COVID-19-associated coagulopathy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Synonyms and keywords:

Historical Perspective

• Coronavirus, named due to the "crown" like appearance of its surface projections, was first isolated from chickens in 1937.,
• In 1965, Tyrrell and Bynoe used cultures of human ciliated embryonal trachea to propagate the first human coronavirus (HCoV) in vitro.
• There are now approximately 15 species in this family, which infect not only humans but cattle, pigs, rodents, cats, dogs and birds (some are serious veterinary pathogens, especially chickens).

• The etiological agent, a novel coronavirus, SARS-CoV-2, named for the similarity of its symptoms to those induced by the severe acute respiratory syndrome, causing coronavirus disease 2019 (COVID-19), is a virus identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China.
• Initially, the patients were believed to have contracted the virus from seafood/animal markets which suggested animal-to-human spread.
• The growing number of patients however, suggest that human-to-human transmission is actively occurring.
• The outbreak was declared a Public Health Emergency of International Concern on 30 January 2020.
• On March 12, 2020 the World Health Organization declared the COVID-19 outbreak a pandemic.

Classification

There is no established system for the classification of the hypercoagulability seen in COVID-19.

The coagulopathy may be classified according to the type of vessels and organs involved into:

• Venous thrombosis
• Arterial thrombosis
• Microvascular thrombosis

Pathophysiology

COVID-19 induces a hypercoagulable state in the body. An increased risk of mortality has been noted in patient’s with coagulopathy in COVID-19. It is thought that the coagulopathy in COVID-19 is the result of

• Virchow’s triad
  • Vascular endothelial damage
  • Endothelitis- direct invasion of endothelial cells by SARS-CoV-2
  • Complement mediated damage to pericytes
  • Pro-inflammatory cytokines- IL-1, IL-6, and TNF- α, that activate the coagulation pathway and the fibrinolytic system
• Stasis- Prolonged hospital admissions causing immobilization of the patient
• Hypercoagulabe state- Evidenced by elevated fibrinogen, prothrombotic factors and hyperviscosity
• Some patients have been found to have Lupus anticoagulant (anti-cardiolipin) and anti-β2GP1 antibodies that may be contributory.

Causes

Coagulopathy in COVID-19 is caused by-

• Direct invasion of endothelial cells by SARS-CoV-2
• Pro-inflammatory cytokine storm.
• Prolonged immobilization in hospitalized patients causing stasis.

Differentiating COVID-19 associated coagulopathy from other Diseases

Coagulopathy in COVID-19 must be differentiated from other diseases that cause DIC.

The main feature of COVID-19 coagulopathy is thrombosis while the acute phase of DIC presents with bleeding:

• Similar laboratory findings are marked increase in D-dimer and normal/slightly low platelets and prolonged PT.
• Findings distinct in COVID 19 are high fibrinogen and high factor VIII activity
• The scoring system of the International Society on Thrombosis and Hemostasis should be used to detect DIC (platelet count, PT, fibrinogen, D‐dimer, antithrombin and protein C activity monitoring), but the diagnosis and subsequent treatment should be done clinically.

Epidemiology and Demographics

The incidence of venous thromboembolism in ICU patients with COVID-19 was analyzed in a study by Klok et al.

• It concluded that the cumulative incidence of acute pulmonary embolism (PE), deep vein thrombosis (DVT), ischemic stroke, MI, or systemic arterial embolism was 31%.
• The most common thrombotic complication was pulmonary embolism seen in 81% of patients. All these patients were on at least standard doses of thromboprophylaxis.
• The cumulative incidences of VTE were 16% (95% CI, 10-22) at 7 days, 33% (95% CI, 23-43) at 14 days and 42% (95% CI 30-54) at 21 days.
• Comparatively, the cumulative incidence of VTE was higher in the ICU patients - 26% (95% CI, 17-37) at 7 days, 47% (95% CI, 34-58) at 14 days and 59% (95% CI, 42-72) at 21 days) than on the floor.

Independent predictors of thrombotic complications seen were-

• Age
• Coagulopathy (defined as spontaneous prolongation of the prothrombin time > 3 s or activated partial thromboplastin time > 5 s)
• Active cancer

There is no data on gender, geographic location, and racial predilection to coagulopathy in COVID-19.

Risk Factors

Hypothesized risk factors for coagulopathy in COVID-19 pneumonia based on studies include-

• ICU admission
• Age (> 40 years)
• Hypoxia

General factors for VTE like-

• Male
• Active cancer
• Recent major surgery
• High BMI (obesity)
• Prior VTE
• Immobilization
• Trauma

Screening

Every patient with COVID-19 infection admitted to the hospital should have a baseline of basic blood investigations such as

• Complete blood count (CBC)
• Platelet count
• Prothrombin Time (PT), Activated partial thromboplastin time (aPTT)
• Fibrinogen
• D-dimer
• C- reactive protein

Depending on the clinical state of the patient and suspicion for the development of VTE or arterial thrombi, repeat testing and further imaging investigations are done.

