key: cord-0811626-mikyyyru
authors: Seshadri, Madhav; Ahamed, Jasimuddin; Laurence, Jeffrey
title: Intervention in COVID-19 linked hypercoaguable states characterized by circuit thrombosis utilizing a direct thrombin inhibitor
date: 2020-09-08
journal: nan
DOI: 10.1016/j.tru.2020.100009
sha: 13717045cb6f8839099cc8cbf284b702d98b006e
doc_id: 811626
cord_uid: mikyyyru

• Complex coagulopathies are a feature of severe COVID-19. Circuit thrombosis complicates continuous renal replacement therapy (CRRT) and ECMO, and has a high incidence despite standard heparin-based anticoagulation regimens. • We describe 5 cases of CRRT circuit thrombosis despite use of prophylactic or therapeutic doses of unfractionated or low molecular weight heparin. All 5 were resolved on initiation of a direct thrombin inhibitor, argatroban. • Changes in fibrinogen levels better reflected response to anticoagulation than did extent of changes in d-dimer levels. • Discussion as to potential reasons for better response to a direct thrombin inhibitor in a disorder such as COVID-19, complicated by high fibrinogen levels and decreased anti-0thrombin III levels is offered.

Progressive respiratory failure and acute kidney injury (AKI) are associated with the highest risk of mortality in SARS-CoV-2-associated Coronavirus disease 2019 (COVID-19). [1] [2] [3] These manifestations are linked to a systemic microvascular thrombosis associated with persistent activation of the complement 4 and coagulation 5, 6 cascades.

We investigated five individuals with critical COVID-19, including respiratory failure and an AKI complicated by circuit thrombosis during continuous renal replacement therapy (CRRT), who were hospitalized in an intensive care unit (ICU) setting. Thrombosis occurred despite use of standard ICU anti-coagulation regimens. 6, 7 This is a frequent complication of COVID-19, noted in 28 of 29 cases in one series of CRRT cases. 8 Appropriate interventions are unknown. Circuit thrombosis was heralded by a marked rise in D-dimer levels in 4 of our 5 cases, and a persistent elevation of fibrinogen in all cases. Although fibrinogen is not an independent risk factor for COVID-19 mortality, its elevation is relevant to CRRT clotting for two reasons: high levels of fibrinogen are associated with heparin resistance, 5 and ultrafiltration results in concentration of fibrinogen on dialyzer capillaries. 8 Resolution of the need for repetitive filter replacement and a decline in D-dimer and fibrinogen levels followed substitution of argatroban, a direct thrombin inhibitor.

All five patients had co-morbidities classic for severe/critical COVID-19 as well as elevated lactate dehydrogenase (LDH) and absolute neutrophil counts (ANC) ( Table 1) .

Measures of organ and tissue dysfunction consistent with a hypercoaguable state, including liver function abnormalities and skeletal muscle damage, assessed by aspartate transaminase (AST) and creatine kinase (CK), respectively, were also J o u r n a l P r e -p r o o f prevalent (Table 1) . COVID-19-associated coagulopathies have been shown to correlate with pro-inflammatory cytokines interleukin (IL)-6 and C-reactive protein (CRP). 5 CRP levels were high in all 5 cases, and IL-6 levels elevated in all 3 cases tested (Table 1) .

International Society on Thrombosis and Hemostasis diagnostic criteria, SOFA (sequential organ system failure assessment) scoring, or elevation of the International Normalized Ratio in the setting of thrombocytopenia (Table 1) . Although 4T scores to evaluate the possibility of a heparin-induced thrombocytopenia (HIT) were <4 in all cases, indicating a low probability of this phenomenon, ELISAs for anti-platelet factor 4 (PF4) antibodies were performed in Cases 2, 3, and 5 and were negative. (Table 1) , and a 60% decrease in D-dimers, though persisting >7000ng/ml ( Figure) . Fibrinogen levels declined from a peak of 585ng/ml (normal 180-400ng/ml) at the initiation of argatroban to normal levels within 3 days (Table) , despite the fact that Ddimers, though declining, remained elevated ( Figure) . Successful transition back to therapeutic UFH was achieved five days later.

A steady decline in D-dimers paralleled initiation of therapeutic UFH, with aPTT times >80 seconds (Figure) . Despite this salutary trend, fibrinogen levels remained elevated at >550mg/dL, and circuit clotting was observed on initiation of CRRT (Figure) .

