Steady-State Von Willebrand Factor Antigen Levels Predict Low Platelet Counts and Risk for Complications in Hospitalizations for Painful Sickle Cell Vaso-Occlusive Episodes

We previously reported that a >20% decline in platelet counts from steady state to presentation predicted severe complications during hospitalization for vaso-occlusive pain crisis (VOC) in 130 adult sickle cell disease (SCD) patients.¹ Sharp platelet decline in acute chest syndrome was reported to be accompanied by large von Willebrand Factor (VWF) aggregates adherent to pulmonary vascular endothelium in SCD.² A prospective study of 24 SCD patients found a significant increase of VWF reactivity in VOC admissions relative to steady state, which correlated with low platelet counts and the development of acute chest syndrome.³ We aimed to investigate the role of steady-state VWF antigen level and ADAMTS13 activity as predictors of platelet count decline and severe complications in VOC admissions.

Plasma levels of VWF antigen and ADAMTS13 activity were measured⁴ for 56 patients at steady-state outpatient visits (Baseline). VWF antigen was expressed as fold increase or decrease from the concentration in normal pooled plasma of 12.2 ug/ml; ADAMTS13 activity was expressed as fold of the value from normal pooled plasma which was considered 100% activity.

Electronic records of VOC admission that occurred >21 days after Baseline were reviewed. Exclusion criteria included non-VOC admissions defined as elective admission for surgery, admission for accident or injury, admission for delivery of an infant, or admission with a pain score <8/10 at presentation.⁵ A total of 98 qualifying admissions were identified. Severe complication during the admission was defined as having any of the following: 1) acute chest syndrome, new infiltrate on chest X-ray, or use of ventilator; 2) acute kidney injury;⁶ 3) acute liver injury;⁷ 4) thrombotic or hemorrhagic stroke; 5) venous thromboembolism including deep vein thrombosis, atrial thrombosis, and pulmonary embolism; 6) need for transfer to the intensive care unit; 7) need for exchange blood transfusion; 8) death during hospitalization. Platelet counts at presentation to the emergency room (ER) leading to the admissions under study were recorded, as well platelet counts at Baseline.

The 56 patients had a median (range) age of 37 (21-66) years; 52% are female, 89% with hemoglobin SS or Sβ⁰-thalassemia, and 57% on hydroxyrea (HU). Severe complication occurred in 35 (36%) of the 98 admissions involving 27 (48%) of the patients.

Focusing on the first admissions, higher steady-state VWF antigen levels correlated strongly with lower ER platelet counts (ρ= -0.50, P=0.00011, Figure 1A) and higher steady-state ADAMTS13 activity correlated weakly with ER platelet counts (Spearman’s ρ= 0.30, P=0.025). The ratio of VWF antigen to ADAMTS13 activity ratio also correlated strongly with lower ER platelet counts (ρ= -0.52, P=0.000052, Figure 1B). In contrast, steady-state VWF antigen level (ρ= -0.17, P=0.23), ADAMTS13 activity (ρ= 0.19, P=0.17), and VWF antigen to ADAMTS13 activity ratio (ρ= -0.23, P=0.098) showed no significant correlation with steady-state platelet counts. The correlations remained by adjusting for age, gender, Hb genotype severity, HU, and treatment of anticoagulant, aspirin, or non-steroidal anti-inflammatory drugs at VOC visits.

In analyses restricted to admissions >1 year after Baseline, the correlation between steady-state VWF antigen level and ER platelet counts appeared to persist. Focusing on the 28 first admissions, steady-state VWF antigen level (ρ= -0.50, P=0.0071) and VWF antigen to ADAMTS13 activity ratio (ρ= -0.44, P=0.018) correlated negatively with ER platelet counts. Steady-state ADAMTS13 activity did not correlate with ER platelet counts in admissions that occurred >1 year after Baseline (ρ= 0.16, P=0.43).

We further examined the association of steady-state VWF antigen level, ADAMTS13 activity, and their ratio with risk for severe complication in admission. Focusing on the first 56 admissions, which involved 23 complications, steady-state VWF antigen level in the top quartile (1.63) associated with risk for severe complications (OR=6.5, 95% CI 1.4-31, P=0.018, n=56), adjusting for age, gender, Hb genotype severity, and HU.

Our observations suggest that steady-state VWF antigen level and the ratio of VWF antigen level to ADAMTS13 activity predict low platelet counts at presentation to VOC admissions, and that steady-state VWF antigen level in SCD patients may be a relatively stable marker for risk of severe VOC complications.