombosis.

Total absence of protein C or mutations resulting in the generation of pathological forms of the protein can lead to sudden and severe syndrome of intravascular coagulation and purpura fulminans in neonates.

The acquired deficiency of protein C can be found in the case of vitamin K deficiency, disseminated intravascular coagulation, sepsis, liver damage during treatment with warfarin and L-asparaginase (Gladson et al 1987)

Protein S - a glycoprotein produced with the participation of vitamin K by the hepatocytes (the main source), cells of endothelial, megakaryocytes, Leydig cell nuclei.

Its found in plasma, comes in two forms: free and bound to protein component of complement C4b

The name comes from the first letter of the city in which the discovery - Seattle.

Best known function of protein S is its participation in the process of blood clotting. It has anticoagulatory properties and plays important role in antithrombosis. As a cofactor of activated protein C it inactivates factors Va and VIIIa. Mutations in PS gene(PROS1) has been shown to cause deficiency of Protein S which subsequently lead to increased risk of thrombosis.

Factor V Leiden - mutated human clotting factor V. Factor V mutation involves replacing of arginine by glutamine at position 506 of the heavy chain. The mutation is an autosomal dominant. It is the most common cause of inherited thrombophilia affecting up to 25% of people with deep vein thrombosis. The mutated factor V at the time of activation by thrombin becomes insensitive to proteolytic activity of protein C this way impairing haemostasis and causing increased risk of venous thromboembolic events in the body. Resistance to activated protein C is caused by mutation of factor V Leiden in 95% of cases, where resistance was detected, should be confirmed by genetic mutation.

In the U.S. factor V Leiden is the most common congenital disorder of the coagulation system. This mutation is more common in people of European origin occurs in approx. 5% of Caucasians. A patient with factor V Leiden mutation may be heterozygous (have one mutated and one normal copy of the gene) or homozygous (have two mutated copies of the gene). In heterozygotes the risk of VTE is 5-10% higher than normal, in homozygotes the risk is significantly higher by about 80% (J. Kujovich 2010)

Prothrombin 20210 - is a variant of prothrombin which results from a point mutation in the 3' utranslated region of prothrombin gene. PT 20210 is associated with an increased risk of thrombosis.

Mutations in the genes of factor V Leiden and prothrombin 20210 are independent.

Patients with one copy of the gene is heterozygous PT 20210, with two copies of the mutated gene - homozygous. Both heterozygous and homozygous individuals with PT 20210 mutation have mildly or moderately increased production of thrombin. This can slightly but not significantly increase the risk of thrombotic events. (Gordon D.O.Love 2006)

Fibrinogen gamma gene - fibrinogen gamma gene (FGG) 10034C>T mutation have been found to increase the risk for DVT. Patients with at least one episode of deep vein thrombosis had twice as many TT variants of FGG than control patients without history of venous or arterial thromboses. Subjects with one T allele were 1.35 more prone to develop DVT than homozygous individuals carrying normal alleles. Although thrombophilic mechanism of fibrinogen gamma gene (FGG) 10034C is still unknown a strong association have been found between the gene and incidence of DVT.

( G Grunbacher et al 2007)

Air travel and DVT

Air travel has been associated with increased risk of DVT and subsequent pulmonary emboli. Factors such as dehydration, immobilization, decreased oxygen tension have all been suggested to be contributory factors.

The risk of developing DVT from a long haul flight has been approximated to be 0.01-0.04%

There is increased risk of pulmonary emboli associated with long distance air travel

The incidence in high risk groups has been shown to be 4-6%

Measures to minimize risk of DVT include leg exercises, increased water intake and refraining from alcohol during the flight

(Longmore, Wilkinson 2010)

Collectively there are three major factors contributing to clot formation in DVT

(Virchov's triad)

rate of blood flow

state and quality of blood vessels

viscosity of blood

Clinical picture

Deep vein thromboses are asymptomatic in approximately 50% of patients and are recognized only after embolization (Kumar and Clark, 2004)

Major feature is pain in the lower limb often with swelling and redness (erythema). The affected leg might be warmer and there may be pitting oedema. Also increase in resistance or pain during dorsiflexion of the foot (Hofman's sign) might be noted.