Anti-thrombin (AT)III levels, drawn on UFH, were suppressed at 58% (normal 82-136%). With persistent filter clotting over the next four days, UFH was replaced by argatroban on day four. This led to resolution of filter clotting, with successful transition back to prophylactic UFH eight days later. Cessation of circuit clotting was accompanied by normalization of fibrinogen (Table 1) , albeit D-dimers remained ~2500ng/ml (Figure) . Argatroban was then discontinued in favor of therapeutic UFH, with maintenance of aPTT levels >80 seconds. Over the next four days, fibrinogen levels increased to 672mg/dL ( Table) in the context of a resurgence of D-dimers ( Figure) , and circuit clotting and arterial thrombi were noted 4 days later.

The development of persistent circuit thrombosis during CRRT in the context of standard anticoagulation regimens, observed in our five cases, and by others for both CCRT and extracorporeal membrane oxygenation (ECMO), greatly exceed rates typical in the ICU setting. 5, 8 This is another example of the fact that resistance to UFH, as well as sub-optimal peak anti-Xa levels following therapeutic low molecular weight heparin (LMWH), appears to be common among COVID-19 patients in the ICU. 9 A direct thrombin inhibitor such as argatroban may prove superior to therapeutic heparins in these situations. Our data also illuminate the need for active surveillance using both D- successfully treated with argatroban. 10 None had circuit thrombosis with CRRT or ECMO while on this therapy. The investigators suggested that heparin resistance was a consequence of low ATIII levels in their cohort, which ranged from 19-49 IU/dl, as levels >50 IU/dl are considered necessary to achieve an anticoagulant effect with heparin. 10 However, it appears that ATIII was measured while these patients were on heparin.

Heparin lowers levels of detectable ATIII antigen and activity detection by ~30%, a phenomenon thought secondary to accelerated clearance, while having no impact on its anticoagulant activity. 11 In fact, a large case series found that ATIII levels rarely fall below 80% in COVID-19, regardless of disease severity. 12 In the two patients from our cohort for whom ATIII levels were measured, both were >50%: Case 4 at 92% (off UFH), and Case 3 at 58% (measured during UFH use).

Changes in ATIII function in vivo in severe COVID-19 remain a possibility, however, as it can be inactivated by metalloproteinases and coagulation proteases, both elevated in J o u r n a l P r e -p r o o f the inflammatory milieu of COVID-19, 4,5 that cleave its catalytic domain without reducing protein levels. 13 In addition, abnormalities in fibrinolysis may be involved.

There is a delicate balance between host coagulation and fibrinolytic pathways. SARS-CoV infection of mice can overwhelm pro-fibrinolytic signaling via the urokinase pathway. 14 A thromboelastography study similarly documented abnormalities of fibrinolysis in severe COVID-19. 15 Argatroban, unlike heparin, can enhance fibrinolysis by differential inhibition of thrombin-mediated activation of thrombin activatable fibrinolysis inhibitor (TAFI) and a decreased, though persistent, activation of factor XIII. 16 

All three authors contributed to study design and data analysis. Patient data were collected by Ms. S. and J.L. J.L. wrote the paper, which has been reviewed by all authors.

JL has received grants and honoraria from Alexion, Inc. and Omeros, Inc., manufacturers of anti-complement drugs. The remaining authors declare no competing financial interests. concern for a bleed following an acute drop in hemoglobin.

J o u r n a l P r e -p r o o f

Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study

Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area

Kidney disease is associated with in-hospital death of patients with COVID-19

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases

COVID-19 and its implications for thrombosis and anticoagulation

COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure

Heparin thromboprophylaxis in medicalsurgical critically ill patients: a systematic review and meta-analysis of randomized trials

High risk of thrombosis in severe SARS-CoV-2 infection: a multicenter prospective cohort study

Heparin resistance in COVID-19 patients in the intensive care unit

Anticoagulation with argatroban in patients with acute antithrombin deficiency in severe COVID-19

Laboratory tests for antithrombin deficiency

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Anticoagulant and signaling functions of antithrombin

Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury

Hypercoagulability of COVID-19 patients in intensive care unit. A report of thromboelastography findings and other parameters of hemostasis

Argatroban enhances fibrinolysis by differential inhibition of thrombin-mediated activation of thrombin activatable fibrinolysis inhibitor and factor XIII