key: cord-269009-0i2bvt77 authors: D’Souza, Rohan; Malhamé, Isabelle; Teshler, Lizabeth; Acharya, Ganesh; Hunt, Beverley J.; McLintock, Claire title: A critical review of the pathophysiology of thrombotic complications and clinical practice recommendations for thromboprophylaxis in pregnant patients with COVID‐19 date: 2020-08-05 journal: Acta Obstet Gynecol Scand DOI: 10.1111/aogs.13962 sha: doc_id: 269009 cord_uid: 0i2bvt77 Those who are infected with Severe Acute Respiratory Syndrome‐related CoronaVirus‐2 are theoretically at increased risk of venous thromboembolism during self‐isolation if they have reduced mobility or are dehydrated. Should patients develop coronavirus disease (COVID‐19) pneumonia requiring hospital admission for treatment of hypoxia, the risk for thromboembolic complications increases greatly. These thromboembolic events are the result of at least two distinct mechanisms – microvascular thrombosis in the pulmonary system (immunothrombosis) and hospital‐associated venous thromboembolism. Since pregnancy is a prothrombotic state, there is concern regarding the potentially increased risk of thrombotic complications among pregnant women with COVID‐19. To date, however, pregnant women do not appear to have a substantially increased risk of thrombotic complications related to COVID‐19. Nevertheless, several organizations have vigilantly issued pregnancy‐specific guidelines for thromboprophylaxis in COVID‐19. Discrepancies between these guidelines reflect the altruistic wish to protect patients and lack of high‐quality evidence available to inform clinical practice. Low molecular weight heparin (LMWH) is the drug of choice for thromboprophylaxis in pregnant women with COVID‐19. However, its utility in non‐pregnant patients is only established against venous thromboembolism, as LMWH may have little or no effect on immunothrombosis. Decisions about initiation and duration of prophylactic anticoagulation in the context of pregnancy and COVID‐19 must take into consideration disease severity, outpatient vs inpatient status, temporal relation between disease occurrence and timing of childbirth, and the underlying prothrombotic risk conferred by additional comorbidities. There is currently no evidence to recommend the use of intermediate or therapeutic doses of LMWH in thromboprophylaxis, which may increase bleeding risk without reducing thrombotic risk in pregnant patients with COVID‐19. Likewise, there is no evidence to comment on the role of low‐dose aspirin in thromboprophylaxis or of anti‐cytokine and antiviral agents in preventing immunothrombosis. These unanswered questions are being studied within the context of clinical trials. In March 2020, the World Health Organization declared the disease caused by Severe Acute Respiratory Syndrome-related CoronaVirus-2 (SARS-CoV-2) -COVID-19 -a global pandemic. While infection with SARS-CoV-2 may be asymptomatic, COVID- 19 can present with a range of manifestations from a mild flu-like illness and symptoms such as rhinorrhea, anosmia and diarrhea, to severe disease. The latter could involve pneumonia with hypoxia that requires admission to hospital, and may sometimes develop into acute respiratory distress syndrome or result in multiorgan failure and death. 1 Hemostatic changes and high rates of thrombotic complications have been reported in patients with severe COVID-19. 2 As pregnancy is a prothrombotic state, the possibility of an increased risk of thrombosis in pregnant women with COVID-19 has become an area of concern, and a number of international organi- Patients with severe COVID-19 may be at risk for pulmonary thromboembolic complications through at least two distinct mechanisms -immunothrombosis and hospital-associated venous thromboembolism (VTE). [2] [3] [4] [5] [6] An appreciation of these different pathophysiological mechanisms is crucial to understanding the rationale behind recommendations for thromboprophylaxis. In evolutionary terms, the blood coagulation system developed as an effector of the immune response, with the laying down of fibrin restricting the dissemination of pathogens within the body. 7 Acute viremia, as with SARS-CoV-2, results in the activation of monocytes/ macrophages, which produce cytokines such as interleukin-6 (IL- 6) and tumor necrosis factor that can potentially trigger the blood coagulation cascade. 8 The entry of SARS-CoV-2 into human target cells is facilitated by the angiotensin converting enzyme-2 (ACE-2) receptor. 