Bleeding and Bleeding Risk in COVID-19

Coronavirus disease 2019 (COVID-19) is a new, emerging medical challenge worldwide, with those affected showing a variety of clinical presentations, ranging from asymptomatic or mild conditions to critical illness. Patients affected by the causative virus—severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)—usually experience cough, fever, dyspnea, myalgia, less frequently gastrointestinal (GI) manifestations and, rarely, neurological complications. Coagulopathy is common among those afflicted and appears to be one of the most significant adverse prognostic signs.[1] [2] Coagulopathy results from concomitant activation of coagulation and fibrinolytic systems, most likely due to a severe proinflammatory state (i.e., the so-called cytokine storm) and/or by viral sepsis that sometimes leads to consumption of coagulation factors and decreased platelet count, resulting in thrombohemorrhagic events.[3] In this process, plasmin breaks down fibrin present in plasma and the bronchoalveolar lavage fluid, as well as potentially other organs, and leading to excess D-dimer/fibrin(ogen) degradation product (FDP) formation. This may also lead to reduction in platelet count and increased risk for hemorrhage.[4] In a systematic review of 6,892 patients and meta-analysis of 3,496 patients, platelets were low in 22.9% and D-dimer was high in 34.8%; D-dimer was associated with a severe clinical course with an odds ratio (OR) of 4.03, and low platelets with an OR of 1.78.[5] Disseminated intravascular coagulation (DIC) in COVID-19 is accompanied by a significant decrease of fibrinogen, and a marked increase of FDP and D-dimer, which are characteristics of DIC with hyperfibrinolysis, whereas the DIC caused by infection is accompanied by plasminogen activator inhibitor-1 release and suppression of fibrinolysis. Administration of antiproteases may prove beneficial.[6] Elevated D-dimer, and FDP, often mildly prolonged prothrombin time and mildly decreased platelet counts were also reported as common findings by Tang et al, more common and more profound in severely affected patients.[2] Fibrinogen levels are sometimes lowered, but may instead be elevated, while activated partial thromboplastin time is sometimes prolonged, but may instead be shortened, with these potentially suggestive of acute phase events.[2] [6] Although hypercoagulability and thrombotic events are common in COVID-19, bleeding may occur at any time during the course of disease. Several factors make patients with COVID-19 prone to bleeding, including thrombocytopenia, hyperfibrinolytic state, consumption of coagulation factors, and thromboprophylaxis administration of anticoagulants. A proposed cytokine storm, prolonged tissue hypoxia, and direct invasion of affected tissues are other possible causes.[2] [7] [8] Although thrombosis is relatively well studied in COVID-19, bleeding and bleeding risk appear to be the forgotten side of this story, most probably due to the less-fatal consequences; however, hemorrhagic diatheses represents a significant morbidity and potential cause of death in COVID-19 in at least in a subset of patients.[7] [8]

Thrombocytopenia

In one early study, about one-third and about half of patients developed thrombocytopenia and increased D-dimer, respectively, while among severely affected patients the rates were around 60%.[1] In another recent large-scale retrospective study on 1,476 consecutive patients, approximately 20% had thrombocytopenia (< 150 × 10⁹/L).[9] Those who died had a progressive decrease in platelet count, and when the platelet count was lower the risk of death was higher. For example, the relative risk of death and the morality rate were 3.42 (95% confidence interval [CI]: 2.36–4.96), 9.99 (95% CI: 7.16–13.94), and 13.68 (95% CI: 9.89–18.92), and 17.5, 61.2, and 92.1%, for platelet counts of 100–150, 50–100, and 0–50 × 10⁹/L, respectively. Of all patients with thrombocytopenia, approximately 25% were severely ill, with platelet count between 0 and 50 ×10⁹/L.[9] These patients are at risk of bleeding, and most guidelines recommend platelet transfusion when their platelet count is between < 30–50 × 10⁹/L, for bleeders or for those at high risk of bleeding, and < 10 × 10⁹/L, whether bleeding or not.[10] [11] Therapeutic response of platelet replacement is lower in patients with DIC, high fever, or splenomegaly.[10] In the setting of COVID-19, currently lacking randomized clinical trials, there is no definite guidance on threshold for platelet transfusion.

