key: cord-0965274-cqbibd4t
authors: Warkentin, Theodore E.; Kaatz, Scott
title: COVID-19 versus HIT hypercoagulability
date: 2020-08-10
journal: Thromb Res
DOI: 10.1016/j.thromres.2020.08.017
sha: 901df4ea6b2ee42f0b37abd7166398db66fb50b7
doc_id: 965274
cord_uid: cqbibd4t

A striking feature of COVID-19 is the high frequency of thrombosis, particularly in patients who require admission to intensive care unit because of respiratory complications (pneumonia/adult respiratory distress syndrome). The spectrum of thrombotic events is wide, including in situ pulmonary thrombosis, deep-vein thrombosis and associated pulmonary embolism, as well as arterial thrombotic events (stroke, myocardial infarction, limb artery thrombosis). Unusual thrombotic events have also been reported, e.g., cerebral venous sinus thrombosis, mesenteric artery and vein thrombosis. Several hematology abnormalities have been observed in COVID-19 patients, including lymphopenia, neutrophilia, thrombocytopenia (usually mild), thrombocytosis, elevated prothrombin time and partial thromboplastin times (the latter abnormality often indicating lupus anticoagulant phenomenon), hyperfibrinogenemia, elevated von Willebrand factor levels, and elevated fibrin d-dimer. Many of these abnormal hematologic parameters—even as early as the time of initial hospital admission—indicate adverse prognosis, including greater frequency of progression to severe respiratory illness and death. Progression to overt disseminated intravascular coagulation in fatal COVID-19 has been reported in some studies, but not observed in others. We compare and contrast COVID-19 hypercoagulability, and associated increased risk of venous and arterial thrombosis, from the perspective of heparin-induced thrombocytopenia (HIT), including the dilemma of providing thromboprophylaxis and treatment recommendations when available data are limited to observational studies. The frequent use of heparin—both low-molecular-weight and unfractionated—in preventing and treating COVID-19 thrombosis, means that vigilance for HIT occurrence is required in this patient population.

of the alveolar epithelium, renal tubular epithelium, hepatocytes, enterocytes, cardiomyocytes).

Targeting vascular endothelium likely plays an important part in the prothrombotic diathesis of COVID-19, through endotheliilitis (endothelialitis), i.e., viral invasion of endothelial cells and resulting accumulation of inflammatory cells (host inflammatory response) [2-4].

2. COVID-19: comparison with HIT and severe sepsis. Table 1 lists some comparisons between COVID-19 and HIT. Both severe COVID-19 and HIT occur in a minority of at-risk patients (those infected with SARS-CoV-2 and those exposed to heparin, respectively). Both feature a hypercoagulable state, including high frequency of thrombosis, and occurrence of unusual thrombotic events. Both feature abnormalities in blood cell counts (leukocytes, platelets), coagulation values indicating likely hemostasis activationelevations in prothrombin time (PT) and fibrin D-dimer-and potential for -high-fibrinogen disseminated intravascular coagulation (DIC)‖. One major distinction: while it is now widely accepted that treatment of acute HIT requires therapeutic-dose anticoagulation (even if no evidence of thrombosis is apparent) [5] , the dosing of anticoagulation needed to prevent thrombosis in COVID-19 is controversial.

-Pancellular‖ activation in HIT involves platelets [6] , monocytes [7] , neutrophils [8, 9] , and endothelium [10, 11] . Most striking in HIT is -strong‖ platelet activation-including formation of procoagulant platelet-derived microparticles [12]-that occurs when HIT antibodies recognize platelet factor 4 (PF4)/polyanion and activate platelets through their FcγIIa receptors Guan and colleagues [25] reported on almost 1100 patients diagnosed with COVID-19 in China. They evaluated admission laboratory findings, comparing these between patients with non-severe (N=926) and severe (N=173) pulmonary disease, and further comparing admission laboratory values among patients who subsequently developed one or more of the following (versus those who did not): death, mechanical ventilation, admission to ICU. Zhou et al. [26] similarly evaluated various admission laboratory abnormalities as risk factors for mortality in 191 COVID-19 patients, 54 of whom died.

