Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19 infection

West Suffolk NHS Foundation Trust CG10393-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

CLINICAL GUIDELINE CG10393-3

Purpose of the Guideline

There is limited international guidance on how to manage thrombotic risk, coagulopathy and disseminated intravascular coagulation (DIC) in patients with COVID-19 (SARs-CoV-2) infection. This document provides pragmatic guidance concerning adult, non-pregnant patients with suspected or confirmed COVID-19 infection on the following:

• Safe and appropriate thromboprophylaxis and discharge;

• Management of Acute Coronary Syndrome (ACS);

• Management of patients already on therapeutic anticoagulants on admission and discharge;

• Monitoring of thromboprophylaxis and therapeutic anticoagulation;

• Management of coagulopathy;

• Management of haemorrhage with no coagulopathy;

• Management of acute thrombosis;

• Haemofiltration in critical care.
Background and rationale
A striking feature of COVID-19 infection is the acute phase response (APR). Several pro-coagulant factors are positive acute phase reactants: Factor VIII, VWF, Fibrinogen and the APR are associated with an increased risk of thrombosis. Published data and local experience confirm that fibrinogen is often markedly elevated in the COVID-19 infected patients.
Pneumonia and sepsis are often complicated by disseminated intravascular coagulation (DIC), but although COVID-19 patients do have abnormalities of coagulation, they are not typical of DIC. The most marked abnormality is an elevation in d-dimer but without a parallel fall in platelets or prolongation of clotting times. This suggests that local rather than disseminated thrombin generation and fibrinolysis is taking place. Some elevation of PT/APTT is seen and may be independent prognostic marker for thrombosis.
The site of thrombin and fibrin formation appears to be the lungs, based on limited post-mortem data and clinical observations from CT scans and ventilation parameters (V/Q mismatch). Some patients have overt pulmonary emboli, but in others it is presumed to be microvascular thrombi.
The above is consistent with limited evidence from China indicating that patients receiving prophylactic dose UFH/LMWH had significantly better survival than those who did not. Despite the use of pharmacological thromboprophylaxis the incidence of pulmonary embolism (PE) is higher in patients with symptomatic COVID-19 infection. There is little evidence to guide altering or intensifying standard of care.
In response to these findings expertise from Haematology, ITU, Nephrology and Pharmacy has been combined to create this guidance. A consensus statement from the International Society of Thrombosis and Haemostasis (ISTH) forms the basis of these recommendations, along with measures implemented by other UK NHS hospitals.
Source: Issue date: July 2020 Page 1 of 20 Status: Approved Review date: July 2021

For use in (clinical areas):

All clinical areas (except paediatrics and maternity)

For use by (staff groups):

All clinicians

For use for (patients):

For use for all adult patients (excludes pregnancy)

Document owner:

Thrombosis Committee

Status:

Approved (last updated 16/7/2020) – version 3

As the primary literature is being updated on a regular basis, this document will be reviewed within the next 2 months

from the date of publication (the date this document was last edited will be stated above in the status section.

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

Linked clinical guidelines:

• CG10193 – VTE thromboprophylaxis in adults (non-pregnant) patients

• CG10166 – Initiating and prescribing oral anticoagulants

• CG10229 – Management of direct oral inhibitor anticoagulants (DOAC) part 1
Contents
Thromboprophylaxis in patients NOT currently on therapeutic anticoagulation
Bleeding risk factors
Standard/intermediate dose thromboprophylaxis recommendations for patients not currently on therapeutic anticoagulants – for platelet counts >50×109/L with NO other bleed risks and a:

• CrCl ≥30mL/min (table 1)

• CrCl <30mL/min (table 2)
Acute coronary Syndrome (ACS) recommendations – for platelet counts >70×109/L and NO other bleeding risks
and a:

• CrCl ≥30mL/min (table 3)

• CrCl <30mL/min (table 4)
Discharge of patients on pharmacological thromboprophylaxis Management of patients already on anticoagulation on admission
Discharge of patients on therapeutic anticoagulation
Monitoring of thrombosis risk and bleeding risk for safe thromboprophylactic/therapeutic anticoagulation

• D-dimer, platelets, PT and fibrinogen

• Anti-Xa level monitoring

• Bleeding risk factors

• Frequency of monitoring for low molecular weight heparins (LMWHs), e.g. tinzaparin and enoxaparin)

• Dose adjustment based on anti-Xa levels Acute thrombosis

• Investigation

• Treatment Coagulopathy

• Disseminated Intravascular (DIC) score

• Pharmacological thromboprophylaxis in patients with coagulopathy
Management of haemorrhage in patients with NO coagulopathy Haemofiltration (CVVHDF) guidance on Critical Care

Page

3 4 5

7 8 8 9

14 15 15

18 19 20

Page 2 of 20

Pharmacokinetic considerations

References
Development of the guideline

Appendix 1: Protamine for LMWH overdose Appendix 2: IMPROVE Predictive VTE score Appendix 3: Quick reference guide

Source:
Status: Approved

Issue date: July 2020 Review date: July 2021

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

Thromboprophylaxis in suspected/confirmed COVID-19 infection in patients NOT currently on therapeutic anticoagulation

•

Do not omit thromboprophylaxis due to coagulopathy, unless evidence of bleeding

Monitor:

FBC da•ily

•

(see coagulopathy section)

•

Clotting screen (including fibrinogen) and D-dimer every 1-2 days, according to DIC score

Platelets <30×109/L or active bleeding

Platelets ≥30×109/L but <50×109/L or other bleeding risk1
Assess for contra-indications

Platelets ≥50×109/L with no other risk factors for bleeding1
Assess for contra-indications

1. Offer IPC2,5

2. Discuss with
Haematology Consultant

1. Offer IPC2,5

2. Standard dose
pharmacological thromboprophylaxis as per CG10193
If no contra-indication and bleeding risk taken into account, dose according to actual body weight and calculated CrCl (as per Cockcroft-Gault equation)

1. Offer IPC2, 5

2. If no contra-indications and bleeding risk taken into
account, offer standard or intermediate dose pharmacological thromboprophylaxis5:

a. For CrCl ≥30ml/min – see table 1

b. For CrCl < 30ml/min – see table 2

c. For CrCl <15ml/min or dialysis patients discuss
with Nephrology Consultant

3. Consider treatment dose anticoagulation if deteriorating pulmonary status/ARDS4 without established VTE

4. For anti-Xa monitoring and subsequent dose adjustments refer to monitoring section

On Discharge

Consider pharmacological thromboprophylaxis in patients with low bleeding risk1 and with key VTE risk factors3,53