Natural History, Complications, and Prognosis

If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].

OR

Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].

OR

Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.

Diagnosis

Diagnostic Study of Choice

The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: [criterion 1], [criterion 2], [criterion 3], and [criterion 4].

OR

The diagnosis of [disease name] is based on the [criteria name] criteria, which include [criterion 1], [criterion 2], and [criterion 3].

OR

The diagnosis of [disease name] is based on the [definition name] definition, which includes [criterion 1], [criterion 2], and [criterion 3].

OR

There are no established criteria for the diagnosis of [disease name].

History and Symptoms

The majority of patients with [disease name] are asymptomatic.

OR

The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3]. Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3].

Physical Examination

Patients with [disease name] usually appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].

OR

Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

The presence of [finding(s)] on physical examination is diagnostic of [disease name].

OR

The presence of [finding(s)] on physical examination is highly suggestive of [disease name].

Laboratory Findings

An elevated concentration of serum/blood pro-coagulant factors is diagnostic of coagulopathy associated with COVID-19. Laboratory findings consistent with the diagnosis of COVID-19 associated coagulopathy include-

Coagulation testing- Pro-coagulant profile

• Platelet Counts- Normal or increased
• Prothrombin time (PT) and activated partial thromboplastin time (aPTT)- normal or slightly prolonged
• Fibrinogen- increased
• D-dimer- increased
• Factor VIII activity- increased
• VWF antigen- increased
• Protein C, Protein S, Antithrombin III - slightly decreased

TEG findings-

• Reaction time (R) - decreased
• Clot formation time (K)- decreased
• Maximum amplitude (MA)- increased
• Clot lysis at 30 minutes (LY30)- decreased

Electrocardiogram

There are no ECG findings associated with [disease name].

OR

An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

X-ray

There are no x-ray findings associated with [disease name].

OR

An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with [disease name].

OR

Echocardiography/ultrasound may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no echocardiography/ultrasound findings associated with [disease name]. However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

CT scan

There are no CT scan findings associated with [disease name].

OR

[Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

MRI

There are no MRI findings associated with [disease name].

OR

[Location] MRI may be helpful in the diagnosis of [disease name]. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Other Imaging Findings

There are no other imaging findings associated with [disease name].

OR

[Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

There are no other diagnostic studies associated with [disease name].

OR

[Diagnostic study] may be helpful in the diagnosis of [disease name]. Findings suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

OR

Other diagnostic studies for [disease name] include [diagnostic study 1], which demonstrates [finding 1], [finding 2], and [finding 3], and [diagnostic study 2], which demonstrates [finding 1], [finding 2], and [finding 3].

Treatment

Medical Therapy

There is no treatment for [disease name]; the mainstay of therapy is supportive care.

OR

Supportive therapy for [disease name] includes [therapy 1], [therapy 2], and [therapy 3].

OR

The majority of cases of [disease name] are self-limited and require only supportive care.

OR

[Disease name] is a medical emergency and requires prompt treatment.

OR

The mainstay of treatment for [disease name] is [therapy].

OR   The optimal therapy for [malignancy name] depends on the stage at diagnosis.

OR

[Therapy] is recommended among all patients who develop [disease name].

OR

Pharmacologic medical therapy is recommended among patients with [disease subclass 1], [disease subclass 2], and [disease subclass 3].

OR

Pharmacologic medical therapies for [disease name] include (either) [therapy 1], [therapy 2], and/or [therapy 3].

OR

Empiric therapy for [disease name] depends on [disease factor 1] and [disease factor 2].

OR

Patients with [disease subclass 1] are treated with [therapy 1], whereas patients with [disease subclass 2] are treated with [therapy 2].

Surgery

Surgical intervention is not recommended for the management of [disease name].

OR

Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either [indication 1], [indication 2], and [indication 3]

OR

The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either [indication 1], [indication 2], and/or [indication 3].

OR

The feasibility of surgery depends on the stage of [malignancy] at diagnosis.

OR

Surgery is the mainstay of treatment for [disease or malignancy].

Primary Prevention

There are no established measures for the primary prevention of [disease name].

OR

There are no available vaccines against [disease name].

OR

Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

OR

[Vaccine name] vaccine is recommended for [patient population] to prevent [disease name]. Other primary prevention strategies include [strategy 1], [strategy 2], and [strategy 3].

Secondary Prevention

There are no established measures for the secondary prevention of [disease name].

OR

Effective measures for the secondary prevention of [disease name] include [strategy 1], [strategy 2], and [strategy 3].

References

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