Prophylactic Dose Low Molecular Weight Heparin (dalteparin) For Treatment Of Vaso-Occlusive Pain Crisis In Patients With Sickle Cell Disease

The most common cause for hospitalization and the hallmark of sickle cell disease (SCD) is painful vaso-occlusive crisis (VOC). Several studies including our own have documented a hypercoagulable state in patients with SCD, which becomes further accentuated during pain crisis. Therefore, there has been increasing interest in the use of anticoagulation in patients with SCD to prevent and treat VOC. For patients admitted for VOC, deep vein thrombosis (DVT) prophylaxis with low molecular weight heparin (LWMH) is currently used at the discretion of the treating physician. No formal guidelines in the United States advocate universal use of DVT prophylaxis for patients with SCD and DVT risk assessment tools such as the Padua risk assessment model do not include SCD as a thrombophilic condition. We hypothesized that the daily use of prophylactic dose LMWH would decrease markers of hypercoagulability and daily pain scores for patients admitted for VOC.

We performed a double blind placebo controlled trial using prophylactic dose dalteparin for patients with SCD admitted for VOC. Adult patients >18 years of age were enrolled at Duke University and included sickle cell type SS, SC, and Sβ⁰. Patients were treated for the initial 7 days of hospitalization, had pain scores (visual analog scale) recorded twice daily, and had hypercoagulable markers drawn on days 1, 3 and 5. Hypercoagulable markers tested included D-dimer, thombin-antithrombin (TAT), and calibrated automated thrombography (CAT). Analysis was performed to compare the amount of change in hypercoagulable markers and pain scores for each patient treated with either dalteparin or placebo.

We enrolled 34 patients (median 27 years old, range 20-56) over 18 months, including 29 patients who were randomized and administered study drug. Ten patients treated with dalteparin and ten treated with placebo had blood drawn on day 1 and 3. Mean age, clinical history, and baseline laboratory values were not significantly different between dalteparin and placebo groups except for LDH, which was lower in the dalteparin group (303.9 U/L ± 120.9 vs. 432.6 ± 188, p=0.03). There was no significant difference between dalteparin and placebo treated patients for hypercoagulable markers on day 1 and 3 including: D-dimer (167.4 ng/mL ± 262.6 vs. 814 ± 621.8, p=0.19), TAT, and each phase of thrombin generation by CAT including endogenous thrombin potential (59.1 nM ± 26.8 vs. -24.3 ± 60.6, p=0.13). There also was no significant decrease between all hypercoagulable markers on day 1 when compared to day 5. Pain scores were found to significantly decrease each day during hospitalization from enrollment (day 0) to day 3 for each treatment group. Importantly, when comparing patients treated with dalteparin versus placebo, there was a greater decrease in pain scores from day 0 to 1 (-1.6 vs. -0.3, p=0.06) and from day 0 to 3 (-2.4 vs. -0.9, p=0.07).

No studies to date have evaluated the use of prophylactic dose LMWH for the treatment of inpatient pain crisis. We found that prophylactic dose dalteparin did not seem to significantly affect hypercoagulable markers including D-dimer and CAT. Interestingly, there was also no significant decrease in markers through hospitalization from day 1 to day 5. This may be due to the underlying accentuated hypercoagulable state in SCD and the prophylactic dosing of dalteparin. We did find, however, a greater decrease in pain scores from day 0 to 1 as well as day 0 to 3 for patients treated with prophylactic dose dalteparin as compared to patients treated by placebo. This decrease in pain seems promising for larger multi-center studies to evaluate the use of prophylactic dose anticoagulation for VOC.