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Celebrating Diversity Within the Sickle Cell Community: Commitment, Innovation, Practice
Friday, October 12 • 4:15pm - 4:30pm
Sickle Cell Patients with Leg Ulcers have a Pro-Thrombotic Profile

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Abstract

Authors:
Dr. Ugochi Ogu, Montefiore Medical Center, Ms. Ashley Buscetta, National Human Genome Research Institute/National Institutes of Health, Ms. Elena Crouch, Montefiore Medical Center, Dr. Shuo You, Montefiore Medical Center, Prof. Moonseong Heo, Montefiore Medical Center, Ms. Khadijah Abdallah, National Human Genome Research Institute/National Institutes of Health, Dr. Giacomo Vinces, ontefiore Medical Center,Mr. Vence Bonham, National Human Genome Research Institute/National Institutes of Health, Prof. Caterina Minniti, Montefiore Medical Center

OBJECTIVE: 
- To review coagulation profile in sickle cell disease (SCD). 
- To describe coagulation profile in SCD patients with leg ulcers. 
BACKGROUND:
Leg ulcers are a serious complication of Sickle Cell Disease, often linked to a hemolytic phenotype that includes, priapism, pulmonary hypertension and renal disease. In the SCD pathogenesis, hemolysis and ischemia-reperfusion injuries lead to WBC, platelet and endothelial cell activation, pro inflammatory cytokine production and subsequent activation of coagulation that tips the balance towards a prothrombotic state. Decreased levels of the naturally occurring anticoagulants (protein C, protein S, antithrombin III), have been observed in patients with SCD in steady state, with some reports stating no differences between steady state and crisis. These decreases occur due to decreased production, increased consumption, or a combination of both. However, the definite mechanisms have not yet been elucidated. Factor V Leiden and prothrombin G20210A mutations are rare in African Americans and in patients with SCD. We speculated that patients with leg ulcers would have a more pronounced pro-thrombotic phenotype than patients who never developed them. 
METHODS: 
127 adults with and without SCD leg ulcers were evaluated at steady state in the prospective cross-sectional INSIGHTS study - Insights into Microbiome and Environmental Contributions to Sickle Cell Disease and Leg Ulcers (ClinicalTrials.gov Identifier NCT02156102). At the time of enrollment, a clinical examination and a complete past medical history were completed. Routine blood work including a full coagulation profile and analysis of blood clotting genetic mutations (thrombophilia genetic tests) were obtained. Laboratory results were compared between groups with and without leg ulcers using Chi-square or Fisher exact tests.
RESULTS: 
The study cohort consisted of 109 adults with Hb SS, 10 with Hb SC, 5 with Hb S beta thalassemia zero, and 3 with Hb S beta thalassemia plus. Of these, there were 35 subjects with leg ulcers (33 with Hb SS, 1 with Hb S beta thalassemia zero, 1 with Hb SC disease). Naturally occurring anticoagulants were found to be decreased in the sub-group of subjects with leg ulcers. In SCD patients with leg ulcers, 49% had functional protein C levels that were below the lower limit of normal, compared to 27% in SCD patients without leg ulcers (*p=0.0220); 74% had functional protein S levels that were below the lower limit of normal, compared to 51% in SCD patients without leg ulcers (*p=0.0181); 23% had antithrombin III (AT III) levels that were below the lower limit of normal, compared to 17% in SCD patients without leg ulcers (p=0.4820); and 29% tested positive for lupus anticoagulant, compared to 25% in SCD patients without leg ulcers (p=0.6818). In SCD patients with leg ulcers, none of the subjects had the prothrombin gene mutation, while 3 subjects without leg ulcers were heterozygous for the prothrombin mutation. None of the subjects in our cohort had factor V Leiden mutation.
CONCLUSIONS: 
In SCD patients with leg ulcers, protein C and protein S levels are significantly lower than in SCD patients without leg ulcers. Additionally, in SCD patients with leg ulcers, there is a trend towards decreased levels of AT III, and higher percentage of patients that are positive for lupus anticoagulant. Factor V Leiden and prothrombin gene mutations were rare in our cohort, consistent with the general population. 
Our results of decreased naturally anticoagulants confirm previous reports from our group that demonstrated similar findings. Of greater significance, however, is our finding that sickle cell patients with leg ulcers have further decreased levels of the naturally occurring anticoagulants, compared to their counterparts without leg ulcers. This finding lends credence to the hypothesis that sickle cell patients with leg ulcers have a procoagulant phenotype.1,2 In such patients, the clinical index of suspicion for thromboembolic events should be high. It is important to consider and evaluate for venous clots in such patients. A deep venous thrombus (DVT) found in a sickle cell patient with leg ulcer, could be the primary inciting factor for the ulcer or deterrent for wound healing.  
Future directions of our study involve correlating these laboratory values with clinical history and findings in these patients. History of thromboembolic events such as DVT and pulmonary embolism (PE) will be evaluated to detect if the laboratory findings clinically correlate to a procoagulant phenotype. 
References: 
1-Am J Hematol. 2011 Aug; 86(8): 705–708. 
2-Am J Hematol. 2014 Jan; 89(1): 1–6



Speakers
avatar for Ugochi Ogu, M.D.

Ugochi Ogu, M.D.

Assistant Professor/ Asssitant Director, Montefiore Medical Center Division of Hematology, Department of Oncology
Dr. Ogu is an Assistant Professor of Clinical Medicine and Pediatrics at the Albert Einstein College of Medicine. She obtained her medical degree at Windsor University School of Medicine in the West Indies, completed residency in Pediatrics at the University of Iowa, and fellowship... Read More →


Friday October 12, 2018 4:15pm - 4:30pm
Constellation C

Attendees (6)