MAEDICA – a Journal of Clinical Medicine Mædica - a Journal of Clinical Medicine 2021; 16(2): 268-273 https://doi.org/10.26574/maedica.2021.16.2.268 Review Patients with Sticky Syndrome, Sickle Cell Disease and Glanzmann Syndrome May Promulgate Severe if Infected with Covid-19 Nitin Ashok JOHNa, Jyoti JOHNb, Praful KAMBLECa, Anish SINGHALa, Vandana DAULATABADc, I. S. VAMSHIDHARa aDepartment of Physiology, All India Institute of Medical Sciences, Bibinagar, Telangana, India bDepartment of Biochemistry, All India Institute of Medical Sciences, Nagpur, Maharashtra, India cDepartment of Physiology, Dr. V. M. Government Medical College, Solapur, Maharashtra, India

ABSTRACT Covid-19 pandemic has been a very serious cause of health concern worldwide. Thrombosis has been a critical manifestation in severe Covid-19 infection. The increased arterial and venous thrombosis in patients with Covid-19 is proving to be life threatening. Sticky platelet syndrome and sickle cell disease are genetic disorders with procoagulant nature of the disease, while in Glanzmann syndrome there is an enhanced tendency, with pathological defect leading to altered platelet aggregation and delayed clot formation. Considering the thrombotic episodes of Covid-19, we decided to review the literature on data bases such as PubMed and Medline for knowing the coagulant status in genetically associated diseases such as sticky platelet syndrome, sickle cell disease and Glanzmann syndrome. We planned to review various published studies with the aim to find whether the coagulant profiles in these conditions alter the thrombotic manifestations and prognosis if these patients contract Covid-19. Various research studies revealed that patients with sticky platelet syndrome develop arterial and venous thrombosis, while those with sickle cell disease are known to develop complications such as and . Moreover, patients with Glanzmann syndrome who usually have a bleeding tendency also rarely present with severe venous and arterial thrombosis and pulmonary embolism. Patients with sticky platelet syndrome and sickle cell disease and,, occasionally those with Glanzmann syndrome have a higher risk for thrombosis if infected with Covid-19. More studies are needed to better understand the clinical manifestations and designing standard management protocol for patients with sticky platelet syndrome, sickle cell disease and Glanzmann syndrome who contract Covid-19 infections. Keywords: Sticky platelet syndrome, sickle cell disease, Glanzmann syndrome, thrombosis, pulmonary embolism, Covid-19.

Address for correspondence: Dr. Nitin Ashok John, MD, Professor & Head Department of Physiology, All India Institute of Medical Sciences, Bibinagar, Telangana, 508126, India Email: [email protected]

Article received on the 1st of May 2021 and accepted for publication on the 27th of May 2021