Guan et al. found lymphopenia (<1.5×10 9 /L) in 83% of COVID-19 patients, with a higher frequency among patients with severe versus non-severe disease (96% vs 80%, respectively) as well as a higher frequency among those who died, required mechanical ventilation or admission to ICU (93% vs 83%, respectively) [25] . Zhou et al. observed that 76% of non-survivors had a lymphocyte count <0.8×10 9 /L on admission, versus only 26% of survivors; further, absolute lymphocyte counts tended to rise among survivors whereas they tended to decline further in non-survivors [26] . Although neither study reported on neutrophil levels, others have reported a high frequency of neutrophilia (approximately one-third of patients) in ; further, progressive increase in absolute neutrophil counts often occurs in non-survivors [28] . Fu and colleagues [29] found a high neutrophil/lymphocyte ratio to be associated with severe disease to a greater extent than other proinflammatory markers such as Mild thrombocytopenia is a common feature of COVID-19. Guan and coworkers [25] found the median (IQR) platelet count on admission to be 168 (132, 207)×10 9 /L, with one-third having a platelet count below 150×10 9 /L. The frequency of thrombocytopenia was higher in patients with severe versus non-severe COVID-19 (58% vs 32%). Zhou et al. [26] also found the admission platelet count to be significantly lower in non-survivors versus survivors (166 [107, 229] vs 220 [168, 271]×10 9 /L, respectively; P<0.0001). Almost 20% of COVID-19 patients had thrombocytopenia on admission in another study [27] .

Among survivors, the platelet count tended to rise during the second hospital week in one study, whereas among non-survivors, thrombocytopenia tended to persist or worsen [31] .

Thrombocytosis (platelet count >450×10 9 /L) was seen in 10% of patients on admission in a study of 5 Boston (Massachusetts) hospitals [32] .

HIT features high thrombotic risk despite an oftentimes mild to moderate degree of thrombocytopenia. For example, the median platelet count nadir in HIT is approximately 55 to 70×10 9 /L [33] [34] [35] , with a high proportion of patients (~30-50%) with platelet count nadirs >100×10 9 /L or even >150×10 9 /L developing thrombotic events [36] . Perhaps, as in HIT, COVID-19 associated platelet count declines-even within the -normal‖ range-could portend progressive hypercoagulability and high thrombotic risk.

marker: 93% of non-surviving patients had a D-dimer over 0.5 mg/L on admission versus only 57% of survivors; using a 1.0 mg/L D-dimer cut-off, the mortality difference was even greater (81% vs 24%, respectively), a difference highlighted in the paper's abstract. Significantly higher D-dimer levels in critically-ill vs other COVID-19 patients were reported by others [27, 28] , with Wang et al. [28] and Li et al. [37] noting progressive increase in D-dimer levels among nonsurvivors.

Tang and colleagues [38] analyzed various coagulation markers in their study of COVID-19 in Wuhan, China, including a comparison of initial values and subsequent changes in survivors versus non-survivors. Fig. 1 [41] found that 25/56 (45%) COVID-19 patients had lupus anticoagulant, with only 3 patients also testing positive for anticardiolipin or anti-β2-glycoprotein 1 antibodies. Heparin contamination did not appear to explain positive lupus anticoagulant testing [39, 41] Fibrinogen values are elevated-often markedly-in patients with COVID-19 [32, 38, [42] [43] [44] . This reflects the proinflammatory state, given that patients also have elevations in the other proinflammatory markers, procalcitonin [25, 26, 32] , CRP [25, 32] , and ferritin [26, 32] . Similarly, VWF levels are elevated in COVID-19 patients [40], often markedly [44] . ADAMTS13 levels tend to be normal [43] or mildly reduced [44] , perhaps contributing to VWF-platelet microvascular thrombosis. Varatharajah and Rajah have speculated that endothelial-derived ultralarge VWF multimers could form large microthrombi -strings‖ comprised of platelets and large VWF complexes [45] . Pathologic evidence of complement deposition in lungs and skin suggests that vascular injury involves generalized activation of both alternative and lectin-based pathways [46] .