Some patients describe DVT as annoying "pulling sensation" in the calf muscles.

Other signs include: increased tissue tourgor, distension of superficial veins, prominent venous collaterals

Pulmonary embolism might occur with any DVT but its more frequent from iliofemoral thrombosis limited to the veins below knee. In 20-30% of patients thrombi can spread proximally without any clinical evidence so careful observation of the leg is required. (Robbins and Cotran, 2006)

Ways to prevent

Avoid prolonged bed rest during an illness, frequent and regular exercises facilitate proper blood circulation in the veins of the lower extremities (flexing the knees, alternate tensing and relaxing of muscles of the calf)

The use of special compression stockings or knee before surgery.

Prior to the surgery use of special preparations, low molecular weight heparin, administered in the form of subcutaneous injections which works by preventing formation of blood clots in veins

After surgery it is advisable to perform exercises, mobilization of the patient as soon as possible - in the case of most surgical procedures is possible in the first postoperative day

During the long journey by plane, bus or car exercises of the lower limbs or possibly even a short walk is encouraged (at least every 2 hours)

Smoking cessation

Investigations

Since the medical history and symptoms are often vague there is necessity for the use of extensive diagnostic tests.

The most commonly used are:

test for concentration of D dimer in plasma

D dimer is formed by degradation of stable fibrin. It contains two crosslinked D fragments of the fibrinogen protein hence the name. Determination of high concentrations of D dimers is of particular importance in the diagnosis of deep vein thrombosis and pulmonary embolism. Positive results can indicate thrombosis but does not rule out other potential causes. (Van Der Graaf et al 2000)

Thrombin time (TT)

Thrombin time - clotting time of plasma citrate followed by addition of standard solution of thrombin which converts soluble fibrinogen into insoluble fibrin . Normal thrombin time: 14-20 s. Its length depends mainly on the concentration of fibrinogen and the presence of heparin. Thrombin time measurement is useful in the control of anticoagulant therapy.

Reduced thrombin time indicates a high level of fibrinogen. Prolonged period of time indicates reduced concentration of fibrinogen or its changed structure.

activated partial thromboplastin time

APTT messures efficiency of intrinsic coagulation pathway. This test is most useful in the diagnosis of bleeding disorder as well as in monitoring of the heparin treatment.

Prothrombin time

It is a measure of the extrinsic pathway of coagulation which is triggered by tissue injury. It depends on the content of the plasma prothrombin, factors V, VII, X and fibrinogen. But does not depend on the other clotting factors and the number of platelets.

Normal values ​​of prothrombin time ranged from 12 to 16 seconds. Reduced prothrombin time may indicate thrombosis and hypercoagulable states.

Other investigations:

ultrasonography of lower limb veins (Doppler)

phlebography contrast

magnetic resonance imaging

Principles of DVT treatment

In the initial phase of the disease it is necessary to remain in bed since walking can cause dislodgement of the thrombus and lead to pulmonary embolism. Patients lower limb should be kept slightly lifted up-located on the rolled-up blanket or pillow. During the duration of symptoms and for some time after their resolution, sick limb should be bandaged and compression stockings put on. Regular exercises involving the bending of the feet and knees and alternate tensing and relaxation of muscles of the calf are recommended.

There are three major methods of treatment:

Stopping the progress of venous thrombosis using anticoagulants.

In appropriate cases medications counteracting thrombosis is recommended after surgery and for patients that are prone to develop DVT. These are:

Low molecular weight heparin

LMWH are derived from heparin obtained from pig intestinal mucosa. Low-molecular-weight heparin target anti-factor Xa activity rather than anti-thrombin. They are replacing unfractioned heparins as they are more effective, there is less risk of bleeding and don't require frequent monitoring.

