ABSTRACT
ABSTRACT
Introduction
COVID-19 disease has spread worldwide from December 2019 to the present day; the early stage of this disease can be associated with high D-dimer, prolonged PT, and elevated levels of fibrinogen, indicating activation of coagulation pathways and thrombosis. In this article, we analyze the levels of D-dimer in patients with COVID-19.
Area covered
In the current study, three databases, PubMed, Scopus, Web of Science, searched using related keywords and information extracted from articles such as location, sample size, gender, age, coagulation test values, patient results, and disease severity.
Expert opinion
D-dimer level is one of the measures used in patients to detect thrombosis. Studies have reported an increase in D-dimer and fibrinogen concentrations in the early stages of COVID-19 disease a 3 to 4-fold rise in D-dimer levels is linked to poor prognosis. In addition, underlying diseases such as diabetes, cancer, stroke, and pregnancy may trigger an increase in D-dimer levels in COVID-19 patients. Measuring the level of D-dimer and coagulation parameters from the early stage of the disease can also be useful in controlling and managing of COVID-19 disease.
1. Introduction
1.1. COVID-19
On 29 December 2019, a patient with symptoms of pneumonia was diagnosed by Chinese doctors, who reported to the World Health Organization (WHO) on 31 December 2019 [1]. The virus was identified as a coronavirus on 26 January 2020. The WHO later named the SARS-CoV-2 virus, and the disease COVID-19, the third RNA virus in the coronavirus family [2]. The disease has spread widely and continues to spread to most countries around the world since the first COVID-19 study in Wuhan, China, in December 2019. According to the WHO report (updated: 4 September 2020), the number of infected people is more than 26,121,000 and the number of confirmed deaths is more than 864,000 [3]. In humans, the infection can be asymptomatic in carriers or the virus can cause symptoms in infected individuals such as fever, dry cough, dyspnea, and fatigue [4,5]. In more severe cases, infection with COVID-19 can cause acute respiratory distress syndrome (SARS) and even death [5,6]. In the early phase of COVID-19 infection, leukopenia, lymphocytopenia, high level of CRP, high D-dimer, prolonged PT, and high levels of fibrinogen have been reported [7,8]. Several studies have demonstrated poor prognosis for coagulopathy in patients with severe COVID-19 [4,7,9–15]. COVID-19 has several differential diagnosis such as bacterial pneumonia, influenza, and other flu-like viral respiratory diseases. Such disorders can lead to misdiagnosis particularly in the autumn and winter seasons [16]. On the other hand, VTE and heart failure may cause manifestations of respiratory distress similar to COVID-19. The rate of VTE, PE, stroke, and myocardial infarction is evident in different communities [17]. D-dimer is one of the methods for thrombotic-state identification [18]. This analysis aims to highlight the role of D-dimer in COVID-19 infection by presenting the latest information available from studies evaluating D-dimer levels in COVID-19 patients.
1.2. D-dimer and thrombus
Fibrinolytic system breaks down the fibrin mesh after the formation of clot. The D-dimer, which comprises two D fragments of the fibrin, is formed by the activation of the plasmin enzyme. This indicates the presence of a demolished fibrin in the bloodstream. D-dimer represents the activation of coagulation and fibrinolysis systems [19]. Technically, the amount of D-dimer level is measured using various commercial kits on the market, based on a monoclonal antibody. The D-dimer test is usually used in clinical practice to exclude a diagnosis of deep vein thrombosis (DVT) and pulmonary embolism (PE) and confirm the diagnosis of disseminated intravascular coagulation (DIC) [20,21]. The D-dimer levels rise almost in all patients with severe VTE. In physiological conditions such as pregnancy and pathological conditions such as cancer, inflammation, and surgery the elevated level of D-dimer can be seen [22]. Sensitivity of D-dimer kits differs from one manufacturer to another; and reports between 93% and 95% [23]. Furthermore, several studies have shown that COVID-19 predisposes patients to thrombosis, both in arteries and veins [8]. Hence, people with COVID-19 were also at risk for DVT, venous thromboembolism (VTE), and possible PE up to 25% [8,24]. Pathological episodes such as excessive inflammation (cytokine storm, endothelial, and macrophage activation), diffuse intravascular coagulation (DIC), immobilization, hypoxia secondary to excessive lung injury in COVID-19 can result to VTE events [25]. Reported evidence of coagulopathy in COVID-19 infection showed increased levels of D-dimer, lactate dehydrogenase, mild to no changes in PT and PTT, and increased levels of antiphospholipid antibodies [26,27].
