Panel of Experts

1. Professor Akhil Ranjon Biswas, Head of Department of Haematology, Mymensingh Medical College
2. Professor Masuda Begum, Department of Haematology, BSMMU
3. Professor Md. Mahbubur Rahman, Head of Department of Haematology, NICRH
4. Professor Md. Abdul Aziz, Chairman, Department of Haematology, BSMMU
5. Professor (Colonel) Huque Mahfuz, Head of Haemato-Oncology and BMT, Dhaka CMH

Background

Association of haemostatic abnormality with COVID-19 is well established and not merely like other infective pneumonia or critical illness. Cumulative incidence of venous thrombo-emblism (VTE) in hospitalized COVID-19 patients has been observed to be 16%, 33% & 42% on day 7, 14 and 21 respectively. For ICU patients, it was 26%, 47% and 59% respectively in comparison to 5% to 20% in other ICU patients historically [1, 2]. About 71 % of non-survivors of COVID-19 met the International Society on Thrombosis and Haemostasis (ISTH) criteria for disseminated intravascular coagulation (DIC) in contrast to only 0.6% survivors at any time point of hospital stay. Curiously, it is not like typical DIC where platelet count and fibrinogen are reduced rather than generally normal or only slightly reduced number of platelet and frequently and often markedly elevated fibrinogen level. However, increased D-dimer level is quite remarkable finding which is a marker of fibrin generation [3, 4]. Autopsy finding of a small series of death in Germany revealed that pulmonary embolism (PE) is the cause of death in 33% death in COVID-19, with thrombi derived from deep vein of lower limbs. Alveolar capillary microthrombi were 9 times as prevalent in patients with COVID-19 as in patients with H5N1 influenza [5, 6]. There has never been a disease like COVID-19 that so consistently causes thrombotic DIC [7]. Early reports also revealed improved survival of hospitalized COVID-19 patients with anticoagulation treatment especially in patients with markedly raised D-dimer [4, 8].

On above background, various groups, though having few subtle differences, recommend use of anticoagulant therapy as a part of supportive treatment of COVID-19 disease [9-13]. Extracting from reviewed documents, expert panel of Hematology Society of Bangladesh hereby make recommendation regarding use of antithrombotic therapy for COVID-19 treatment in Bangladesh. Panel also recommends to add a different section on ‘Management of COVID Induced Haemostatic Abnormality’ in ‘National Guidelines on Clinical Management of Coronavirus Disease 2019 (COVID-19)’.

Objectives

This recommendation was created as a part of proposals to be included in the national guideline for covid-19 patients management in Bangladesh. Haematology Society of Bangladesh had set a panel of experts for this purpose to make the proposals regarding the haematological issues in Covid patients management. The panel of experts set 3 objectives:

1. Preparing recommendation for ‘management of COVID associated haemostatic abnormality’.
2. Preparing recommendation for blood and blood product transfusion in COVID-19
3. Preparing recommendation for haematological laboratory investigation and monitoring in COVID-19.

Recommendations for Thromboprophylaxis

Recommendations of the panel are applicable for all confirmed as well as highly suspected COVID-19.

