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Acquired Causes of Blood Clots
- Acquired Disorders
This website area provides an overview of a variety of disorders and issues that can lead to acquired clotting conditions.
Antiphospholipid Syndrome / Lupus anticoagulant
In antiphospholipid antibody syndrome (APS) the body produces antibodies against a phospholipid (aPL), a cell membrane substance. This is called an autoimmune disorder because the body produces antibodies against its own cells. APS is characterized by antibodies against cardiolipin (anti-cardiolipin antibodies) and β2 glycoprotein I. Antiphospholipid antibodies were first identified in patients with systemic lupus erythematosus (SLE; lupus) and were therefore called lupus anticoagulants. However, this term is inaccurate. The vast majority of patients identified with lupus anticoagulants do not have SLE. These antibodies interfere with one or more phospholipid-dependent laboratory tests of coagulation, such as APTT, KCT, dRVVT. For example, some tests for syphilis may be positive in patients with antiphospholipid antibodies because these antibodies bind to the lipids in the test to give a false-positive result, although the more specific tests for syphilis that use recombinant antigens will be negative.
Originally it was thought that lupus anticoagulants may be associated with bleeding as they prolong clot-based assays such as the APTT. They were later found to be actually associated with clotting. The development of a lupus anticoagulant may be temporary, particularly in children in the setting of a recent infection. Lupus anticoagulants are clearly different from the anticardiolipin antibody (ACA).
In patients with a lupus anticoagulant, 70% of the clotting events occur in the veins (venous clots), and the remaining 30% events occur in the arteries (arterial clots). The most common site for arterial clotting events is the circulation of the brain. The clotting episodes may be temporary or permanent and often recur. Between 18% and 46% of unselected young patients test positive for APS, and in older patients the range is 10% to 18%.
APS can increase the risk of clotting in several ways, such as promoting platelets to clump together, reducing the production of activated protein C (a natural anticoagulant), and inhibiting the anticoagulant activity of antithrombin, another naturally occurring anticoagulant.:
The Sapporo APS Classification Criteria1 are used to diagnose APS. The criteria include various clinical and laboratory abnormalities, such as the presence of blood clots in any organ or tissue, the occurrence of one or more miscarriages or premature births, and persistently positive results with a lupus anticoagulant test, moderate-to-high titer anticardiolipin antibodies, or moderate-to-high titer β2-glycoprotein-I antibodies. For more details on the Sapporo APS Classification Criteria, visit the provider portal of this website.
Catastrophic APS is an accelerated form of APS that results in multisystem organ failure. Although catastrophic APS occurs in less than 1% of all patients with APS, it is usually a life-threatening medical situation that requires a high degree of clinical awareness. The International Consensus Statement2 is commonly used for a definitive diagnosis of catastrophic APS. Further information on the criteria for catastrophic APS is available on the provider portal.
The most common cause of maternal death in pregnancy is a blood clot, with an incidence of 1 to 5 per 1,000 pregnancies, including the time period after childbirth. In women with a previous history of a DVT, the risk of a subsequent DVT with pregnancy is 12% to 35% and increases to 75% in women with prothrombotic disorders such as antithrombin deficiency. Causes of pregnancy-related blood clots include:
- decreased levels of natural anticoagulants such as total and free protein S, or antithrombin
- increased levels of procoagulant proteins such as FVIII, von Willebrand factor and fibrinogen
- decreased rate of blood flow, increasing the risk of blood pooling
Estrogens and oral contraceptives mimic the pregnant state, leading to coagulation changes. The use of hormone therapy, therefore, may be associated with an increased risk of blood clots, especially in women with abnormalities of coagulation, such as factor V Leiden.
Cancerous (malignant) cells may produce procoagulant substances such as tissue factor-containing microparticles that lead to an increased risk of blood clots. Cancer may also lead to blockages in veins and an increase in inflammatory chemicals, which also increase the potential for clots.
Myeloproliferative disorders are blood diseases in which patients experience chronic increases in some or all of the blood cells, such as red blood cells, platelets, and white blood cells. Increases in red blood cells and platelets prevent the blood from flowing smoothly and increase the risk of clot formation. A leading cause of death in people with myeloproliferative disorders is blood clots. In fact, clotting episodes may occur before the diagnosis of the myeloproliferative syndrome.
Heparin-induced thrombocytopenia (HIT) occurs when a patient receives heparin and subsequently forms antibodies against heparin and the platelet factor-4 (PF4) complex. Immune complexes of HIT antibodies and PF4/heparin bind to the surface of platelets and cause platelet activation. These activated platelets adhere to the vascular endothelium, promoting clotting activity. Platelets activated by HIT antibodies increase the release and surface expression of PF4. As a result, even more platelet activation takes place. When this occurs, the platelets aggregate or clump together, resulting in platelet consumption and a fall in the patient’s platelet count (thrombocytopenia). Damage to the vascular endothelium and platelet clumping associated with HIT can lead to blood clots despite the presence of heparin. It is unclear why some patients treated with heparin develop this problem.
