MANAGEMENT OF COAGULOPATHY OF PATIENTS INFECTED WITH COVID-19 Reza aghabozorgi MD medical oncologist and hematologist
• we will review data for coagulation abnormalities that occur in association with COVID-19, and clinical management questions likely to arise • Our considerations are based on evolving data and consensus
• Evidence of abnormal coagulation parameters associated with COVID-19 appeared in early reports from China • a D-dimer level greater than 1.0 mcg/mL at admission was associated with increased mortality with an OR of 18.42 (2.64- 128.55, p=0.003)
elementary data showed that LMWH or UFH are associated with a reduced 28-day mortality in more severe COVID-19 patients displaying a sepsis-induced coagulopathy (SIC) score ≥ 4 (40.0% vs 64.2%, p=0.029) or D-dimer levels >6-fold the upper limit of normal (32.8% vs 52.4%, p=0.017)
INFLAMMATION AND COAGULATION • In addition to respiratory failure, patients with severe illness are also likely to have coagulopathy Infection pathogens initiates complex systemic inflammatory responses as part of innate immunity
mechanisms of thrombus formation ■ imbalance of pro and anticoagulant states during infection ■ the endothelium plays an important role in homeostasis regulation and it is disrupted in viral infections ■ viral infection-induced elevation of von Willebrand factor ■ tissue factor pathway activation
thromboinflammation or immunothrombosis ■ Activation of host defense systems ■ subsequent activation of coagulation and thrombin generation ■ critical communication components among humoral and cellular amplification pathways
Polyphosphates, derived from microorganisms, activates platelets, mast cells, and FXII in the contact pathway of coagulation, and exhibit other downstream roles in amplifying the procoagulant response of the intrinsic coagulation pathway Complement pathways contribute to activation of coagulation factors The inflammatory effects of cytokines also result in activated vascular endothelial cells and endothelial injury with resultant prothrombotic properties
Given the tropism of the virus for ACE2 receptors, endothelial cell activation and damage with resultant disruption of the natural antithrombotic state is likely This inflammation associated withCOVID-19 and subsequent activation of coagulation is the probable cause for the elevated Ddimer levels
EN ENDO DOTHELIAL THELIALOP OPATHY THY an and COVID VID19 19 ■ The receptor for viral adhesion is an ACE 2 receptor on endothelial cells ■ ■ viral replication causing inflammatory cell infiltration, endothelial cell apoptosis, and microvascular prothrombotic effects ■ microcirculatory dysfunction contributes to the clinical sequelae in patients with COVID-19.
RECOMMENDATION • All patients presenting to hospital for COVID-19 should have the following test obtained at baseline: D-dimer, PT, PTT, fibrinogen and CBC with differential
■ All patients admitted to hospital for COVID-19 should have the following tests obtained at baseline and every 2 days: D-dimer, PT, PTT, fibrinogen daily y if ini nitial l or subse seque uent t D-dimer imer is elevated ed
■ The most common pattern of coagulopathy observed in patients is characterized by elevat ations ions in f n fibri brinogen ogen and nd D- dimer er levels els ■ prolongation of the aPTT and/or PT is minimal, thrombocytopenia is mild (platelet count ~100 x10 9 /L)
■ Rarely patients with severe COVID-19 infection and multiorgan failure progress to a coagulopathy meeting criteria for overt DIC ■ moderate to severe thrombocytopenia (platelet count <50 x10 9 /L), prolongation of the PT and aPTT, extreme elevation of D-dimer, and decreased fibrinogen (< 1.0 g/L)
■ Worsening of coagulation parameters, specifically the D-dimer, indicates progressive severity of COVID-19 infection and predicts that more aggressive critical care will be needed experimental therapies for COVID-19 infection might be ■ considered in this setting ■ Improvement of these parameters along with stable or improving clinical condition provides confidence that stepping down of aggressive treatment may be appropriate
