a. Definition. Hypercoagulable states are clinical disorders of the blood that increase the patient’s risk for developing thromboembolic disease. A risk factor (inherited or acquired) for the development of a thrombus can be identified in more than 80% of patients with a clot, and there may be multiple factors present. An inheritable genetic abnormality is found in up to 7% of individuals presenting with deep vein thrombosis (DVT).
b. Pathogenesis. Homeostasis in blood clotting is maintained by interrelationships between procoagulant and anticoagulant proteins and their interactions with the vascular endothelium. The pathogenesis of thrombus formation is summarized by Virchow’s triad:
i. Defects in blood flow (stasis)
ii. Defects in vascular endothelium (trauma)
iii. Defects in blood coagulation (leading to hypercoagulability)
B. Clinical Manifestations of Hypercoagulable States. A hypercoagulable state should be suspected in a patient who develops:
a. Multiple or recurrent clots
b. Clots in unusual locations (e.g., the upper extremities, mesenteric vessels, arteries)
c. Thromboembolic disease at an early age
C. Causes of Hypercoagulable States. These causes are important to consider when a patient has a blood clot.
a. Inherited clotting disorders
i. Factor V Leiden mutation is the most common inherited factor associated with hypercoagulability. This mutation causes resistance of factor V to the cleaving action of activated protein C.
ii. Prothrombin G20210A mutation is the second most common inheritable factor associated with hypercoagulability and results in an mRNA that has an increased half-life, leading to elevated levels of prothrombin protein. When coinherited with a factor V Leiden mutation, patients have a substantially increased risk for the development of a clot as well as an increased risk for recurrent DVT.
iii. Protein C or Protein S deficiency is uncommon but displays a high penetrance for the occurrence of venous thromboembolism (VTE). These proteins normally function to reduce levels of factor Va and factor VIIIa, leading to decreased thrombin generation. Patients with deficiencies fail to properly regulate the coagulation cascade.
iv. Antithrombin (or antithrombin III) deficiency is a rare autosomal dominant disorder with a relatively high level of penetrance for DVT. The normal protein functions as a protease inhibitor of factor IIa (thrombin) and factor Xa Its activity is modulated by heparin, leading to the basis of its clinical use. Deficiencies in antithrombin lead to dysregulation of the clotting cascade.
v. Rare disorders include dysfibrinogenemia, plasminogen deficiency, heparin cofactor II deficiency, factor XII deficiency, and elevated clotting factor levels.
b. Acquired clotting disorders
i. Malignancy, known or occult, is a common cause of thrombosis. Common offenders include cancers of the lung, pancreas, colon, kidney, and prostate.
1. Heparin-induced thrombocytopenia and thrombosis (HITT), an acquired disorder associated with the development of arterial or venous thrombi concurrent with the development of thrombocytopenia, occurs in 1% to 5% of patients receiving intravenous or subcutaneous heparin therapy. If HITT is being considered, heparin should be stopped promptly, appropriate serologies sent for diagnosis, and anticoagulation with a direct thrombin inhibitor initiated until platelet levels improve (see Chapter 60).
2. Oral contraceptives increase the risk for thrombosis independently and in conjunction with other risk factors. The increase in risk varies with the dose of estrogen, type of progesterone, and route of administration of the contraceptive.
3. Additional medications (e.g., hormone replacement therapy, tamoxifen)
iii. Pregnancy is associated with increased rates of thrombosis that may be secondary to vascular stasis due to the enlarged uterus compressing pelvic blood vessels, vascular injury at the time of delivery, or increase in number of clotting factors as pregnancy progresses.
iv. Chronic renal disease, including nephrotic syndrome as well as end-stage renal disease, are associated with an increased incidence of thromboses through unclear mechanisms. Alterations in levels of procoagulant proteins and anticoagulant factors as well as alterations in platelet activity are thought to contribute to this risk.
v. Trauma/surgery causes increased risk for thrombosis for multiple reasons, including decreased venous blood flow, increased levels of tissue factor, immobilization, and alterations in the balance of endogenous procoagulants and anticoagulants after the trauma. Orthopedic, vascular, and neurosurgical procedures in particular are associated with an elevated risk for venous thrombosis and thromboembolism.
vi. Hyperhomocysteinemia is both an inherited (due to polymorphisms in the MTHFR gene) and acquired (due to vitamin deficiencies) condition characterized by high serum levels of homocysteine. Although elevated homocysteine levels are associated with thromboembolic disease and atherosclerotic disease, modulating these levels with folate supplementation does not appear to reduce this risk.
vii. Myeloproliferative neoplasms such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis are associated with thrombophilia. Patients presenting with idiopathic hepatic or portal vein thrombosis should be considered for screening for an underlying myeloproliferative neoplasm.
viii. Antiphospholipid antibody syndrome is marked by the presence of antiphospholipid antibodies, hypercoagulability, recurrent spontaneous abortions, and thrombocytopenia.
c. The causes of the most important hypercoagulable states (both primary and secondary) can be recalled using the mnemonic, “DAMN THROMBUS.”