2. Materials and methods
2.1. Search strategy and criteria
On 25 May 2020, three databases including PubMed, Scopus, and Web Of Science were searched to review and mine the latest published information about COVID-19 and D-dimer in the literature. The keywords used were ‘D-dimer’ AND ‘2019 novel coronavirus disease’ OR ‘COVID19’ OR ‘SARS-CoV-2 infection’ OR ‘COVID-19 virus disease’ OR ‘2019 novel coronavirus infection’ OR ‘2019-nCoV infection’ OR ‘coronavirus disease 2019’ OR ‘coronavirus disease-19’ OR ‘2019-nCoV disease’ OR ‘COVID-19 virus infection.’
The criteria for inclusion were the texts written in English and date of publication was between 1/1/2020 and 25/5/2020. The submissions accepted included original articles, brief reports, letters, and abstracts from the conference. The studies with inadequate data and contact letters to the editors were removed from the report. Ultimately, 71 of the 251 abstracts collected were entered for full material reporting (Figure 1).
Published online:
12 October 2020Figure 1. Flow diagram of the selection process of contributions at reviewing stage
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/ierr20/2020/ierr20.v013.i11/17474086.2020.1831383/20210507/images/medium/ierr_a_1831383_f0001_b.gif"})
Figure 1. Flow diagram of the selection process of contributions at reviewing stage
2.2. Data extraction
The related documents were extracted in compliance with the criterion for inclusion and exclusion. Based on the study’s objectives, the following data were collected: first author, region, sample size, gender of studied patients, age of studied patients, D-dimer levels, PT, PTT, fibrinogen levels, platelet count, the outcomes of the patients, and severity of the disease (if available) (Tables 1–5).
Table 1. Distribution by region of reported papers on COVID19 and D-dimer
Table 2. The mined hemostatic findings of the 71 studied articles
Table 3. Articles with high sample size and their major findings
Table 4. The mined several demographic findings and D-dimer levels in reported COVID-19 patients
Table 5. Demographic findings of the articles investigating the relation of D-dimer in COVID-19 with disease severity (continued)
3. Results
3.1. D-dimer and COVID-19
Seventy-one original papers have been reviewed in this study. China had produced 54 studies and 76% of cases (Table 1). In total, 1,022 patients were screened for D-dimer with a median of 1.53 µg/ml (cutoff <0.50 µg/ml) (Table 2). Increased rates of D-dimer have a significant connection to mortality, according to earlier studies [4,7,10–15]. Nine papers examined the relationship between D-dimer levels and rate of survival. The relative findings have been reported in depth in Table 4. Out of 2118 patients, 1521 patients survived and 597 patients died, with D-dimer levels of 0.79 and 3.78 (μg/ml), respectively [4,7,9–15]. Moreover, several studies have examined the relationship of D-dimer levels and the severity of the disease, as shown in Table 5. The mean D-dimer level was registered to be 0.58 (μg/ml) in 1551 patients with mild disease and 3.55 (μg/ml) in 708 patients with severe disease [28–45]. Twenty studies examined the levels of D-dimer in COVID-19 patients, regardless of the nature and outcome of the disease, as shown in Table 6 [5,46–64].
Table 6. Demographic and some laboratory findings of the articles that assessed only the D-dimer levels in COVID-19 patients without examining specific clinical impacts
In a case–control study, 44 COVID-19 patients and 22 control samples were analyzed by Luca Spiezia et al. Their findings showed that patients with COVID-19 had increased levels of D-dimer [65]. In addition, the findings of another study in 1,047 patients with COVID-19 and 1,140 patients with influenza found that patients with influenza had higher concentrations of D-dimer than patients with COVID-19 [66]. In another study, two groups of patients with severe COVID-19 (449 patients) and pneumonia induced by other pathogens (104 patients) were examined by Shiyu Yin et al.; D-dimer levels were found to be higher in non-COVID-19 pneumonia patients than COVID-19 patients [67]. Studies with high sample size and their main findings are written in the Table 3.
3.2. D-dimer in children with COVID-19
Overall, the D-dimer had tested in 79 babies with COVID-19 on admission. Patients split into two classes of severe type (age 6.89 Years (0.97–13.83)) and non-severe type (age: 6.89 Years (3.08–10.82)) in a sample of 43 children with COVID-19 in Wuhan, China. In the severe category, the D-dimer levels were higher and suggested in them intravascular coagulation (Univariate OR: 17.4) [68]. In another study, Haiyan Qiu et al. conducted a study of observer cohorts on 36 COVID-19 students. In this study, there was an increase in D-dimer rates among three children on admission, all of whom were over 5 years old [69].