9 These receptors are found in many tissues including pneumocytes, the heart, kidney, endothelium, macrophages and intestine. The bulk of ACE-2-expressing cells are the alveolar epithelial type II cells (type-II pneumocytes) of the lung. 10 The abundance of ACE-2-expressing cells in the pulmonary alveoli and the lung's vast surface area, make it highly susceptible to inhaled viruses and it is the most vulnerable target organ. 11 Acute viremia, such as with SARS-CoV-2, could result in a severe, multifaceted inflammatory reaction mediated through proinflammatory cytokines. 12 A recent study of patients with severe COVID-19 demonstrated a correlation between IL-6 and fibrinogen levels, 3 further supporting the theory that massive activation of the acute phase response, with increased production of coagulation factors, appears to be the predominant prothrombotic mechanism in COVID-19. The hallmark of acute lung injury is extravascular fibrin deposition. Immunothrombosis describes the process where the inflammatory reaction, together with hypoxia, and the local expression of tissue factor results in pulmonary microvascular thrombosis, which is a likely contributor to the progressive respiratory dysfunction that develops in patients with SARS-CoV-2 infection. 4 Activation of monocytes and the subsequent cytokine surge can also result in endothelial cell activation, which involves the change from an antithrombotic phenotype to procoagulant phenotype. Endothelial activation, which extends beyond the lungs, results in multiple changes including the exocytosis of large von Willebrand factor multimers from Weibel Palade granules, loss of heparan sulfate from the endothelial surface, platelet activation, downregulation of thrombomodulin and production of nitric oxide. 13 Endothelial activation thus further contributes to the prothrombotic state. and antiviral agents in preventing immunothrombosis. These unanswered questions are being studied within the context of clinical trials. COVID-19, pregnancy, SARS-CoV-2, thromboembolic complications, thromboprophylaxis, venous thromboembolism We review the pathophysiology of thromboembolic complications associated with COVID-19 and critically appraise recommendations for thromboprophylaxis in pregnant women with COVID-19. 2, 5, 6 An alternative explanation is that the high rates of VTE, and in particular the pulmonary emboli described on computerized tomography (CT) or pulmonary angiography, may reflect localized pulmonary immunothrombosis rather than thrombi that have embolized from the deep veins of the lower limb. This is supported by the lower incidence of deep vein thromboses of the extremities and that the majority of emboli in the pulmonary vasculature are segmental and sub-segmental thrombi as opposed to central or lobar pulmonary emboli. 5 Thus, patients with severe or critical COVID-19 are at risk of both immunothrombosis as well as hospital-associated VTE. Although thromboprophylaxis is well-established to prevent the risk of hospital-associated VTE, its role in preventing immunothrombosis remains uncertain. 14 Initial reports from Wuhan, China, suggested disseminated intravascular coagulation (DIC) as a possible explanation for the markedly elevated D-dimers and prolonged prothrombin time (PT) in non-survivors with COVID-19 pneumonia. 16 However, it is now clearer that the clinical picture is not that of DIC, as there is no increased bleeding, platelet levels are not low, fibrinogen levels (which should be low in DIC due to consumption) are very elevated, and the changes do not fulfill the International Society on Thrombosis and Haemostasis (ISTH) guidelines on diagnosing DIC. 17 The hemostatic changes encountered in COVID-19 are explained below. Although D-dimers are a breakdown product of fibrin (fibrinolysis), D-dimers are also produced in inflammatory states and in lung injury 18 and are known to be elevated, often significantly, with various viral infections. 19 Not surprisingly, in patients with COVID-19, very high levels of D-dimers have been seen, and data from Wuhan suggest that D-dimers have value as a prognostic marker and may correlate with the severity of illness. 20, 21 The origin of the very elevated D-dimer levels in COVID-19 patients may at least in part be the pneumocytes, which can produce urokinase. Contrary to what is described in DIC, fibrinogen levels are not reduced in patients with COVID-19, despite marked increases in D-dimer. 