For ACS patients see tables 3 and 4

1 See section on bleeding risk factors
2 IPC (Intermittent pneumatic compression device) – only offer if no contra-indication. Prioritise for those in critical care/those with haemorrhage/risk precluding use of pharmacological thromboprophylaxis
3 See section on discharge of patients with suspected/confirmed COVID-19 infection on pharmacological thromboprophylaxis
4ARDS (Acute respiratory distress syndrome)
5ISTH recommendation

Bleeding Risk Factors

Source: Issue date: July 2020 Page 3 of 20 Status: Approved Review date: July 2021

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

Bleeding Risk Factors

Remember to consider bleeding risks when introducing thromboprophylaxis. King’s Critical Care Units + Chelsea and Westminster Hospitals guideline has been used as a basis:

• Active bleeding (or within 3 months prior to admission)

• Acquired bleeding disorders

• Uncontrolled hypertension

• Concurrent use of anticoagulants

• Acute stroke (if acute stroke and sequential compression devices (SCDs) contraindicated, review anticoagulant prophylaxis daily in the MDT)

• Thrombocytopenia (platelet counts <50×109/L, checked on admission) – if platelets below 30-50×109/L, consider standard dose anticoagulant prophylaxis in the absence of additional bleeding risk factors and monitor platelet count daily

• Uncontrolled inherited bleeding disorders (such as haemophilia)

• Trauma patient*

• Neurosurgery, spinal surgery, or eye surgery*

• For at least 4-6 hours after surgery

• LP/epidural/spinal anesthesia within the previous 4-6 hours or expected within the next 12 hours

• Other procedures with high bleeding risk*

• PT (prothrombin time) >6 seconds above upper limit of normal (ULN) or APTT (activated partial thromboplastin
time) >6 seconds above ULN and NOT due to coagulopathy

• CrCl <30mL/min

• Haematological disorder affecting platelet function (e.g. myelodysplasia (MDS)); platelets >1000×109/L in
myeloproliferative disorders (MPN)
* review the bleeding risk and thrombotic risk daily in the MDT

Source: Issue date: July 2020 Page 4 of 20 Status: Approved Review date: July 2021

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

Table 1 –Standard/intermediate dose thromboprophylaxis recommendations for patients with suspected/confirmed COVID-19 infection – for platelet counts >50x𝟏𝟎𝟗/L and NO other bleeding

risks and a CrCl of ≥30mL/min

D-dimer

Weight (kg)

First line

2nd line

Contraindication to heparin (allergy, HIT, or religious reasons) – 1st line

Contraindication to heparin – 2nd line (stated in order of preference in relation to cost effectiveness)

<50

Tinzaparin
2500 units od s/c

Enoxaparin 20mg od s/c

Fondaparinux
2.5mg s/c alternate days or OD*

N/A

<1000 ng/mL FEU

Standard dose thromboprophylaxis

50-100

Tinzaparin
4500 units od s/c

Enoxaparin 40mg od s/c

Fondaparinux 2.5mg od s/c

Apixaban 2.5mg bd PO

Argatroban
2 micrograms/kg/minute IV infusion
OR
Danaparoid IV as per BNF and medusa (based on weight)

101-150

Tinzaparin
4500 units bd s/c

Enoxaparin 40mg bd s/c

Fondaparinux 5mg od s/c

Apixaban 2.5mg bd PO

Argatroban
2 micrograms/kg/minute IV infusion
OR
Danaparoid IV as per BNF and medusa (based on weight)

>150

Tinzaparin
6000 units bd s/c

Enoxaparin 60mg bd s/c

Fondaparinux 7.5mg od s/c

Apixaban 5mg bd PO

Argatroban
2 micrograms/kg/minute IV infusion
OR
Danaparoid IV as per BNF and medusa (based on weight)

<50

Tinzaparin
2500 -4500 units bd s/c

Dosing depends on d-dimer and weight

Heparin
5000 units tds s/c

Fondaparinux 2.5-5mg od s/c

Dosing depends on d- dimer and weight

Apixaban 2.5-5mg bd PO

Argatroban
2 micrograms/kg/minute IV infusion

Dosing depends on d-dimer and weight

>1000* ng/mL FEU

Intermediate dose thromboprophylaxis

50-100

Tinzaparin 4500 units bd

Enoxaparin 40mg bd s/c

Fondaparinux 5-7.5mg od s/c

Dosing depends on d- dimer and weight

Apixaban 5mg bd PO

Argatroban
2 micrograms/kg/minute IV infusion
OR
Danaparoid IV as per BNF and medusa (based on weight)

101-150

Tinzaparin 9000 units bd

Enoxaparin 80mg bd s/c

Fondaparinux 5mg bd s/c

Apixaban 5mg bd PO

Argatroban
2 micrograms/kg/minute IV infusion
OR
Danaparoid IV as per BNF and medusa (based on weight)

>150

Tinzaparin 12,000 units morning and 10,000 units evening s/c

Enoxaparin 120mg bd s/c

Apixaban
10mg bd PO for the first 7 days then 5mg bd PO thereafter

Argatroban
2 micrograms/kg/minute IV infusion
OR
Danaparoid IV as per BNF and medusa (based on weight)

NOTE: A change of anticoagulant regimen (i.e. from standard prophylactic or intermediate-dose to treatment-dose regimen) can be considered in patients without established VTE but deteriorating pulmonary status or ARDS (ISTH recommendation).
* discuss with a Haematologist to consider a peak anti-Xa level after the 5th dose.

See notes at the end of table 4

Source: Issue date: July 2020 Page 5 of 20 Status: Approved Review date: July 2021

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

Table 2 –Standard/intermediate dose thromboprophylaxis recommendations for patients with suspected/confirmed COVID-19 infection in patients – for platelet counts >50x𝟏𝟎𝟗/L and NO other bleeding risks other than CrCl <30mL/min – NOTE: increased risk of bleeding and thrombosis in

severe renal impairment

D-dimer Weight (kg)

First line

2nd line

Heparin 5000 units bd s/c Heparin 5000 units bd s/c Heparin 5000 units tds s/c Heparin 10,000 units bd s/c

Heparin 5000 units bd – 5000 units tds s/c

Dosing depends on d-dimer and weight

Heparin 5000 units tds s/c Heparin 12,500 units bd s/c

Discuss with Consultant Haematologist. Consider unfractionated infusion (aim for APTT ratio of 1.5-2)

Contraindication to heparin (allergy, HIT, or religious reasons) – 1st line
N/A

Apixaban 2.5mg bd PO** Apixaban 2.5mg bd PO** Apixaban 2.5mg bd PO**

Apixaban 2.5-5mg bd PO**

Apixaban 2.5-5mg bd PO** Apixaban 5mg bd PO** Apixaban 5mg bd PO**

<1000 ng/mL FEU Standard dose

<50 Enoxaparin 20mg od s/c**

50-100 Enoxaparin 20mg od s/c

thromboprophylaxis 101- 150

>1000* ng/mL FEU

Intermediate dose thromboprophylaxis

Enoxaparin 40mg od s/c >150 Enoxaparin 60mg od s/c

<50 Enoxaparin 20mg – 40mg od s/c

Dosing depends on d-dimer and weight

50-100 Enoxaparin 40mg od s/c

101- Enoxaparin 80mg od s/c 150
>150 Enoxaparin 120mg od s/c

*A change of anticoagulant regimen (i.e. from prophylactic or intermediate-dose to treatment-dose regimen) can be considered in patients without established VTE but deteriorating pulmonary status or ARDS (ISTH recommendation).