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INTRODUCTION tations and prognosis if these patients contracted Covid-19. Sticky platelet syndrome and sickle ovid-19, an abbreviation for corona cell disease are genetic disorders with a proco- virus disease 2019, is caused by se- agulant nature of the disease, while in Glanz­ vere acute respiratory syndrome co- mann syndrome there is an enhanced bleeding rona virus 2 (SARS-CoV-2). Covid-19 tendency, with the pathological defect leading to pandemic, which originated in altered platelet aggregation and delayed clot for- CWuhan, China, in 2019, has led to a severe so- mation. cioeconomic and health devastation worldwide. Sticky platelet syndrome is an autosomal The severity of Covid-19 manifestation across dominant disease and a rare clinical condition communities has been countered with a dedi- with unknown etiology; it is characterized by hy- cated management approach, including social peraggregation of the , with an increased isolation, quarantine management of active ca­ risk of arterial and venous thrombosis and throm- ses and contacts, symptomatic medical manage- boembolism. Sticky platelet syndrome has been ment along with Covid-19 vaccination. For ful- the causative factor in nearly 21% of all arterial filling this obligation towards effective public thrombosis and 13% of venous thrombosis, with health services, every country requires adequate both conditions being of unknown origin (3). manpower of doctors and nurses, medicines, Sickle cell disease is due to mutation of beta oxygen cylinders and ventilators. This results in globin chain of hemoglobin in which glutamate an increasing global health burden, which is also is replaced by valine at the sixth amino acid posi- heavily affecting national economies, especially tion of the beta chain. According to epidemio- those of developing and underdeveloped coun- logical studies, around 20–25 million individuals tries. worldwide have sickle cell disease, and about The signs and symptoms associated with 50–80% of infants born with this disease in Afri- Covid-19 infection include fever, dry cough, sore ca die before the age of five years (4). Patients throat, body ache, headache, myalgia, fatigue, with sickle cell disease present with complains of shortness of breath, diarrhea, and sometimes recurrent chest infection, acute chest syndrome, loss of smell, taste or appetite. Severe Covid-19 painful vaso-occlusive crisis, stroke, deep vein infection is associated with dyspnea along with thrombosis and pulmonary embolism (4). hypoxemia, acute respiratory distress syndrome, Glanzmann syndrome is a very rare autoso- pneumonia, thrombosis, thromboembolism, co- mal recessive genetic disorder in which the agulopathy, arrhythmias and shock (1). Although platelets contain defective or low levels of glyco- the pandemic has been lasting for more than protein IIb/IIIa: GPIIb-IIIa. These glycoproteins 18 months, mortality rates are still rising on a are receptors for fibrinogen. Due to this, fibrino- daily basis worldwide. Many countries are facing gen bridging between platelets is not possible. a second wave of the pandemic as a result of the This will lead to a severe bleeding tendency and rapid circulation of mutant strains of SARS-CoV-2 defective haemostatic plug formation. Glanz­ across continents. World Health Organization mann thrombasthenia is prevalent in about dashboard reported 146,054,107 confirmed 1:1,000,000 of the general population world- cases and 3,092,410 deaths on the 25th of April wide. But recent hospital-based research studies 2021 (2). and reports have pointed out to an increasing Increased arterial and venous thrombosis is number of cases with unexplained thrombosis, one of the most critical manifestations in criti- pulmonary embolism as well as severe proximal cally ill Covid-19 patients. Considering the deep vein thrombosis in a Glanzmann thrombas- thrombotic episodes of Covid-19, we decided to thenia variant (5). The causes of thrombosis in review the literature in order to find out which Covid-19, sticky platelet syndrome, sickle cell was the coagulant status in genetically associated disease and Glanzmann syndrome are showed diseases such as sticky platelet syndrome, sickle in Figure 1. cell disease and Glanzmann syndrome. We These facts gave us an impetus to search the planned to review various published studies with literature for understanding the clinical perspec- the aim to find whether the coagulant profiles in tive of higher risk of thrombosis and thromboem- these conditions altered the thrombotic manifes- bolism in patients with sticky platelet syndrome,

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FIGURE 1. Causes of thrombosis in Covid-19, sticky platelet syndrome, sickle cell disease and Glanzmann syndrome sickle cell disease and Glanzmann syndrome and DISCUSSIONS whether these conditions may promulgate se- vere thrombosis if these patients get infected ovid-19 and thrombosis with Covid-19. CThere has been a high risk of venous throm- boembolism in patients with Covid-19, whose MATERIAL AND METHODS infection with SARS-CoV-2 was found to cause a hypercoagulable state. Research carried out on e planned to have a thorough search of patients with Covid-19 hospitalized in intensive Wthe literature of all recently published ar- care units revealed that 31% to 79% of the de- ticles from various data bases such as Medline, veloped thrombosis (6). There is a cytokine storm PubMed and World Health Organization web- with increased release of pro-inflammatory sub- site. Sticky platelet syndrome and Glanzmann stances and interleukins, mainly interleukin 6, syndrome have not been very commonly dis- which indicates a progressive inflammatory re- cussed by researchers. Therefore, we decided to sponse and a hypercoagulable state of blood analyze various research and review papers pu­ (7, 8). These pro-inflammatory cytokines impair blished in English, describing pathological mani- the natural anti- pathway and ob- festations and management of sticky platelet syn- scures the fibrinolysis process, leading to pro- drome, sickle cell disease and Glanzmann thrombotic changes in circulation and causing syndrome, which were conducted in the last arterial and venous thrombosis. The impairment three decades, using the above-mentioned key of prothrombotic changes is due to interaction of words. All articles published in line with national mononuclear cell with platelets and coagulation and international guidelines and recommenda- cascade leading to binding of thrombin with spe- tion of International Committee of Medical Jour- cific protease activated receptors. Moreover, in- nal Editors were included in our review. creased levels of D-dimer, interleukin 6 and fi-