3.3. D-dimer and diabetes
Four studies had paid to D-dimer in patients with COVID-19 and diabetes [70–73]. In the first study by Yang Zhang et al., 166 patients with COVID-19 divided into three groups based on fasting plasma glucose (FPG). The first group was control (84 patients), the second group showed just one FPG increase (21 patients), and the third group displayed high FPG and hemoglobin A1c (HbA1c) (61 patients), which was known as diabetic group. The median D-dimer levels for these three groups were 0.8, 2, and 1.8 (μg/ml), respectively. Overall, the two elevated FPG groups (82 patients) had 67 patients (81.7%) and the first group had 58 patients (69%) with an increase in D-dimer levels compared to standard values (<0.5 μg/ml) [70]. In the second study conducted on 24 diabetic patients with COVID-19, without any other underlying disorders, the levels of D-dimer, CRP, and serum ferritin increased significantly. This result may indicate that patients with diabetes are more likely to become seriously ill [71]. The third study carried out on 193 COVID-19 patients, diabetic individuals (48 patients) had higher D-dimer levels than non-diabetic ones [72]. In the last study of 28 COVID-19 patients with underlying diabetes, the level of D-dimer in patients admitted to the ICU was significantly different from that of the non-ICU patients (Table 7) [73].
Table 7. The D-dimer levels in studies of diabetic patients with COVID-19
3.4. Cancer
A study of 52 cancer patients with COVID-19 (mean age = 63 years) was conducted by Fan Yang et al. in Wuhan, China. In this report, 19.2%, 17.3%, 15.4%, and 9.6% of patients had lung cancer, breast cancer, rectal cancer, and colon cancer, respectively, while the remaining 38.5% had other types of cancer. In this survey, 33 patients had mild conditions and 19 patients had severe conditions; the findings revealed that the D-dimer level in mild and critical patients on admission was 1.0 (0.6–2.3) and 2.8 (1.7–6.6) (μg/ml), respectively [74].
3.5. Pregnancy
There was only one study on the D-dimer level in pregnant women with COVID-19. Xu Qiancheng et al. in Wuhan conducted a study on two groups of 28 pregnant women and 54 non-pregnant women of the same age, all of whom had COVID-19. The results showed that the level of D-dimer in pregnant women had increased significantly compared to the non-pregnant group on admission [75].
3.6. Diarrhea
In a study of 84 patients with COVID-19 at Wuhan Union Hospital, Xiao-Shan Wei et al. reported a median D-dimer level of 0.47 (μg/ml) on admission. The mean level of D-dimer was 0.49 (μg/ml) in 26 patients with diarrhea and 0.46 (μg/ml) in 58 diarrhea-free patients [76]. In a separate study of 230 COVID-19 patients, 49 patients with diarrhea and 181 patients without diarrhea had D-dimer levels of 1 and 1.6 (μg/ml) on admission, respectively [77].
3.7. Stroke
In a study on 3556 hospitalized patients with COVID-19, 32 patients were diagnosed with ischemic stroke, following a radiological test, compared with another group of patients with ischemic stroke and without COVID-19 infection (46 patients). Medium Level of D-dimer was estimated to be as 3.913 (μg/ml) in patients with COVID-19 at the time of closest to stroke diagnosis, while 0.526 (μg/ml) was estimated in patients without COVID-19. In addition, during treatment, the level of D-dimer of the COVID-19 group was increased by more than 10 (μg/ml). Although the group without COVID-19 infection did not show an increase in the level of D-dimer during treatment [78].
3.8. VTE
The key manifestation of VTE involves DVT and PE, which may be a fatal sequence [79–81]. Studies indicate an increased risk of DVT and PE in COVID-19 patients [8,24,82,83]. A retrospective research performed by Zhang et al. in Wuhan, China, on 143 patients with COVID-19. The patients spilt into DVT and non-DVT groups. The findings indicated that the prevalence of DVT was higher in elderly patients. Moreover, the level of D-dimer was significantly higher in patients with COVID-19 and DVT than patients with COVID-19 but without DVT during hospitalization [24]. Importantly, DVT was associated with poor prognosis and increased mortality rates. In addition, 88.5% of DVT cases and 47.1% of non-DVT cases had D-dimer levels above 1 (μg/ml) [24]. Another study conducted on 156 patients hospitalized at a Madrid found that the level of D-dimer increased in COVID-19 patients with DVT (23 patients) compared to non-DVT cases (133 patients) (P <0.001). In addition to that, P. Demelo-Rodríguez et al. reported that the D-dimer with a cutoff point of 1.57 (µg/ml) had a sensitivity of 95.7%, a specificity of 29.3%, and an area under the curve (AUC) 0.729. Such criteria proposed for diagnosis of asymptomatic DVT [82]. Songping Cui et al. investigated the prevalence of VTE in 81 ICU hospitalized patients with COVID-19. They recorded that D-dimer with cutoff point of 1.5 (μg/mL) had a sensitivity (85%) and a specificity (88.5%) for VTE prediction [8]. In a study of 106 patients with COVID-19 in France, patients with PE had higher levels of D-dimer than those without PE and were more likely to have an aggressive type. In severe cases, they treated with low-weight molecular heparin or unfractionated heparin [9,83].