**CrCl <15mL/min discuss with Consultant Haematologist and Nephrology Consultant as contraindicated (Note: LMWH are contraindicated if the CrCl <30mL/min but may be considered with anti Xa monitoring if CrCl 15-29 mL/min). Discuss anti-Xa monitoring with Haematology Consultant.

See note at the end of table 4

Table 3 – Acute Coronary Syndrome (ACS) recommendations in suspected or confirmed COVID-19 infection.

For platelet counts >70x𝟏𝟎𝟗/L and NO other bleeding risks and a CrCl of ≥ 30mL/min

D-dimer

Weight (kg)

<75 years of age

>75 years of age

<1000 ng/mL FEU

<50

Fondaparinux 2.5mg od

50-100

Fondaparinux 2.5mg od

101-150

Enoxaparin 1mg/kg bd*

Enoxaparin 0.75mg/kg bd*

1000-3000 ng/mL FEU

<50

Fondaparinux 2.5mg od

50-100

Enoxaparin 1mg/kg bd*

Enoxaparin 0.75mg/kg bd*

101-150

Enoxaparin 1mg/kg bd*

Enoxaparin 0.75mg/kg bd*

>3000 ng/mL FEU

<50

Enoxaparin 1mg/kg bd*

Enoxaparin 0.75mg/kg bd*

50-100

Enoxaparin 1mg/kg bd*

Enoxaparin 0.75mg/kg bd*

101-150

Enoxaparin 1mg/kg bd*

Enoxaparin 0.75mg/kg bd*

* round to the nearest 10mg dose

Source: Issue date: July 2020 Page 6 of 20 Status: Approved Review date: July 2021

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

Table 4 – Acute Coronary Syndrome (ACS) recommendations in suspected or confirmed COVID-19 infections. For platelet counts >70x𝟏𝟎𝟗/L and NO other bleeding risks other than a CrCl of

– NOTE: increased risk of bleeding and thrombosis in severe renal impairment

Please note: If CrCl<15mL/min discuss with Nephrology Consultant

<30mL/min

D-dimer

Weight (kg)

CrCl 20-30mL/min

CrCl 15-20mL/min

<1000

<50

Fondaparinux 2.5mg od

Enoxaparin 1mg/kg od*

50-100

Fondaparinux 2.5mg od

Enoxaparin 1mg/kg od*

101-150

Enoxaparin 1mg/kg od*

1000-3000

<50

Fondaparinux 2.5mg od

Enoxaparin 1mg/kg od*

50-100

Enoxaparin 1mg/kg od*

101-150

Enoxaparin 1mg/kg od*

>3000

Enoxaparin 1mg/kg od*

<50

Enoxaparin 1mg/kg od*

50-100

Enoxaparin 1mg/kg od*

101-150

Enoxaparin 1mg/kg od*

* round to the nearest 10mg dose

Points for consideration with regards to tables 1-4:

1a. D-dimer changes should be monitored (using the e-Care order set) and doses from table 1 and 2 should be adjusted accordingly. Ultimately it is always a clinical decision as other factors must be considered, by the clinician, such as bleeding risk, renal function and clinical status (e.g. patient is being palliated or not or active proven thrombus/organ failure).

1b. Reassess bleeding risk daily

2. Apixaban and other direct oral anticoagulants (DOACs) show significant drug-drug interactions, please liaise with your ward Pharmacist. This is particularly in reference to the RECOVERY trial utilising experimental anti-viral therapy e.g. sarilumab (Kevzara).

3. If danaparoid requires anti-Xa level monitoring, note that this is an off-site test.
4. For HIT (heparin induced thrombocytopenia), discuss with a Haematology Consultant.

Discharge of patients on pharmacological thromboprophylaxis

Consider pharmacological thromboprophylaxis on discharge for all patients who meet high VTE risk criteria but with a low bleeding risk. The duration can be approximately at least 14 days and up to 30 days.
Key VTE risk factors include:

• • • • • • • • •

Source: Issue date: July 2020 Page 7 of 20 Status: Approved Review date: July 2021

Advanced age

>7 days of hospital

Stay in ICU/escalated care

Cancer (current)

A prior history of VTE

Thrombophilia

Severe immobility

An elevated D-dimer (>1000 ng/mL FEU at the time of discharge) i.e. > 2 x ULN

An IMPROVE predictive VTE score of 4 or more (see appendix 2).

standard dose tinzaparin s/c* thromboprophylaxis for 14 days on discharge – contraindicated if CrCl <20mL/min

1st line:

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

OR 2nd line: rivaroxaban 10mg od** (unlicensed) for 14 days on discharge – contraindication CrCl <15mL/min If CrCl <15mL/min or on dialysis, discuss with Nephrology Consultant
(ISTH recommendations)

*Offer sharps bin, provide education for patient/relative/carer within the household. Do not arrange a district Nurse for the sole purpose of administering s/c injections.
**Inform patient of unlicensed use of DOAC; only offer if tinzaparin not an option.
***Provide all above cases the WSH Trust patient information leaflet on ‘are you at risk of blood clots’ and highlight signs/symptoms of venous thromboembolism (VTE) and when to seek urgent medical attention.

Management of patients already on anticoagulation on admission

Antibiotic and antiviral drugs have significant drug interactions with all classes of anticoagulants, particularly via the CYP3A4 pathway. Monitoring of disseminated intravascular coagulation (DIC)/other coagulopathy in patients on therapeutic anticoagulants, which affect the routine coagulation screen and D-dimers is challenging.

Low molecular weight heparin (LMWH) has some additional anti-inflammatory effect, which can be useful in managing the bi-directional relationship between inflammation and thrombosis.

Patients on warfarin (target INR 2.5)* OR direct oral anticoagulant agent (DOAC) such as dabigatran, apixaban, rivaroxaban, edoxaban for stroke prevention in AF or previous VTE could be switched to a LMWH (ISTH recommendation) as below:

1. Therapeutic dose tinzaparin 175 units/kg (unless contraindicated) and CrCl >30 mL/min

2. Therapeutic dose enoxaparin (if not contraindicated) if CrCl 15-30 mL/min (adjusted to CrCl) or they can stay with their anticoagulation (adjusted according to CrCl) – individual patient case decision.

