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CONFERENCE UPDATE: ASH 2023

Updates to the ASH guidelines on VTE: Thrombophilia testing and anticoagulation in COVID-19 patients

28 Feb 2024

Both thrombophilia (acquired or hereditary) and coronavirus disease 2019 (COVID-19) are associated with an increased risk of venous thromboembolism (VTE).^1,2ASH thus developed guidelines that aimed to provide evidence-based recommendations to support decision-making about thrombophilia testing and the use of anticoagulants for COVID-19 patients.^3,4 During the ASH Annual Meeting & Exposition 2023, Professor Saskia Middeldorp presented the ASH guidelines for thrombophilia testing which focused on whether testing for thrombophilia and tailoring management based on testing results would improve patient-important outcomes in different scenarios.¹ Subsequently, Dr. Deborah Siegal presented the ASH COVID-19 guidelines which focused on anticoagulant dose intensity in hospitalized COVID-19 patients and in those discharged after hospitalization who do not have suspected or confirmed VTE.⁴

While thrombophilia testing can improve risk stratification of VTE and guide the treatment and prevention of VTE, there is a risk of false negatives (missed diagnosis) and false positives (overdiagnosis), as well as potential physical, psychological, and financial harm to patients.¹ For each clinical question, the panel thus compared 2 scenarios: (a) thrombophilia testing and intervention only in individuals found to have thrombophilia and (b) no thrombophilia testing and usual care in all individuals.¹For each recommendation, the panel considered the risk of bleeding vs. recurrent thrombosis, the cost and burden of thrombophilia testing and anticoagulant treatment, as well as patient preference.¹ In total 23 recommendations were provided with nearly all recommendations based on very low certainty in the evidence due to modeling assumptions (table 1).³

Recommendation (R) no.	Population	Recommendation	Strength, certainty in evidence
Patients with symptomatic VTE
R1	Unprovoked VTE	Do not test for thrombophilia	Conditional, very low
R2	VTE provoked by surgery	Do not test for thrombophilia	Conditional, very low
R3	VTE provoked by nonsurgical major transient risk factor	Test for thrombophilia, and indefinite anticoagulant treatment for patients with thrombophilia	Conditional, very low
R4	VTE provoked by pregnancy or postpartum	Test for thrombophilia, and indefinite anticoagulant treatment for patients with thrombophilia	Conditional, very low
R5	VTE associated with use of COC	Test for thrombophilia, and indefinite anticoagulant treatment for patients with thrombophilia	Conditional, very low
R6	An unspecified type of VTE (i.e., not specified as provoked or unprovoked VTE)	Do not test for thrombophilia	Conditional, very low
Patients with symptomatic VTE in unusual sites
R7	CVT	(a) In settings when anticoagulation would otherwise be discontinued after primary short-term treatment: test for thrombophilia, and indefinite anticoagulant treatment for patients with thrombophilia	Conditional, very low
R8	CVT	(b) In settings when anticoagulation would otherwise be continued indefinitely: do not test for thrombophilia	Conditional, very low
R9	Splanchnic venous thrombosis	(a) In settings when anticoagulation would otherwise be discontinued after primary short-term treatment: test for thrombophilia, and indefinite anticoagulant treatment for patients with thrombophilia	Conditional, very low
R10	Splanchnic venous thrombosis	(b) In settings when anticoagulation would otherwise be continued indefinitely: do not test forthrombophilia	Conditional, very low
Asymptomatic individuals with a family history of VTE and/or thrombophilia
Individuals with a minor transient risk factor for VTE
R11	Individuals with a family history of VTE and known thrombophilia	Strategy #1: Selective testing for the thrombophilia known in the family
	Heterozygous FVL or heterozygous PGM	Do not test for thrombophilia	Conditional, very low
	Protein C, S, or antithrombin deficiency	Test for the thrombophilia known in the family and use thromboprophylaxis in individuals with thrombophilia	Conditional, very low
R12	Individuals with a family history of VTE and known thrombophilia	Strategy #2: Doing a thrombophilia panel
	Heterozygous FVL or heterozygous PGM	Do not test for a panel of hereditary thrombophilias (panel)	Conditional, very low
	Protein C, S, or antithrombin deficiency	Test for all hereditary thrombophilia (panel) and use thromboprophylaxis in individuals with thrombophilia	Conditional, very low
R13	Individuals with a family history of VTE and unknown thrombophilia status	Do not test for thrombophilia	Conditional, very low
R14	Individuals with a family history of thrombophilia but no VTE
	Heterozygous FVL or heterozygous PGM	Do not test for thrombophilia	Conditional, very low
	Protein C, S, or antithrombin deficiency in first-degree relatives	Test for the thrombophilia known in the family and use thromboprophylaxis in individuals with thrombophilia	Conditional, very low
	Protein C, S, or antithrombin deficiency in second-degree relatives	Either test or do not test for the thrombophilia known in the family to guide thromboprophylaxis	Conditional, very low
Women considering using COC or HRT
R15	Women from the general population considering COCs	Do not test for thrombophilia	Strong, low
R16	Women from the general population considering HRT	Do not test for thrombophilia	Conditional, low
R17	Women with a family history of VTE and unknown thrombophilia in the family considering COCs	Do not test for thrombophilia	Conditional, very low
R18	Women with a family history of VTE and unknown thrombophilia in the family considering HRT	Do not test for thrombophilia	Conditional, very low
R19	Women with a family history of VTE and thrombophilia considering COCs	Strategy: Selective testing for the thrombophilia known in the family
	FVL or PGM	Do not test for thrombophilia	Conditional, very low
	Protein C, S, or antithrombin deficiency	Test for thrombophilia and avoid COCs in women with thrombophilia	Conditional, very low
R20	Women with a family history of VTE and thrombophilia considering HRT	Strategy: Selective testing for the thrombophilia known in the family
	FVL or PGM	Do not test for thrombophilia	Conditional, very low
	Protein C, S, or antithrombin deficiency	Test for thrombophilia and avoid HRT in women with thrombophilia	Conditional, very low
Women who are planning pregnancy
Antepartum prophylaxis
R21	Women with a family history of VTE and thrombophilia	Strategy: Selective testing for the thrombophilia known in the family
	Known homozygous FVL, combination of FVL and PGM, or antithrombin deficiency	Test for the thrombophilia known in the family and use antepartum thromboprophylaxis in women with thrombophilia	Conditional, very low
	Known protein C or protein S deficiency in the family	Either test or do not test for the thrombophilia known in the family to guide antepartum thromboprophylaxis	Conditional, very low
Postpartum prophylaxis
R22	Women with a family history of VTE and thrombophilia	Strategy: Selective testing for the thrombophilia known in the family
	Known homozygous FVL, combination of FVL and PGM, or antithrombin, protein C, or protein S deficiency	Test for the thrombophilia known in the family and use postpartum thromboprophylaxis in women with thrombophilia	Conditional, very low
	Known combination of FVL and PGM, or antithrombin deficiency in second-degree relatives	Test for the thrombophilia known in the family and use postpartum thromboprophylaxis in women with thrombophilia	Conditional, very low
	Known protein C or protein S deficiency in the family	Either test or do not test for the thrombophilia known in the family to guide postpartum thromboprophylaxis	Conditional, very low
Patients with cancer
R23	Ambulatory patients with cancer who are classified to be at low or intermediate risk for VTE, who have a family history of VTE in first-degree relatives	Strategy: Doing a thrombophilia panel test for all hereditary thrombophilia (panel) and use thromboprophylaxis in individuals with thrombophilia	Conditional, very low

