CME INDIA Presentation by Dr. Anand Malani, MD, Sangli, Maharashtra (Feedback/suggestions/queries welcome -dranandsm@gmail.com).

A Survey about Prevailing Practices.

“Our approach and understanding of d-dimer and its treatment needs lot of reconsideration and our own studies and analysis!”

Editorial in Thrombosis Research commented: D-dimer measurement could be not always a silver bullet but a clinical distraction too. We have seen numerous pitfalls and undue panic with elevated D-dimer during Covid-19 pandemic. Dr. Anand Malani tried to understand the trend in D-dimer estimation and its impact on management at different levels of health care. Although this study is small but an eye opener to health care providers – Editor, www.cmeindia.in.

How this study done?

Responses were sought from various categories of doctors treating Covid-19 about various aspects of d-dimer in the disease of concern through Google forms with link as below:

https://forms.gle/XaWQX9riX9X8YDmA7

The response to the request was Luke-warm and limited to 45 entries. Thank you all for your responses. Tried to analyze the prevailing practices and summarize. A very detailed or statistical analysis is out of scope. The figures are rounded off. Will present only highlights. At the end find some discussion.

Findings Analyzed

The participants were distributed as follows. Each category has been analyzed separately.

A. Responses from Critical care specialist in a level III/IIIB ICU [Very advanced ICUs] in Private/Govt settings.

• All patients underwent d dimer testing.
• 90% of them advised d dimer testing even in all mild home treated illness.
• And found it to be mildly elevated in 25-50% of above patients.
• It was found elevated in almost 100% of admitted cases and in majority within the range of 1000-5000 ng/ml combined together.
• Majority view even milder elevation of d-dimer as fibrin degradation product indicative of an on-going thrombotic process.
• 35% find a linear correlation between d-dimer value and mortality. While 55% found correlation only in severe elevations.
• No treatment for mild-moderate elevation in non-hospitalized patients was endorsed by only 1 respondent. 2 of them treated with antiplatelets and all others preferred some form of anticoagulation.
• Majority preferred to treat moderate-severe elevations of d-dimer among admitted patients with therapeutic doses of LMWH followed by NOACs. Only one respondent preferred to use prophylactic dose of LMWH if there were no risk factors for DVT.
• In post discharge scenario- where highest level was mild, 55% preferred to treat with NOACs while 45% with antiplatelet agents. In moderate elevations 80% preferred NOACs while 20% preferred antiplatelet agents. The ratio was 80/10/10 to NOAC/WARFARIN/Anti-Platelet agents respectively for severely elevated d-dimer levels.
• Preferred duration of treatment was 4 weeks as per 45% of respondents, 6-8 weeks as per 27% and till normalization of d-dimer by another 27%.
• Bleeding was uncommonly reported.
• Testing d dimer in non-Covid viral infections/ Bacterial infection-sepsis is not carried out by most.

B. Responses from Physicians/ Intensivists working in Covid-19 hospitals, Pvt/Govt settings, and managing Covid-19 on OPD basis as well

• Only 45% do perform d-dimer test in 100% of their patients.
• Testing in mild patients was not recommended by 36% of treating respondents
• 68% reported that it was elevated in less than 25% of mild non admitted patients.
• Even in moderate-severe admitted patients, 1 respondent reported elevated d-dimer in only 25% of such cases. 50% reported rise in majority of patients.
• The range of elevation was between 1000-2500 ng/ml in majority of their patients as per 56% of respondents.
• 44% of respondents view milder elevation of d-dimer in non-hospitalized patients just as an inflammatory marker. While only 16% continue to view it same when moderately elevated. In severely elevated cases all consider it as marker + fdp .
• Majority have observed that severe elevation has a linear relation with mortality, and 32% observe very high mortality if elevated >10000ng/ml.
• In mild elevations among non-hospitalized patients, 32% respondents didn’t treat it with anything specific. While the remaining 68% preferred to treat either with some sort of anticoagulation or at least an antiplatelet agent.

Practice Impact of D-Dimer

• In hospitalized patients with mild-moderate elevations 72% of respondents preferred to treat with prophylactic doses of LMWH.
• In hospitalized patients with severe elevations the following diagram shows the trend

• Here one respondent preferred to start NOAC from the beginning.
• In case of post discharge treatment in those with severely elevated 88% preferred NOACs, while 2 respondents preferred antiplatelet agents and 1 did not treat with any specific drug.
• The duration of post discharge treatment was mixed bag

• 32% of respondents now have started testing d-dimer in Non-Covid infections and 12% find them frequently elevated.

C. Responses from physicians/intensivists working in medical college hospitals

There were only 2 respondents from this category. But the number of patients treated at such hospitals is quite large.