22 Instead, levels are generally very elevated, consistent with an ongoing acute phase response. 23 Platelet counts are not substantially reduced in patients with COVID-19. 22 At least two research papers have described antiphospholipid antibodies associated with COVID-19. 24 PT and aPTT may be prolonged as a preterminal event, as DIC is common in multiorgan failure. 16 However, its value in treatment decisions is limited. It should be noted that subtle PT changes may go unnoticed if PT is reported as the international normalized ratio (INR). 27 These acute phase reactants are markedly increased in COVID-19, as part of the acute phase response and, in isolation, should not influence management decisions. Despite these profound changes in hematologic parameters, the general consensus is that it would be premature and potentially dangerous to recommend the use of these biomarkers to guide clinical decision-making with regard to admission, planning diagnostic tests, identifying high-risk cases that need treatment in the ICU, or to guide the administration of blood products in the absence of bleeding. 14,28-30 These decisions must be taken after complete clinical assessment. It is also suggested that blood draws are minimized, as they would prove an unproductive burden on finite phlebotomy and laboratory resources, while also result in iatrogenic anemia in seriously ill patients. 28, 29 It was initially thought that pregnant women could be at high risk are not at an increased risk of death, they are more likely to be hospitalized and to require ICU admission and mechanical ventilation than are non-pregnant women. 33 Similarly, the public health agency of Sweden has reported a fourfold increased risk of intubation in age-matched pregnant vs non-pregnant women with COVID-19. 34 Although mortality from COVID-19 in pregnancy may not be as high as with previous coronavirus epidemics, 35 women with COVID-19 can become severely unwell, and a high level of clinical vigilance is important. 36 The current literature does not signal an increased likelihood of hospital-associated VTE or immunothrombosis in pregnant women with COVID-19 when compared with non-pregnant patients with COVID-19. No VTE were reported in a USA cohort, 37 where 58% and 16% were on prophylactic and therapeutic unfractionated heparin and low molecular weight heparin (LMWH), respectively. 38 Similarly, no VTE was reported in a cohort of 427 pregnant women hospitalized with COVID-19 across the UK, although no details were provided on thromboprophylaxis. 39 Nevertheless, clinicians must remain vigilant. Pregnancy is a hypercoagulable state characterized by increased prothrombotic factors, such as factors VII, VIII, X, XII, von Willebrand factor and fibrinogen, as well as decreased protein S and altered fibrinolysis, especially in the peripartum period. 40 Postpartum, the prothrombotic changes of coagulation and fibrinolysis take up to 12 weeks to return to the pre-pregnancy state. 41 Normal levels of several coagulation biomarkers differ in pregnancy. Fibrinogen levels can double, the aPTT becomes slightly shortened, 40 D-dimer levels increase throughout pregnancy and, in 99% of women, levels in the third trimester are above the established normal for non-pregnant patients. 42 Prognostic coagulation parameters for COVID-19 must be interpreted in the light of pregnancy-specific reference ranges (Table 1) . Coagulation values for COVID-19 severity have not yet been established in pregnancy and it is not known whether thresholds used in the non-pregnant population can be translated to an obstetric population. We reviewed 35 guidelines from professional societies, representing 14 countries and seven international organizations. Of these, 14 made recommendations for the prevention of VTE in pregnant patients with suspected or confirmed SARS-CoV-2 infection. A summary of recommendations from 10 of these guidelines, which made distinct recommendations, is presented in Table 2 . It must be noted that published guidance on thromboprophylaxis for COVID-19 in pregnancy is extremely inconsistent and is not based on evidence, only on expert opinion. (Continues) as COVID-19. Based on these parameters, we present a pragmatic approach to thromboprophylaxis in pregnancy for women with SARS-CoV-2 infection and COVID-19 (Table 