Case reports

Lessons from practice
Hematologic diseases
Volume 200 - Issue 5

Artefactual “in-vitro coagulopathy” in a patient with non-Hodgkin lymphoma and lower gastrointestinal bleeding

Authors:  Roderick O’Day, Golo Ahlenstiel, Anita Chittaranjan Shetty, Emmanuel J Favaloro, Stephen J Williams and Jerry Koutts

Med J Aust 2014; 200 (5): 293-294. || doi: 10.5694/mja13.10921
Published online: 17 March 2014
Abnormal results of coagulation tests do not necessarily indicate an actual coagulopathy; use with caution
Download PDF (138 KB)
Share: Share on Blue Sky Share on Facebook Share on LinkedIn Share by email

Clinical record

An 80-year-old man presented in August 2012 with lower gastrointestinal bleeding 3 days after a routine colonoscopy and polypectomy as a day procedure. Five sessile polyps had been excised from the right colon (one from the caecum, one from the hepatic flexure and three from the transverse colon); the largest polyp measured 8 mm. Additionally, a 20 mm sessile polyp was excised from the rectum by means of chromogel elevation and endoscopic mucosal resection.1 A resultant defect in the muscularis propria was closed with five endoclips. The patient was discharged in the evening, well after the procedure. Subsequent histopathological examination showed that the polyps were tubular or tubulovillous adenomas without dysplasia.

Three days after initial polypectomy the patient was woken from sleep by abdominal discomfort and an episode of passing about 500 mL of fresh blood from the rectum. On presenting to the emergency department, he continued to bleed, although at a slower rate. He was asymptomatic and haemodynamically stable. His haemoglobin level was 115 g/L (reference interval [RI], 130–180 g/L) on presentation, and dropped to 98 g/L after a second large bleed 8 hours later. His blood urea nitrogen level on admission was elevated (12.6 mmol/L; RI, 3.0–8.0 mmol/L), consistent with a gastrointestinal bleed.

The patient had multiple medical comorbid conditions, including non-Hodgkin lymphoma (NHL). He had relapsed with NHL a month earlier with a rise in his IgM paraprotein levels to 5.0 g/L (RI, 0.0 g/L) after 8 years in remission. He also had hypertension, ischaemic heart disease, Paget disease and prostate cancer. Previous surgery included repair of type B aortic dissection and a splenectomy. His medications on admission included aspirin, simvastatin, amlodipine, metoprolol and frusemide.

Initial results of blood tests (Table) showed an apparent coagulopathy, with a prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT), an international normalised ratio (INR) of 2.0, but a normal thrombin time. The haematology team was consulted to assess and, if necessary, haemostatically correct the apparent coagulopathy before endoscopic assessment.2.3

The differential diagnoses of concurrently prolonged APTT and PT are concomitant warfarin and heparin therapy, supratherapeutic warfarinisation or heparinisation, inherited clotting factor deficiencies, acquired clotting factor deficiencies (secondary to disseminated intravascular coagulation, liver disease or vitamin K deficiency) and acquired inhibitors of clotting factors.4 The patient was not receiving anticoagulation therapy. He had no previous history of bleeding or liver disease, and his fibrinogen levels were high (5.6 g/L; RI, 2.0–4.3 g/L), arguing against an acquired or hereditary clotting factor deficiency. Most importantly, mixing studies (which combine patient plasma with donor plasma that contains a normal concentration of clotting factors) did not correct the apparent coagulopathy. This is in keeping with the presence of either a clotting factor inhibitor or antiphospholipid antibodies.4

Further investigations showed moderately positive lupus anticoagulant levels and no specific factor VIII or IX inhibitor. Lymphoproliferative disorders are well known to cause abnormalities of coagulation studies and, in particular, can cause lupus anticoagulant activity.5 It was concluded that the apparent coagulopathy was an in-vitro phenomenon caused by an interaction between lupus anticoagulant and the reagents used in the coagulation studies. In the absence of any clinical features of antiphospholipid syndrome, it was considered that there was no need for active treatment for the lupus anticoagulant results, which would have consisted of anticoagulant therapy.6

After prompt resolution of the possible coagulopathy issue by laboratory staff and haematologists (ie, establishing that there was indeed no in-vivo coagulopathy), the patient underwent urgent flexible sigmoidoscopy for ongoing rectal bleeding that evening, 17 hours after presentation. He was found to have active bleeding from the complicated rectal polypectomy site. Haemostasis was achieved with thermocoagulation and clipping. He recovered well and was discharged home 48 hours later having experienced no further bleeding and maintaining stable haemoglobin levels.

