COVID-19 and Thrombocytopenia: Heparin or Sepsis-Induced?

Citation: Tezza F, Susana A, Monticelli J, Leone LAC, Barbar S (2020) COVID-19 and Thrombocytopenia: Heparin or Sepsis-Induced?. J Geriatr Med Gerontol 6:095. doi.org/10.23937/2469-5858/1510095 Accepted: July 20, 2020: Published: July 22, 2020 Copyright: © 2020 Tezza F, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Open Access ISSN: 2469-5858

bleeding or bruising, pain, redness or skin modification in injection-side. Heparin induce-thrombocytopenia (HIT) without or with thrombosis (HITT) is a known, potentially fatal, side effect caused by antibodies against complexes containing platelet factor 4 (PF4) and heparin. Only 0.2% to 3% of heparin-exposed patients present thrombocytopenia and/or thrombosis [5].
Most important tool is differential diagnosis that could be difficult due to the overlap of HIT with other medical conditions as DIC, immune thrombocytopenia, thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome, and drug-induced thrombocytopenia. The presumptive diagnosis of HIT is made by the so called 4Ts scoring system developed by Cuker, et al. [6].
Herein we report the first case, at the best of our knowledge, of suspected HIT in a patient positive for SARS-CoV-2.

Introduction
The outbreak of a novel-coronavirus related pneumonia was officially identified in Wuhan, on January 2020 and it was declared a Public Health Emergency of International Concern on January 30 th . On February, WHO named the virus SARS-CoV-2 and the subsequent disease COVID-19 [1]. On March 11 th , WHO Director General, Dr. Tedros Adhanom Ghebreyesus, declared that "COVID-19 can be characterized as a pandemic" because "there are now more than 118,000 cases in 114 countries, and 4,291 people have lost their lives" [1].
About 40% of SARS-CoV-2 positive patients are asymptomatic but infectious. More common symptoms are fever, dry cough and dyspnea but some patients might experience also myalgia, diarrhea, anosmia and ageusia. Severe cases present a severe pneumonia that could exitate in an acute respiratory distress syndrome (ARDS) characterized by acute hypoxemic respiratory failure and bilateral lung infiltrates [2].
As recently published in severe COVID-19 patients there is a derangement of coagulation ranging from hypercoagulability to an overt disseminated intravascular coagulation (DIC) [3]. Some patients could experience venous thromboembolism that requires anticoagulation therapy with heparin [4].
The name heparin comprehends a group of glycosaminoglycans having anticoagulant properties used for prevention of clot formation.

Discussion
SARS-CoV-2 infection could be complicated by DIC subsequent to the septic status and Iba [7] proposed the name of "sepsis-induced coagulopathy" for this syndrome. COVID-19 patients, especially those with severe disease, are at high risk of venous thromboembolism requiring prophylactic dose of low molecular weight heparin [4].
Heparin induced-thrombocytopenia (HIT) is a potentially fatal complication during treatment with heparin -unfractioned or low-molecular weight -characterized by platelet count fall with or without new venous or arterial thrombosis [5]. This entity could be underestimated especially when platelet count falls > 50% without causing a real thrombocytopenia. Warkentin [8] recently reported that 15% to 20% of patients could suffer arterial events while 30% to 60% could develop venous thromboembolism.
Spontaneous retroperitoneal hematoma during anticoagulation therapy is well known and usually they are self-limiting [9]. At first the clinical course of the patient could be explained by DIC or hypercoagulability related to a severe COVID-19 pneumonia in a comorbid old-patient.
Nevertheless, retrospectively evaluating this case, we could speculate that patient suffered from a HIT (thrombocytopenia complicated by acute coronary syndrome) associated with an iliopsoas muscle hematoma subsequent either thrombocytopenia than LMWH treatment. This hypothesis could be validated by the 4Ts score resulting in 6 point indicating a high HIT probability. Unfortunately the patient was not tested for PF4/H antibodies and he died before platelet recovery that, as reported by Warkentin, et al. [10], usually occurs 2 weeks after heparin withdrawal.
In conclusion, SARS-CoV-2 positive patients, especially more severe cases, could have a prothrombotic condition due to infection itself, cytokine release and subsequent DIC. It is of paramount importance to keep in mind that HIT can complicate SARS-CoV-2 infection being a life threatening condition.

Conflict of Interest
The authors declare they have no conflict of interest.

Financial Support
No financial support for this work. examination there weren't lung crackles, pleural friction rubs or peripheral oedema. His arterial blood oxygen saturation (SO 2 ) was 95% on 9 liters of supplemental oxygen and he was pyretic (38 °C).
He started antibiotic treatment with Levofloxacin and Ceftazidime, antiviral therapy with lopinavir/ritonavir (Kaletra ® ), methylprednisolone, insulin and 4,000 IU of enoxaparin every 24 hours. He also continued his daily medications (furosemide, aspirin, bisoprolol).
During the following days he presented desaturation (SO 2 88%) requiring treatment with continuous positive airway pressure (CPAP) delivered with a "helmet". The high suspicion for pulmonary embolism, due to clinical signs and elevation of D-dimer (4738 ug/L), was dispelled by CT-pulmonary angiography. During the following days, patient's symptoms improved and fifteen days after hospital admission CPAP was stopped and switched to high flow nasal cannula oxygen therapy.
The next day he experienced hypotension (90/50 mmHg), tachypnea, tachycardia (130 bpm), epigastric pain radiated to back and wrists, and Melaena. Laboratory data highlighted severe anemia (48 g/L), reduction of platelet count (157 G/L), moderate elevation of troponin (46 ng/L), elevation of C-reactive protein (51 mg/L), normal AST and ALT level (25 and 31 U/L respectively). The EKG revealed an anterolateral subepicardial ischemia. The patient underwent chest and abdominal CT-scan showing no aortic dissection but a 7 cm × 5 cm non-active bleeding hematoma at the level of iliopsoas muscle. Aspirin and heparin were immediately withdrawn.
Due to the presence of Melaena the patient also underwent to esophagogastroduodenoscopy showing duodenal ulcer without active bleeding (Forrest III) and hiatal hernia. He started proton pump drug intravenously and continue remaining therapy. In the following 2 days, laboratory data revealed a marked increase of troponin (up to 1260 ng/L) and a progressive reduction of platelets (up to 44 G/L) with stability of d-dimer (4575 ug/L) and hemoglobin at 105 g/L after blood transfusions.
In the next two days (22 days after hospital admission) he improved symptoms but he presented a new febrile episode with desaturation and he died. Blood culture collected around temperature elevation was negative.