HIT may occur in 1% to 3% of individuals receiving heparin for a week or more. HIT is most often encountered in the following populations, but may occur in any population:
- Persons with cardiovascular disease and interventions
- Patients undergoing orthopedic surgery
- Medically compromised patients
The fall in platelet count with HIT most commonly develops 5 to 7 days after the start of heparin for the first time. However, HIT may occur within 1 to 3 days in patients who have been previously exposed to heparin or sensitized in the recent past, usually within the previous 3 months. The diagnosis of HIT requires discontinuation of all forms of heparin including removal of heparin coated catheters or use of low molecular weight heparins. Once heparin is discontinued, the platelet count should begin to recover in 2 to 5 days. Despite the discontinuation of the heparin, however, the patient continues to be at high risk of HIT-related clotting for the next 30 days. Because of this clotting risk, the patient often needs alternative anticoagulation, depending on his or her clinical circumstances. Use of oral anticoagulation with warfarin alone should not be used in patients with this condition because of the high risk of developing warfarin-induced skin necrosis and gangrene in the veins of the limbs.
Laboratory Diagnosis of HIT
There are 4 diagnostic tests for heparin-induced thrombocytopenia (HIT):
- Serotonin release assay (SRA)
- Heparin-induced platelet aggregation assay (HIPA)
- Solid phase immunoassay (H-PF4 enzyme-linked immunosorbent assay [ELISA])
- Particle gel immunoassay (PIFA)
The first 2 tests are referred to as functional assays. Most laboratories use HIPA, which is highly specific but is reported to be less sensitive than the SRA.
Clinical Diagnosis of HIT: The “4Ts”
The “4Ts” criteria are commonly used as a clinical score for diagnosing HIT. Points are assigned to find out the likelihood of HIT.3,4
- 2 points if the fall in platelet count is >50% of the baseline value, or the lowest count (nadir) is 20–100 × 109/liter.
- 1 point if the fall is 30% – 50% or the nadir is 10–19 × 109/liter.
- No points if the fall is less than 30% or the nadir is <10 × 109/liter.
- Timing of platelet count fall:
- 2 points if the fall is between days 5–10 after start of treatment;
- 1 point if the fall is after day 10.
- Previous exposure to heparin
- If someone has been exposed to heparin within the last 30 days and then has a drop in platelet count within a day of re-exposure, 2 points are assigned;
- If the previous exposure was 30–100 days previously, 1 point
- If the fall is early but there has been no previous heparin exposure, no points.
- Thrombosis or other sequelae:
- 2 points in new confirmed thrombosis, skin necrosis (see below), or systemic reaction.
- 1 point if progressive or recurrent clot, silent clot or red skin lesions.
- No points if there are no symptoms.
- Alternative cause possible:
- 2 points if no other cause,
- 1 point if there is a possible alternative cause
- No points if there is a definite alternative cause.
- Other causes of thrombocytopenia:
- 2 points if no other cause,
- 1 point if there is a possible alternative cause,
- No points if there is a definite alternative cause.
The clinical group designations for the likelihood of HIT are as follows:
- Very likely: Score of 6–8
- Possible: score of 4–5
- Unlikely: score of 0–3
Immobilization due to prolonged travel (> 8 hours) or surgical/medical conditions can lead to pooling of blood in the veins. This, in turn can cause clot formation.
Surgical interventions and sometimes the conditions that make surgery necessary may lead to an increase in chemicals involved in swelling (inflammation), blood pooling in the veins, and prevention of clot breakdown, all of which promote clot formation.
Inflammatory disorders such as Crohn’s disease, ulcerative colitis, and infections increase inflammatory mediators, monocyte procoagulants, and C4-binding protein, thereby decreasing free protein S. These conditions may contribute to a prothrombotic state. Large clots or clots in unusual sites have been reported in inflammatory bowel disease, including clots of the inferior vena cava, carotid, and mesenteric and portal veins.
Nephrotic syndrome is a kidney disorder that causes the body to release too much protein in the urine. Nephrotic syndrome usually is caused by damage to the small blood vessels in the kidneys that filter waste and excess water from the blood. When these blood vessels are damaged, protein can leak out of the blood and lead to swelling all over the body (edema). The kidney damage can lead to a decrease of free protein S and an increase in platelet clumping. All of these associated changes may contribute to the formation of blood clots.
Want to Learn More?
- Signs and Symptoms of Blood Clots
- Diagnosis of Blood Clots
- Treatment of Blood Clots
- Inherited Causes of Blood Clots
- Special Considerations for People with Blood Clots
- What Can the IHTC Do for You?
- Clotting Disorders FAQs
- Wilson WA, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop.
- Asherson RA, et al. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus. 2003;12:530-534.
- Warkentin TE, Heddle NM. Laboratory diagnosis of immune heparin-induced thrombocytopenia. Curr Hematol Rep. 2003;2:148-157.
- Lo GK, et al. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006; 4: 759–65. Available at: http://scalpel.stanford.edu/2007-2008/articles/Pretest%204%20Ts%20in%20dx%20HIT,%20%20J%20thrombosis%20and%20hemostasis,%202006.pdf . Accessed March 15, 2010.