4. Conclusion
D-dimer measurement is a laboratory test needed for the evaluation of patients with COVID-19. In view of the fact that thrombosis can occur in various organs with subsequent organ failure in severe COVID-19 case, D-dimer monitoring will be a crucial approach in the clinical practice of COVID-19 infection.
5. Expert Opinion
Since 1970s, when the D-dimer was first introduced, it has evolved over time. Nowadays, physicians commonly use of it to avoid the diagnosis of thrombosis in the lungs or the lower limbs. More recently, it has been used to predict the risk of recurrent thrombosis in the cases with the withdrawal of anticoagulants. The high incidence of coagulopathy and venous thromboembolism (VTE) has been shown in COVID-19. It esteemed that respiratory deterioration is linked to thrombosis. The levels of fibrinogen and D-dimer typically increase during the primary phase of COVID-19 infection. First-line hemostatic screening tests, including platelet count, activated partial prothrombin time, and prothrombin time, are usually normal in this step [84].
The trigger time for the VTE screening in a patient is when the level of D-dimer is three times higher than cutoff. Moreover, in patients with COVID-19, four-fold increase in the level of D-dimer was suggested as a good predictor of mortality in COVID-19 [85]. It is worth keeping in mind that, in parallel with the increase in age, the level of D-dimer increases.
Given that the sensitivity and specificity of D-dimer kits depend on variables such as type of used antibody, the capture method, and the instrumentation used. Hence, the need for more flexible D-dimer kits with more accuracy and precision is therefore a basic necessity. Moreover, planning to develop a point-of-care system can also be very exciting. It will be a step forward in the management of COVID-19.
Medical laboratories report D-dimer levels in fibrinogen equivalent unit (FEU µg/mL) or as D-dimer unit (DDU ng/mL). Indeed, an FEU is the initial quantity of fibrinogen in the blood that can produce the reported D-dimer level. The molecular weight of the fibrinogen is about twice of the molecular weight of a D-dimer fragment. Hence, an amount of 0.5 µg/mL of DDU is therefore equal with 1 µg/mL FEU. In other word, DDU (ng/ml) X 2/1000 = FEU (µg/mL) [86]. The D-dimer cutoff value is 250 ng/ml (DDU) or 0.5 µg/ml (FEU). Although D-dimer levels <0.50 µg/ml (FEU) exclude probability of DVT and PE, the levels >8.0 µg/ml (FEU) are strongly suggestive of DIC.
The D-dimer level is increased in patients of all age groups with COVID-19. In patients with COVID-19, the existence of a concomitant disease such as diabetes, cancer, stroke, and physiological condition such as pregnancy can contribute to higher levels of D-dimer. On the other hand, the relation between high levels of D-dimer and survival rates underlines the importance of detection of D-dimer levels in patients with COVID-19. This test paves the way for better handling of COVID-19.
Understanding the mechanistic level of D-dimer increase in patients with COVID-19 may be helpful in disease management. Increased D-dimer levels in these patients may be due to inflammatory responses to viral infections, dysfunction of endothelial cells that increases thrombin production. Hypoxia causes coagulation disorders by increasing both viscosity and the transcription factor-dependent signaling pathway, as well as age and underlying conditions and long-term hospitalization, raising patients’ risk of coagulation disorders [46].
One of the therapies used in patients with COVID-19 is convalescent plasma therapy [87]. In a randomized clinical trial in China, patients who had treated with convalescent plasma showed decreased platelet and D-dimer levels due to plasma therapy. Plasma therapy and its effect on the reduction of coagulation disorders can be considered as an alternative therapy for COVID-19 [88].
Some surveys have investigated the D-dimer levels in mild and severe COVID-19. Many of them have used of the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia). Some authors have missed this point. It is rational to use of a common and standard criteria collection for mild and severe COVID-19 for better interpretations of the results. In addition, the Clinical Guidelines Committee of the American College of Physicians proposed age-adjusted D-dimer levels rather than a set cutoff value. The age-adjusted cutoff can be calculated as follows: age x 0.01 µg/mL (FEU). For example, in a 59-year-old one would be 59 × 0.01 µg/mL = 0.59 µg/mL (FEU) [89]. The age-adjusted cutoff can be used in patients older than 50 years to assess if imaging is needed in patients with suspected PE.
