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 (

Cancer 2001; 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

PatientNormal 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 
PatientNormal 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 

Disclosure: No relevant conflicts of interest to declare.

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