3. For CrCl <15 mL/min use enoxaparin 1mg/kg od or 0.5mg/kg bd, rounded to nearest 10mg dose, with anti-Xa monitoring based on a pragmatic approach to minimise blood sampling and patient contact

*NOTE: Once INR is below the lower end of their target range, start treatment dose LMWH
Patients on warfarin (target INR >3.5)* AND/OR metallic heart valve (discuss with Cardiology), switch to:

• Tinzaparin/enoxaparin as above
o Monitor peak anti-Xa levels (4 hours after 5th dose and discuss with Haematology

Consultant). Aim for anti-Xa levels at the higher end of the therapeutic range.

Discharge of patients on therapeutic anticoagulation

Check full blood count (FBC), renal/hepatic function, drug interactions and for any contraindications. Switch patient back to original anticoagulant the patient was on prior to admission, where appropriate and at an appropriate dose.

For patients with acute VTE during admission, switch from therapeutic LMWH to an appropriate DOAC if no contraindications.

• For warfarin initiation see CG10166

• For switching to a DOAC see CG10229
Provide verbal and written patient information with the relevant leaflet/booklet and alert card. Inform the
ward Pharmacist and Anticoagulant monitoring service (AMS).
The discharging Doctor is responsible for including the anticoagulant management plan in the discharge summary and appropriate follow-up arrangements to ensure effective communication for transfers of care.
Source: Issue date: July 2020 Page 8 of 20 Status: Approved Review date: July 2021

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

Monitoring of thrombosis risk and bleeding risk for safe thromboprophylactic/therapeutic anticoagulation

D-dimer, platelets, PT and fibrinogen

One of the most common laboratory findings noted in the COVID-19 patients requiring hospitalisation has been the increase in D-dimers. The prothrombin time (PT) has also shown modest prolongation.

Whilst thrombocytopenia is often considered an indicator of sepsis mortality, however this is not the case at admission in many of the COVID-19 patients.

Based on currently available literature, it is recommended to measure D-dimers, prothrombin time and platelet count (decreasing order of importance) in all patients who present with suspected COVID-19 infection. This may help stratify patients who may need admission and close monitoring. Any condition (e.g. liver disease) or medication (e.g. anticoagulants), which may alter the parameters, should be accounted for.

It is already well-established that older individuals and those who have co-morbidities (both groups often have higher D-dimer) have a higher mortality as a consequence of COVID-19 infection. Evidence has also suggested that the D-dimer level on admission was higher in patients requiring critical care support. D-dimer elevation seems to correlate with increased VTE risk and with mortality, and may reflect D-dimer production by damaged lung cells as a direct response to hyper inflammation.

Measure the D-dimer levels on a regular basis (24-48 hourly) for the first 5-7 days at least and refer to the DIC score. A suggestion for frequency for monitoring would be 48 hourly as per the e-Care order. However professional discretion is advised, and you may wish to consider:

• <1000 ng/mL FEU (fibrinogen equivalent units) – 48 hourly

• >1000 ng/mL FEU – 24-48 hourly depending on symptoms and oxygen saturations.

• Check the d-dimer level at the time of discharge, as part of the assessment for the need for
thromboprophylaxis after discharge.
Anti-Xa level monitoring
Although anti-Xa activity levels remains a poor predictor of bleeding risk, it is the most appropriate measure of the pharmacodynamic effects of low molecular weight heparins (LMWHs). The need for Anti-Xa monitoring should be discussed with the Haematology Consultant on call during normal working hours. If approved, specify the following on the electronic request form:

• Name of Haematology Consultant who approved the request

• The therapeutic agent (tinzaparin/enoxaparin/etc)

• Trough anti-Xa level OR peak anti-Xa level

• For fondaparinux in table 1, there is no lower dose than 2.5mg for weight <50kg. A peak anti-Xa level should be
considered to assess for accumulation.
Note: anti-Xa levels for danaparoid and fondaparinux have to be sent away for processing
Anti-Xa levels should NOT be routinely ordered. They should be considered for subgroups of patients to assure therapeutic and non-toxic levels:

• Underweight patient (less than 50kg)

• BMI ≥35; weight >150kg

• CrCl <30mL/min (NB. LMWH contraindicated; UFH should be used, which does not require anti-Xa monitoring

• CrCl 30-60mL/min and >70 years of age/with extended use (more than 7 days)/suspicion of sub-therapeutic
doses

• CrCl is difficult to estimate (e.g. amputee)

• Intermediate dose thromboprophylaxis

• Bleeding/new thrombosis.
Do NOT omit doses, whilst anti-Xa results are pending; level interpretation is not usually an urgent matter so should, in most cases, be discussed with the Haematology Consultant in normal working hours.
Source: Issue date: July 2020 Page 9 of 20 Status: Approved Review date: July 2021

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

**Use CrCl as calculated by Cockcroft-Gault equation, NOT eGFR** – calculate daily as suggested below or via the Microguide app:

Estimating creatinine clearance (using Cockcroft and Gault equation)

𝐶𝑟𝐶𝑙 = 𝐅 × (140 − age in years) × weight (kg) serum creatinine (μ mol⁄L)

• F= 1.04 for women and 1.23 for men Cockcroft and Gault equation will not work for:

• Muscle wasting (patient’s CrCl will be overestimated as patients with very low muscle mass will have a much lower creatinine excretion rate)

• Oedematous patients (use Ideal Body Weight [IBW])

• Ascites (use IBW and consult with Pharmacy)

• Acute renal failure. This may represent non-steady state serum creatinine levels and may underestimate
the level of renal impairment (consult with Pharmacy).
**All of these cases should be discussed with a ward Pharmacist or on-call Pharmacist**
Cautions:

• For obese patients, calculate ideal body weight (IBW) and if actual weight is ≥20% over IBW, use adjusted

body weight (ABW) instead of actual weight to calculate CrCl. For woman: IBW = 45 + (2.3 x each inch over 5ft)
For men: IBW = 50 + (2.3 x each inch over 5ft)

Adjusted body weight = ideal body weight + 0.4 (actual body weight – ideal body weight)
Frequency of monitoring for LMWH (low molecular weight heparins) e.g. tinzaparin and enoxaparin:

*For CrCl <30mL/min take trough sample just before the 4th dose (or peak sample 4 hours post the 4th dose) or concerns of bleeding.

If the patient is on ITU, the ITU Consultant and clinical Pharmacist should agree on the appropriate adaption of thromboprophylaxis dose and frequency of anti-Xa monitoring (approximately 2-3 times weekly).