Management COVID-19 infection infrequently leads to bleeding despite abnormal coagulation parameters blood product transfusion should be individualized Blood component therapy should not be instituted on the basis of laboratory results alone , but reserved for those with active bleeding
■ There are no data to support any particular “ safe ” cut-off for hematological parameters ■ In patients who are not bleeding, there is no evidence that correction of laboratory parameters with blood products improves outcomes ■ Replacement might worsen disseminated thrombosis and further deplete scarce blood products
■ actively bleeding, transfuse platelets (one adult dose) if the platelet count is less than 50 x 10 9 /L ,give plasma (4 units) if the INR is above 1.8 and order cryoprecipitate (10 units) if the fibrinogen level is less than 150 mg/L
ANTICOAGULATION • Patients should receive standard prophylactic anticoagulation with LMWH in the absence of any contraindications ( active bleeding or platelet count less than 25,000 ) abnormal PT or APTT is not a contraindication
• Heparin has been implicated in binding to COVID-19 spike proteins as well as downregulating interleukin-6 (IL-6) unfractioned heparin or LMWH remains as the best choice • of anticoagulant for admitted patients
• If LMWH contraindicated due to renal failure (Creatine Clearance <30mL/min), UFH can be used as an alternative In obese patients, the recommended dose is 40 mg bid
■ If a patient is on a DOAC at time of admission but then requires COVID-19 therapy that interacts with the DOAC, or is/becomes severely ill, that patient should be switched to LMWH (preferred over UFH)
■ prophylactic dose LMWH is recommended for all patients despite abnormal coagulation tests in the absence of active bleeding, and held only if platelet counts are less than 25 x 10 9 /L
Renal adjustment enoxaparin ■ CrCl 15-29:30mg Q24 h ■ CrCl<15 or renal replacment thrapy: avoid use
Prophilaxis dosing obecity UFH 5000 unit Q 8 houre SC ,IF BW is 120 to 150 kg ■ UFH 7500 unit Q 8 houre SC ,IF BW is > 150 kg ■ Enoxapari 40 mg Bid if Crcr> 30 ■ Enoxaprin 40 mg daily if Crcr 30 > ■
Low body weight ■ UFH:5000 q12h ■ Enoxaparin:30mg q 24h
non-hospitalized patients there are currently insufficient data to recommend for or against using this data to guide management decisions
Pat atie ients nts wi with th COVID ID-19 9 Wh Who A o Are Dis ischa harge rged d from rom th the Hos e Hospi pita tal ■ Routine post-discharge VTE prophylaxis is not ot recom comme mend nded ed for patients ents with h COVID VID-19 19 ■ for high-risk patients one regimens is optional ■ rivar aroxaban aban 10 10mg daily y for r 31 to 39 39 days ys
Modified IMPROVE-VTE score a A congenital or acquired VTE risk condition leading to excess VTE risk factor score risk of thrombosis (e.g., factor V Leiden, lupus anticoagulant, factor C or Previous VTE 3 factor S deficiency). Known thrombophilia a 2 b Leg falls to bed by 5 seconds, but has some effort against gravity (taken 2 Current lower limb paralysis or from NIH stroke scale) paresis b c Cancer (excluding nonmelanoma skin cancer) History of cancer c 2 present at any time in the past 5 years (cancer must be ICU/CCU stay 1 in remission to meet eligibility criteria) Complete immobilization d ≥ 1 d Immobilization is being 1 d confined to bed or chair with or without bathroom privileges Age ≥ 60 y 1
■ Modified IMPROVE-VTE score ≥ 4 ■ • Modified IMPROVE-VTE score ≥ 2 and D-dimer level >2 times the upper limit of normal ■ • Age ≥ 75 years ■ • Age >60 years and D-dimer level >2 times the upper limit of normal ■ • Age 40 to 60 years, D-dimer level >2 times the upper limit of normal and previous VTE event or cancer
EUROPEAN HEART JOURNAL - CARDIOVASCULAR PHARMACOTHERAPY
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