Is there any supportive data that low doses of anticoagulation can help to prevent thrombotic events in patients with COVID-19 infection and elevated D-Dimer?

What information is available for COVID patients and DVT prophylaxis?

Comment by InpharmD Researcher

There is little to no published data on appropriate anticoagulation in COVID-19 patients, but guidelines recommend prophylaxis with LMWH or heparin in all patients without contraindications. One retrospective study of 449 patients found a mortality benefit with anticoagulation in COVID-19 patients with markedly elevated D-dimer (>6x ULN). Experts note the risk of VTE and DIC in COVID-19 patients, advocating LMWH (at either treatment or prophylactic doses) based primarily on anecdotal evidence.

Background

According to the interim World Health Organization COVID-19 guidelines, pharmacologic thromboembolism prophylaxis should consist of low molecular-weight heparin (preferred if available) or heparin 5,000 units subcutaneously BID in adolescents and adults without contraindications. For those with contraindications, use mechanical prophylaxis (intermittent pneumatic compression devices). [1]

Interim guidance from the International Society of Thrombosis and Hemostasis (ISTH) recommends considering prophylactic low-molecular-weight heparin (LMWH) in all patients (including non-critically ill patients) who require hospitalization for COVID-19, except in persons with contraindications. This recommendation is based on one study of 449 patients that showed a mortality benefit of LMWH in COVID-19 patients with a sepsis-induced coagulopathy score ≥4. However, there was no observed difference in 28-day mortality between LMWH use and no use. [2], [3], [4]

Per the American Society of Hematology, limited observational data suggests up to 50-10% of COVID-19 patients who require mechanical ventilation have acute pulmonary embolism (PE) or deep vein thrombosis (DVT). The likelihood of PE is moderate to high in those with signs or symptoms of DVT, unexplained hypotension or tachycardia, unexplained worsening respiratory status, or traditional risk factors for thrombosis (e.g., history of thrombosis, cancer, hormonal therapy). D-dimers can be used to rule out PT/DVT, but there is a low risk of a false negative (1-2%). Empiric anticoagulation with heparin/LMWH may offer benefit and anti-viral mechanisms have been demonstrated for factor Xa inhibitors in animal studies; however, this remains controversial due to the risk of major bleeding. [3]

In cases where there are no contraindications for therapeutic anticoagulation and there is no possibility of performing imaging studies to diagnose PE or DVT, empiric anticoagulation has been proposed in the following scenarios: 1) intubated patients who develop sudden clinical and laboratory findings highly consistent with PE, especially when CXR and/or markers of inflammation are stable or improving; 2) patients with physical findings consistent with thrombosis, such as superficial thrombophlebitis, peripheral ischemia or cyanosis, thrombosis of dialysis filters, tubing or catheters, or retiform purpura; 3) patients with respiratory failure, particularly when D-dimer and/or fibrinogen levels are very high, in whom PE or microvascular thrombosis is highly suspected and other causes are not identified. [3]

A retrospective study of 449 Chinese COVID-19 patients compared the survival rates between 99 patients who received anticoagulation for at least 7 days (mainly with low-molecular-weight heparin prophylaxis) against the 350 patients who did not receive anticoagulation. While there was no significant difference in 28-day mortality between anticoagulation and no anticoagulation (30.3% vs 29.7%, P=0.910), there was a significant difference in mortality between heparin users and nonusers with a sepsis-induced coagulopathy (SIC) score ≥4 (40.0% vs 64.2%, P=0.029) and D-dimers >6-fold the upper limit of normal (32.8% vs 52.4%, P=0.017). Additionally, D‐dimer, prothrombin time, and age were positively correlated with 28‐day mortality in a multivariate analysis. The authors concluded that anticoagulation may be associated with better outcomes in severe COVID-19 patients with a markedly elevated D-dimer. [4]

A study of 184 intensive care COVID-19 patients in Dutch hospitals found 25 incidences of PE (13.6%). All patients received thromboprophylaxis with a low-molecular-weight heparin (nadroparin). Of all thrombotic events seen, pulmonary embolism was the most common (80.6%). At the time of this study's release, many patients were in the ICU still, so the true incidence of thrombotic complications may be higher. [5]

A review on the hypothetical pathogenesis of COVID-19 suggests giving early LMWH due to the risks of disseminated intravascular coagulation (DIC). While infection is already a risk factor for DIC, unpublished clinical data suggest severe COVID-19 patients may be at a particular risk of DIC. When the D-dimer reaches 4x the upper limit of normal, the authors recommend LMWH 1 mg/kg q12h x3-5 days. This paper is based on anecdotal experience, not published data. [6]