STANDARD DOSE PROPHYLAXIS LMWH – dose adjustment
The target range for peak anti-Xa level for prophylaxis doses tinzaparin and enoxaparin is 0.2-0.4 (units/mL)

Trough anti-Xa levels (to check for accumulation, e.g. renal impairment)

Just before the 5th dose (up to 30 minutes before) *

Peak anti-Xa levels (to check for efficacy)

4 hours post the 5th dose

Peak anti-Xa activity (units/mL) and dose adjustment

<0.2

0.2-0.4

>0.4

Increase by 10% re-check levels after 4th dose

In range – no dose adjustment needed (consider rechecking levels after 4 further doses)

Omit one dose and decrease by 10% re-check levels after 4th dose

Source: Issue date: July 2020 Page 10 of 20 Status: Approved Review date: July 2021

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

TREATMENT DOSE LMWH – dose adjustment

1. Tinzaparin 175 units/kg od – aim for a peak anti-Xa level between 0.5-1(units/mL)
2. Enoxaparin 1mg/kg (bd or od depending on CrCl) – aim for a peak anti-Xa level between 0.5-1(units/mL) 3. Enoxaparin 1.5mg/kg od – aim for a peak anti-Xa level between 1-2 (units/mL)

For options 1 and 2 above please use the table on the next page, for option 3 discuss with a Consultant Haematologist:

Anti-Xa activity (units/mL)

Action required?

Dosage Change

Next peak anti-Xa level (depending on renal function)

<0.35

Increase by 25%

4 hours after 4th or 5th dose

0.35-0.49

Increase by 10%

4 hours after 4th or 5th dose

0.5-1

Consider next day to verify, then weekly

1.1-1.5

Omit one dose

Decrease by 20%

Then 4 hours after 4th ‘new’ dose

1.6-2

Omit one dose

Decrease by 30%

Then 4-6 hours after 4th ‘new’ dose

Omit dose until <0.5

Decrease by 40% OR change frequency to 24 hourly dosing if receiving 12 hourly dosing

Check at 24 hours then 12 hourly until anti-Xa level is under 0.5
Then 4-6 hours after 4th ‘new’ dose

Acute thrombosis

Investigation

Practitioners should use standard-of-care objective testing (i.e. CTPA, V/Q scan, MRI, venography, Doppler ultrasonography) to diagnose venous thromboembolism (VTE) based on clinical index of suspicion. A pragmatic approach (e.g. point-of-care bedside ultrasonography or echocardiography) can also be combined with standard- of-care objective testing (ISTH recommendation).

The d-dimer is frequently elevated (including values in excess of 5000 ng/mL FEU (fibrinogen equivalent units). In the absence of clinical features of acute thrombosis, there is no need to investigate for VTE as a cause of an elevated d-dimer (ISTH recommendation).

Suspect possible VTE in the following situations (not exclusive):

• Unilateral limb swelling

• Sudden deterioration of oxygenation/respiratory distress

• Hypoxia out of keeping with CXR findings an upward step in d-dimer level

• Reduced blood pressure

• An upward step in d-dimer level
In patients where there is a clinical suspicion of VTE urgent investigation to rule out VTE is essential.
The value of the clinical pre-probability WELLS score is unclear in this patient group due to the high baseline risk, so clinical assessment with a low threshold for further investigation is recommended.
IV contrast medium for CTPA is not recommended if CrCl <30mL/min.
Treatment

• CrCl >30 mL/min: therapeutic tinzaparin 175 units/kg with no baseline
coagulopathy/contraindications

• CrCl 15-29 mL/min: therapeutic enoxaparin 0.75mg/kg bd or 1.5mg/kg od – with established
coagulopathy, monitor peak anti-Xa level 4 hours after 4th dose

• CrCl <15 mL/min: therapeutic enoxaparin 0.5mg/kg bd or 1.0mg/kg od – monitor peak anti-Xa levels
after 4th dose

Source:
Status: Approved Review date: July 2021

Issue date: July 2020 Page 11 of 20

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

Coagulopathy

The coagulopathy and thrombocytopenia in COVID-19 infection represents a form of disseminated intravascular coagulopathy (DIC) or sepsis induced coagulopathy (SIC).

Evidence has shown that around 70% of non-survivors had overt disseminated intravascular coagulation (DIC), as demonstrated by the International Society on Thrombosis and Haemostasis (ISTH) DIC score, compared with only 0.6% of survivors. The DIC score has shown prognostic value in COVID-19 pneumonia and is calculated from measurement of the platelet count, D-dimer, fibrinogen, and prothrombin time as shown in table 3 below.

The DIC score can be calculated as below. If an FBC, clotting screen and d-dimer are requested on a single order set, the laboratory will automatically calculate the DIC score for inpatients. The tests required to calculate the DIC score are part of the order sets on e-Care for suspected/confirmed COVID-19 cases.

Table 3 – DIC score (Taylor et al, 2001; ISTH)

Parameter

Score

Platelet count

>100 x 109/L 50-100 x 109/L <50 x 109/L

0 1 2

D-dimer

No increase
Moderate increase (1-10 times upper limit of normal) Strong increase (>10 times upper limit of normal)

0 2 3

Fibrinogen

>1.0 g/L <1.0 g/L

0 1

Prothrombin time prolongation

<3s 3-6s >6s

0 1 2

Overt Disseminated Intravascular Coagulation probable (repeat score daily)

DIC not present. Repeat score in 1-2 days

0-4

If a patient on ITU, repeat score daily regardless of score

The best management of DIC is to identify and treat the underlying condition, which with COVID-19 infection is difficult. Recovery from DIC is dependent on endogenous fibrinolysis breaking down the disseminated thrombi.

Source: Issue date: July 2020 Page 12 of 20 Status: Approved Review date: July 2021

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

Patient admitted with suspected/confirmed COVID-19 infection and coagulopathy

No evidence of bleeding

Minor bleeding

Clinically relevant non-major bleeding

Major haemorrhage

Monitor FBC clotting screen (includes fibrinogen) daily. Repeat D-dimer every 1-2 days if clinical deterioration

Local haemostatic measures. AVOID tranexamic acid. Support platelets if <50×109/L

If PT/APTT >1.5 times normal

Manage as per WSH protocol for major haemorrhage and discuss with a Haematology Consultant Haematologist

Consider fresh frozen plasma (FFP) 12-15mL/kg (pragmatically 1 unit every 20kg, 4 units in an adult)

+/- Cryoprecipitate 15mL/kg (two 5 unit pools) or fibrinogen concentrate 3-4g

Maintain fibrinogen >1.5g/L

Support platelets if <50×109/L

Consider surgical, endoscopic or radiological intervention

Prothrombin complex concentrate (PCC) such as Octaplex and Recombinant Factor VIIa (rVIIa) e.g. Novoseven are contraindicated in patients with DIC

AVOID systemic tranexamic acid

Thromboprophylaxis with LMWH unless platelets <30×109/L, in which case IPC is essential

If fibrinogen ≤1g/L give cryoprecipitate 15mL/kg; adjust dose for fluid overload risk

Do not correct other coagulopathies, but consider vitamin K (phytomenadione) PO/IV 10mg for 1-3 days if PT > 6 seconds above ULN and review

If APTT >6 seconds above ULN, discuss with Haematology Consultant

Key:

IPC = intermittent pneumatic compression ULN = upper limit of normal

Pharmacological thromboprophylaxis in patients with coagulopathy

Established coagulopathy is not an independent risk factor for bleeding. Patients with DIC are frequently considered to be prothrombotic, even

with deranged coagulation parameters.

