Activation of Clotting Factors in Thrombocytopenia Due to Platelets Destruction: A Possible Compensated Mechanism for Hemostasis.
Authors: Fontana Vincenzo , Jy Wenche , Ahn Eugene , Dudkiewicz Pamela , Horstman Lawrence L. , Bidot Carlos J. , Ahn Yeon S. 
Published: October 2019

Abstract
INTRODUCTION. Thrombocytopenia (TP) due to bone marrow failure, as in aplastic anemia (AA), is often associated with frequent and fatal bleeding, whereas fatal bleeding in TP due to platelet destruction, as in ITP, is rare. It has been suggested that giant platelets or increased cell-derived microparticles (MP) act to limit bleeding in ITP. We investigated clotting factors and MP from 3 cell types, platelets (PMP), leukocytes (LMP), and endothelial (EMP), in patients with different causes of their TP.
METHODS. Group 1 (platelet destruction) consisted of 2 subgroups, Grp 1a having n=35 pts with active ITP (ITP-A) and Grp 1b having n=15 pts with platelet destruction (PD) by other disorders (TTP, PNH, others). Group 2 (impaired production (IP)) consisted of n=19 pts with AA, MDS/MPD, and others. Group 3 comprised n=28 pts with ITP in remission (ITP-R). Laboratory measures included CBC, platelets, FVIII, FIX, FXI, and 3 kinds of MP: PMP, LMP, EMP. Signs and symptoms of bleeding were graded and recorded.
RESULTS. Key data is summarized in Table 1. The percentage of patients with elevated activity of FVIII was significantly more prevalent in Grp 1a vs. Grp 3 (53% vs. 15%, p=0.002) or Grp 1b vs. Grp 2 (73% vs. 11%, p=0.0002). The mean value of FVIII titer was also significantly higher in Grp 1a vs. Grp 3 (1.92 vs. 1.33 U/mL, p=0.0036) or Grp 1b vs. Grp 2 (2.44 vs. 1.18 U/mL, p=0.00007). The mean percentage of patients with elevated FIX or FXI, or the mean value of FIX or FXI titer were also higher in Grp 1a vs. Grp 3 or Grp 1b vs. Grp 2, but the difference did not reach statistical significance. PMP counts were found to correlate with platelet counts in all groups, and were significantly higher in Grp 3 than Grp 1a (p=0.0004). Grp 3 also had higher EMP than Grp 1a (p=0.04). LMP showed no significant differences.
REPRESENTATIVE CASE. A patient with chronic ITP who relapsed with severe acute ITP was monitored sequentially. In acute phase of TP, activities of FVIII, FIX, and FXI surged, in parallel with shortening of aPTT, and patient had minimal signs of bleeding. Serial assays revealed gradual fall of factor activities, reaching normal levels after 5 months. A similar pattern was observed in another patient, with acute TTP: clotting factors returned to normal after 2 months.
CONCLUSION. TP due to platelet destruction appears to trigger activation of intrinsic clotting pathway which may protect from excessive bleeding. Surge in FVIII was most notable. This compensation effect appears to be absent in TP due to depressed platelet production, and likewise for ITP in remission. The mechanism underlying this phenomenon remains to be elucidated. Further study is in progress to delineate the mechanism.
Table 1 Grp1a (ITP-A) Grp1b (PD) Grp2 (IP) Grp3 (ITP-R) p value p value Number 35 15 19 28 1a vs 3 1b vs 2 FVIII (%) 53 73 11 15 0.002 0.0002 FIX (%) 19 27 6 13 NS NS FXI (%) 16 14 0 8 NS NS PMP 8315 15531 9768 17085 0.0004 NS EMP 328 325 393 578 0.04 NS LMP 1388 1230 1255 1486 NS NS