Heparin

The anticoagulant effect of heparin occurs primarily through activation of antithrombin. Mutual interaction between these two compounds is essentially due to pentasaccharide sequences built in chains. Binding of the heparin to antithrombin changes configuration of active center of antithrombin. Consequently it becomes capable of rapid response to activated factor X, II or thrombin. Binding of antithrombin to factor Xa leads to its activation by heparins.

It was found that there are critical chain lengths determining the effect of heparin. Particles of less than critical length (5-17 monosaccharide units of molecular weight <5.4 kDa) catalyze the inactivation of factor Xa but don't catalyze the inactivation of Factor IIa.

Treatment is initiated by intravenous load of 5000U of heparin which is then continued as infusion for a period of 5-7 days. Simultaneously oral anticoagulant-coumarin is started. It is important that simultaneous treatment with these two drugs is continued until the appropriate levels of INR are achieved. In case of primary DVT treatment is continued for a period of 3-6 months. In patients with recurrent thrombosis or at high risk of DVT treatment should last much longer. (Hiatt 2001)

Dissolution of the clot using fibrinolytic drugs

The principle of treatment is aimed at dissolution of thrombus :

- Streptokinase

- Plasminogen activators (urokinase, tissue plasminogen activator)

Unfortunately the streptokinase treatment is hazardous and there is significant risk of bleeding complications. Treatment of this type is used in patients with massive, extensive deep vein thrombosis, such as in patients experiencing cyanotic lower limb venous thrombosis (phlegmasia coerulea dolens)

(Kalleen Barham, M.D., and Tina Shah, M.D, 2007)

Surgical removal of deep vein thromboses

The indications for endarterectomy surgery (deep vein thrombosis thrombectomy):

- Painful swelling of the extremities with cyanosis of the affected limb

- Acute deep vein thrombosis in patients with contraindications to thrombolytic agents or heparin.

- Venous thrombosis in patients in whom the thrombolytic therapy or anticoagulant led to excessive bleeding or allergic shock.

The effectiveness of treatment of venous thrombosis

The effectiveness of anticoagulation therapy is not yet satisfactory. A full recovery is achieved in approximately 20% of patients. In the remaining thrombus undergoes fibrosis and there might be complication called thrombotic syndrome. 

Well's criteria for deep vein thrombosis

Active cancer?

 Yes +1

Bedridden recently >3 days or major surgery within four weeks?

 Yes +1

Calf swelling >3cm compared to the other leg?

 Yes +1

Collateral (nonvaricose) superficial veins present?

 Yes +1

Entire leg swollen?

 Yes +1

Localized tenderness along the deep venous system?

 Yes +1

Pitting edema, greater in the symptomatic leg?

 Yes +1

Paralysis, paresis, or recent plaster immobilization of the lower extremity

 Yes +1

Previously documented DVT?

 Yes +1

Alternative diagnosis to DVT as likely or more likely?

 Yes -2

http://www.mdcalc.com/wells-criteria-for-dvt

Well's score:

>3 points: high probability- treatment required

1-2 points intermediate probability- treatment required

<0 low probability- D-dimer test is recommended

(Longmore, Wilkinson 2009)

Mechanism of blood coagulation

Blood coagulation is a process of clot formation and important part of hemostasis. It's a cascade of reaction in which fibrin strands form a mesh/scaffolding that allows binding of blood components to form a blood clot.

There are two major pathways:

intrinsic - activated when blood comes into contact with damaged vessel and is exposed to collagen

extrinsic - activated when blood is exposed to products of damaged tissue (tissue factor)

Under physiological conditions, blood clotting is triggered by disruption of vascular structures and is designed to prevent extravasation and blood loss.. Although the primary clot temporarily stops the bleeding, formation of the stable clot strengthened by fibrin strands efficiently stops the bleeding .

Both pathways lead to formation of activated FactorXa and further steps are identical.

Active form of Factor X with cooperation of non-enzymatic cofactor - factor Va and phospholipids forms prothrombinase complex, which transforms prothrombin to thrombin. Thrombin in turn converts fibrinogen into fibrin (insoluble protein) which creates a network of fibers forming the stable clot.

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