MNEMONIC: Causes of Hypercoagulable States (DAMN THROMBUS)
Deficiencies or alterations in coagulation factors (e.g., protein C, protein S, antithrombin
III, factor V, prothrombin, fibrinogen, plasminogen, heparin cofactor, factor XIII)
Antiphospholipid antibody syndrome
Malignancy (e.g., Trousseau’s syndrome)
Hyperhomocysteinemia or Heparin-induced thrombocytopenia and thrombosis (HITT) or
Hemoglobinuria (i.e., paroxysmal nocturnal hemoglobinuria [PNH])
Rheumatologic causes (i.e., vasculitis)
Oral contraceptives (and other medications)
Baby-carrying (i.e., pregnancy)
Surgery or postoperative states (particularly neurosurgical and orthopedic)
D. Approach to the Patient
a. In a patient with a new DVT, patient history (including prior VTE), physical examination, location and extent of the thrombus, complete blood count (CBC), urinalysis, prothrombin time (PT), and partial thromboplastin time (PTT) are often used to initially evaluate for one of the more common acquired hypercoagulable states. Beyond the acute medical treatment of VTE, the key in the management of patients with thromboses is deciding whether to screen the patient for a heritable or acquired hypercoagulable state. Most patients do not benefit from additional screening of this nature. That is, a heritable factor can only be found in about 30% of patients with a first DVT, so there are a limited number of patients who would benefit from these expensive extensive tests.
i. Additional testing should be strongly considered in patients with the following characteristics:
1. An unprovoked DVT or pulmonary embolism before the age of 50 years
2. A patient with a first-degree family member with an unprovoked DVT or pulmonary embolism before the age of 50 years
3. A recurrent DVT or pulmonary embolism
4. A thrombus in an unusual location (hepatic or portal vein or upper extremity vein)
ii. Additionally, the timing of the screening is important to consider because the presence of a thrombus, as well as administration of anticoagulants, can affect levels or activity of a number of coagulation cascade proteins.
1. Most hematologists recommend pursuing hypercoagulable evaluation—especially for antithrombin, protein C, and protein S—at least 2 weeks after the cessation of anticoagulation to limit false-positive results.
2. When screening for thrombophilias in the setting of a pregnancy, a number of coagulation factors are altered, including elevated factor VIII levels and decreased protein S levels. Therefore, the optimal time to assess for thrombophilia is after the completion of therapy for thrombosis as well as after delivery of the baby.
b. The following laboratory studies may help evaluate for specific factors associated with hypercoagulability:
i. Factor V Leiden mutation test
ii. Prothrombin G20210A mutation test
iii. Screening tests for the presence of antiphospholipid antibodies include the PTT, lupus anticoagulant assay, anticardiolipin antibodies, anti–β2-glycoprotein 1 antibodies, and the dilute Russell’s viper venom test (dRVVT)
iv. Homocysteine level (test after overnight fast)
v. Quantitative and functional assays for proteins C and S, antithrombin III, and fibrinogen
vi. Rarer antigenic testing (plasminogen levels, heparin cofactor II levels, and factor XII levels) can be performed if the index of suspicion is high even though initial screening is negative.
vii. HIT enzyme-linked immunosorbent assay (ELISA) and confirmation with a serotonin release assay in patients with presumed HITT
viii. Flow cytometry assessment (CD55 and CD59) for PNH in the proper clinical scenario
Acute thrombosis can reduce levels of antithrombin, protein C, and protein S. Heparin reduces antithrombin levels. Warfarin reduces protein C levels before those of all other vitamin K–dependent factors as protein C has the shortest half-life. Therefore, warfarin can lead to a falsely low result on a protein C assay but can also affect protein S activity.
