The incidence of venous thromboembolism (VTE; defined as deep vein thrombosis [DVT] or pulmonary embolism [PE]) in adults with sickle cell disease (SCD) is high, with up to 12% of patients experiencing an event before the age of 40 years. VTE recurrence rates in this population are similar to those seen in the general population with unprovoked VTE.
Hypercoagulability, measured by many biomarkers that denote activation of prothrombotic factors or decreased antithrombotic proteins, is well described in patients with SCD and likely contributes to the prevalence of VTE in this population.
Clinical trials that could inform VTE management and anticoagulation practices in SCD have not been conducted, so treatment decisions are often extrapolated from general VTE treatment paradigms. Within these guidelines, unanswered questions specific to patients with SCD include:
- Should SCD, in and of itself, be considered a strong persistent underlying risk factor for recurrent VTE, warranting indefinite anti-coagulation after an incident VTE?
- Should SCD be considered a mild thrombophilia, with secondary pharmacological prophylaxis needed for a shorter duration, and further therapy required only during exposure to periods of higher risk?
- Are provoked and unprovoked VTE defined similarly in this population?
- Are patients with SCD and VTE at increased risk of bleeding?
In this overview, Drs. Shet and Wun discuss three commonly encountered patient scenarios of VTE in SCD to illustrate the diagnosis and management of this clinical problem, from quantifying VTE risk to selecting the type and duration of anticoagulation.
Diagnosis of VTE in SCD
Assessing Pretest Probability of VTE
As with any patient in whom a diagnosis of VTE is being considered, the pretest probability of disease should be assessed. Factors that increase VTE risk in patients with SCD include:
- sickle cell anemia (HbSS) and sickle beta (Sb0)-thalassemia
- genotypes history of splenectomy for other diseases
- >3 hospital admissions per year
- female sex
- presence of indwelling catheters
Distinguishing VTE From Other SCD Complications
Symptoms and signs of VTE may overlap with other clinical complications of SCD. For example, lower-extremity edema might be attributed to right heart failure, kidney, or liver disease, but its unequal distribution may provide a clue indicating VTE. Therefore, a high clinical suspicion for VTE in patients with SCD with a low threshold for diagnostic evaluation is recommended.
Diagnostic Testing
No studies directly address the diagnostic algorithm for VTE in patients with SCD, but the FIGURE shows a proposed algorithm for clinically suspected DVT or PE. D-dimer levels are not included in identifying VTE because their role in SCD is uncertain, given baseline elevations even when patients are clinically well.
In this diagnostic algorithm, initial imaging includes the use of compression ultrasound Doppler for people suspected of upper- or lower-extremity DVT. Multidetector computerized tomographic pulmonary angiography (CTPA) and radionuclide scanning (ventilation-perfusion [V/Q] scan) are used in suspected PE. V/Q scan offers practical advantages over CTPA for the diagnosis of PE in SCD due to the minimal radiation exposure and well-defined diagnostic criteria. However, diagnostic testing with V/Q scanning can offer advantages over CTPA in patients who undergo frequent testing and offers specific advantages in establishing the diagnosis of chronic thromboembolic pulmonary hypertension.
Case 1: Type and Intensity of Anticoagulation
A 42-year-old man with HbSS presents to the hospital with acute-onset left leg swelling. He has no previous history of VTE, had not been hospitalized for two years, and had no recent operations. He has no cardiopulmonary symptoms. Bilateral Doppler ultrasound revealed an acute occlusive DVT of the left femoral vein extending from the popliteal trifurcation to the iliac vein. The patient was administered rivaroxaban 15 mg twice daily for 21 days, which was then reduced to 20 mg once daily.
The patient’s symptoms resolved and, after three months of treatment, he was re-evaluated in clinic to discuss extension of anticoagulation beyond three months to reduce his risk of recurrence. He elected to discontinue anticoagulation after three months of therapy, due to concerns about bleeding risk. Aspirin to reduce VTE recurrence (albeit less effectively than either warfarin or a DOAC but with a more favorable bleeding risk profile) was declined because he did not want an additional medication for an indefinite period.
Anticoagulant Choice
As in the general population, there is no direct clinical evidence that the type of anti-coagulant for the treatment of VTE should differ in patients with SCD. Direct oral anticoagulants (DOACs) are a first choice for VTE treatment.
Accurately estimating glomerular filtration rate and/or creatinine clearance guides appropriate selection of heparin and DOACs, all of which have varying degrees of renal clearance that can affect efficacy. For example, edoxaban may be less efficacious for nonvalvular atrial fibrillation when the creatinine clearance is >95 mL/min, which is common in patients with SCD. In those at high risk for bleeding, access to and availability of agents that can reverse the anticoagulant effect of DOACs also may influence anticoagulant choice.
