Delivering Integrated Care Management
The IHTC pharmacy and healthcare professionals interact on a daily basis at our center to maximize coordination and quality of care. Our pharmacists and physicians are on call and available 24 hours a day, seven days a week.
The IHTC pharmacy and healthcare professionals effectively coordinate ongoing care by proactively communicating with our patients to manage clotting factor needs, therapy compliance, and bleeding episodes.
Acquired Causes of Thrombosis
- Acquired Disorders
This website area provides an overview of a variety of disorders and issues that contribute to acquired thrombotic conditions.
Antiphospholipid Syndrome / Lupus anticoagulant
Antiphospholipid antibody syndrome (APS) occurs due to the autoimmune production of antibodies against a phospholipid (aPL), a cell membrane substance. In particular, the disease 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) and were therefore called lupus anticoagulants. However, this term is a misnomer. The vast majority of patients identified with lupus anticoagulants do not have SLE. These antibodies interfere with one or more in vitro phospholipid-dependent tests of coagulation, such as APTT, KCT, dRVVT). For example, some serological tests for syphilis may be positive in aPL-positive patients (aPL binds 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 paradoxically to be associated with thrombosis. The development of a lupus anticoagulant may be a transient phenomenon, 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 thrombotic events are venous, and the remaining 30% events arterial. The most common site for arterial thromboembolic events is the cerebral circulation. Ischemic episodes may be transient or permanent and are often recurrent. Between 18% and 46% of unselected young patients test positive for APS, and in older patients the range is 10% to 18%.
APS has a variety of pathophysiologic effects through which a prothrombotic state may be produced. These effects are as follows:
- Inhibition of prostacyclin production: APS inhibits mobilization of arachidonic acid from endothelial cell membranes. Arachidonic acid is required for the synthesis of prostacyclin, a potent vasodilator and inhibitor of platelet aggregation.
- Down regulation of the protein C pathway: this leads to decreased production of activated protein C.
- Inhibition of anticoagulant function of antithrombin: Sera of patients with lupus anticoagulants interact with a disaccharide sequence found in the critical AT-binding region of heparin and heparin sulfate. This interaction inhibits the anticoagulant function of AT. Heparin sulfate is found on the surface of endothelial cells and acts as an endogenous anticoagulant through its interaction with antithrombin.
The Sapporo APS Classification Criteria1 for the diagnosis of APS comprises a variety of clinical and laboratory abnormalities.
a) Vascular Thrombosis: blood clots in any organ or tissue
b) Pregnancy Event: one or more miscarriages after 10th week of gestation, three or more miscarriages before 10th week of gestation, or one or more premature births before 34th week of gestation due to eclampsia, and
c) Persistently (6 weeks apart) Positive aPL: lupus anticoagulant test, moderate-to-high titer anticardiolipin antibodies, or moderate-to-high titer β2-glycoprotein-I antibodies.
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 diagnosis of catastrophic APS. Based on this statement, a definitive diagnosis of catastrophic APS requires:
a) Vascular thrombosis in three or more organs or tissues, and
b) Development of manifestations simultaneously or in less than a week, and
c) Evidence of small vessel thrombosis in at least one organ or tissue, and
d) Laboratory confirmation of the presence of aPL.
The most common cause of maternal death in pregnancy is thromboembolism, with an incidence of 1 to 5 per 1,000 pregnancies, including the postpartum period. 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 thrombosis 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 stasis
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 thromboembolism, especially in individuals with abnormalities of coagulation, such as factor V Leiden.
Malignant cells may produce procoagulant substances such as tissue factor-containing microparticles that lead to an increased risk of thromboembolism. Malignancies may also lead to venous obstruction and an increase in inflammatory mediators, which also increase the potential for thrombosis.
A leading cause of death in myeloproliferative disorders is thromboembolism. This may result from abnormal platelets and increased viscosity. In fact, thrombotic episodes may occur prior to 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, inducing procoagulant activity. Platelets activated by HIT antibodies increase their release and surface expression of PF4. Thus, a positive feedback loop is created as further release of PF4 with platelet activation occurs. When this occurs, the platelets aggregate or clump together resulting in platelet consumption and a fall in the patient’s platelet count. Damage to the vascular endothelium and platelet aggregation associated with HIT can lead to the development of 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 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 thrombosis for the next 30 days, and alternate anticoagulation is often required, depending on the patient’s clinical circumstances. Use of oral anticoagulation with warfarin alone is contraindicated in this entity because of the high risk for development of warfarin-induced skin necrosis and venous limb gangrene.
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 the diagnosis of HIT with assignment of points to determine the likelihood of this diagnostic entity.3,4
- 2 points if the fall in platelet count is >50% of the baseline value, or the lowest count or 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 commencement 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 thrombosis, silent thrombosis 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 is apparent;
- 1 point if a cause of thrombocytopenia is possible;
- 0 points if another cause is definite.
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 leads to venous stasis, which in turn can initiate thrombogenesis.
Surgical interventions and sometimes the conditions that necessitate these procedures may lead to an increase in inflammatory mediators, venous stasis, and a suppression of fibrinolytic activity, all of which contribute to a prothrombotic state.
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 and/or thromboses in unusual sites have been reported in inflammatory bowel disease, including thrombosis of the inferior vena cava, carotid, and mesenteric and portal veins.
Nephrosis leads to an increase in inflammatory mediators and a decrease of free protein S due to an increase of C4 binding protein. Additionally, urinary loss of antithrombin and proteins C and S are increased resulting in acquired deficiencies. Moreover, thrombocytosis and increased platelet aggregability may occur. All of these associated changes may contribute to thromboembolism in nephrosis.
Want to Learn More?
- Signs and Symptoms of Thrombosis
- Diagnosis of Thrombosis
- Treatment of Thrombosis
- Inherited Causes of Thrombosis
- Special Considerations for People with Thrombosis
- What Can the IHTC Do for You?
- Thrombosis 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.