a. Anticoagulation therapy
i. Initial therapy of a patient presenting with DVT or pulmonary embolism consists of treatment with heparin infusion, subcutaneous low-molecular-weight heparin (LMWH), or a direct oral anticoagulant. Once patients are started on a heparin infusion or LMWH they can then safely be transitioned to warfarin if necessary. Because protein C has the shortest half-life of all the vitamin K–dependent factors, warfarin therapy alone can lead to a deficiency of protein C relative to the other procoagulant factors (i.e., factors II, VII, IX, and X). Patients with an underlying protein C deficiency who are given high-dose warfarin alone may be susceptible to a transient hypercoagulable state, leading to “Coumadin skin necrosis.” Coumadin necrosis can be avoided by administering heparin or low-molecular weight heparin as a bridge to warfarin. In addition, because Coumadin will not be fully effective for 3–5 days, the concomitant use of a heparin-based product ensures that the patient’s blood is rapidly anticoagulated, preventing further clot extension.
1. Unfractionated heparin is given by continuous intravenous infusion, and dosing is initiated and adjusted using a weight-based nomogram to a goal PTT that is 1.5–2.5 times the normal range.
2. LMWH is an alternative to unfractionated heparin. This subcutaneous depot form of heparin is dosed every 12–24 hours and can even be used in select patients for outpatient management of thromboembolic disease. Dosing is weight based but should be used with caution in patients with renal insufficiency. Blood testing is rarely needed but can be checked if desired by measuring anti–factor Xa levels 4–6 hours after dosing.
3. Direct oral anticoagulants (DOACs). Rivaroxaban, apixaban, edoxaban, and dabigatran are examples of direct oral anticoagulants approved for the treatment of VTE and stroke prophylaxis in nonvalvular atrial fibrillation. In contrast to warfarin, these agents require little routine monitoring and are well-tolerated with few medication interactions. They may cause an elevation in international normalized ratio (INR), but this is variable and not reflective of therapeutic effect as it is for warfarin. Furthermore, given their rapid onset of action (1-4 hours), they do not require bridging anticoagulation with treatment initiation like warfarin. They are safe, highly effective, and do not have the consistent vitamin K diet restriction that warfarin requires. However, these medications do have limitations, and thus factors such as renal function, liver function, age, bleeding risk, and cost are important when considering these agents.
ii. Long-term therapy. Heparin or low-molecular-weight heparin may be continued along with warfarin until the PT reaches the therapeutic range (i.e., an INR between 2 and 3), which usually takes about 5 days. Warfarin or low-molecular-weight heparin is usually continued for a minimum of 3–6 months, although the optimal treatment duration is not well established.
iii. Hypercoagulable states. Patients identified as having a factor associated with a hypercoagulable state may benefit from prolonged or lifelong anticoagulation, although the degree of anticoagulation and the absolute length of therapy is unknown.
iv. Recurrent DVT or pulmonary embolism. Patients with recurrent thrombi are at an elevated risk for additional recurrences; therefore, subsequent treatment is given for longer than 6–12 months. Like with hypercoagulable states, the risk for recurrent thrombi must be balanced with the risk for bleeding complications from the anticoagulation.
b. Inferior vena cava (IVC) filter. An IVC filter may be placed in patients with active bleeding, contraindications to anticoagulation therapy, or in patients with recurrent pulmonary emboli despite therapy. However, the placement of IVC filters may lead to an increased risk for lower extremity DVT because of alterations in blood flow through the IVC.
c. Thrombolytic therapy can potentially normalize blood flow sooner than anticoagulation therapy alone but is typically considered only in patients with profound DVT or pulmonary embolism resulting in circulatory or hemodynamic compromise.
Suggested Further Readings
Carrier M, Lazo-Langner A, Shivakumar S, et al. Screening for occult cancer in unprovoked venous thromboembolism. N Engl J Med 2015;373:697–704.Find this resource:
Greer IA. Pregnancy complicated by venous thrombosis. N Engl J Med 2015;373:540–7.Find this resource:
Gupta A, Sarode R, Nagalla S. Thrombophilia testing in provoked venous thromboembolism: a teachable moment. JAMA Intern Med 2017;177:1195–6.Find this resource:
Petrilli CM, Heidemann L, Mack M, Durance P, Chopra V. Inpatient inherited thrombophilia testing. J Hosp Med 2016;11:801–4.Find this resource:
van Es N, van der Hulle T, van Es J, et al. Wells rule and D-dimer testing to rule out pulmonary embolism: a systematic review and individual-patient data meta-analysis. Ann Intern Med 2016;165:253–61.Find this resource: