Coagulopathy is an under-recognised complication of acquired HLH

Abstract

Acquired haemophagocytic lymphohistiocytosis (aHLH) is a rare and often fatal process of uncontrolled cytokine release driven by the inability of natural killer cells to eliminate infected or malignant cells. Herein, we report two cases of aHLH complicated by bleeding secondary to coagulopathy due to hypofibrinogenaemia and thrombocytopenia despite appropriate correction with blood products. These cases highlight the effect coagulopathy and thrombocytopenia can have on patient outcomes when trying to confirm and manage the underlying process driving aHLH.

Background

Acquired haemophagocytic lymphohistiocytosis (aHLH) is a potentially fatal syndrome that is caused by immune dysregulation and excessive cytokine production driven by the inability of natural killer cells to eliminate infected or malignant cells. In contrast to its familial counterpart, an underlying genetic defect is absent or is heterozygous only and the presentation is in adulthood following a trigger, usually infective or neoplastic. Identifying and addressing the underlying driver are critical to successful management. Thrombocytopenia and hypofibrinogenaemia are recognised features of HLH, forming part of the diagnostic criteria, though the mechanisms are not fully understood.^{1 2}

Case presentation

Case one

A man in his 70s was admitted with septic shock secondary to Pseudomonas aeruginosa bacteraemia. Intravenous antibiotics and vasopressors resolved the bacteraemia and shock; however, fevers continued for 2 weeks following clearance of blood cultures. The patient developed pancytopenia (including profound lymphopenia), liver dysfunction, hypofibrinogenaemia and hyperferritinaemia (22 100 µg/L). Bone marrow examination demonstrated haemophagocytosis. Soluble CD25 was 32 161 pg/mL (normal range <2678 pg/mL). The diagnosis of aHLH was established with six of eight HLH2004 criteria and an HScore of 245 (99% likelihood of HLH).^{1 3}

Despite ongoing appropriate antimicrobials and the addition of corticosteroids, the patient’s condition deteriorated and the driver of the aHLH remained unclear. While D-dimer was elevated to 3.2 mg/L (normal range <0.49 mg/L) and concomitant disseminated intravascular coagulation (DIC) may have been present, it was unlikely to have a significant effect on coagulopathy in the setting of appropriate sepsis management, as measured by subsequent negative blood cultures. Several fluorodeoxyglucose-positron emission tomography-avid lung nodules were identified and showed no resolution with ongoing antibiotic treatment. Bronchoscopy was unremarkable; thus, a CT-guided percutaneous biopsy was sought. The coagulation studies demonstrated a Clauss fibrinogen of 0.8 g/L with a normal prothrombin time (PT) and activated partial thromboplastin time (APTT). D-dimer was elevated to 3.2 mg/L. The platelet count was 45×10⁹/L. Ten units of cryoprecipitate and two units of platelets were administered to good effect, which improved the platelet count to 66×10⁹/L and the fibrinogen to 1.9 g/L.

Despite these measures, the patient had a major and ultimately fatal pulmonary haemorrhage post-biopsy despite further blood product support. Rotational thromboelastometry (ROTEM) following the haemorrhage demonstrated a prolonged INTEM (ellagic acid-activated intrinsic pathway) of 230 s (normal range 161–204 s) but was otherwise preserved (figure 1 and table 1). Post-humous examination of the lung tissue was consistent with organising pneumonia.

Figure 1.

Reaction curve from ROTEM in case one. APTEM, EXTEM-based assay which inhibits fibrinolysis; EXTEM, tissue factor-triggered extrinsic pathway; FIBTEM, EXTEM-based assay with platelet inhibitor to evaluate contribution of fibrinogen to clot formation; INTEM, ellagic acid-activated intrinsic pathway; ROTEM, rotational thromboelastometry.

Table 1.

Corresponding ROTEM values in case one

	CT (s)	A5 (mm)	A10 (mm)	A20 (mm)	A30 (mm)	CFT (s)	MCF (mm)	Alpha (degrees)
FIBTEM	73	11	12	12	13	—	12	67
EXTEM	84	37	47	54	57	107	58	72
INTEM	230 (normal 161–204)	36	46	53	56	113	57	69
APTEM	79	36	46	53	56	114	57	71

A5, amplitude 5 min after CT; A10, amplitude 10 min after CT; A20, amplitude 20 min after CT; A30, amplitude 30 min after CT; alpha, alpha-angle; APTEM, EXTEM-based assay which inhibits fibrinolysis; CFT, clot formation time; CT, clotting time; EXTEM, tissue factor-triggered extrinsic pathway; FIBTEM, EXTEM-based assay with platelet inhibitor to evaluate contribution of fibrinogen to clot formation; INTEM, ellagic acid-activated intrinsic pathway; MCF, maximum clot firmness; ROTEM, rotational thromboelastometry.

Case two

A man in his 30s was initially admitted to hospital with liver dysfunction, bicytopenia and coagulopathy following an episode of presumed gastroenteritis 2 weeks prior. He rapidly developed acute hepatitis and subsequent liver and multiorgan failure, eventually developing encephalopathy that required intubation. Viral hepatitis, autoimmune and infective screening was performed and the patient was found to have Epstein-Barr virus (EBV) infection, with a serum viral load of 1.2×10⁷ copies/mL. Liver dysfunction and coagulopathy worsened with associated hyperferritinaemia (300 000 µg/L). While D-dimer was elevated to 8.99 mg/L, an isolated EBV infection is a rare cause of DIC and an alternative or contributory diagnosis was sought, particularly in light of the hyperferritinaemia. Bone marrow aspirate was performed which showed haemophagocytosis. Soluble CD25 was 35 842 pg/mL (normal range <2678 pg/mL). The diagnosis of aHLH was established with seven of eight HLH2004 criteria and an HScore of 268 (99% likelihood of HLH).^{1 3}

In the setting of acute liver failure and the development of abdominal pain, an exploratory abdominal laparoscopy and liver biopsy were performed. The coagulation studies demonstrated a Clauss fibrinogen of 1.2 g/L with a prolonged APTT (85 s) and normal PT. D-Dimer was elevated to 8.99 mg/L.

Histology was consistent with intravascular coagulation and mild ischaemic hepatitis. No infiltrative or malignant process was identified on liver biopsy. Despite appropriate correction of underlying coagulopathy and thrombocytopenia with blood product support (PT 11 s, APTT 50 s, fibrinogen-C 1.9 g/L, platelets 99×10⁹/L), continuous haemorrhage occurred over the ensuing week from operative/biopsy sites requiring multiple blood transfusions, product replacement and ultimately laparotomy for abdominal compartment syndrome. Haemorrhage did not cease until the addition of tranexamic acid and control of the HLH with the HLH-94 protocol. Preoperative ROTEM again demonstrated prolonged INTEM of 492 s (normal range 161–204 s) with reduced A10 (amplitude 10 min after CT) of 34 mm (normal range 43–62 mm). A10 was also reduced for EXTEM (tissue factor-triggered extrinsic pathway) and APTEM (EXTEM-based assay which inhibits fibrinolysis); notably, FIBTEM (EXTEM-based assay with platelet inhibitor to evaluate contribution of fibrinogen to clot formation) was normal (figure 2 and table 2).

Figure 2.

Reaction curve from ROTEM in case two. APTEM, EXTEM-based assay which inhibits fibrinolysis; EXTEM, tissue factor-triggered extrinsic pathway; FIBTEM, EXTEM-based assay with platelet inhibitor to evaluate contribution of fibrinogen to clot formation; INTEM, ellagic acid-activated intrinsic pathway; ROTEM, rotational thromboelastometry.

Table 2.

Corresponding ROTEM values in case two

	CT (s)	A5 (mm)	A10 (mm)	A20 (mm)	A30 (mm)	CFT (s)	MCF (mm)	Alpha (degrees)
FIBTEM	84	8	9	11	12	—	13	55
EXTEM	78	24	34 (normal 43–63)	42	45	223	48	63
INTEM	492 (normal 161–204)	23	34 (normal 43–62)	41	44	236	47	55
APTEM	89	23	32 (normal 39–61)	41	44	246	48	59

A5, amplitude 5 min after CT; A10, amplitude 10 min after CT; A20, amplitude 20 min after CT; A30, amplitude 30 min after CT; alpha, alpha-angle; APTEM, EXTEM-based assay which inhibits fibrinolysis; CFT, clot formation time; CT, clotting time; EXTEM, tissue factor-triggered extrinsic pathway; FIBTEM, EXTEM-based assay with platelet inhibitor to evaluate contribution of fibrinogen to clot formation; INTEM, ellagic acid-activated intrinsic pathway; MCF, maximum clot firmness; ROTEM, rotational thromboelastometry.

Outcome and follow-up

Case one

As described above, the patient died while in hospital within 20 min of the CT-guided percutaneous lung biopsy. He was not responsive to several transfusions of blood products, per local massive transfusion policy, and his management was changed to palliative care.

Case two

In this case, postoperative bleeding was controlled within 1 week with tranexamic acid and HLH treatment per HLH-94 protocol. The patient spent 2 weeks in the intensive care unit for monitoring and eventually returned to the ward. No further procedures were required or performed on the patient. He was discharged after a 2-month hospital admission and returned to work and his usual activities post-discharge. He is planned for outpatient follow-up over the next 2 years and has been stable since discharge; he has not required any further treatment and has not had any subsequent bleeding events.

Discussion

aHLH is often fatal without establishment of the underlying cause. Hypofibrinogenaemia and thrombocytopenia are recognised features of aHLH though bleeding is not well described. Herein, we have reported two cases of major bleeding in patients with aHLH-induced coagulopathy despite appropriate correction with blood products.

The coagulopathy aetiology is poorly understood. Thrombocytopenia is multifactorial and likely relates to marrow suppression from high levels of endogenous cytokines such as tumour necrosis factor-alpha and interferon-gamma as well as haemophagocytosis of platelets in the marrow, liver and spleen. The hypofibrinogenaemia may in part be explained by the hyperfibrinolysis driven by secretion of plasminogen activator by activated macrophages.² It is possible that a component of DIC occurred and contributed to the bleeding phenotype in our patients; however, we believe it is unlikely that it was the dominant primary aetiology on the basis that (a) in case one, the putative driver of DIC (bacterial sepsis) had resolved with adequate treatment almost 2 weeks prior to the bleeding event, and (b) systemic EBV infection, as in case two, is not a well-recognised cause of DIC. It is possible, however, that a DIC-like process contributes to the coagulopathy resulting from HLH itself.

Severe coagulopathy is associated with increased mortality in aHLH.^{4 5} However, this likely reflects the underlying severity of the aHLH itself rather than haemorrhagic complications. As patients with HLH often need biopsies to establish a diagnosis, bleeding may be an under-recognised complication requiring a careful consideration of risks versus benefits and aggressive correction with cryoprecipitate/fibrinogen concentrate, fresh frozen plasma and platelets. Severe bleeding occurred in both patients with hypofibrinogenaemia, which is consistent with the notion that it is the most important predictor of haemorrhage in this patient group, and aggressive platelet transfusion, cryoprecipitate and tranexamic acid are critical.⁵

While ROTEM analysis is not required to make a diagnosis of aHLH, it can be a beneficial tool to assess bleeding risk and guide transfusion strategy given it is a rapid, real-time whole blood assessment of coagulation, including platelet function and fibrinogen. In this way, ROTEM may assist in bleeding risk assessment in patients with aHLH. Where available, ROTEM use can complement traditional coagulation studies and help localise the deficiency in coagulation, which may assist with rationalisation of blood product support.⁶

Learning points.

• Severe coagulopathy is associated with increased mortality in acquired haemophagocytic lymphohistiocytosis (aHLH); this may reflect the underlying severity of the aHLH rather than the haemorrhagic complications.

• Severe bleeding occurred despite normal prothrombin time and activated partial thromboplastin time.

• Bleeding may be an under-recognised complication of HLH; thus, careful risk–benefit analysis of interventions such as biopsies is prudent given the frequent requirement for histological tissue to establish an underlying HLH driver.

• Thrombocytopenia and hypofibrinogenaemia appear to play a significant pathogenic role; aggressive platelet transfusion, cryoprecipitate and tranexamic acid are critical.

• Rotational thromboelastometry may assist in bleeding risk assessment of patients with aHLH. Prolonged INTEM (ellagic acid-activated intrinsic pathway) times occurred in both cases.

Ethics statements

Patient consent for publication

Obtained.