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brin degradation product (FDP) have been surface of the red blood cell. It has been noted associated with severe thrombosis in critically ill that there was an expression of CD 47 and alpha Covid-19 patients (8, 9). 4 Beta 1 proteins on the surface cell membrane of red blood cell in patients with sickle cell dis- Sticky platelet syndrome and thrombosis ease (13, 14). The CD 47 protein binds to throm- Sticky platelet syndrome the autosomal domi- bospondin in circulation and initiates a cascade nant diseases have reported to be associated of reaction, eventually activating alpha 4 Beta 1 with unexplained thrombosis. Both arterial and proteins, which binds to the vessel wall protein venous thrombosis has been noted very com- thrombospondin, being responsible for red monly in patients with sticky platelet syndrome. blood cell adhesion. Thus, sticky patches with Depending upon the hyperaggregability of this polymerization of the HbS molecules are causing disease, the recognized forms of sticky platelet vaso-occlusion, which can result in vein throm- syndrome include types I, II and III. The hyper- bosis and pulmonary embolism (14, 15). Thus, aggregability characteristics on conducting plate- increased thrombotic episodes in sickle cell di­ let aggregation test by addition of epinephrine sease may further lead to a two-fold increased and adenosine-diphosphate defines the three risk of sickle cell disease if those patients also forms of sticky platelet syndrome. Platelet aggre- contract a Covid-19 infection. gation is observed by adding epinephrine and adenosine-diphosphate in type I, or epinephrine Glanzmann syndrome and coagulation profile in type II, or adenosine-diphosphate in type III Glanzmann syndrome is an autosomal recessive (3, 10). Despite the thrombotic nature of that disorder or may sometimes occur as an autoim- disease, not much research has been carried out mune disease, with patients presenting with to explore its exact pathophysiology and to iden- bleeding episodes from minor bruising to severe tify what could have caused the thrombosis. Pa- bleeding. Platelet count and morphological fea- tients with sticky platelet syndrome shall be ex- tures of platelets on microscopy are normal, but posed to a two-fold increased risk of developing platelet aggregation study reveals an impaired thrombotic complications if they contract a aggregation with ADP, epinephrine or both, Covid-19 infection. Sticky platelet syndrome has while aggregation after addition of ristocetin is been identified as one of the main causes of life normal. Assuming these facts, patients may have threatening thrombosis (11, 12). The sticky plate- a favorable protection against developing throm- let syndrome being difficult to diagnose, we re­ botic complications if they contract a Covid-19 commend that a complete coagulation profile infection (16, 17). should be conducted in any patient with In contrast, a study conducted by Yves Gruel Covid-19 infection reporting in OPD with either et al showed that severe thrombosis was possible past history of any coagulation disorders or as- in patients with Glanzmann thrombasthenia sociated symptoms such as chest pain, dyspnea, even if they had a severely deficient platelet swelling of lower limb, stroke, etc suggestive of agreeability, with the likely cause being attribu­ thrombotic episodes. ted to prolonged airplane flight, which was thought to have triggered the occurrence of Sickle cell disease and thrombosis thrombosis. In patients with Glanzmann throm- The characteristic manifestation of sickle cell dis- basthenia, the contact phase of platelet adhe­ ease includes increased adhesiveness of the sick- rence to the subendothelium was found to be led red blood cell to the vascular endothelium. normal and granule secretion occurred satisfac- Whenever sickle cell disease patients are ex- torily. Moreover, the sites where fibrin mono- posed to hypoxia there is a polymerization of the mers bind on thrombasthenic platelets have HbS molecules, leading to an alteration in the been also found to be normally exposed (18). shape of red blood cell, which makes them more Moreover, Sakariassen KS et al noted that plate- prone to haemolysis. Moreover, the altered re- lets adhered in the normal range at shear rates placement of glutamate, which is carrying a ne­ up to 1 000 s. At higher shear rates, platelets had gative charg,e with a neutral hydrophobic mo­ a lesser contact spread over the subendothelium lecule of valine renders a sticky patch on the and there was no platelet aggregation (19).