Source: Issue date: July 2020 Page 13 of 20 Status: Approved Review date: July 2021

Coagulopathy should not prevent the prescribing and administration of pharmacological

thromboprophylaxis, unless there is evidence of active bleeding.

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

Management of haemorrhage in patients with suspected/confirmed COVID-19 infection with NO coagulopathy

Management is as for cases with no COVID-19 infection, i.e. general resuscitation with fluids, local haemostatic measures and, as appropriate, surgical, endoscopic or radiological intervention.

Tranexamic acid 1g IV should be given.

Haemofiltration (CVVHDF) guidance on Critical Care in suspected/confirmed COVID-19 infection
Detailed recommendations for this pandemic and use with haemofiltration can be found on metavision through the King’s Critical Care Renal Replacement Therapy Guidelines PowerPoint document. Recommended practice within the Critical Care national groups suggests that CVVHDF patients should be initiated on the following:

Prismocitrate + continuous unfractionated heparin (UFH) infusion:

• Effective unfractionated heparin infusion requires an appropriate clinical area capable of timely out
of hours monitoring and prompt dose adjustments as appropriate and should be discussed with the
Haematology Consultant.

• APTT ratio (APTT-R) monitoring is unreliable in patients with existing/evolving coagulopathy. Anti-Xa
monitoring for UFH is recommended but currently unavailable on site. In COVID-19 suspected/confirmed cases, the presence of raised fibrinogen and factor VIII levels as part of the acute phase response contributes to the poor reliability of the APTT-R in such cases. It is acceptable to establish an APTT-R within range and confirm efficacy of the regimen with a peak anti-Xa level once available on discussion with the Haematology Consultant.

• Any significant change in the UFH infusion rate should be assessed with the APTT-R and ideally later with a peak anti-Xa once available.
De-escalation of therapy is however more challenging. Simple utilisation of D-dimer may not be possible as it can often be raised due to other factors including sepsis, lung cancer/metastases and so on. Therefore, decisions for de-escalation from this should be based on a patient by patient decision. This should be discussed with an ITU Consultant before proceeding; you may want to consider de-escalation in the following manner:
Prismocitrate + as per table 1 based on D-dimer, weight and DIC score* OR (depending on availability of prismocitrate)
Non-citrate CVVHDF protocol with heparin (primed) in the circuit + as per table 1 based on D-dimer, weight and DIC score*
*If high risk of bleeding – consider using heparin, discuss dosing with ward Pharmacist
Source: Issue date: July 2020 Page 14 of 20 Status: Approved Review date: July 2021

Aim for an APTT ratio of 2-2.5 if there is a low bleeding risk
• NOTE: use of unfractionated heparin increases the risk of heparin induced

thrombocytopenia (HIT) which does not have a rapid diagnostic test (discuss with the Consultant Haematologist) and is a highly prothrombotic state

If the patient is deemed a high bleeding risk, then consider aiming for an APTT ratio of 1.5-2

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

Pharmacokinetic considerations

Tinzaparin (LMWH)

Enoxaparin (LMWH)

Fondaparinux (synthetic polysaccharide)

UFH (e.g. heparin 5000 units bd)

Apixaban

Absorption half life

3.3 hours (90% bioavailable based on anti-Xa activity)

3-4 hours (100% absolute bioavailability)

Half Cmax concentration is reached in 25 minutes (100% absolute bioavailability)

Depends on the dose administered, the route of administration and is subject to wide inter- and intra- individual variation

1-2 hours

(50% oral bioavailability)

Peak onset

4-6 hours

3-5 hours

2 hours

Depends on the dose administered, the route of administration and is subject to wide inter- and intra- individual variation

3-4 hours

Elimination half life

1.5 hours

5-7 hours

17-21 hours

Depends on the dose administered, the route of administration and is subject to wide inter- and intra- individual variation

12 hours

Elimination

Renal

Renal & hepatic clearance

Renal

Anti Xa:IIa ratio

2-2.7:1

2.7-4.1:1

Pure Anti-Xa

N/A

Anti-Xa

References:

. 1) Varley J et al. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom. Thromb Res, 2020; Manuscript accepted in press

. 2) Imperial College Hospital. Thromboprophylaxis and anticoagulation in COVID-19 infection Trust guideline. 2020

. 3) Thachil et al. ISTH Interim guidance on recognition and management of coagulopathy in COVID-19. British Society of
Haematology 4/4/2020.

. 4) Taylor, J et al. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular
coagulation. (DIC): Scientific Subcommittee (SSC) of the International Society of Thrombosis and Haemostasis (ISTH).
Journal of Thrombosis and Haemostasis (JTH). 2001 Nov; 86(5):1327-30

. 5) Hunt et al. Practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated
intravascular coagulation of patients infected with COVID-19. British Society of Haematology. Thrombosis UK. 25th March
2020. Accessed via https://thrombosisuk.org/covid-19-thrombosis.php (22/4/2020)

. 6) Specialist Pharmacy Service. Coronavirus (COVID-19), Summary of COVID-19 medicines guidance: Haematological
disorders. Accessed via https://www.sps.nhs.uk/articles/summary-of-covid-19-medicines-guidance-haematological-
disorders/ (22/4/2020)

. 7) Electronic medicines compendium. Summary product characteristics https://www.medicines.org.uk/emc/ (19/4/2020)

. 8) British National Formulary online. Accessed via Medicines complete https://about.medicinescomplete.com/ (19/4/2020)

. 9) UK Clinical Pharmacist Association Critical Care Group. Drug dosing in extremes of body weight in critically ill patients.
Accessed via https://www.scottishintensivecare.org.uk/uploads/2014-07-24-19-55-33-Drugdosingatextremesofbod-
45662.pdf (19/4/2020)

. 10) Evidence Based Medicine Consult. Dosing differences and Rationale among low molecular weight heparins (LMWH).
Accessed via https://www.ebmconsult.com/articles/lmwh-enoxaparin-lovenox-dalteparin-fragmin-dosing-differences
(22/4/2020)

. 11) Comparison of formulary low molecular weight heparins and fondaparinux. Accessed via
http://www.vhpharmsci.com/vhformulary/Tools/LMWH%20Comparison.pdf (22/4/2020)

. 12) Bakhtiari, K., Meijers, J.C.M., de Jonge, E. & Levi, M. (2004) Prospective validation of the International Society of
Thrombosis and Haemostasis scoring system for disseminated intravascular coagulation*. Critical Care Medicine, 32, 2416– 2421.

