Delivering Integrated Care and Cost Management
The IHTC works collaboratively with payors to optimize care. We ensure that the patients and families we serve have access to care and therapies, thereby helping to contain costs and reduce both bleeding events and utilization of resources.
The IHTC Pharmacy’s ability to purchase clotting factor through the Public Health Service 340B discount program and our overall pricing structure benefit payors and patients by dispensing clotting factor at significantly reduced prices.
- What Is Thrombosis?
- What Is Thrombophilia?
- Incidence of Venous Thrombosis
- Causes of Thrombosis
Thrombosis is defined as the development of a blood clot in the venous or arterial systems. The symptoms that occur with a thrombosis relate to the part of the vascular system in which they occur, the extent of the clot, and whether the clot breaks off and travels to another part of the body (e.g., the lungs- pulmonary embolus, the brain- embolic stroke). Venous thromboembolic events predominantly occur in the extremities, but they can also affect the venous system of the internal organs such as portal, splenic, or mesenteric vein thromboses. The clinical spectrum of venous thromboembolism (VTE) ranges from deep vein thrombosis (DVT) to pulmonary embolism (PE). Arterial thrombotic events can also affect a variety of organs including the brain, heart, or intestine and are commonly referred to as stroke, myocardial infarction or abdominal angina, respectively.
Thrombophilia is a term used to describe a group of conditions in which there is an increased tendency, often repeated and over an extended period of time, for excessive clotting. Inherited or acquired abnormalities of coagulation can predispose an individual to the development of thrombosis. These prothrombotic conditions are commonly known as thrombophilia. For more detailed information on thrombophilia, click here. According to the US Centers for Disease Control and Prevention (CDC),1 between 5% and 8% of the US population has a thrombophilic condition. Inherited thrombophilias such as deficiencies in antithrombin, protein C or protein S lead to a lifelong increased risk of thrombosis. Identifying an underlying thrombophilic condition clearly has important implications for an individual’s life and medical care.
The risk of VTE is higher in individuals who have multiple thrombotic risk factors— for example, a person with inherited thrombophilia Factor V Leiden [FVL], protein S deficiency, or antithrombin deficiency) who also has other risk factors such as pregnancy, oral contraceptive use, or elevated levels of homocysteine or factor VIII is at increased risk for development of thrombosis than an individual with an isolated or single risk factor.
The precise number of individuals affected by venous thrombosis is unknown. According to the CDC, 200,000 to 400,000 people per year experience DVT.1 Of those who experience a DVT, nearly one third develop postthrombotic syndrome, a chronic disabling condition characterized by swelling, pain, discoloration, and scaling of the affected limb. For some individuals DVT becomes a chronic illness; ~30% of people who experience a DVT are at risk for a subsequent episode. It is important to note that many episodes of DVT are preventable and treatable if diagnosed accurately and early.
An estimated 100,000 to 200,000 people per year experience a PE, and in nearly one third (30,000–60,000), the PE is fatal.1 Some studies suggest that the actual numbers of affected individuals may be much higher, as fewer than 50% of cases are symptomatic.2 Estimates of the incidence and prevalence of PE are less reliable than those for DVT as many patients with PE go unrecognized.
Incidence of Venous Thrombosis in Pediatric Populations
Although VTE is more common in adults, it affects children as well. The annual incidence in pediatric populations is 0.07 to 0.14 per 10,000 children, or 5.3 per 10,000 pediatric hospital admissions, and 24 per 10,000 neonatal intensive care unit admissions. Newborns and infants younger than 1 year are at greatest risk for childhood VTE. A second peak occurs in adolescence. Children in neonatal and pediatric intensive care units and those with oncologic disorders are particularly at high risk. Teenage females have twice the rate of VTE as compared to teenage males; this observed difference is related to the use of oral contraceptives and pregnancy. Despite the presence of inherited or acquired VTE risk factors, children are relatively protected compared to adults due to their generally healthy vasculature. Idiopathic venous thrombotic disease occurs in less than 5% of children compared to approximately 40% of adults. Furthermore, the majority of the thrombotic events in children are “triggered,” meaning that children may develop several “transient” risk factors associated with thrombosis. Central venous catheters are an important risk factor for development of a thrombotic event in children, yet account for only a small percent of venous thrombi among adults. As in adults, children with malignancy, trauma/surgery, and systemic lupus erythematosus (SLE) are at increased risk of developing VTE. The most important inherited conditions contributing to development of thromboembolic events in children include deficiencies of natural anticoagulants such as proteins C and S, and antithrombin. When considered individually, other inherited thrombophilias, such as the factor V Leiden mutation (also called activated protein C [APC] resistance) or the prothrombin 20210 mutation are less important risk factors in children.