Coagulation abnormalities are also a feature of severe HIT, including increase in PT [47] , next section, typically elevated levels of fibrinogen in patients with HIT and COVID-19 complicate the diagnosis of DIC.

A controversial issue is whether progressively severe COVID-19 causes DIC in the absence of another superimposed DIC trigger, such as complicating bacterial sepsis. D-dimer elevation alone does not necessarily indicate DIC, but can simply indicate presence of thrombosis, such as deep-vein thrombosis (DVT) or PE [51] . This is relevant given the association between COVID-19 and thrombosis (discussed subsequently). It has been suggested that progressive lung disease with associated alveolitis and in situ pulmonary microthrombosis could also explain elevated D-dimer in COVID-19 [52, 53] , perhaps as a result of high pulmonary levels of lung urokinase [54].

The most compelling study pointing to an association between COVID-19 and DIC is from Tang et al. [38] They reported a remarkable association between evolution to DIC in COVID-19 non-survivors versus survivors: whereas only 1/162 (0.6%) survivors met the International Society on Thrombosis and Haemostasis (ISTH) criteria for overt DIC [55] , 15/21 (72%) non-survivors developed DIC. Fig. 1 shows progressive rise in PT and D-dimers, and decline in fibrinogen and antithrombin levels, in non-survivors versus survivors. Further, the DIC criterion, -thrombocytopenia‖ (yielding 1 point for platelet count fall to <100×10 9 /L, and 2 points if <50×10 9 /L) [55] ), was met by 12/21 (57%) non-survivors. Despite these striking findings, they do not rule out the possibility of superimposed bacterial sepsis (a common trigger of overt DIC), rather than COVID-19 progression per se. 

Clinicians often rule out DIC when fibrinogen values are normal or elevated. However, fibrinogen levels are often normal in patients who otherwise meet criteria for DIC [56] . Indeed, one author (T.E.W.) has observed -high-fibrinogen DIC‖ in some patients who develop symmetrical peripheral gangrene [57] . Such patients can have high fibrinogen levels on hospital admission reflecting several days of prodromal illness (e.g., initial Klebsiella pneumonia evolving to pneumosepsis). A similar phenomenon occurs in HIT-as approximately two-thirds of cases of HIT occur in postoperative patients [35, 58] -featuring high postoperative fibrinogen values-occurrence of HIT can lead to fibrinogen consumption but with -normal‖ fibrinogen J o u r n a l P r e -p r o o f Journal Pre-proof levels. Such -high-fibrinogen DIC‖ helps explain severe thrombotic events in patients with HIT and sepsis, and, potentially, in patients with COVID-19. However, progressive-usually marked-declines in platelet count are usually seen in patients with high-fibrinogen DIC associated with sepsis or HIT [35, 57, 58] , and so absence of major platelet count declines in COVID-19 argues against this phenomenon.

Thrombosis complicating COVID-19 is emerging as a major explanation for patient morbidity and mortality. Just as greater severity of HIT (judged by lower platelet count nadirs) corresponds to higher thrombosis frequency [33, 34] , so too with COVID-19, greater severity of illness (judged by need for ICU vs ward admission) is associated with greater frequency of thrombosis.

We identified 16 cohort studies (Table 2) [32, 40, [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] that quantified rates of thromboembolic disease during hospitalization, from which several observations emerge.