A clinical commentary from Chinese infectious disease experts recommends early intravenous immunoglobulin (IVIG) and LMWH in COVID-19 patients. After 7-14 days of COVID-19 infection, patients will begin to develop a hypercoagulable state and the D-dimer may become abnormal. It has been observed that some of the non-survivors suffered from ischemic changes (such as ecchymosis of the fingers and toes) and worsening organ functions, which leads to the diagnosis of DIC. Early anticoagulation may block clotting formation and reduce microthrombosis, thereby reducing the risk of major organ damages. [7]

Coagulopathy has been shown to be associated with high mortality in COVID-19, with high D-dimers being a particularly telling marker. Anecdotal reports from Italy also suggest an increased risk of VTE in admitted COVID-19 patients, suggesting a benefit of prophylactic LMWH. While little data is published in COVID-19 patients, LMWH does show a mortality benefit in acute respiratory distress syndrome (ARDS). Heparin also has anti-inflammatory properties including binding to inflammatory cytokines, inhibiting neutrophil chemotaxis and leukocyte migration, neutralizing the positively charged peptide complement factor C5a, and sequestering acute-phase proteins. Without much published data, the role of heparins in COVID-19 is not fully elucidated, but some authors postulate prophylactic doses or higher may be clinically beneficial in this setting. [8]

One paper postulates the use of tissue plasminogen activator (tPA) as compassionate salvage use in severe COVID-19. In the treatment of ARDS, tPA has been shown to have a reduction of death and an increase in arterial pO2 compared to untreated controls, urokinase plasminogen activator (uPA) and plasmin. While there is no anecdotal or published evidence of tPA in COVID-19, the authors recommend considering this treatment in patients with COVID-19-induced ARDS who have a P/F ratio <50 and a pCO2>60 despite prone positioning and maximal mechanical ventilatory support. [9]

Literature Review

A search of the published medical literature revealed 7 studies investigating the researchable question:

What information is available for COVID patients and DVT prophylaxis?

Please see Tables 1-7 for your response.

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy
Design	Retrospective chart review N=449
Objective	To validate the usefulness of the sepsis-induced coagulopathy (SIC) score and other coagulation parameters in screening patients who can benefit from anticoagulant therapy through retrospective analysis of COVID-19 patients treated with heparin for seven days or longer or no treatment/treatment less than seven days
Study Groups	Anticoagulation (n=99) No anticoagulation (n=350)
Methods	Inclusion criteria: patients with severe COVID-19 admitted to a single Chinese hospital Exclusion criteria: bleeding diathesis, hospital stay <7 days, lack of information about coagulation parameters and medications, age <18 years A retrospective review and comparison of characteristics of severe COVID-19 patients was performed from a single hospital in Wuhan, China. Medications and 28-day mortality were monitored until March 13, 2020. Patients were separated into those who received anticoagulation with unfractionated heparin (UFH) or low molecular weight heparin (LMWH) for at least 7 days or those who got no heparin or <7 days of heparin. The most commonly used agent was LMWH. The SIC score system included prothrombin time (PT), platelet count, sequential organ failure assessment (SOFA). A SIC score of ≥4 was an indication for treatment.
Duration	January 1 to February 13, 2020 (monitoring up to March 13, 2020)
Outcome Measures	28-day mortality, SIC score, laboratory values
Baseline Characteristics		Total (N=449)	Survivors (n=315)	Non-survivors (n=134)	P-value
	Age, years	65.1 ± 12.0	63.7 ± 12.2	68.7 ± 11.4	<0.001
	Male	268 (59.7%)	178 (56.5%)	90 (67.2%)	N/A
	Underlying conditions	272 (60.6%)	181 (57.5%)	91 (67.9%)	0.136
	SIC score ≥4 (met SIC criteria)	97 (21.6%)	42 (13.3%)	55 (41%)	<0.001
	Received ≤7 days of anticoagulation	99 (22%)	69 (21.9%)	30 (22.4%)	0.910
	Prothrombin time, sec	15.2 ± 5.0	14.6 ± 2.1	16.5 ± 8.4	<0.001
	Platelet count, x10⁹	215 ± 100	231 ± 99	178 ± 92	<0.001
	D-dimer, µg/mL (range)	1.94 (0.0-9.44)	1.47 (0.78-4.16)	4.70 (1.42-21.0)	<0.001
Results		Anticoagulation (n=99)	No anticoagulation (n=350)	P-value
	28-day mortality SIC score ≥4 D-dimer >1 ULN D-dimer >3 ULN D-dimer >5 ULN D-dimer >6 ULN D-dimer >8 ULN	30 (30.3%) 40% 30.2% 31.1% 34.9% 32.8% 33.3%	104 (29.7%) 64.2% 32.7% 42.5% 48.8% 52.4% 54.8%	0.910 0.029 0.788 0.093 0.071 0.017 0.011
	When D-dimer exceeded 3.0 ug/mL (6 fold of upper limit of normal, 6 ULN), an approximate 20% reduction in mortality with heparin treat was found (32.8% vs 52.4%; P=0.017). UNL=upper limit of normal
Adverse Events	Bleeding (unspecified)
Study Author Conclusions	Anticoagulant therapy mainly with LMWH appears to be associated with better prognosis in severe COVID-19 patients meeting SIC criteria or with markedly elevated D-dimer.
InpharmD Researcher Critique	Retrospective studies may suffer from selection bias. This was conducted in an early set of patients when little-to-no data had been published on COVID-19. The use of other therapies, which were not reported, may have introduced confounding.