Source:
Status: Approved Review date: July 2021

Issue date: July 2020 Page 15 of 20

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

. 13) Dhainaut, J.F., Yan, S.B., Joyce, D.E., Pettila, V., Basson, B., Brandt, J.T., Sundin, D.P. & Levi, M. (2004) Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation . Journal of Thrombosis and Haemostasis , 2, 1924–1933.

. 14) Levi, M., Toh, C.H., Thachil, J. & Watson, H.G. (2009) Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Journal of Haematology, 145, (1): 24–33.

. 15) Tang, N., Li, D., Wang, X. & Sun, Z. (2020) Abnormal Coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. Journal of thrombosis and haemostasis : JTH, (2020); 10.1111/JTH

. 16) Taylor, J., Toh, C.H., Hoots, W.K., Wada, H. & Levi, M. (2001) Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation: On behalf of the scientific subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and . Thrombosis and Haemostasis, 86, 1327– 1330.

. 17) Klok et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thrombosis research. Elsevier. 13/4/2020

. 18) Scully M et al. How we manage patients with heparin induced thrombocytopenia. British Journal of Haematology. 2016 174, 9-45

. 19) Crystal Phend. Anticoagulation Guidance emerging for severe COVID-19 – pragmatic choices dominate as guidelines are shaping up. 8/4/2020

. 20) Intensive Care Society, UCL Partners, NIHR Applied Research Collaboration North Thames. COVID-19, thromboprophylaxis and anticoagulation of ICU patients: shared clinical experience. Published 25/4/2020

. 21) Garcia DA, Baglin TP, Weitz JI and Samama MM. Parenteral anticoagulants: Antithrombotic therapy and prevention of thrombosis. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition). CHEST 2012; 141(2)(Suppl):e24S-e43S.

. 22) Lim, W. Using low molecular weight heparin in special patient populations. J Thromb Thrombolysis, 2010;29(2): 233–240.

. 23) UKMI, Medicines Q&A: Are low molecular weight heparins preferred to unfractionated heparin in people with renal
impairment for treatment indications? Last updated December 2018

. 24) UKMI, Medicines Q&A: Low molecular weight heparins – should prophylactic doses be used in patients with renal
impairment? Last updated January 2020

. 25) Guidance on thromboprophylaxis, thrombosis and coagulopathy management in COVID-19. Chelsea and Westminister
Hospital April 2020 Version 2.

. 26) University of Liverpool: COVID-19-druginteractions.org

. 27) The Renal drug database. Accessed via: https://renaldrugdatabase.com/ (01/07/2020)

. 28) Ten VS, et al. Endothelial response to hypoxia: physiological adaptation and pathology dysfunction. Current Opinion
Critical Care. 2002 June; 8 (3): 242-50

. 29) Spyropoulos AC, Anderson FA, Jr., et al. Predictive and associative models to identify hospitalized medical patients at risk
for VTE. Chest.2011;140:706-14. Improve VTE score

Source:
Status: Approved Review date: July 2021

Issue date: July 2020 Page 16 of 20

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

Development of the guideline Changes compared to previous document

See additional information below for further information – revisions may occur upon review of new literature, at the latest within 2 months of publication

Statement of clinical evidence

This document is based on best interpretation of evidence based primary literature. This document will be updated frequently depending on the most current evidence published regarding COVID-19 in relation to hematological disorders, specifically regarding thromboprophylaxis.

Distribution list/dissemination method

Recommendations within this document has been disseminated to relevant specialists, including the Thrombosis committee (Chair action) and the Drugs and Therapeutics Committee (core group agreement) as part of a rapid launch of this guidance.

Author(s):

Dr Dipti Chitnavis (Consultant Haematologist)
Matthew Youngman (Lead Antimicrobial Pharmacist)
Dr Bhowmick (Consultant Anaesthetist and Intensivist) Diana Luis De Pina (Clinical Pharmacist Directorate Support)

Other contributors:

Dr Ayush Sinha – Consultant Anaesthetist and Intensivist Dr Will Petchey – Consultant Nephrologist
Dr Vivian Yiu – Consultant Nephrologist
Dr Liam Ring – Consultant Cardiologist

Claudia Wand – Medical directorate Pharmacist Alexis Marcos – Specialist e-Care Pharmacist Oliver Scott – Specialist e-Care Pharmacist Rachel Wilkins – Rotational Pharmacist

Approved by:

Thrombosis committee – Chair action via Dr Margaret Moody Drugs and Therapeutics committee

Key words:

COVID-19, coronavirus, SARs-CoV-2, thromboprophylaxis, anticoagulation, thrombosis, coagulopathy, DIC, disseminated intravascular coagulation

Issue no:

File name:

Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19 infection

Supercedes:

Additional Information:

Version 1 released 24/4/2020
Version 2 (discussion 29/4/2020, agreed and published 1/05/2020):

– Additional author who has contributed to evidence base for renal impairment dosing and monitoring of anti-Xa levels has been added. From this a table 2 provides clear guidance for options for CrCl <30mL/min. Evidence from the ICS thromboprophylaxis guidance that was released 25/4/2020 (reference 18) was utilised for an informed decision process.

– Perioperative considerations were discussed and whether heparin should be used due to the shorter half-life, however due to concerns of HIT with overuse of UFH this is not currently recommended due to the lack of evidence.

– Extended VTE was discussed as Addenbrookes have started recommending 14 days post discharge of LMWH or DOAC. However due to the lack of evidence for its safety or efficacy, this will not be available considered for inclusion at this time.

– Changing patient’s usual DOAC or warfarin to treatment dose LMWH whilst an inpatient was discussed, and an addition was made under table 1 for clarity.
Version 3 released late May 2020

– Expansion of title of CG and its purpose

– Further clarification on when to use standard vs intermediate dose pharmacological
thromboprophylaxis added, with regard to platelet count and bleeding risk

– New section on management of acute thrombosis

– Additional information regarding monitoring of UFH infusions

– Additional information regarding anti-Xa monitoring for LMWH

– Information on reversal of tinzaparin with protamine sulphate

– ACS tables 3 and 4 added as per Claudia Wand’s recommendations

– Changes to risk stratification in the table of dose recommendations

– New section on extended VTE for discharge

– New section on management of coagulopathy including haemorrhage

– New section on management of patients already on therapeutic anticoagulation

– Addition of Improve VTE score

– Addition of quick reference guide

Source: Issue date: July 2020 Page 17 of 20 Status: Approved Review date: July 2021

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

Appendix 1 – Protamine for LMWH overdose

This REFERS only to tinzaparin (Innohep) for prophylaxis.