1. We recommend thromboprophylaxis by prophylactic dose anticoagulant for COVID-19 patients in following conditions in absence of any contraindication (stated later) –
   1. All confirmed or highly suspected COVID-19 patients require hospital admission for their clinical condition.
   1. All confirmed or highly suspected COVID-19 patients who are not admissible otherwise but having D-dimer level >3 times upper limit of normal (>1.5 mg/L), to be admitted and prophylactic dose anticoagulant to be given,  
   1. When patients with above 2 categories cannot be hospitalized due to unavoidable circumstances, use of prophylactic anticoagulant at home is recommended for category A.1, and should be considered case by case in category A.2 (panel opinion).
2. We recommend escalation of anticoagulant dose to ‘intermediate dose thromboprophylaxis’ for –
   1. Critically ill patients requiring ICU care,
   1. Those with clinical deterioration (increasing oxygen requirement) along with increasing D-dimer level (>6 times upper limit of normal i.e. >3.0 mg/L). Only increasing D-dimer should not guide dose escalation.
3. Further escalation to therapeutic dose is recommended when-
   1. There is further clinical deterioration such as requiring ventilation support,
   1. There is highly suspected pulmonary embolism (PE) clinically, such as sudden, marked desaturation of oxygen,
   1. There is imaging proven PE or deep vein thrombosis (DVT),
   1. Imaging is not possible but expert clinician judge as DVT and opine for therapeutic anticoagulation.
4. We recommend mechanical thromboprophylaxis by consistent application of intermittent pneumatic pressure in lower limbs for whom thromboprophylaxis is indicated but pharmacologic anticoagulant is either contraindicated or not applicable (e.g. in-home treatment).
5. Anticoagulation intensity for pregnant ladies are similar. However, obstetrician and anaesthesiologist should be consulted if delivery is imminent and epidural or spinal anaesthesia or caesarean section might be needed.
6. Children are unlikely to develop severe COVID-19 disease and use of thromboprophylaxis should only be considered by a paediatrician/paediatric haematologist, considering the risk of thromboembolism.
7. Thrombolytic therapy may be considered in following conditions-
   1. Highly suspected or imaging (CTPA) proven acute PE,
   1. Acute coronary syndrome
8. Post discharge anticoagulation: We don’t routinely recommend post discharge anticoagulation therapy except for following categories-
   1. Those who required therapeutic anticoagulation should receive post discharge therapy for 3 months.
   1. Those who may not be fully ambulant after discharge due debility or comorbidity should receive post discharge therapy for 1 month.
9. Contraindication for anticoagulation:
   1. When there is no bleeding but platelet count <25K/cmm
   1. When there is bleeding-
      1. Platelet count <50K/cmm
      1. Plasma fibrinogen level <1.5 g/L
      1. PT ratio >1.5 or INR >1.8 (To be noted that prolonged APTT is not a contraindication for anticoagulation. Anticoagulant can be/should be restarted after correction of contraindicating condition by transfusion).
10. Choice of anticoagulants:
    1. Low molecular weight heparin (LMWH)/Enoxaparin, when creatinine clearance rate (CCR) is ≥30ml/min. It is the 1^st choice because of –
       1. Less chance of bleeding,
       1. Less chance of heparin induced thrombocytopenia (HIT) with thrombosis,
       1. Less requirement of laboratory monitoring
    1. Unfractionated heparin (UFH), when CCR is <30 ml/min. Though it has advantage of renal safety, rapid onset of action and better anti-inflammatory activity, it is not chosen over LMWH because of –
       1. Strict requirement of coagulation status monitoring which is not convenient for COVID patients due to risk of transmission,
       1. More chance of HIT which may remain un-noticed due to lack of laboratory monitoring
    1. FXa inhibitor/Fondaparinux: For those who developed or have history of HIT.
    1. Direct oral anticoagulant (DOAC)/Rivaroxaban is not routinely recommended due to its potential interaction with other drugs and unpredictable absorption in presence of active inflammation. Rivaroxaban is recommended in following situation only –
       1. Those who is indicated for anticoagulation but cannot take injectable anticoagulants (section A.3) (panel opinion),
       1. Those who need post discharge anticoagulation.   
11. Doses of anticoagulants:

*To be titrated to achieve target aPTT ratio between 1.5 to 2.3.

Recommendations for Blood and Blood Product Transfusion

1. Red cell transfusion: Anaemia is not associated with COVID-19, unless there is bleeding or pre-existing anaemia. Red cell transfusion should be given when haemoglobin level is <8 gm/dl. Aggressive transfusion of red cell increases the viscosity of blood hence risk of thrombosis. So, transfusion should be minimum just to maintain haemoglobin level >8 gm/dl. Each unit of red cell increases haemoglobin by 1 gm/dl in a 65 to 70 kg adult.
2. Platelet transfusion: Platelet count <50K/cmm is extremely unusual in COVID-19. Platelet concentrate should be transfused in following conditions –
   1. When platelet count is <20k/cmm,
   2. When platelet count is <25k/cmm and patient needs to continue anticoagulant,
   3. When platelet count is <50k/cmm with active bleeding and patient need to continue anticoagulant,
   4. When platelet count is <50k/cmm with active bleeding and patient meets the ISTH criteria for overt DIC.