References:

Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;[E-pub].

Risk assessment of venous thromboembolism and bleeding in COVID-19 patients
Design	Retrospective chart review N=138
Objective	To identify in-hospital venous thromboembolism (VTE) risk and bleeding risk in COVID-19 patients
Study Groups	Critically ill (n=15) Non-critically ill (n=123)
Methods	Inclusion criteria: laboratory-confirmed COVID-19, hospitalized at a single center in Shanghai Exclusion criteria: none described THis was a single-center, retrospective study of COVID-19 patients in China. Critically ill patients were defined as those admitted to the intensive care unit (ICU) who required mechanical ventilation or had a fraction of inspired oxygen (FiO₂) of at least 60% or more. Routine thromboprophylaxis was provided to patients whose Padua score more than four points. For those with Improve score more than 7, intermittent pneumatic compression (IPC) or low intensive thromboprophylaxis was suggested. Lower extremity compression ultrasound (CUS) was performed for all critically ill patients and those with a high risk of VTE and high level of D-dimer.
Duration	January 21 to February 21, 2020
Outcome Measures	VTE incidence, Pauda score risk factors
Baseline Characteristics		All patients (N=138)	Critically ill (n=15)	Non-critically ill (n=123)	P-value
	Age, years	52.4 ± 16.7	60.1 ± 14.3	50.5 ± 16.0	<0.01
	Male	81(58.7%)	12(80.0%)	69(56.1%)	0.06
	D-dimer, µg/mL (inerquartile range)	0.43 (0.30-0.89)	0.74 (0.44-1.35)	0.39 (0.29-0.83)	<0.01
	Atrial fibrillation	6 (4.3%)	3 (20%)	3 (2.4%)	0.02
	Pauda score ≥4	23 (16.7%)	15 (100%)	7 (6.5%)	<0.001
Results		All patients (N=138)	Critically ill (n=15)	Non-critically ill (n=123)	P-value
	Received prophylactic anticoagulation	41 (30.1%)	15 (100%)	26 (21.5%)	<0.001
	Confirmed VTE	4 (2.9%)	3 (20%)	1 (0.1%)	<0.001
	Pauda score predictions Reduced mobility Aged ≥70 years Heart and/or respiratory failure Obesity	21 (15.2%) 17 (12.3%) 55 (39.9%) 2 (1.4%)	15 (100%) 7 (46.7%) 11 (73.3%) 2 (13.3%)	6 (4.9%) 10 (8.3%) 44 (36.4%) 0	<0.001 <0.001 0.006 0.01
	All 4 VTE patients were males (aged 25-70 years) who had one or more comorbid conditions. Three of these patients received mechanical ventilation and central venous catheter treatment; one of whom used continuous renal replacement therapies (CRRT); and one had extracorporeal membrane oxygenation (ECMO) treatment.
Adverse Events	N/A
Study Author Conclusions	Critically ill patients with COVID-19 suffered both high risk of thrombosis and bleeding risks. More effective VTE prevention strategies based on an individual assessment of bleeding risks were necessary for critically ill patients with COVID-19.
InpharmD Researcher Critique	This is a non-published, non-peer-reviewed preprint. The study size was small (especially the critically ill patients) and from a single center in China. Some of the subjects were still hospitalized at the time of this manuscript submission, so the incidence of VTE could be higher. Additional limitations include the high degree of confounding typical of retrospective studies and the extensiveness of COVID-19 treatment with little data.

References:

Xu JF, Wang L, Zhao L, et al. Risk assessment of venous thromboembolism and bleeding in COVID-19 patients. Research Square. 2020;[Preprint].