Reversal of tinzaparin (Innohep) heparinization (prophylactic dose) with protamine sulphate treatment

The dosage for tinzaparin thromboprophylaxis in high-risk surgery such as orthopaedic surgery is 50 anti Xa U/kg or a fixed dose of 4500 anti Xa U irrespective of body weight, and in general surgery is a fixed dose of 3500 anti Xa U irrespective or body weight. The sign of tinzaparin overdosage is bleeding. Although we have no clinical experience with overdosage, studies in healthy volunteers indicate that:

1mg protamine sulphate* per 100 anti-Xa units tinzaparin administered should be given over 10-15 minutes1- 3. This neutralises 65-80% of the anti-Xa activity almost immediately.

This may be administered at any time up to and including 180 minutes (3 hours) after tinzaparin administration#.

A partial return of tinzaparin’s anti-Xa, anti-IIa and APTT activities (to 76%, 58%, 44% of original respectively) are seen 3 hours after its reversal probably due to continuous absorption of Innohep from the subcutaneous depot. Repeat protamine sulphate infections or a continuous infusion may be administered to achieve or maintain neutralization. Suggested timescales for repeat injections are 30-60 minutes after 1st injection and if necessary, every 60 minutes thereafter until APTT normalises.

Bodyweight (kg)

Tinzaparin dose (anti-Xa units)

Tinzaparin dose (mL)

Protamine sulphate dose (mg)

2500

0.25

25.0

2750

0.28

28.0

3000

0.30

30.0

3250

0.33

33.0

3500

0.35

35.0

3750

0.38

38.0

400

0.40

40.0

4250

0.43

43.0

4500

0.45

45.0

4750

0.48

48.0

100

5000

0.50

50.0

*Potential side effects of protamine must be considered, and patients carefully observed. In particular, protamine is contraindicated in patients with allergies to fish and fish products.

#If protamine sulphate is first administered much later than three hours after tinzaparin was given, you may wish to consider an adjustment to reflect decreasing tissue level of tinzaparin. Volunteer data shows peak plasma levels occurring 4-6 hours post s/c administration4, with absorption half-life approximately 200 minutes and elimination half-life approximately 80 minutes5.

1. Holst J et al; Blood Coag. Fibrinol 5.795 (1994)

2. British National Formulary (BNF) accessed via (28/5/2020)

3. Prosulf 10mg/mL solution for injection monograph. Electronic medicines compendium. Wockhardt. Last updated 9/5/2018, accessed via
https://www.medicines.org.uk/emc/product/8/smpc (28/5/2020)

4. Matzsch T et al; Thromb, Haemost, 5.7 97 (1987)

5. Pedersen P et al; Thorn Res 6.1 477 (1991)

Source:
Status: Approved Review date: July 2021

Issue date: July 2020 Page 18 of 20

West Suffolk NHS Foundation Trust CG10393-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

Appendix 2 – IMPROVE predictive VTE score

The IMPROVE [International Medical Prevention Registry on Venous Thromboembolism] Predictive score was designed to assess the risk of VTE in hospitalized medical patients. The IMPROVE Predictive score for VTE includes 4 independent risk factors for VTE present at admission.

Criteria

Points

Previous VTE

3 points

Malignancy (treated or untreated within the previous 6 months)

1 points

Thrombophilia

3 points

Age >60

1 point

Max score

8 points

IMPROVE predictive score

VTE risk on admission

0-1

Low: Observed VTE risk <1%

2-3

Moderate

≥4

High: Observed VTE risk 5.7%

Source: Issue date: July 2020 Page 19 of 20 Status: Approved Review date: July 2021

West Suffolk NHS Foundation Trust CG103093-3 Thromboprophylaxis, coagulopathy management and thrombosis in COVID-19

Appendix 3 – Quick reference guide

Thromboprophylaxis in suspected/confirmed COVID-19 infection in patients NOT currently on therapeutic anticoagulation – Quick reference guide

Do not omit thromboprophylaxis due to coagulopathy, unless evidence of bleeding

Monitor:

FBC daily
Clotting screen (including fibrinogen) and D-dimer every 1-2 days, according to DIC score (see coagulopathy section)

Platelets <30×109/L or active bleeding

Platelets ≥30×109/L but <50×109/L or other bleeding risk1
Assess for contra-indications

Platelets ≥50×109/L with no other risk factors for bleeding1
Assess for contra-indications

1. Offer IPC2,6

2. Standard dose
pharmacological thromboprophylaxis as per CG10193
If no contra-indications and bleeding risk taken into account
Dose according to actual body weight and calculated CrCl (as per Cockcroft-Gault equation)

1. Offer IPC2,6

2. If no contra-indications and bleeding risk taken into
account offer standard or intermediate dose pharmacological thromboprophylaxis as below3,4,6:

3. If high risk for VTE consider treatment dose anticoagulation

4. For anti-Xa monitoring and subsequent dose adjustments refer to monitoring section of guideline CG103093

1. Offer IPC2,6 2. Discuss with

Haematology Consultant

On Discharge

Consider pharmacological thromboprophylaxis for a minimum of approximately 14 days up to a maximum of 30 days in patients with low bleeding risk1 and with key VTE risk factors4,5,6

1st line: standard dose tinzaparin s/c thromboprophylaxis – contraindicated if CrCl <20mL/min
OR 2nd line (only if tinzaparin is not an option): rivaroxaban 10mg OD (unlicensed) – contraindicated if CrCl <15mL/min

1 See section on bleeding risk factors
2 IPC (Intermittent pneumatic compression device) – only offer if no contra-indication. Prioritise for those in critical care/those with haemorrhage/risk precluding use of pharmacological thromboprophylaxis
3For alternative options see CG103093
4If CrCl <15mL/min or on dialysis discuss with Nephrology Consultant
5 Key VTE risk factors include: Advanced age, >7 days of hospital, stay in ICU, cancer, prior history of VTE, thrombophilia, severe immobility, elevated D-dimer (>1000 at the time of discharge), an IMPROVE VTE score of 4 or more
6ISTH recommendation

Source: Issue date: July 2020 Page 20 of 20

Note: For ACS patients follow table 3 and 4 of the CG103093 guideline
Status: Approved Review date: July 2021