Although stroke, myocardial infarction/acute coronary syndrome (MI/ACS) and limb gangrene are apparent, venous thromboembolism (VTE) dominates. All studies still had patients in hospital (1 study did not report) and therefore, the true rates of thromboembolic complications during hospitalization are not known. Some studies use cumulative rates adjusted for competing risk of death to estimate the true rate (although this could underestimate the true frequency of thrombosis if deaths were caused by unrecognized thromboembolism) [64] . The rate and type of VTE prophylaxis varies widely among the studies, with some reporting no prophylaxis, other utilizing standard-dose pharmacologic prophylaxis on the wards and intermediate-dose

prophylaxis in the ICU, to others with a predominance of therapeutic-dose anticoagulation.

J o u r n a l P r e -p r o o f Fig. 2 suggests that the frequency of thrombosis in isolated HIT [58] could be similar to that observed in severe COVID-19 requiring ICU admission [63, 64, 68] .

Since none of the 16 studies reported rates exclusively for patients who had completed hospitalization (discharged alive or died), the true rate of in-hospital thromboembolism is unknown. The cumulative rate was estimated in 4 studies [64, 66, 68, 72] , each reporting different follow-up times, and results differ from crude rates because of competing risk (death) or longer follow-up in sicker patients than those discharged earlier. Nearly half the studies screened all patients for DVT [59] [60] [61] 65, [68] [69] [70] 73] and the importance of asymptomatic DVT likely is not the same as clinically symptomatic disease. Some studies reported arterial thromboembolism in addition to VTE, with venous disease predominating. HIT also features venous thrombosis predominance, with venous:arterial thrombosis ratio of approximately 4:1 in two studies [35, 58] .

Similarly, venous thrombosis predominance is seen in COVID-19; however, it is less clear whether pulmonary -embolism‖ reflects DVT-source embolism or rather in situ pulmonary artery thrombosis (discussed subsequently). patients admitted to their ICU over a 2-week period; 3 of the PE were already apparent at admission [75] . Poissy and colleagues [76] , in France, identified 22 (21%) patients with PE among 107 consecutive patients admitted to ICU because of COVID-19. This high frequency of PE was approximately three-fold higher than that seen in the same time period one year earlier (6.1%), as well as in patients admitted during 2019 with influenza (7.5%).

Bompard and colleagues [77] found an overall 24% frequency of PE (segmental > proximal > subsegmental) in patients with COVID-19 pneumonia who underwent imaging because of clinical suspicion (including D-dimer elevation); the frequency was higher in ICU patients who presented abruptly with PE [79, 80] .

Diffuse alveolar disease can be complicated by pulmonary microthrombosis, irrespective of cause. For example, a 1983 study on ARDS reported a high frequency of pulmonary microthrombosis [81] . In COVID-19 ARDS, there also is evidence for in situ pulmonary artery thrombosis involving small vessels (pulmonary microthrombosis) as well as larger arteries Lax and colleagues [82] reported an 11-patient autopsy study from Switzerland which showed diffuse alveolar damage in 11 randomly-selected autopsy patients who died of COVID-J o u r n a l P r e -p r o o f Journal Pre-proof 19 . In the authors' words, -Notably, the most striking and unexpected finding was the obstruction of pulmonary arteries by thrombotic material present at both the macroscopic and microscopic level in all cases. … The key finding of thrombosis in small to mid-sized pulmonary arteries was unexpected. On the basis of the occurrence of this finding in all patients, we assume that these thrombotic events were disease-related and were the immediate cause of death, through acute pulmonary hypertension and cessation of pulmonary circulation. … [w]e consider our findings to be caused by thrombosis rather than by thromboembolism, because most vessels were completely occluded by thrombotic material and small arteries were involved, with a diameter less than 1 mm.‖ Menter and colleagues [83] reported on 21 autopsies performed on patients who died of COVID-19. They noted that -[i]n five of eleven cases where immunohistochemistry for fibrin was performed, microthrombi were detected in alveolar capillaries‖; moreover, -[f]our cases presented with peripheral and prominent central pulmonary embolisms.‖ Ackermann and colleagues [3] reported on the lung pathology of 7 patients who died of COVID-19. They found features of lung injury common also to influenza-associated respiratory failure, namely diffuse alveolar damage with lymphocytic infiltration, as well as precapillary vessel pathology (microthrombi in small pulmonary arteries with diameter of 1 to 2 mm); however, COVID-19 featured alveolar capillary microthrombi that were 9 times as prevalent as seen in control lungs with influenza respiratory failure.