Examination of coagulation tests from the start of the diagnosis can be useful for monitoring the disease and for an effective management. The ISTH score for detection of DIC (platelet count, PT, fibrinogen level, D-dimer, antithrombin and protein C activity monitoring) can be used to achieve this objective [90]. On the basis of recent research, coagulopathy and pathological thrombosis in these patients are among the reasons for the shift to the active stage of COVID-19 disease. Hence, the use of different anticoagulants in complex treatment regimens aimed at reducing the severity of the disease and complications of thrombosis in clinical practice [90]. As our knowledge is limited, further work is needed in this field to shed light on the pathophysiology of COVID-19.
| Country | Articles (N) |
|---|---|
| China | 54 |
| Italy | 6 |
| America | 3 |
| France | 4 |
| Spain | 2 |
| Ireland | 1 |
| U.k. | 1 |
| Total | 71 |
| Parameters | Articles (n) | Tests (n) | Normal range | Median |
|---|---|---|---|---|
| D-dimer | 71 | 10,220 | <0.50 | 1.53 (µg/mL) |
| Fibrinogen | 26 | 4140 | 2.0–4.0 | 4.62 (g/L) |
| PT | 33 | 6428 | 11.5–14.5 | 13.34 (sec) |
| APTT | 28 | 4932 | 29.0–42.0 | 33.88 (sec) |
| Platelet | 43 | 7245 | 150–450 | 202.6 (×109/L) |
Abbreviations: PTT, partial thromboplastin time; PT, prothrombin time; n, number; µg, microgram; ml, milliliter; sec, second; L, liter; g, gram.
| First author | Region | Study period | Sample size | Ref. | Main findings | |
|---|---|---|---|---|---|---|
| Ning Tang | Tongji hospital (Wuhan, china) | From January 1 to 13 February 2020 | 449 | [9] | In patients with a SIC score ≥4,or D-dimer> 6-fold of the upper limit of normal, heparin use was associated with a 28-day reduction in mortality compared with those non-users. | |
| Ruchong Chen | Guangzhou, China | To 22 March 2020 | 548 | [14] | During hospitalization, non-survivors had higher levels of neutrophils, IL-6, procalcitonin, D-dimer, amyloid A protein, and C-reactive protein, while survivors had a declining or steady trend. | |
| Ying Zou | Shanghai Public Health Clinical Center | from January 20 to 24 February 2020 | 303 | [28] | The median levels of coagulation parameters change more in the severe group than in the mild group. In particular, fibrinogen and D-dimer changes in the two groups are significantly different (p < 0.05). | |
| Zhihua Lv | Renmin Hospital Wuhan, China | from February 4, to 28 February 2020 | 354 | [29] | Co-infection, lymphocyte count, and D-dimer levels are associated with the severity of COVID-19. | |
| Weifeng Shang | Wuhan, China | from January 16 to February 28,2020 | 443 | [30] | The neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP) and platelets can help predict the severity of COVID 19. | |
| Litao Zhan | Asia General Hospital (Wuhan, china) | From 12 January 2020, to 15 March 2020 | 343 | [46] | D-dimer levels increased four-fold (greater than 2.0 μg/ml) increase the risk of mortality in patients. | |
| Matthew J Cummings | New York, American | from March 2 to 1 April 2020 | 257 | [47] | High levels of D-dimers in COVID 19 patients were associated with mortality rate in-hospital. | |
Ref, reference; SIC, sepsis‐induced coagulopathy; μg/ml, microgram/milliliter.