Prevalence of Venous Thromboembolism in Patients with Severe Novel Coronavirus Pneumonia
Design	Retrospective, single-center, chart review N=81
Objective	To determine the incidence of VTE in patients with severe COVID-19 pneumonia
Study Groups	VTE (n=20) Non-VTE (n=61)
Methods	Inclusion criteria: diagnosed with SARS-CoV-2 according to the World Health Organization guidelines, received antiviral and supportive treatment after diagnosis, and no preventive anticoagulant was administered Exclusion criteria: not included This was a retrospective study of patients who were diagnosed with COVID-19 from a hospital in China. All the patients received antiviral and supportive treatment after diagnosis, and no preventive anticoagulant was administered.
Duration	January 30 to March 22, 2020
Outcome Measures	Venous thromboembolism
Baseline Characteristics		All patients (N=81)
	Age, years	59.9 ± 14.1
	Women	44 (54%)
	Clinical outcomes Remained in hospital Discharged Died	9 (11%) 69 (85%) 3 (4%)
Results		VTE (n=20)	Non-VTE (n=61)	P-value
	Age, years	68.4 ± 9.1	57.1 ± 14.3	<0.001
	Leucocytes, x10⁹/L	7.8 ± 3.1	6.6 ± 2.6	0.120
	Lymphocytes, x10⁹/L	0.8 ± 0.4	1.3 ± 0.6	<0.001
	Platelets, x10⁹/L	246.6 ± 110.6	248.8 ± 111.7	0.938
	Hemoglobin, g/L	123.2 ± 16.5	125.3 ± 16.7	0.633
	Activated partial thromboplastin time (APTT), s	39.9 ± 6.4	35.6 ± 4.5	0.001
	Prothrombin time, s	15.4 ± 1.0	15.6 ± 1.0	0.465
	D-dimer, µg/mL	5.2 ± 3.0	0.8 ± 1.2	<0.001
Adverse Events	N/A
Study Author Conclusions	The incidence of VTE in patients with severe COVID-19 pneumonia is 25% (20/81), which may be related to poor prognosis. The significant increase of D-dimer in severe NCP patients is a good index for identifying high-risk groups of VTE.
InpharmD Researcher Critique	This is a retrospective, single-center, small sample study. Also, endpoints and inclusion/exclusion are not clearly defined.

References:

Cui S et al. Prevalence of Venous Thromboembolism in Patients with Severe Novel Coronavirus Pneumonia. Journal of Thrombosis and Haemostasis 2020;[E-pub ahead of print].

Findings of Acute Pulmonary Embolism in COVID-19 Patients
Design	Retrospective chart review N=25
Objective	To uncover the findings of acute pulmonary embolism (PE) diagnosed by computed tomography pulmonary angiography (CTPA) in COVID-19 patients
Study Groups	PE (n=10) No PE (n=15)
Methods	Inclusion criteria: enrolled for COVID-19, undergone computed tomography pulmonary angiography (CTPA) due to suspected PE, had D-dimer drawn Exclusion criteria: none specified This was a retrospective study of patients with suspected PE (25/1,008; 2.5%) at a single center in Wuhan, China. All CT and CTPA image analyses were performed by two radiologists experienced in thoracic radiology.
Duration	January to February 2020
Outcome Measures	Pulmonary embolism
Baseline Characteristics		PE (n=10)	No PE (n=15)
	Age, years (IQR)	66.5 (57-71.5)	65 (54-70)
	Male	6 (60%)	9 (60%)
	Outcome Still hospitalized Discharged Died	3 (30%) 5 (50%) 2 (20%)	6 (40%) 5 (33%) 4 (27%)
	IQR=interquartile range
Results		PE (n=10)	No PE (n=15)	P-value
	D-dimer, µg/mL (IQR)	11.07 (7.12-21.66)	2.44 (1.68-8.34)	0.003
	C-reactive protein, mg/dL (IQR)	3.09 (2.21-7.03)	3.41 (2.16-6.19)	0.978
	Brain natriuretic peptide (BNP), pg/mL (IQR)	213.50 (131.75-500.03)	95.90 (55.00-245.30)	0.091
	IQR=interquartile range
Adverse Events	N/A
Study Author Conclusions	Patients with COVID-19 pneumonia are at risk of PE. When D-dimer remarkable increases, CTPA facilitates the diagnosis of PE and assesses its change during the course. Special attention needs to be paid to the danger of PE associated with COVID-19 infection.
InpharmD Researcher Critique	This is a pre-print of an article that has not yet been peer-reviewed. It suffers from a small sample size and the retrospective aspect allows for confounding. In addition, ultrasonography for screening lower extremity deep vein thrombosis was not performed for these patients for various reasons, thus whether inflammation or secondary lower extremity deep vein thrombosis was the primary cause of acute pulmonary embolism could not be verified

References:

Chen J et al. Findings of Acute Pulmonary Embolism in COVID-19 Patients. Lancet. 2020;[pre-print].