Van Dam and colleagues [84] observed that the radiologic picture of PE features more peripheral (versus central) thrombosis, indirectly supporting a potential role for in situ thrombosis in the pathogenesis of pulmonary -emboli‖ in some COVID-19 patients. Several studies have focused on strokes complicating COVID-19. In a Chinese report [87] that reviewed 214 consecutive patients hospitalized with COVID-19, the frequency of stroke was higher in patients with severe versus non-severe COVID-19 (5/88 [6%] vs 1/126

[1%], respectively). Oxley and coauthors [88] reported 5 cases of acute ischemic stroke involving large cerebral arteries in COVID-19 outpatients under the age of 50 observed during a two-week period in New York city (at most, 1 young patient would have been expected during this time period); most patients had relatively mild symptoms of COVID-19. Jain et al. [89] J o u r n a l P r e -p r o o f Among other studies reporting on various thrombotic manifestations, the frequency of ischemic strokes was also relatively high (approximately 2-3%) in the studies of Klok [63, 64] and Lodigiani [66] . The topic of cerebral venous sinus thrombosis (CVST) associated with COVID-19 is discussed later (see section 5.5 Unusual venous and arterial thromboses).

Peripheral limb artery thrombosis manifesting as limb ischemia with absent pulses is another potential complication of COVID-19, particularly in the critically ill. Bellosta and colleagues reported 20 patients who developed peripheral limb artery thrombosis after admission for COVID-19 pneumonia [91] . The frequency of acute limb ischemia was at least 5-fold greater than in the year earlier period, for which the authors proposed that COVID-19 produced a -virusrelated hypercoagulable state.‖ Surgical revascularization was performed in 17 patients (3 were too ill), with successful outcomes infrequently seen. Mestres and colleagues, in Barcelona [92] , described 4 patients who developed acute limb ischemia, 3 with infrapopliteal artery thrombosis in one or both limbs, and 1 patient with femoral-popliteal and radial-ulnar artery thromboses.

A clinical picture in keeping with symmetrical peripheral gangrene in COVID-19 ICU patients has also been reported [93] . Laboratory markers (falling platelet count, rising D-dimer levels to >20.0 mg/L, elevated PT) suggested possible overt DIC. However, the authors stated 

Hypercoagulable states can be characterized by a propensity for unusual sites of thrombosis. This is also a feature of COVID-19, where patients have developed such unusual thrombotic events as J o u r n a l P r e -p r o o f Journal Pre-proof cerebral venous sinus thrombosis [95] [96] [97] , mesenteric artery thrombosis [98] [99] [100] , aortic graft thrombosis [101] and mesenteric vein thrombosis [102] . However, unlike HIT, adrenal vein thrombosis with secondary adrenal infarction/hemorrhage has not been reported in COVID-19.

As with HIT [103] , catheter-associated upper-limb DVT can complicate COVID-19 [104] .

Seven of the 16 studies in Table 2 reported adjusted analysis for laboratory thrombosis risk factors, with increased D-dimer the most consistent, identified in 5 studies. Al-Samkari and coworkers [32] found elevated D-dimer, platelet count and CRP at presentation were independent predictors of thrombosis. Adjusted odd ratios (OR) with 95% CI for D-dimer (expressed in ng/mL) were 3.04 (1.26-7.31) for D-dimer levels of 1001-2500 and 6.79 (2.39-19.30) >2500.