Case 2: VTE Prophylaxis During Pregnancy
A 32-year-old Ghanaian woman with HbSS is 10 weeks pregnant. This is her first pregnancy. She developed a left femoral vein DVT at age 26 during a hospitalization for a vaso-occlusive crisis and was treated with LMWH followed by warfarin for six months. She has not had recurrent VTE.
The patient was started on prophylactic-dose LMWH at the beginning of her second trimester and continued receiving LMWH through six weeks postpartum, with a short interruption around the time of delivery. She had an uneventful spontaneous normal delivery. There also was discussion about the need for indefinite anticoagulation, given her prior VTE history and SCD. She decided against extended anticoagulation beyond six weeks postpartum, based on the provoked nature of her prior event, the time elapsed, her infrequent hospitalizations, and the increased risk for bleeding.
VTE and Anticoagulation During Pregnancy
Pregnancy is a well-established risk factor for VTE for women, and this risk is magnified in pregnant women with SCD. The risk for pregnancy-related VTE appears to be 1.5 to 5 times greater in women with SCD than in the general population.
In the management of pregnancy and SCD, some groups suggest low-dose aspirin as prophylaxis against pre-eclampsia, and consideration of low-molecular-weight heparin (LMWH) when additional risk factors are present. These risk factors include but are not limited to previous VTE, family history of VTE, known thrombophilia, older age, obesity, severe varicose veins, pre-eclampsia, immobility, and frequent hospitalization.
Regarding oral contraceptives in women with SCD, progesterone-only methods are the least thrombogenic and are routinely considered first-line.
Duration of Anticoagulation
Anticoagulation after an acute VTE is recommended for at least three months. Shorter treatment periods are associated with higher risk of VTE recurrence. The choice to extend anticoagulation is determined by weighing the risk and seriousness of recurrent VTE with the risk of major bleeding.
In patients with SCD, the risk of recurrent VTE at five years is estimated at 20 to 25% and appears to increase for patients with more hospital admissions per year. The risk of major bleeding on therapeutic anticoagulation for VTE is low for patients without risk factors for bleeding. However, it is unknown whether SCD is associated with an increased risk of bleeding on anticoagulation, absent other known risk factors, when compared with the general population of patients with VTE. Also, bleeding risk can vary over time in patients with VTE.
The high risk of both recurrent VTE and bleeding in SCD-related VTE is similar to the situation seen in cancer-associated thrombosis. In the latter setting, anticoagulation should be continued as long as there is active cancer. In the absence of clinical trials of anticoagulation in patients with SCD, these patients should be treated similarly. Because provoked VTEs in SCD may be associated with a much higher risk of recurrence than provoked VTE in the general population, consider extended anticoagulation in those with low bleeding risk – even if the event was provoked by hospitalization for medical illness.
Case 3: Catheter-Related Thrombosis
A 21-year-old woman with SCD on chronic, monthly exchange transfusion therapy for a history of ischemic stroke at age 12 presents with sudden-onset pain and swelling of her right upper extremity. Two years ago, a double-lumen port-a-cath was placed in her left chest with entry through the left subclavian vein. A Doppler ultrasound reveals an occluding thrombosis of the right axillary, subclavian, and internal jugular vein. She is placed on rivaroxaban.
The patient’s symptoms resolved after starting anticoagulation, with reduction in swelling and pain. The catheter position was confirmed to be appropriate. A V/Q scan was performed and ruled out the presence of PE. Due to concerns about the potential for dislodging a clot during red cell exchange, a repeat ultrasound was performed after three weeks of anticoagulation. Imaging revealed an organizing clot. Red cell exchange was then carried out without complication. Anticoagulation will continue with a plan to stop therapy if the catheter is ever removed.
In patients with suspected catheter-related VTE, the thrombosis can be managed similarly to other suspected VTEs. For symptomatic, upper-extremity catheter-related thrombosis, we recommend a minimum of three months of anticoagulation. If the catheter is functional and required, we would continue therapeutic anticoagulation until catheter removal. Attention to the location of the catheter tip and routine catheter care, including anticoagulation flushes, also is important to maintain catheter function and prevent mural thrombosis.
It is unknown whether patients with SCD who have incident VTE can be risk stratified for recurrence, with duration of anticoagulation accordingly adjusted. Patient choice, health care costs associated with indefinite anticoagulation, and the potential long-term use of aspirin or low doses of DOACs should also be considered in making this decision.