Results of the patient's coagulation studies on admission

Study

Value

Reference interval

Prothrombin time (PT)

25 seconds

11–18 seconds

Activated partial thromboplastin time (APTT)

75 seconds

25–36 seconds

International normalised ratio

2.0

na

Mixing study

No correction of prolonged APTT and PT

Thrombin time

16 seconds

10–17 seconds

na = not applicable.

Bleeding after polypectomy is not uncommon, occurring in about 2% of patients overall, and up to 7% of patients after an endoscopic mucosal resection involving a muscularis propria defect.1,7 The main predictors of bleeding include the type and size of the polyp (sessile polyps larger the 20 mm confer a high risk), anticoagulation or antiplatelet therapy and multiple comorbid illnesses.1,8 The management of bleeding after polypectomy consists of resuscitating the patient, correcting any coagulopathy and then performing a colonoscopy or urgent computed tomography angiography.3 Despite remaining haemodynamically stable, our patient was considered to be at high risk because of his multiple comorbid illnesses, persistent bleeding, anaemia, aspirin use and elevated blood urea nitrogen test result.1,8 In the absence of the haemostatic anomaly, he would have undergone urgent endoscopic intervention within 2 hours of presenting to the emergency department. By contrast, the flexible sigmoidoscopy was delayed for more than 10 hours to allow further investigation of the apparent coagulopathy.

In this patient's case, the initial blood workup — with mixing studies not correcting the anomalies — suggested the presence of either a clotting factor inhibitor or lupus anticoagulant.4 Differentiating between these was both crucial to the patient's care in the short and long term, and very challenging to achieve. If a clotting factor inhibitor was found, the patient would have required high level and expensive haemostatic support, potentially including the use of activated factor VII. On the other hand, the finding of a moderate level of lupus anticoagulant would not be a cause for active intervention, because the patient did not have any clinical features of antiphospholipid syndrome.6

Lessons from practice

  • Abnormalities in coagulation studies may not represent an in-vivo coagulopathy.
  • If abnormal coagulation results are not corrected by mixing studies, the main differential diagnoses are the presence of a clotting factor inhibitor or lupus anticoagulant activity.
  • Differentiating between these is essential, as one is a true coagulopathy that might require high-level haemostatic support and the other represents a pro-thrombotic state.
  • The diagnosis of lupus anticoagulant activity is complex, especially in a clinical scenario with circulating serum paraprotein, and many laboratories misinterpret these cases as clotting factor inhibitors.

Distinguishing between lupus anticoagulant activity and the presence of a clotting factor inhibitor was particularly difficult because of the high levels of paraprotein in the patient's serum.9,10 In a recent study of 93 members enrolled in the lupus anticoagulant module of the Special Haemostasis Program of the Royal College of Pathologists of Australia Quality Assessment Program, only 58% of laboratories correctly diagnosed the presence of lupus anticoagulant in a sample that was strongly positive for lupus anticoagulant and that also had a high titre of paraprotein.9 Many laboratories instead incorrectly identified specific factor inhibitors. If this had happened in our case, it would have led to efforts to reverse the apparent coagulopathy.

This case is an example of a rare haematological diagnostic problem, described only in case reports, leading to delayed definitive therapy in a bleeding patient. It highlights the importance of a sound knowledge of the science underlying the investigations that we order. Physicians must understand the distinction between abnormal results and actual abnormality. Early involvement of the haematology team prevented us from attempting unnecessary reversal of a suspected coagulopathy. Attempting to do so would have (i) further delayed the definitive treatment of this patient; (ii) exposed the patient to needless intervention and possible adverse events; (iii) been potentially very expensive (should activated factor VII been contemplated); and (iv) would likely have failed to correct the in-vitro identified defect in any case.

Authors

  • Roderick O’Day MB BS(Hons), LLB(Hons), BSc1
  • Golo Ahlenstiel MD1
  • Anita Chittaranjan Shetty MB BS2
  • Emmanuel J Favaloro PhD, FFSc(RCPA)3
  • Stephen J Williams MB BS, MD, FRACP1
  • Jerry Koutts MB BS, MD, FRACP3
  • 1. Westmead Hospital, Sydney, NSW.
  • 2. Nepean Hospital, Sydney, NSW.
  • 3. Institute of Clinical Pathology and Medical Research, Pathology West, Sydney, NSW.

Correspondence: Roderick.oday@gmail.com

Competing interests

No relevant disclosures.

References

Provenance: Not commissioned; externally peer reviewed.

View this article on Wiley Online Library