Platelet count above 450×10 9 /L had an adjusted OR of 3.56 (1.27-9.97) and CRP levels >100, The subdistribution hazard ratio for elevated median neutrophil-to-lymphocyte ratio was 1.7 (1.2-2.5) and 1.4 (1.1-1.9) for D-dimer in the study by Middeldorp [68] . Stoneham [71] found elevations in white blood cell count, fibrinogen and D-dimer to be associated with VTE with OR of 1.18, 1.66 and 1.39 respectively. D-dimer >1.0 at admission had an adjusted OR of 5.82 (1.42-23.81) in the study led by Zhang [73] for screen-detected DVT. And third, the patient also evinced a 43% decline in platelet count beginning about 10 days after starting enoxaparin thromboprophylaxis. It is possible that this platelet count fall, together with PE occurrence, reflects occurrence of HIT (not otherwise suspected nor investigated for).

HIT occurrence reflects not only exposure to heparin but also the clinical setting, heparin type, and duration of exposure. For example, HIT occurs more often with unfractionated heparin (UFH) than with low-molecular-weight heparin (LMWH) [105] , more often in surgical than medical patients [106] , and more often with exposure beyond 10 days than patients who receive 4 or fewer days [107] . Further, among immunized patients, higher heparin dosing can lead to J o u r n a l P r e -p r o o f greater frequency of HIT -breakthrough‖, and so dosing increase from prophylactic to intermediate to therapeutic could also increase the HIT risk [108] . Inflammation is a risk factor for HIT [109] , so it is possible that COVID-19 represents a high-than-usual risk for HIT than standard -medical‖ patients receiving thromboprophylaxis, especially as many COVID-19 patients are hospitalized for over 1 week.

There are anecdotal reports of HIT occurrence in COVID-19 patients. Riker and colleagues [110] Patell and coworkers [112] reported 5 patients with possible HIT-based upon suspicious platelet count decline and a positive latex immunoturbidimetric assay (LIA) for anti-PF4/heparin antibodies-among 88 COVID-19 patients who received at least 5 days of UFH (median, 11 days of UFH exposure). This corresponded to a cumulative incidence of LIA positivity of 12% at undergo SRA testing, but that patient's LIA result was strong-positive (>16 units/mL), which predicts for high (~90%) probability of HIT [113] . Although the true frequency of HIT in this study was unclear, the implication is that HIT is a definite potential complication of COVID-19 patients, particularly if there is prolonged exposure to UFH.

Given the importance of HIT ascertainment in this novel patient population, we recommend referral of EIA-positive or LIA-positive blood samples for testing by functional (platelet activation) assay, such as the SRA. However, given emerging data regarding occasional false-negative SRA results [114] , we also suggest that SRA-negative blood samples (but with strong clinical suspicion of HIT corroborated by strong-positive EIA or LIA) be referred to a laboratory with experience in performing newer PF4-dependent platelet activation assays, such as the PF4-SRA [114] , PF4/heparin-SRA [115] , or the P-selectin expression assay [116] .

Parzy and colleagues [117] reported 3 patients with laboratory-confirmed HIT among 13 critically-ill patients requiring venovenous extracorporeal membrane oxygenation (ECMO) with heparin anticoagulation. Since all 13 ECMO patients developed one or more venous thrombotic events, the contributory role of HIT in explaining thrombosis in this study is uncertain.

Unfortunately, clinical and laboratory data supporting the HIT diagnoses were not provided.

A non-peer-reviewed paper from China found that non-surviving ICU patients frequently had progressive, severe thrombocytopenia [118] . Many of these patients were receiving LMWH.

The authors found high levels of -HIT antibodies‖ by enzyme-immunoassay among ICU patients, and they speculated that HIT may have contributed to severe thrombocytopenia and adverse outcomes. In some patients, antibodies were detectable even before heparin treatment, raising the possibility of COVID-19-associated -spontaneous‖ HIT syndrome [119] . However, J o u r n a l P r e -p r o o f Journal Pre-proof HIT antibody assays with higher specificity (e.g., SRA) were not performed, so the implications of these observations are uncertain.