Table 1: Summary of recommendations for thrombophilia testing³

COC: Combined oral contraceptive; CVT: Cerebral venous thrombosis; FVL: Factor V Leiden; HRT: Hormone replacement therapy; PGM: Prothrombin 20210A gene mutation; R: Recommendation; VTE: Venous thromboembolism

Similarly, recognizing and minimizing the risk of harm from anticoagulants is a critical component for the treatment of VTE in COVID-19 patients.⁴The updated ASH focused on providing recommendations on adjusting the intensity of anticoagulants for acutely or critically ill hospitalized COVID-19 patients, and for patients who were discharged after hospitalization for COVID-19 who do not have suspected or confirmed VTE (table 2).^2,4 The guideline also included an initial phase and a living phase, during which monthly updated searches for baseline risk estimates, prognostic factors, and the effect of anticoagulation strategies are performed, allowing guideline recommendations to be continuously revisited if new evidence meets pre-specified criteria.⁴

Recommendation	Strength, certainty in evidence
R1: The ASH guideline panel suggests using prophylactic-intensity over intermediate-intensity or therapeutic-intensity anticoagulation for patients with COVID-19-related critical illness who do not have suspected or confirmed VTE	Conditional, very low
R2a: The ASH guideline panel suggests using prophylactic-intensity over intermediate-intensity anticoagulation for patients with COVID-19-related acute illness who do not have suspected or confirmed VTE R2b; The ASH guideline panel suggests using therapeutic-intensity over prophylactic-intensity anticoagulation for patients with COVID-19-related acute illness who do not have suspected or confirmed VTE	Conditional, very low
R3: The ASH guideline panel suggests against using post-discharge prophylactic-intensity anticoagulation in patients with COVID-19 discharged from the hospital who do not have suspected or confirmed VTE	Conditional, very low

Table 2: Summary of recommendations on the use of anticoagulation in COVID-19 patients^2,4

ASH: American Society of Hematology; COVID-19: Coronavirus disease 2019; R: Recommendation; VTE: Venous thromboembolism

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