Super‐elevated <scp>LDH</scp> and thrombocytopenia are markers of a severe subtype of vaso‐occlusive crisis in sickle cell disease
Authors: Kate Gardner, Swee Lay Thein
Journal: American Journal of Hematology (2015)

Sickle cell disease (SCD) is characterized by recurrent acute vaso-occlusive crises (VOCs) that can progress to life-threatening complications. Serum lactate dehydrogenase (LDH) is normally elevated in steady-state SCD, then increases further during VOC; the increase being an indication of tissue damage 1, 2. To further understand the role of LDH as a biomarker, we retrospectively reviewed the clinical and laboratory profiles of sickle-related VOCs over a ten-year period (2004–2013 inclusive) involving our cohort of 751 adult patients (4,136 patient-years of observation) attending King's College Hospital, London, UK. Laboratory data were categorized as “steady state” or “acute.” A patient's “baseline” steady-state values were defined as the mean of all outpatient clinic results over the study period. “Acute hospital admission” was defined as an emergency admission to a hospital ward for continuing care. Demographic details and laboratory results were collected by interrogating the Electronic Patient Records (EPR). Statistical analyses were performed in Microsoft Excel 2010 using Student's t test (including comparison of “steady state” and “acute” data, as well as comparing the “cohort” with the “case series”) and Pearson's correlation coefficient. Non-parametric variables were compared using chi-squared testing. Over the 10 years, 504 of the 751 patients experienced 2,822 hospital admissions. As observed in other studies, our data found a significant increase in LDH levels during VOC (mean of peak LDH 564 ±432 IU/L, increase of 56% relative to steady-state (P < 0.00001)). Peak LDH occurred on Day 2.83 (±5.10) of admission (Fig. 1). Platelet counts also changed significantly in VOC—initially becoming significantly lower compared to steady-state reaching a nadir (mean minimum of 295 ± 151 × 109/L) on Day 3.11 (±5.07) of admission, and then increasing to levels significantly higher than steady-state reaching a mean maximum of 424 (±226 × 109/L) on Day 4.55 (±6.68) of admission (P < 0.00001, for both minimum and maximum values, compared to steady-state values). The platelet count nadir coincides with the LDH peak (see Fig. 1). Temporal relationship between LDH and platelet trajectories during an APE admission in cohort and case series. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Among the 2,822 VOCs, we noted a small but distinct subgroup (18 patients) with very elevated LDH values (>1,500 IU/L—≥400% of baseline LDH) accompanied by concomitant thrombocytopenia (<150 × 109/L) (Supporting Information Fig. 1). Details of the 18 cases are in Supporting Information Table I. Average age on admission of the 18 patients was 33.02 years (±14.75 years); 12 patients were male, 15 had HbSS, and 3 HbSC. Their clinical histories varied from minimal sickle problems to major co-morbidities (Supporting Information Table I). Median number of admissions over 10 years for these patients was nine (IQR 3.25–24.75 admissions) compared to three for the whole 504-admitted cohort. Five of the 18 patients had at least three hospital admissions per year due to VOC. All other hospital admissions for these same patients were accompanied by mild elevations in LDH (Supporting Information Fig. 2 for trajectory of LDH over time for individual patients, and Supporting Information Fig. 3 for LDH values vs. platelet counts). Two patients were on hydroxyurea therapy, two were on regular exchange transfusion programs, and none were on simple transfusion programs. Five of the 18 cases had causes extrinsic to SCD as the primary contributor of the admission: two had a surgical cause for their presentation etiology both resulting in a septic, coagulopathic state; and three patients developed a delayed hemolytic transfusion reaction. The remaining 13 patients were admitted with a seemingly typical VOC accompanied by acute pain and fever, mild hemoglobin decrease, mild LDH increase, and platelets similar to steady state. In the subsequent days, the patients became severely unwell, and hyper-acutely, they developed both a strikingly elevated LDH, and a synchronous drop in platelet count. Peak LDH to mean 2,530 (±775) IU/L) occurred a median 2.5 (IQR 2–3.75) days after admission, with minimum platelet count to mean 74 (±40) × 109/L) at 1 (IQR 0–2) day later (Fig. 1). Of the 18 patients, 15 required red cell transfusion: 10 patients had a simple blood transfusion and five, a red cell exchange transfusion. Separately, two patients were plasma exchanged and three received plasma infusions. LDH swiftly reduced with transfusion (either red cell or plasma) and treatment of the underlying cause (Supporting Information Fig. 2), and hemoglobin rose (with or without transfusion). Subsequently, most had a rebound thrombocytosis with peak platelet count (mean maximum 643 ±512 × 109/L) a median of 10.5 (IQR 5.25–13.75) days after the minimum platelet count, i.e. Day 14 of hospital admission. Except for the three patients with hemolytic transfusion reactions, all patients’ direct anti-globulin test tests were negative where tested (6 of 12 patients). The outcome was poor in five of the 18 cases: two patients died, another suffered cauda equina syndrome with residual paraparesis, one now requires home oxygen therapy, and the fifth had a splenic sequestration a week later. The mean length of stay for these 18 patient admissions was 19.8 ± 11.8 days, significantly higher than both the mean length of stay for their other hospital admissions (6.3 ± 4.7 days) over the 10-year study period (P < 0.001) and for the mean hospital stay of 7.5 ± 8.4 days for the overall cohort (P < 0.001). In conclusion, our data suggests that super-elevated LDH levels with thrombocytopenia in sickle VOC represent a distinct, unpredictable but severe acute sickle phenomenon, leading to longer length of hospital stay and high transfusion rate. Severe acute phenomena in SCD have previously been associated with thrombocytopenia. Shome et al. suggested that VOC with markedly elevated LDH and thrombocytopenia represents an acute thrombotic microangiopathy; in this case series, all patients received blood transfusion and plasma exchange successfully (no documented ADAMTS13 level) 3. Indeed, prior to ADAMTS13 discovery, plasma exchange was considered a therapeutic strategy in multi-organ failure in SCD 4. Hassell et al. described 17 episodes of typical sickle acute pain that subsequently progressed to multi-organ failure, with most patients developing significant hemolysis and thrombocytopenia 5. Thrombocytopenia in severe sickle VOC was also noted by the US National Acute Chest Syndrome Study Group 6. It is not clear whether “super-elevated” LDH and thrombocytopenia marks the “severe” end of the sickle VOC spectrum or represents a micro-angiopathic hemolytic process, but this combination should prompt early intervention such as transfusion. KG and SLT wrote the manuscript. Authors thank Claire Steward for help in preparation of the manuscript, and Clive Stringer (Systems Delivery Manager and Deputy IT Director, Information and Communications Technology (ICT) Directorate, King's College Hospital NHS Foundation Trust) for assistance in obtaining medical records of the patient cohort. Kate Gardner1,2, Swee Lay Thein1,2,3* 1Division of Cancer Studies, Faculty of Life Sciences & Medicine, Molecular Haematology, King's College London, London SE5 9NU, United Kingdom; 2Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London SE5 9RS, United Kingdom; 3Sickle Cell Branch, NIH, National Heart, Lung, and Blood Institute, Bethesda, Maryland Additional Supporting Information may be found in the online version of this article. Additional Supporting Information may be found in the online version of this article. 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