ISTH interim guidance on recognition and management of coagulopathy in COVID19



## | introduc ti on
The novel corona virus infection (now classified as COVID-19), first identified in December 2019 in Wuhan, China, has contributed to significant mortality in several countries with the number of infected cases increasing exponentially worldwide. [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref] The majority of the most severely ill patients initially present with single organ failure (ie, respiratory insufficiency) but some of them progress to more systemic disease and multiple organ dysfunction. One of the most significant poor prognostic features in those patients is the development of coagulopathy. [bib_ref] Clinical Characteristics of Coronavirus Disease 2019 in China, Guan [/bib_ref] In patients who develop sepsis from various infectious agents, development of coagulopathy is one of the key and persistent features which is associated with poor outcomes. [bib_ref] Abnormal coagulation parameters are associated with poor prognosis in patients with novel..., Tang [/bib_ref] In this context, the role of International Society of Thrombosis and Haemostasis (ISTH) will be crucial in guiding health-care professionals in how to manage the coagulopathy of COVID-19. A simple and easily followable algorithm for the management of COVID-19 coagulopathy would currently be useful in both the well-resourced and less-resourced settings as a guide in managing this complication. This pragmatic statement should clearly be considered as an interim guidance because the clinical experience of managing this pandemic is increasing. The authors are certain that this statement will be modified with developing knowledge and therapeutics in managing COVID-19. The aim of this guidance document is to provide a risk stratification at admission for a COVID-19 patient and management of coagulopathy which may develop in some of these patients, based on easily available laboratory parameters.

## | coag ul ati on mark er s at admiss ion
One of the key issues recognized with the management of COVID-19 infection has been the very high volume of patients presenting to health centers or hospitals. It clearly overwhelms the human and mechanistic capacities available, in particular the need for critical care support. As such, risk stratification measures would clearly be helpful.
Currently, this is based on the clinical characteristics of severe pneumonia and a consistent finding of lymphopenia in most patients. [bib_ref] Therapeutic and triage strategies for 2019 novel coronavirus disease in fever clinics, Zhang [/bib_ref] In addition, one of the most common laboratory findings noted in COVID-19 patients requiring hospitalization has been the increase in D-dimers. [bib_ref] Abnormal coagulation parameters are associated with poor prognosis in patients with novel..., Tang [/bib_ref] It is already well established that older individuals and those who have co-morbidities (both groups tend to have higher D-dimer) are more likely to die from COVID-19 infection. In the largest analysis Thrombocytopenia is often considered an indicator of sepsis mortality. [bib_ref] Thrombocytopenia in critically ill patients receiving thromboprophylaxis, Williamson [/bib_ref] Interestingly, this is not the case at admission in many of the COVID-19 patients. In the study of 41 patients published in the Lancet, a platelet count less than 100  10 9 /L was only seen in 2/40 (5%) patients with one each in ICU and non-ICU category while <150  10 9 /L was seen in 38/40 (95%) with similar numbers needing or not needing critical care support. [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref] On admission, thrombocytopenia determined as 150  10 9 /L was also noted in 36.2% in the largest series but further subclassification was not given although while 31.6% of the patients had non-severe illness, 57.7% had severe illness. 2 A meta-analysis of nine studies including COVID-19 patients with nearly 400 with severe disease identified that the platelet count was significantly lower in patients with more severe COVID-19 (weighted mean difference 31  10 9 /L; 95% confidence interval [CI], from 35 to 29  10 9 /L). [bib_ref] Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis, Lippi [/bib_ref] Subgroup analysis comparing patients by survival noted lower platelet count correlated with mortality. Thrombocytopenia was also asso- infection. This may help in stratifying patients who may need admission and close monitoring or not (see . Any underlying condition (eg, liver disease) or medication (eg, anticoagulants) which may alter the parameters should be accounted for while using the algorithm.

## | monitoring coag ul ation marker s
It is common practice in most critical care units to monitor hemostatic markers to identify worsening coagulopathy. In addition to the platelet count, PT, and D-dimers, it may be useful to measure fibrinogen in this scenario, as recommended by the ISTH guidance on disseminated intravascular coagulation (DIC). [bib_ref] Guidance for diagnosis and treatment of DIC from harmonization of the recommendations..., Wada [/bib_ref] With respect to COVID-19 infection, this is an area which has not yet been well studied except by Tang et al. [bib_ref] Abnormal coagulation parameters are associated with poor prognosis in patients with novel..., Tang [/bib_ref] 

## | manag ement of covid -19 coag ulopathy
This section is based on the only currently available evidence that markedly increased D-dimer is associated with high mortality in COVID-19 patients. It is also based on the evidence that multi-organ failure is more likely in patients with sepsis if they develop coagulopathy and inhibiting thrombin generation may have benefit in reducing mortality. [bib_ref] Sepsis definitions task force. Developing a new definition and assessing new clinical..., Shankar-Hari [/bib_ref] [bib_ref] Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation, Iba [/bib_ref] The only widely available treatment in this respect 28-day mortality in those who received heparin compared to those who did not, if a SIC (sepsis-induced coagulopathy) score 4 were to be applied to the patients, anticoagulant therapy with LMWH appears to be associated with better prognosis in relation to mortality (40.0% versus 64.2%, P = .029). [bib_ref] New criteria for sepsis-induced coagulopathy (SIC) following the revised sepsis definition: a..., Iba [/bib_ref] A similar benefit was noted in those with D-dimer >six-fold of upper limit of normal (32.8% versus 52.4%, P = .017). LMWH will also protect critically ill patients against venous thromboembolism. In addition, LMWH has been shown to have anti-inflammatory properties which may be an added benefit in COVID infection where pro-inflammatory cytokines are markedly raised. [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref] [bib_ref] Clinical Characteristics of Coronavirus Disease 2019 in China, Guan [/bib_ref] [bib_ref] More than an anticoagulant: do heparins have direct anti-inflammatory effects?, Poterucha [/bib_ref] Bleeding is rare in the setting of COVID-19. If bleeding does develop, similar principles to septic coagulopathy as per the harmonized ISTH guidelines with respect to blood transfusions may be followed 7 (see . There are several other therapies for COVID-19 which can only be considered experimental at the moment including antithrombin supplementation, recombinant thrombomodulin, and hydroxychloroquine based on mitigating the excess thrombin generation hypothesis and immunosuppressive agents including inhalational therapies which may put a check on the "immunothrombosis" model (bidirectional relationship between inflammation and thrombosis).

## Co n fli c t s o f i nte r e s t
None declared.

## Auth o r co ntr i b uti o n s
JT conceived and wrote the initial draft of the paper. NT, SG, MC, AF, ML, CC, and TI made comments. All authors approved the final submission.

## O rci d

## Satoshi gando
https://orcid.org/0000-0002-3525-0750

## R e fe r e n c e s