| Study | Study Region | Time of sampling | Ref. | Sample size (n) | Age (years) | Sex (male/female) | D-dimer (µg/mL FEU) | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Survivors | Non-survivors | Survivors | Non-survivors | Survivors | Non-survivors | Survivors | Non-survivors | |||||
| Fei Zhou | China | OA | [4] | 137 | 54 | 52 (45 ·0–58 ·0) | 69 (63 ·0–76 ·0) | 81/56 | 38/16 | 0.60 (0 ·3–1 ·0) | 5.2 (1 ·5–21 ·1) | |
| Ning Tang | China | OA | [7] | 162 | 21 | 52.4 ± 15.6 | 64 ± 20.7 | 82/80 | 16/5 | 0.61 (0.35–1.29) | 2.12 (0.77–5.27) | |
| Ning Tang | China | OA | [9] | 315 | 134 | 63.7 ± 12.2 | 68.7 ± 11.4 | 178/137 | 90/44 | 1.47 (0.78–4.16) | 4.70 (1.42–21.00) | |
| HuaFan | China | OA | [10] | 26 | 47 | 46.2 ± 12.01 | 65.4 ± 9.74 | 17/9 | 32/15 | 0.52 (0.31–1.12) | 1.51 (0.80–7.18) | |
| Tao Chen | China | OA | [11] | 161 | 113 | 51 (37.0–66.0) | 68 (62.0–77.0) | 88/73 | 83/30 | 0.60 (0.3–1.3) | 4.60 (1.3–21.0) | |
| Jinping Zhang | China | OA | [12] | 11 | 8 | 68 (38–87) | 77 (66–91) | 6/5 | 5/3 | 0.48 (0.42–0.97) | 2.15 (1.4–9.2) | |
| Helen Fogarty | Ireland | OA | [13] | 50 | 33 | 60.5 ± 17.7 | 67.9 ± 11.9 | 33/17 | 22/11 | 0.80 (0.51–1.29) | 1.00 (053–1.78) | |
| Ruchong Chen | China | OA | [14] | 445 | 103 | 53.5 ± 13.9 | 66.9 ± 12.1 | 244/201 | 69/34 | 0.69 (0.41, 1.49) | 2.70 (1.04, 16.92) | |
| Xiaomin Luo | China | OA | [15] | 214 | 84 | 51 (37–63) | 71 (64–80) | 99/115 | 51/33 | 0.50 (0.29–1.10) | 4.59 (0.95–17.14) | |
Note: Data are mean ± SD, median (IQR) or n.
Abbreviations: n, number; µg, microgram; ml, milliliter; SD, standard deviation; IQR, interquartile range; OA, on admission; FEU, fibrinogen equivalent unit; ref, References.
| Study | Study Region | Sampling time | Ref. | Sample size (n) | Age (years) | Sex (male/female) | D-dimer (µg/mL FEU) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mild | Severe | Mild | Severe | Mild | Severe | Mild | Severe | |||||||||
| Ying Zou | China | OA | [28] | 277 | 26 | 50 (36–63) | 65 (63–76) | 138/139 | 20/6 | 0.43 (0.31–0.77) | 1.04 (0.73–1.72) | |||||
| Weifeng Shang | China | OA | [30] | 304 | 139 | 58 (47.00–67.00) | 64 (54.00–73.00) | 138/166 | 82/57 | 0.51 (0.28–1.04) | 0.84 (0.35–2.76) | |||||
| Guang Chen | China | OA | [31] | 10 | 11 | 51.4 (13.7) | 63.9 (9.6) | 7/3 | 10/1 | 0.4 (0.3) | 8.2 (9.0) | |||||
| Jin-jin Zhang | China | OA | [32] | 82 | 58 | 51.5 (26–78) | 64 (25–87) | 38/44 | 33/25 | 0.2 (0.1–0.3) | 0.4 (0.2–2.4) | |||||
| Ruyuan He | China | OA | [33] | 135 | 69 | 43 (31–53) | 61 (52–74) | 42/93 | 37/32 | 0.32 (0.20–0.70) | 0.95 (0.41–3.10) | |||||
| Guqin Zhang | China | OA | [34] | 166 | 55 | 51 (36.0–64.3) | 62 (52.0–74.0) | 73/93 | 35/20 | 0.18 (0.1–0.32) | 0.44 (0.21–1.30) | |||||
| Suxin Wan | China | OA | [35] | 95 | 40 | 44 (33‐49) | 56 (52‐73) | 52/43 | 21/19 | 0.3 (0.2‐0.5) | 0.6 (0.4‐1.1) | |||||
| Jianhong Fu | China | OA | [36] | 59 | 16 | 45.1 ± 14.0 | 51.8 ± 12.8 | 35/24 | 10/6 | 0.190 (0.07–1.18) | 0.32 (0.07–1.22) | |||||
| Yang Liu | China | OA | [37] | 46 | 30 | NR | NR | NR | NR | 0.26 (0.16, 0.45) | 1 (0.33, 2.42) | |||||
| Yong Gao | China | OA | [38] | 28 | 15 | 43 ± 14.00 | 45.2 ± 7.68 | 17/11 | 9/6 | 0.21 (0.19, 0.27) | 0.49 (0.29, 0.91) | |||||