3) . This approach draws from published guidance and limited evidence and is also based on expert opinion. Women who are relatively inactive may be at greater risk of developing VTE. Hence, advice on mobilization and hydration is crucial. Several societies recommend considering the use of pharmacological prophylaxis, even in the absence of additional risk factors. However, such an approach seems overzealous, especially in the absence of evidence to suggest a significantly increased risk of thrombosis, and considering that many of these women are likely to be otherwise well. Risk stratification is vital to determine which There is a general consensus that hospitalized patients with COVID- inpatients. 29, 43 Prolonged PT or aPTT is not a contraindication to administering thromboprophylaxis. In keeping with published protocols for the peripartum period, LMWH would need to be withheld for 12 hours prior to anticipated delivery, or to facilitate administration of regional analgesia. As outlined in Table 3 Risk stratification according to personal risk factors, and oxygen requirements: Weak risk = no prophylaxis, Medium risk = LMWH given at standard prophylaxis, High risk = LMWH given at higher prophylaxis dosage. Duration of prophylaxis should be maintained until recovery. Do not start prophylaxis if delivery is approaching NA Swiss Society of Gynecology and Obstetrics (Switzerland) 58 COVID-19 patients have a higher thromboembolic risk, which is further increased by the pregnancy and postpartum situation. Consequently, thromboembolic prophylaxis should be provided on an interdisciplinary basis for COVID-19 patients during the pregnancy and postpartum. Swedish Society of Obstetrics and Gynecology (Sweden) 59 Patients with mild to moderate symptoms = normal dose prophylaxis; Patients with pronounced symptom picture, where immobilizing hospital care is necessary; regardless of hemostasis effect = High-dose prophylaxis, and correction of hemostasis if necessary. This assessment must be done individually. Doses are based on entry weight being above or below 90 kg. for obstetric and other conditions that are unrelated to COVID-19 and those who are only mildly symptomatic or asymptomatic vs those who have COVID-19 pneumonia requiring supplemental oxygen or ICU admission and mechanical ventilation. There is considerable uncertainty around the optimal duration of anticoagulation following discharge, in the postpartum pe- probably through structural analogies with heparan sulfate. 44 Early data from Wuhan where routine thromboprophylaxis was initially not given to severely ill patients with COVID-19 pneumonia showed that subsequent use of heparin was associated with decreased mortality. 22 Although the mechanisms are unknown, it seems likely this may relate to reduced rates of VTE. A crucial consideration in patients with COVID-19 is that thrombotic complications also include immunothrombosis, which may not be prevented by administration of anticoagulants. 23, 45 Other treatments that could be considered are discussed below. The simultaneous administration of anti-cytokine agents such as IL-6 and IL-1 antagonists could both ameliorate diffuse immunothrombosis and reduce the prothrombotic changes resulting in an increased risk of overt VTE. 23, 46 Anakinra (IL-1 receptor antagonist) and tocilizumab (humanized monoclonal antibody against the IL-6 receptor) have a favorable safety profile during pregnancy and lactation, and could be considered within the confines of a clinical trial. 47 Although anti-cytokines are effective in low-grade arterial inflammation in the absence of overt infection, severe and ongoing viral infection may render the use of anti-cytokines in isolation ineffective. 23 Antivirals could help prevent replication of the virus and therefore could be considered in addition to anti-cytokine agents and anticoagulation. Antiretroviral lopinavir/ritonavir and other antivirals such as remdesivir are considered relatively safe for use during pregnancy and lactation and are being studied as part of ongoing clinical trials. 47 Hypoxia plays a critical role in perpetuating the hemostatic abnormalities. Supplemental oxygen should be administered to those unable to maintain an oxygen saturation >95% on room air. 48 The authors have stated explicitly that there are no conflicts of interest in connection with this article. 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