Acute pulmonary embolism and COVID-19 pneumonia: a random association?
Design	Case report
Case Presentation	A 75-year-old COVID-19 positive woman was hospitalized for severe bilateral pneumonia. She was hemodynamically stable and without strong predisposing risk factors for venous thromboembolism. After 10 days, a modest leucocytosis was present (11.360/mm²) with increased values of C-reactive protein (180 mg/L), troponin I (3240.4 ng/mL), and D-dimer (21 μg/mL). A resulting CT scan documented bilateral pulmonary embolism associated with extensive ground-glass opacifications involving both the lung parenchymas with predominant consolidation in the posterior basal segment of the left lower lobe. Lower-limb compression ultrasonography was negative. Based on these findings, treatment with low molecular weight heparin, lopinavir/ritonavir, and hydroxychloroquine was started.
Study Authors' Conclusions	In conclusion, the absence of major predisposing factors in this case of diffuse bilateral COVID-19 pneumonia seems to confirm the role of severe infections as a precipitant factor for acute venous thromboembolism and the causal relationship.

References:

Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association?. Eur Heart J. 2020;

COVID-19 pneumonia with hemoptysis: Acute segmental pulmonary emboli associated with novel coronavirus infection
Design	Case report
Case Presentation	A 42-year-old man with mild COVID-19 12 days prior was admitted to the hospital for worsening symptoms. He started to develop exertional dyspnea, central pleuritic chest pain, and hemoptysis (estimated 10 mL). His physical exam revealed mild respiratory distress with bibasilar rhonchi but otherwise no other acute findings. His laboratory evaluation was notable for a D-dimer of 4.8 µg/dL and chest radiograph was significant for a right lower lobe infiltrate. His electrocardiogram (ECG) showed show flattening of the T-waves in the inferior leads. Given this presentation, he underwent a CT scan. His CT revealed bilateral segmental pulmonary emboli and an additional area of consolidation in the right lower lobe concerning for infarct. Additional findings of peripheral ground-glass opacities consistent with COVID-19 pneumonia were also noted. The patient was admitted to a negative pressure room, started on anticoagulation with heparin and eventually discharged home on a novel oral anticoagulant.
Study Authors' Conclusions	This case is one of the first to report segmental PEs in a patient infected with SARS-CoV-2 without an otherwise recognized VTE risk factor. An association between COVID-19 and PE creates a diagnostic challenge for emergency medicine clinicians given the overlap in symptoms between the two clinical entities. Elevated D-dimer levels (>1.0 mg/dl) have been identified as a potential predictor of increased mortality, but are not specific to the diagnosis of VTE.

References:

Casey K, Iteen A, Nicolini R, Auten J. COVID-19 pneumonia with hemoptysis: Acute segmental pulmonary emboli associated with novel coronavirus infection. Am J Emerg Med. 2020;[E-pub ahead of print].

COVID-19 Complicated by Acute Pulmonary Embolism
Design	Case series
Case 1	A 57-year-old Chinese man with COVID-19 was admitted to the hospital for 10 days. An unenhanced chest CT on day 10 from the onset of fever showed bilateral peripheral ground-glass opacities. Two days after hospitalization, a CT pulmonary angiography diagnosed acute pulmonary embolism.
Case 2	A 70-year-old Chinese man with COVID-19 was admitted to the hospital for 7 days. An unenhanced chest CT on admission showed bilateral ground-glass opacities and consolidation in a peripheral distribution. On day 6 of admission, a CT pulmonary angiography showed acute pulmonary embolism.
Study Authors' Conclusions	Acute pulmonary embolism is a cause of clinical deterioration in viral pneumonia. These cases evolved with respiratory deterioration and elevated serum D-dimer level. As patients with COVID-19 are admitted for treatment and isolation, it is important to follow prophylactic measures for avoiding venous thromboembolism. In this scenario, respiratory deterioration with other clinical evidence of venous thrombosis should raise suspicion for pulmonary embolism.

References:

Xie Y, Wang X, Yang P, Zhang S. COVID-19 Complicated by Acute Pulmonary Embolism. Radiology: Cardiothoracic Imaging. 2020;2(2):[E-pub ahead of print].