In a study of 61 severe intensive care unit (ICU)-treated and 93 severe non-ICU patients, 41% of the former had severe thrombocytopenia (< 50 × 10⁹/L), 96% of which had fatal consequences. Fatal consequences were observed in ICU-treated nonsurvivors with progressively worsening thrombocytopenia, but this was rarely observed in non-ICU severe cases or ICU-treated survivors. More than 55% of nonsurvivors had a platelet count less than < 50 × 10⁹/L, and approximately 20% of nonsurvivors had a platelet count less than < 10 × 10⁹/L in the very late stage of the disease, 2 to 3 days prior to death. Continuous renal replacement therapy (CRRT) significantly decreased the platelet count in more than 80% of CRRT-treated patients: in approximately 50%, platelet count was < 10 × 10⁹/L a few days after treatment onset; subsequently bleeding might occur in these patients. The overall survival rate was approximately 6% for patients treated with CRRT.[12] Among severely affected ICU-treated patients, those under low-molecular-weight heparin (LMWH) therapy had a lower platelet count than patients not on therapy. ICU-treated patients under LMWH therapy also had a lower survival rate than those without heparin. Heparin exposure was considered a risk factor for progression toward mortality in severe COVID-19 patients.[12] In fact the authors found that CRRT, heparin exposure, and significant platelet decrease were risk factors for the severely ill. Significant heparin-induced thrombocytopenia (HIT) was observed, both spontaneously and after heparin exposure, which might contribute to occurrence of severe thrombocytopenia. Spontaneous HIT may be due to endogenous release of heparin in viral infection.[12] Although the usefulness of heparin-involving anticoagulation therapy in patients with severe COVID-19 was mentioned by Tang et al, the risk of HIT should also be considered in these cases.[2] [12] Critically ill patients with COVID-19 and CRRT have a high mortality rate, mostly due to HIT. Therefore, careful clinical and laboratory monitoring should be performed to identify those with a risk of HIT; in these cases, heparin-involved therapy should be avoided or discontinued, alternative anticoagulants such as direct oral anticoagulants (DOACs) are recommended.[12]

Bleeding and Bleeding Risk

Although respiratory failure (70%), multiorgan failure (MOF; 28%), cardiac failure (15%), hemorrhage (6%), and renal failure (4%) were reported as leading causes of death in COVID-19 in one study,[13] a valuable recent prospective study revealed that pulmonary embolism (PE) was the direct cause of death in four (∼33%), and deep vein thrombosis was observed in seven (58%).[14] In an autopsy report of four patients, one (25%) had large intra-alveolar hemorrhages and intra-alveolar fibrin cluster formation.[15] Another study analyzing mortality revealed that 1 (∼7%) out of 14 patients died due to GI bleeding.[16] It is worth noting, however, that the patient had lymphoma, thus comorbidities may represent a part of the risk profile.

Bleeding, when seen as the first presentation in COVID-19, may lead to misdiagnosis and inappropriate clinical and laboratory work-up for other viral infections like dengue.[17] Fatal GI bleeding and intracranial hemorrhage (ICH) are other reported forms of severe bleeding.[18] [19] Although anorexia is the most common digestive finding (up to 50%) in adults, and diarrhea is most common in both adults and children (up to ∼50%) with COVID-19, GI bleeding was observed with a frequency of 4 to 13.7%, primarily among severely affected patients, 40% of whom were stool polymerase chain reaction positive.[19] [20] It seems that prolonged hypoxia causes cell necrosis and mucosal injury, leading to ulceration and GI hemorrhage.[12] Focal hemorrhage in the kidney also has been reported.[21] Rare cases of COVID-19 with ICH have been reported, but further studies are required to clarify this finding.[18] This phenomenon could be attributed to the proposed cytokine storm, and even without direct viral invasion within the intracranial space could result in breakdown of the blood–brain barrier.[7] A rare case of COVID-19 with immune thrombocytopenic purpura that developed a subarachnoid microhemorrhage, while the patient had a platelet count of 2 × 10⁹/L, has been reported.[22] It seems that pathological immune conditions may be relatively frequent in this disease. Multiple cerebral infarctions were reported in COVID-19 associated with immunoglobulin A antiphospholipid antibodies, although lupus anticoagulant was not present in these patients, and persistence was not investigated.[23] Thus, the association may not in general hold true.

Thus, overall, the above findings demonstrate that hemorrhage and risk of hemorrhage are not necessarily an infrequent finding in COVID-19, albeit most probably associated to contributing factors.

