An Unusual Inhibitor of Coagulation Tests in a Patient with Lymphoproliferative Disease
Authors: Munro Roger C , Wakeman Lisa J , Al-Ismail Saad 
Published: April 2020

Abstract
We report the complex coagulation profile in a 74 year old female with progressive CLL and IgM paraproteinaemia and discuss the possible implication of these results in such a clinical setting. A 74 year old female with CLL was investigated for progression to high grade lymphoma and abnormal liver profile. Blood count parameters measured on a Sysmex 2100 were: Hb 10.5 g/dL (12–15.2); WBC 9.5 × 109/L (3.6–9.2) with lymphocytosis; PLT 71 × 109/L (180–380). She had deranged liver function with cholestatic picture thought to be due to NHL. Liver enzymes (U/L) were: Alk Phos 718 (30–250); AST 83 (&lt;40); GGT 502 (&lt; 75); ALT 41. She had a monoclonal IgM Lambda type paraprotein (5g/L) She also had a raised IgM ACA &gt;80.0 MPLU/mL (0–7). IgG and IgA ACAs were normal. She had no bleeding diatheses.
Coagulation parameters measured on a Sysmex CA1500 using Dade-Behring reagents and mixing with normal plasma showed markedly prolonged prothrombin time (PT) (Innovin) of 92 sec with no correction with normal plasma. The APTT was also markedly prolonged using (Actin FS) of 76sec and less prolonged at 48sec using lupus anticoagulant sensitive agent (Actin FSL) with no correction on mixing with normal plasma. Fibrinogen (Clauss) and TCT were normal. Thrombotest INR 1.2 (&lt;1.1). DRVVT ratio 1.93; with no platelet neutralisation (0%.) KCT test ratio 0.99 (0.9–1.2); KCT mix ratio 2.19. All extrinsic coagulation factor assays performed with Thromborel-S (human placenta thromboplastin) were essentially normal. Similarly, intrinsic factor assays were also normal or above the normal range but there was some degree of non-parallelism.
The inhibitor in our patient did not satisfy the criteria for diagnosis of a lupus-type anticoagulant (LTA). Furthermore, the more prolonged APTT result with Actin FS rather than with the more LTA-sensitive reagent Actin FSL mitigates the presence of LTA. The findings of a normal Thrombotest result and normal Thromborel-S derived coagulation factor assays suggest that the prolongation of the rTP-derived PT and the prolonged APTTs were not due to deficiencies of vitamin K dependent coagulation factors.
We have previously described the phenomenon of non-correctable inhibition of rTP-derived PTs associated with anti-cardiolipin antibodies (ACA) in patients with lymphoproliferative disease and also in one patient with IgM lambda paraproteinaemia. This case showed more complex coagulation results. It is possible that the combined presence of IgM ACA and IgM Lambda paraproteins in this patient may have resulted unusually aggressive activity directed against the limited number of phospholipids used for relipidation of rTPs. We believe that the finding of prolonged rTP-derived PT in the presence of a normal conventional thromboplastin-derived PT should be followed up by routine screening for the presence of unsuspected ACA or paraproteinaemia in patients with lymphoproliferative disease. Further investigations are required to elucidate the nature of the antibodies produced in these patients and to determine the extent to which their inhibitory effects may be the consequence of a laboratory epiphenomenon.