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Girolami A et al have also described manifesta- chers should first explore which anti-coagulants tions of severe arterial and venous thrombosis in are to be started and at what doses, and then patients with Glanzmann thrombasthenia (20). obtain a relevant scientific body’s certification. Hence, physicians should be cautious when The real challenge will be to care for patients treating Covid-19 patients with pre-existing with Glanzmann syndrome, whose routine ma­ Glanzmann thrombasthenia, given that the un- na­gement consists of hemostatic agents, recom- derlying disorder is associated with a bleeding binant activated factor VII, platelet transfusions tendency and the rare occurrence of thrombosis and antifibrinolytic drugs. If those patients de- in those patients can prove to be life threatening. velop Covid-19, the anti-thrombotic nature of Also, physicians should ensure that Glanzmann the pre-existing disease might prevent the occur- thrombasthenia is diagnosed via light transmis- rence of thrombosis; but in a different scenario, sion aggregometry test for platelet aggregation; patients suffering from Glanzmann thrombasthe- molecular analytical studies and platelet glyco- nia with severe proximal deep vein thrombosis protein expression studies are carried out. More- were effectively managed with a low molecular over, the thrombotic nature of Covid-19 exposes weight heparin (18). Moreover, given the mani- infected patients with pre-existing Glanzmann festation of pulmonary thrombosis as well as se- thrombasthenia to a high risk for thrombosis. vere arterial and venous thrombosis in patients with Glanzmann syndrome, physicians need to Management be alert while addressing such situations. Admi­ nistering in Glanzmann syndrome with The management of Covid-19 patients with pre- complicated pulmonary thrombosis was found existing diseases such as sticky platelet syndrome, to be an effective way of resolving thrombosis sickle cell disease and Glanzmann syndrome symptoms (26). needs to be carefully monitored and conducted. The coagulation profile including complete CONCLUSIONS blood count, platelet count, prothrombin time, activated partial thromboplastin time as well as n conclusion, patients with sticky platelet syn- light transmission aggregometry test for platelet Idrome and sickle cell disease may have an in- aggregation to rule out the sticky platelet syn- creased risk of developing severe thrombosis if drome, Hb electrophoresis for diagnosing sickle infected with Covid-19. While due to the dual cell disease, molecular and platelet glycoprotein nature of Glanzmann syndrome manifestations expression studies for diagnosis of Glanzmann with typical bleeding tendencies and rare occur- syndrome are all needed. Starting an anti-coagu- rence of severe venous and arterial thrombosis, lant therapy in critically ill Covid-19 patients with physicians have to be alert and administering the pre-existing sticky platelet syndrome, sickle cell adequate treatment as per individual manifesta- disease and Glanzmann syndrome with evidence tions. More studies are needed for a better under- of thrombosis is also a challenge. standing of the clinical manifestations and investiga- The International Society on Thrombosis and tions as well as for designing standard management­ Haemostasis (ISTH) and the American Society of protocols in patients with sticky platelet syndrome, Hematology (ASH) have recommended the use sickle cell disease or Glanzmann­ syndrome who of low-molecular-weight heparin as anticoagu- contract Covid-19 infection. q lant for the treatment of thrombosis in Covid-19 Conflicts of interest: none declared. patients, but the best effective dosage is yet to be Financial support: none declared. defined and needs further exploration (21). Aspi- Acknowledgments: Authors would like to rin and such as warfarin and clo­ thank Dr Maj Gen (Dr) Vibha Dutta, SM Director pidogrel have been given to patients with sticky and CEO, All India Institute of Medical Sciences, platelet syndrome (22, 23) and non-steroidal Nagpur, India, for her constant encouragement, anti-inflammatory drugs have been used for guidance and support for writing the manuscript, managing vaso-occlusive crises along with intra- as well as Dr Vikas Bhatia, Director, venous fluids in patients with sickle cell disease All India Institute of Medical Sciences, (24-26). If patients with those diseases contract Bibinagar, Telangana, India, for encouraging us in Covid-19 infection and get critically ill, resear­ writing this review article.

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