Anticoagulant dosing in HIT offers an interesting perspective. Due to its (relative) rarity, heterogeneous clinical presentation, and (until recently) difficulty in achieving rapid real-time laboratory confirmation of a diagnosis of HIT, randomized trials evaluating different treatment approaches have not been available for HIT. Yet, the recognition of HIT as a profound hypercoagulable state, together with relevant observational studies, have led to the current treatment paradigm where-in the absence of contraindications-patients with HIT are typically treated with therapeutic-dose anticoagulation. An example of an observational study that informed this practice was one by Farner and colleagues, who reported their experience treating HIT with danaparoid [120] . Paradoxically, patients with HIT-associated thrombosis who were treated with danaparoid had a lower frequency of subsequent thrombosis than patients who had -isolated‖ HIT, i.e., HIT diagnosed on the basis of a platelet count fall rather than because of thrombosis occurrence that led to a diagnosis of HIT. The authors' explanation was that patients with HIT-associated thrombosis typically received therapeutic-dose danaparoid, whereas patients with isolated HIT were usually given lower (prophylactic-dose) danaparoid.

There is wide variation in dosing of pharmacologic VTE prophylaxis in COVID-19 patients. Of interest is the observation that continuation of pre-hospital therapeutic-dose anticoagulation may have an important effect on reducing development of VTE. Klok and coworkers [64] noted that the risk of VTE in patients on therapeutic anticoagulation prior to ICU The effect of prophylactic-dose LMWH or UFH was evaluated in 449 Chinese patients with severe COVID-19, of whom 22% received an anticoagulant. There was no difference in 28day mortality, however, in patients with a Sepsis Induced Coagulopathy (SIC) score > 4 and who received prophylactic-dose heparin, mortality was lower (40.0% vs 64.2%, P=.029) [122] . These observations suggest anticoagulation may have a favorable effect on mortality in the sickest patients.

Several organizations have developed guidelines, guidance statements, answers to frequently asked questions, or state-of-the-art reviews (Table 3) [123] [124] [125] [126] [127] [128] . There is general agreement that all patients should receive, or be evaluated for, pharmacologic VTE prophylaxis; none recommend therapeutic-dose VTE prophylaxis unless done in the context of a clinical trial.

Recommendations to use usual prophylactic-or intermediate-dose anticoagulation varies, as does dose adjustment for extremes of body weight, and some organizations differentiate approaches J o u r n a l P r e -p r o o f Journal Pre-proof depending on whether the patient is in the ICU. Some statements recommend LMWH over UFH because of less patient exposure and personal protective equipment utilization. There is not strong agreement for extended prophylaxis post-discharge, but several groups recommend considering. Randomized trials are needed to address the best anticoagulant dose for VTE prevention, and we identified 9 proposed or ongoing trials comparing different doses of LMWH or UFH (Table 4) . Reprinted from [38] , with revisions, with permission. 

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Serotonin-release assaynegative heparin-induced thrombocytopenia

Beneficial effect of exogenous platelet factor 4 for detecting pathogenic heparin-induced thrombocytopenia antibodies

A novel PF4-dependent platelet activation assay identifies patients likely to have heparin-induced thrombocytopenia/thrombosis

Venous thromboembolism events following venovenous extracorporeal membrane oxygenation for severe acute respiratory syndrome coronavirus 2 based on CT scans

Heparin-induced thrombocytopenia is associated with a high risk of mortality in critical COVID-19 patients receiving heparin-induced treatment, MedRxiv (preprint, not peer-reviewed)

Spontaneous heparin-induced thrombocytopenia syndrome: 2 new cases and a proposal for defining this disorder

A comparison of danaparoid and lepirudin in heparininduced thrombocytopenia

Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the Anticoagulation Forum

Scientific and Standardization Committee Communication: Clinical guidance on the diagnosis, prevention and treatment of venous thromboembolism in hospitalized patients with COVID-19

Prevention, diagnosis, and treatment of VTE in patients with COVID-19: CHEST guideline and expert panel report

Online ahead of print

COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: J o u r n a l P r e -p r o o f JACC state-of-the-art review