Venous thrombosis is related to three pathologic factors commonly known as “Virchow’s triad”. The components of Virchow’s triad include the following:
- vessel damage
- blood hypercoagulability
- blood stasis
Maintaining normal blood flow involves a delicate balance between the three main clotting processes; procoagulant, anticoagulant, and fibrinolytic systems. Over the past 30 years, our understanding of the mechanisms that lead to VTE and its resolution has significantly improved.
Procoagulant clotting proteins are critical in initiation and propagation of normal clot formation. The naturally occurring anticoagulant proteins are required to regulate clotting once it is initiated. This clotting process confines the clot to the area of injury through down-regulation of the procoagulant system. Once a stable clot has formed and bleeding has been controlled, the fibrinolytic system removes the clot and restores normal vascular architecture.
In thromboembolic diseases, the causes of thrombosis may be related to increased levels of procoagulants, decreased levels of natural anticoagulants, or defects in the fibrinolytic system. In addition, vessel abnormalities contribute to development of clots.
Inherited causes of thrombosis are related to a genetically determined tendency for VTE that characteristically occurs at a young age (e.g., occurring before 40 or 45 years), with or without an apparent cause, and with a tendency to recur.
In 1964, deficiency of antithrombin III, a naturally occurring anticoagulant, was discovered as a cause of familial thrombophilia. For many years, antithrombin was the only known protein regulating clot formation. In the 1980s the protein C and protein S pathways were described and individuals with deficiencies of these proteins identified. Deficiencies of natural anticoagulants such as antithrombin, protein C, and protein S account for less than 15% of selected cases of juvenile and/or recurrent thrombosis, and less than 10% of unselected cases.
In 1993, it was observed that plasma samples of some members of a kindred with inherited thrombophilia without a deficiency of antithrombin, protein C or protein S were resistant to the anticoagulant action of activated protein C (APC). APC resistance has now been demonstrated to be the most common cause of inherited thrombophilia, accounting for 20% to 50% of cases.
In 1994, mild hyperhomocysteinemia was found in 19% of cases of juvenile venous thrombosis. Family studies revealed that this abnormality was inherited. Inherited hyperhomocysteinemia may be caused by defects in several genes coding for enzymes involved in the metabolism of the amino acid homocysteine.
In 1996 an alteration in the prothrombin gene (P20210) that results in an increased expression of prothrombin was identified and linked to an increased risk of thrombosis. Age-related increases in coagulation proteins, specifically increased levels of factors VIII, IX and XI, have also been linked to an increased risk of VTE.
|Table 1. Inherited Causes of Venous Thrombosis|
|Increased Levels of Procoagulants||Decreased Levels of Anticoagulants||Abnormal Fibrinolysis||Other Inherited Causes|
|Factor V Leiden mutation or activated protein C resistance*||Antithrombin||Plasminogen Deficiency||Paroxysmal Nocturnal Hemoglobinemia|
|Prothrombin 20210 mutation||Protein C||Decreased Levels of Tissue Plasminogen Activator (t-PA)|
|Hyper-homocysteinemia||Protein S||Increased Levels of Plasminogen Activator Inhibitor-1 (PAI-1)|
|FVIII, FIX, FXI, FVII, VWF||Thrombomodulin||Elevated Thrombin-Activatable Fibrinolysis Inhibitor (TAFI)|
|Heparin Cofactor II|
|Tissue Factor Pathway Inhibitor (TFPI)|
|*The Factor V Leiden mutation does not result in increased FV levels but a resistance to the anticoagulant action of activated protein C.|
Acquired Causes of Thrombosis
A variety of factors can contribute to acquired thrombotic conditions. These factors are summarized in Table 2. To learn more about specific acquired causes of thrombosis, click here.
Want to Learn More?
- Signs and Symptoms of Thrombosis
- Diagnosis of Thrombosis
- Treatment of Thrombosis
- Inherited Causes of Thrombosis
- Acquired Causes of Thrombosis
- Special Considerations for People with Thrombosis
- What Can the IHTC Do for You?
- Thrombosis FAQs
- Centers for Disease Control and Prevention (CDC). Available at: http://www.cdc.gov/ncbddd/dvt/hcp_data.htm. Accessed August 25, 2010.
- Heit, JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol 2008;28:370-372.