Note: Heparin induced thrombocytopenia is absolute contraindication for platelet transfusion. An haematologist should be consulted then.

3. Fresh plasma/ fresh frozen plasma/ cryoprecipitate: Fibrinogen is generally normal and frequently increased in COVID-19. Rarely reduction of fibrinogen me necessitate plasma or cryoprecipitate transfusion,
   1. When fibrinogen is <1.5 g/L with active bleeding and patient need to continue anticoagulant,
   2. When fibrinogen is <1.5 g/L with active bleeding and patient meets the ISTH criteria for overt DIC.
4. Any cytopenia or haemostatic abnormality due to pre-existing haematological condition should be consulted with haematologist.

Recommendations for Haematological Laboratory Investigation and Monitoring

1. Complete Blood Count (CBC): At presentation, day 4 of anticoagulation and every 2-day interval subsequently. Every 2-day interval from very beginning for those with previous heparin exposure. The important information from CBC are – platelet count, absolute lymphocyte count, neutrophil to lymphocyte ratio and haemoglobin level.
2. Prothrombin time (PT): At presentation and subsequently if there any evidence of bleeding.
3. D-dimer: At presentation and subsequently if there any clinical deterioration.
4. Activated partial thromboplastin time (aPTT): At presentation and for those who are on UFH once daily. Those who are on therapeutic dose UFH, aPTT to be monitored 3-4 hourly till target aPTT ratio between 1.5 to 2.3 is achieved.
5. Plasma fibrinogen level: At presentation. It is optional but preferable.

References/Bibliography:

1. Middeldrop S, Coppens M, Happs T F V, Foppen M, et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. Pre-publication. Doi:10.1111/JTH. 14888
2. https://www.medscape.com/viewarticle/929368
3. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18.844-847. https://doi.org/10.1111/jth.14768
4. Tang N, Bai H, Chen X, Gong J, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020; 18: 1094-1099.
5. Wichmann D, Sperhake J P, Lütgehetmann M, Steurer S, et al. Autopsy findings and venous thromboembolism in patients with COVID-19. Ann Intern Med. May 6, 2020.
6. Ackermann M, Verleden S E, Kuehnel M, Haverich A, et al. Pulmonary vascular endothelialitis, thrombosis and angiogenesis in COVID-19. New Eng J Med. May 21, 2020. DOI: 10.1056/NEJMoa 2o15432.
7. Barrett C D, Moore H B, Yafee M B and Moore E E. ISTH interim guidance on recognition and management of coagulopathy in COVID-19: A comment. J Thromb Haemost. Pre-pub. Doi: 10. 1111/JTH.14860
8. Yin S, Huang M, Denglu L, Tang N. Difference of coagulation features between severe pneumonia induced by SARS-Cov-2 and non-SARS-Cov-2. J Thromb Haemost. Online April 3, 2020. https://doi.org/10.1007/s11239-020-02105-8.
9. Thacil J, Tang N, Gando S, Falanga A, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18.1023-1026.
10. NIH COVID-19 treatment guidelines. Antithrombotic therapy in patients with COVID-19. Last updated: May 12, 2020. https://www.covid19treatmentguidelines.nih.gov/antithrombotic-therapy/
11. Thacil J. COVID-19 coagulopathy- What we know and don’t (yet) know. EHA-ISTH joint webinar. May 14, 2020. https://www.youtube.com/watch?v=Fpavi75xw4A&feature=youtu.be
12. Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: Interim clinical guidance from anticoagulation forum. J Thromb Haemost. May 21, 2020. https://doi.org/10.1007/s11239-020-02138-z
13. COVID-19 and VTE/anticoagulation: Frequently asked question. ASH COVID-resources. https://www.hematology.org/covid-19/covid-19-and-vte-anticoagulation
14. Anticoagulation in COVID-19. Atallah B, Mallah S I, Mahmeed W A (on behalf of European Society of Cardiology). European Heart Journal- Cardiovascular Pharmacotherapy. doi 10:1093/ehjcvp/pvaa036. 

Last Updated on 22/06/2020 by Editorial Staff