A Fatal Bleeding Disorder Due to Antibody Mediated Acquired Factor X and Prothrombin Deficiency.
Authors: Rochanda Leanne , Feinstein Donald I. , del Zoppo Gregory J. , Liebman Howard A. 
Published: April 2020

Abnormalities in hemostasis are well described in patients with malignant disorders. While hemostatic activation resulting in thrombosis is most often described, acquired hemorrhagic disorders have also been reported. We report a case of a fatal hemorrhagic disorder in a lymphoma patient due to an acquired Factor X and prothrombin deficiency. The patient’s plasma contained a non-inhibitory IgG antibody that cross-reacted with and cleared from the circulation both Factor X and Prothrombin. The patient was a 72 year old male who was first noted to have persistant bleeding after angioplasty in 1991. Over the subsequent 10 years he had repeated bleeding episodes and was noted to have a prolonged PT and a PTT which corrected with a 50–50 mix of normal plasma. In 2002 he was diagnosed with a monocytooid B cell lymphoma. In April 2002 the patient had an extensive hemostatic evaluation by one of the authors (DIF) which is included in Table 1.

These studies again showed a prolonged PT and aPTT which corrected with a 50–50 mix. Factor II activity and antigen were significantly reduced. While Factor X activity was low normal, Factor X antigen was decreased compared to the normal controls. Patient IgG was then isolated by Stap A chromatography and anit-prothrombin antibodies directed were isolated by affinity chromatography on prothrombin-sepharose. Isolated antibodies were subtyped as an IgG subclass 4. The antibodies were assayed for their interaction with prothrombin by a direct binding ELISA and found to be calcium dependent since they did not bind in the presence of 5 mM EDTA. The interaction of the affinity isolated antibody with prothrombin, Factor X and Factor IX was assessed using the Western Blot method. Surprisingly, the antibody also bound strongly to Factor X and to a lesser degree to Factor IX. Western blot analysis of the Factor X and Factor IX preparations using a monoclonal anti-prothrombin antibody failed to demonstrate any prothrombin contamination of these proteins. A competition ELISA using prothrombin, Factor X and Factor IX showed that the antibody had a 3-fold greater affinity to Factor X then prothrombin. A Western blot using purified prothrombin fragment F1.2 confirmed that the antibody bound to a metal dependent conformational determinant on the amino-terminal Gla containing region of Factor II.

In April 2003 the patient developed weakness in his left leg and was found to have a right parietotemporal subdural hematoma. Factor II activity was again only 34%. Intravenous IgG 1gm/kg on two separate days did not correct his coagulation studies. In June 2003 the patient developed a new large left sudural hematoma. He rapidly deteriorated and expired. We previosuly reported a lymphoma patient who developed acquired prothrombin deficiency associated with a non-inhibitory antibody (Cancer2001; 91: 636), however, this is the first reported case of combined acquired Factor X and Prothrombin deficiency due to a cross-reactive non-inhibitory IgG antibody.

Table1: Hemostatic Assays Patient Normal Range PT (INR) 13.4(1.3) 4.1–10.2 PT 50/50 10.3 aPTT(ratio) 52.5(1.8) 26.5–36.1 aPTT 50/50 29.7 Thrombin Time 17.7 14.8–18.4 Fibrinogen(mg/dL) 398 155–369 Factor V (Activity%) 129 60–180 Factor II (Activity%) 42 70–150 Factor II (Antigen mcg/ml) 46.1 102–126 Factor X (Activity%) 65 60–150 Factor X (Antigen mcg/ml) 6.2 7.9–11.5 Lupus Anticoagulant Negative Negative