Also, due to a high risk of thrombosis, thromboprophylaxis with LMWH is recommended by the International Society of Thrombosis and Hemostasis (ISTH) interim guidance for all hospitalized patients with COVID-19.[24] This recommendation is based on expert opinion and a few case series. However, others recommend more aggressive anticoagulant therapy with unfractionated heparin (UFH), potentially accompanied by antithrombin supplementation.[25] [26] Others believe that administration of LMWH may increase the risk of bleeding in special situations, such as those otherwise requiring a more aggressive anticoagulation, such as PE that is missed because of primary lung injury by the virus.[26] In Japan, nafamostat mesylate—an inhibitor of plasmin, thrombin, and trypsin—is used for the management of DIC in COVID-19. Unlike heparin, nafamostat mesylate does not have hemorrhagic side effects, even at high doses. Due to its antifibrinolytic actions, the drug is useful for the management of DIC with increased fibrinolytic activity. Moreover, it seems that nafamostat mesylate also has antiviral activity and may potentially be effective in treating DIC in COVID-19, but its low anticoagulant activity may also be a disadvantage.[27] Another study shows that thrombosis- and bleeding-predicting tools are useful in the management of patients.[28] The study assessed the potential usefulness of Padua prediction score—to predict thrombosis risk—and the improved bleed risk assessment model—to predict risk of bleeding—in COVID-19 patients under thromboprophylaxis with UFH and LMWH. According to the bleeding predicting tool, nine (6.5%) patients had a high risk of bleeding (improved score ≥ 7), six of whom (∼67%) experienced hemorrhagic events during the course of thromboprophylaxis, including mild or microscopic hematuria (n: 3), GI bleeding (n: 1), epistaxis (n: 1), and severe hemothorax (n: 1).[28] More detailed thromboprophylaxis of patients with COVID-19 and venous thromboembolism is outside the scope of this work and is presented elsewhere.[28] Anticoagulant therapy is contraindicated for patients with active bleeding and for those with a low platelet count (according to ISTH guidance < 25 × 10⁹/L).[17] In COVID-19 patients under treatment with DOACs, the coadministration of antivirals significantly increased the plasma concentration of DOACs; the trough level of DOAC was 6.14 times higher during hospitalization than before admission.[29] To prevent bleeding in such patients, it was suggested that DOACs be withheld during COVID-19 infection.[30]

Although clinical presentations in symptomatic children are relatively similar to adults, in severe cases, septic shock with irreversible bleeding and coagulation dysfunction may occur.[31] Among the newborns of infected mothers, thrombocytopenia accompanied by abnormal liver function was observed in two (20%) and GI bleeding in four (40%). Of the first two patients, one developed refractory shock, MOF, and DIC, which led to death in spite of platelet, plasma, and red blood cell transfusions. Another neonate, with GI bleeding and DIC, responded to intravenous administration of gamma globulin.[32]

Conclusion

In conclusion, despite its prevalence, COVID-19 remains a barely understood disease with a high rate of heterogeneous and disparate clinical pictures. New presentations may be observed among affected patients, and health care providers should update their knowledge to prevent severe and fatal consequences arising from insufficient knowledge. Due to a high rate of coagulopathy among COVID-19 patients, the risk of bleeding should always be considered in every case, as bleeding, although rare, may be one of the first clinical presentations at the time of diagnosis.

Conflict of Interest

None declared.

Acknowledgment

We highly appreciate Daisy Morant's valuable work in improving the English language of the manuscript.