| Jing Liu | China | OA | [39] | 27 | 13 | 43.2 ± 12.3 | 59.7 ± 10.1 | 8/19 | 7/6 | 0.4 (0.2–0.8) | 0.9 (0.7–1.5) | |||||
| Yulong Zhou | China | OA | [40] | 12 | 5 | 41.5 ± 14.31 | 42.2 ± 14.91 | 6/6 | 0/5 | 0.29 ± 10.11 | 0.28 ± 0.11 | |||||
| Changcheng Zheng | China | OA | [41] | 34 | 21 | 59 (29–77) | 62 (29–91) | 16/18 | 8/13 | 0.24 (0.2–2.9) | 1 (0.2–5.0) | |||||
| Study | Region | Sampling time | Ref. | Sample size (n) | Age (years) | Sex (male/female) | D-dimer (µg/mL FEU) | |||||||||
| Mild | Severe | Critical | Mild | Severe | Critical | Mild | Severe | Critical | Mild | Severe | Critical | |||||
| Zhihua Lv | China | OA | [29] | 115 | 155 | 84 | 61 (23–79) | 62 (25–89) | 65.5 (35–90) | 58/57 | 77/78 | 40/44 | 1.9 (3.78) | 5.74 (13.15) | 11.97 (25.00) | |
| Ying Sun | China | OA | [42] | 36 | 10 | 9 | 47 (13, 78) | 59 (33, 85) | 63 (34, 79) | 19/17 | 6/4 | 5/4 | 0.35 ± 0.25 | 3.15 ± 3.31 | 1.95 ± 2.38 | |
| Feng Wang | China | OA | [43] | 30 | 20 | 15 | 52.2 (12.4) | 60.8 (12.3) | 62 (12.4) | NR | NR | NR | 1.6(3) | 4.7 (7.4) | 6.9 (8.4) | |
| Xiaoyan Liu | China | OA | [44] | 87 | 25 | 12 | NR | NR | NR | NR | NR | NR | 0.74 (0.06–1.88) | 1.17 (0.035–21.61) | 4.13 (0.082–26.31) | |
| Huan Han | China | OA | [45] | 49 | 35 | 10 | NR | NR | NR | NR | NR | NR | 2.14 | 19.11 | 20.04 | |
Note: Data are mean ± SD, median (IQR) or n.
Abbreviations: n, number; µg, microgram; mL, milliliter; SD, standard deviation; IQR, interquartile range; NR, Not reported; OA, on admission; FEU, fibrinogen equivalent unit; Ref, Reference.
| Study | Study Region | Sampling time | Ref. | Sample size (n) | Age (range in years) | Sex (male/female) | No. of patients tested | D-dimer (µg/mL FEU) | No. of patients tested | Fibrinogen (g/L) | No. of patients tested | PT (sec) | No. of patients tested | PTT (sec) | No. of patients tested | Platelet Count (n/µl) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Chaomin Wu | China | OA | [5] | 201 | 51(43–60) | 128/73 | 189 | 0.61(0.35–1.28) | NR | NR | 195 | 11.1(10.20–11.90) | 195 | 28.7(23.30–33.70) | 195 | 180(137–241.5) |
| Litao Zhang | China | OA | [46] | 343 | 62(48.0–69.0) | 169/174 | 343 | 0.54(0.2–1.41) | 343 | 4.1(3.1–5.1) | 343 | 11.7(11.2–12.3) | 343 | 29.4 ± 4.5 | 343 | 242.8 ± 92.3 |
| Matthew J Cummings | American | OA | [47] | 257 | 62 (51–72) | 171/86 | 244 | 1.6 (0.9–3.5) | NR | NR | 241 | 14.7(14–15.8) | NR | NR | 257 | 199 (148–270) |
| Bobin Mi | China | OA | [48] | 10 | 68 | 2/8 | 10 | 7.19 | NR | NR | 10 | 18.81 | 10 | 44.06 | 10 | 177 |
| Kun Wang | China | OA | [49] | 296 | 47.32 ± 14.95 | 140/156 | 296 | 0.2(0.1–0.4) | NR | NR | 296 | 13.3 ± 1.9 | 296 | 30.7 ± 4.0 | NR | NR |
| Yi Zheng | China | OA | [50] | 34 | 66(58–76) | 23/11 | 34 | 0.6(0.38–1.11) | NR | NR | NR | NR | NR | NR | 34 | 178(147–196) |
| Yucai Hong | China | OA | [51] | 75 | 46.37 ±13.34 | 41/34 | 75 | 0.36 (0.26–0.78) | NR | NR | 75 | 13.21 ±0.55 | 75 | 39.30 ±5.39 | 75 | 188(158.5–222) |
| unqiang Lei | China | OA | [52] | 1 | 33 | 0/1 | 1 | 0.58 | NR | NR | NR | NR | NR | NR | NR | NR |
| Yong Li | China | OA | [53] | 279 | 55 (39–68) | 151/128 | 279 | 0.3 (0.1–1.3) | NR | NR | NR | NR | NR | NR | NR | NR |
| Maurizio Cecconi | Italy | OA | [54] | 239 | 65.2 (53.8–74.5) | 169/70 | 212 | 0.47 (0.29–0.89) | 229 | 5.7(4.50–6.65) | NR | NR | NR | NR | 238 | 195 (148–240) |