• No major difference in trend observed.
• Any level of d-dimer elevation is seen as inflammatory + fdp.
• Treatment of non-hospitalized patients was as below

Treatment Impact

• Treatment of hospitalized patients was as below

• Post discharge treatment for severely elevated d-dimer includes NOACs for 4-6 weeks.
• They do not test d dimer in other infective conditions and don’t find them elevated if done.

D. Non-physician/ non-intensivist managing covid

• Only 2 responses.
• Mostly manage in sync with Physician colleagues and data almost similar.

E. Family physicians managing covid

• Not all patients undergo d-dimer testing.
• All patients with elevated d-dimer do receive some form of treatment.

What does guidelines say?

India – latest guidelines

CDC/NHS – guidelines

• None of the guidelines recommend d dimer testing in mild Covid cases.
• None of the guidelines recommend to use anti-platelet agents or anticoagulants in mild Covid cases.
• Only prophylactic anticoagulation doses recommended for admitted patients. And therapeutic doses only if evidence of thromboembolism.
• Post discharge oral anticoagulants only if high risk for thromboembolic condition.
• Anti-platelet agents are not indicated for prevention of venous thromboembolism and arterial thrombotic prevention not recommended in Covid-19.
• Anticoagulation or Aspirin/ Antiplatelet agents to be continued if patient is already receiving them for some other indications.

Highlights of observations vs guidelines

• D-dimer test is either overprescribed or under prescribed sometimes in Covid-19 patients.
• Mild-modest D-dimer elevation may be looked upon as inflammatory marker and not necessarily a product of thrombotic process.
• Even milder patients are being treated with anticoagulants or antiplatelets or both.
• Therapeutic anticoagulation is more commonly used than indicated.
• Post discharge or extended anticoagulation is more commonly used than indicated.
• Antiplatelet drugs are being overused.
• Fortunately, serious adverse effects like bleeding are being reported infrequently.
• D-dimer elevation is also seen in other viral and bacterial infections. We hardly used to perform the test without definite indications in the pre Covid era. I have personally seen D-dimer in many Dengue patients where treating it was out of question.
• Our approach and understanding of D-dimer and its treatment needs lot of reconsideration and our own studies and analysis!

CME INDIA Highlights

(by Dr. S. K. Gupta, MD (Med), FICP, CFM (France) Clinical Asst. Professor GS Medical College, CCSU, Uttar Pradesh India. Visiting Consultant, Max Super Specialty Hospital, New Delhi.)

 How find age adjusted D-dimer Value?

• The formula is: Age (years) x 10 ug/L for patients > 50 years of age.
• Example: Patient age 88 = age adjusted d-dimer of 880 ug/L would be normal for 88 years.

Limitations of D-dimer

• D-dimer has been shown to increase with age, which can cause a lower specificity (i.e., more false positive tests) in older patients.

Role of D-dimer value in Covid?

• D-dimer levels are related to the prognosis of clinical outcome in Covid. D-dimer levels were more likely to be abnormal in severely and critically ill patients compared with mild and ordinary cases, while D-dimer levels of patients who had died were significantly higher than those of surviving patients according to the results of the first and last lab tests. 
• Covid patients with advanced age, male gender, dyspnea symptoms, and some underlying diseases like obesity DM HT heart disease have a higher D-dimer values

Role of D-dimer in treatment decision making

• D dimer value has more negative predictive value in clinical practice as Normal D-dimer value helps rule out thrombosis and helps clinician in stopping the anti-coagulation therapy.
• Anti-Coagulant therapy should not be initiated/guided/escalated solely by D-dimer Values.
• In most of the patients of Moderate Covid who have been initiated on oral anti-coagulants for initial few days with corticosteroids, all attempts should be made to stop anticoagulation therapy as soon as patient becomes actively mobile irrespective of D-dimer values or rising trends of the same.
• However, extended anticoagulation may be considered in few patients with past history of DVT, VTE Cancer, immobility, Hip/Leg fracture etc.

Good to Remember

• Anti-Coagulants e.g., Apixaban Rivaroxaban etc. (DOACs) are dangerous drugs with potential to cause serious bleeding.
• Once given their effects can’t be reversed as they don’t have any (readily available) antidote.
• DOAC therapy can’t be monitored by aPTT, INR.

Do not panic if get very high D-dimer in pregnancy

• For pregnant women, the following D-Dimer reference value ranges are proposed: in the first trimester of pregnancy, 167-721 ng/mL; in the second trimester of pregnancy, 298-1653 ng/mL; and in the third trimester of pregnancy, 483-2256 ng/mL.
• D-Dimer concentrations, which are products of the action of plasmin on stabilized fibrin, and fibrinogen (Fb), are increased in pregnant women compared to nonpregnant women, and their increase progresses with the stage of pregnancy.

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