• References

• 1 Guan WJ, Ni ZY, Hu Y. et al; China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382 (18) 1708-1720
• 2 Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18 (04) 844-847
• 3 Henry BM, Vikse J, Benoit S, Favaloro EJ, Lippi G. Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: a novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis. Clin Chim Acta 2020; 507: 167-173
• 4 Ji HL, Zhao R, Matalon S, Matthay MA. Elevated plasmin(ogen) as a common risk factor for COVID-19 susceptibility. Physiol Rev 2020; 100 (03) 1065-1075
• 5 Kumar A, Arora A, Sharma P. et al. Clinical features of COVID-19 and factors associated with severe clinical course: a systematic review and meta-analysis. medRxiv 2020; (in press) DOI: 10.2139/ssrn.3566166.
• 6 Song JC, Wang G, Zhang W, Zhang Y, Li WQ, Zhou Z. People's Liberation Army Professional Committee of Critical Care Medicine, Chinese Society on Thrombosis and Haemostasis. Chinese expert consensus on diagnosis and treatment of coagulation dysfunction in COVID-19. Mil Med Res 2020; 7 (01) 19-26
• 7 Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B. COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology 2020; (e-pub ahead of print) DOI: 10.1148/radiol.2020201187.
• 8 Tian Y, Rong L, Nian W, He Y. Review article: gastrointestinal features in COVID-19 and the possibility of faecal transmission. Aliment Pharmacol Ther 2020; 51 (09) 843-851
• 9 Yang X, Yang Q, Wang Y. et al. Thrombocytopenia and its association with mortality in patients with COVID-19. J Thromb Haemost 2020; (e-pub ahead of print) DOI: 10.1111/JTH.14848.
• 10 Levi M, Opal SM. Coagulation abnormalities in critically ill patients. In: O'Donnell J, Nácul F. eds. Surgical Intensive Care Medicine. 3rd ed. Cham, Switzerland: Springer; 2016: 463-471
• 11 Lippi G, Favaloro EJ, Buoro S. Platelet transfusion thresholds: how low can we go in respect to platelet counting?. Semin Thromb Hemost 2020; 46 (03) 238-244
• 12 Liu X, Zhang X, Xiao Y. et al; Heparin-induced thrombocytopenia is associated with a high risk of mortality in critical COVID-19 patients receiving heparin-involved treatment. medRxiv 2020; (in press) DOI: 10.1101/2020.04.23.20076851.
• 13 Zhang B, Zhou X, Qiu Y. et al. Clinical characteristics of 82 death cases with COVID-19. medRxiv 2020; (in press) DOI: 10.1101/2020.02.26.20028191.
• 14 Wichmann D, Sperhake JP, Lütgehetmann M. et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study. Ann Intern Med 2020; (e-pub ahead of print) DOI: 10.7326/M20-2003.
• 15 Tian S, Xiong Y, Liu H. et al. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Mod Pathol 2020; (e-pub ahead of print) DOI: 10.1038/s41379-020-0536-x.
• 16 Tian S, Liu H, Liao M. et al. Analysis of mortality in patients of COVID-19: clinical and laboratory parameters. Open Forum Infect Dis 2020; (e-pub ahead of print) DOI: 10.1093/ofid/ofaa152.
• 17 Joob B, Wiwanitkit V. Hemorrhagic problem among the patients with COVID-19: clinical summary of 41 Thai infected patients. Clin Appl Thromb Hemost 2020; (e-pub ahead of print) DOI: 10.1177/1076029620918308.
• 18 Sharifi-Razavi A, Karimi N, Rouhani N. COVID-19 and intracerebral haemorrhage: causative or coincidental?. New Microbes New Infect 2020; 35: 100669
• 19 Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology 2020; 158 (06) 1831.e3-1833.e3
• 20 Yang X, Yu Y, Xu J. et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020; 8 (05) 475-481
• 21 Li H, Liu L, Zhang D. et al. SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet 2020; 395 (10235): 1517-1520
• 22 Zulfiqar AA, Lorenzo-Villalba N, Hassler P, Andrès E. Immune thrombocytopenic purpura in a patient with Covid-19. N Engl J Med 2020; 382 (18) e43
• 23 Zhang Y, Xiao M, Zhang S. et al. Coagulopathy and antiphospholipid antibodies in patients with covid-19. N Engl J Med 2020; 382 (17) e38
• 24 Thachil J, Tang N, Gando S. et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemos 2020; 18 (05) 1023-1026
• 25 Bikdeli B, Madhavan MV, Jimenez D. et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol 2020; (e-pub ahead of print) DOI: 10.1016/j.jacc.2020.04.031.
• 26 Barrett CD, Moore HB, Yaffe MB, Moore EE. ISTH interim guidance on recognition and management of coagulopathy in COVID-19: a comment. J Thromb Haemost 2020; (e-pub ahead of print) DOI: 10.1111/jth.14860.
• 27 Asakura H, Ogawa H. Potential of heparin and nafamostat combination therapy for COVID-19. J Thromb Haemost 2020; (e-pub ahead of print) DOI: 10.1111/jth.14858.
• 28 Xu J, Wang L, Zhao L. et al. Risk assessment of venous thromboembolism and bleeding in COVID-19 patients. Version 2020 (preprint) available at Research Square
• 29 Obi AT, Barnes GD, Wakefield TW. et al. Practical diagnosis and treatment of suspected venous thromboembolism during COVID-19 pandemic. J Vasc Surg Venous Lymphat Disord 2020; (e-pub ahead of print) DOI: 10.1016/j.jvsv.2020.04.009.
• 30 Testa S, Prandoni P, Paoletti O. et al. Direct oral anticoagulant plasma levels' striking increase in severe COVID-19 respiratory syndrome patients treated with antiviral agents: the Cremona experience. J Throm Hemos 2020; (e-pub ahead of print) DOI: 10.1111/jth.14871.
• 31 Chen Z-M, Fu J-F, Shu Q. et al. Diagnosis and treatment recommendations for pediatric respiratory infection caused by the 2019 novel coronavirus. World J Pediatr 2020; 05: 5-14
• 32 Zhu H, Wang L, Fang C. et al. Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia. Transl Pediatr 2020; 9 (01) 51-60

Publikationsverlauf

Artikel online veröffentlicht:
08. Juni 2020