| Yongli Zheng | China | OA | [55] | 99 | 49.4 ±18.45 | NR | 94 | 1.41 ±2.51 | NR | NR | 94 | 13.1 ±0.80 | NR | NR | NR | NR |
| Franklin L. Wright | American | OA | [56] | 44 | 54 (42–59) | 28/16 | 44 | 1.84(0.93–4.08) | 44 | 6.56(5.6–7.79) | 44 | 14.5(13.5–15.9) | 44 | 37(31–49) | 44 | 232(186–298) |
| Julie Helms | France | OH | [57] | 150 | 63(53–71) | 122/28 | 150 | 2.27(1.16–20) | 150 | 6.99(6.08–7.73) | NR | NR | NR | NR | 150 | 200(152–267) |
| Mauro Panigada | Italy | OA | [58] | 30 | 56 (23–71) | NR | 30 | 4.87(1.12–16.95) | 30 | 6.8(2.34–1.344) | NR | NR | NR | NR | 30 | 348(59–577) |
| Sheng Yin | China | OA | [59] | 33 | 46 | 16/17 | 28 | 0.92(0.8 − 1.11) | NR | NR | NR | NR | NR | NR | 28 | 186(157 − 212.75) |
| Jing Yuan | China | Discharged | [60] | 25 | 28 | 8/17 | 25 | 0.37(0.26) | NR | NR | NR | NR | NR | NR | NR | NR |
| Martina Zaninotto | Italy | OH | [61] | 75 | 67(56–76) | 56/19 | 61 | 0.23(0.15–0.6) | NR | NR | NR | NR | NR | NR | 75 | 223(162–311) |
| Marco Ranucci | Italy | OA | [62] | 16 | 61(55–65) | 15/1 | 16 | 3.5 (2.5–6.5) | 16 | 7.94(5.83–9.33) | NR | NR | 16 | 36.4(29–41.6) | 16 | 271(192–302) |
| Qingchun Yao | China | OA | [63] | 108 | 52(37–58) | 43/65 | 108 | 1.55 (0.71–2.88) | NR | NR | NR | NR | NR | NR | 108 | 187(139–239) |
Note: Data are mean ± SD, median (IQR) or n.
Abbreviations: PTT, partial thromboplastin time; PT, prothrombin time; n, number; µg, microgram; ml, milliliter; sec, second; L, liter; g, gram; SD, standard deviation; IQR, interquartile range; NR, Not reported; OH, on hospitalization time; OA, on admission; FEU, fibrinogen equivalent unit; Ref, Reference.
| Study | Study Region | Sampling time | Ref. | Sample size (n) | Age (years) | Sex (male/female) | D-dimer (µg/mL FEU) | Fibrinogen (g/L) | PT (sec) | PTT (sec) | Platelet Count (n/µl) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Yang zhang | China | OA | [70] | 61 | 65.6 ±11.4 | 33/28 | 1.8 (0.6–3.3) | 5.3 ±1.8 | NR | NR | 243.8 ±94.8 |
| Weina Guo | China | OA | [71] | 37 | 61 (55–69) | 20/17 | 1.15 (0.83–2.11) | 5.1 (4.6–6.3) | NR | NR | NR |
| Yongli Yan | China | OA | [72] | 48 | 70 (62–77) | 33/15 | 2.6 (1.0–21.0) | 4.85 (3.32–6.70) | 14.4 (13.6–17.0) | 38.4 (35.7–45.5) | 161 (126.5–232.5) |
| Feng Wang | China | OA | [73] | 28 | 68.6 ±9.0 | 21/7 | 6.05(0.3 − 21) | NR | 14.3 (13.5, 17.5) | 39.85 | 180.85 |
Note: Data are mean ± SD, median (IQR) or n.
Abbreviations: PTT, partial thromboplastin time; PT, prothrombin time; n, number; µg, microgram; ml, milliliter; sec, second; L, liter; g, gram; SD, standard deviation; IQR, interquartile range; NR, Not reported; n, number; OA, on admission; FEU, fibrinogen equivalent unit; Ref, Reference.
Article highlights box
• COVID-19 has been active in many countries around the world and has created many challenges for healthcare systems.
• Large proportion of patients with COVID-19 experience serious illness. Their infection may lead to mortality.
• The latest literature review suggests that the D-dimer test can be a reliable predictor of thrombosis growth in COVID-19 and its prognosis.
• Elevated levels of D-dimer in patients with COVID-19 are associated with poor prognosis.
Declaration of interest
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.