COVID-19-associated coagulopathy

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Main article: COVID-19

For COVID-19 frequently asked inpatient questions, click here

For COVID-19 frequently asked outpatient questions, click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ifrah Fatima, M.B.B.S[2]

Synonyms and keywords: Hematological findings and COVID-19, hypercoagulability in COVID-19, clotting disorder in COVID-19

Overview

Hypercoagulability is a major complication seen in as many as 31% of patients with COVID-19. It leads to many life-threatening outcomes with pulmonary embolism being the most common thrombotic complication. Fibrinogen and D-dimer levels are elevated. Coagulopathy in COVID-19 must be differentiated from other diseases that cause disseminated intravascular coagulation (DIC). Prophylactic anticoagulation with low molecular weight heparin is given to all inpatients in the absence of active bleeding. Full dose anticoagulation is done in patients with documented and confirmed venous thromboembolism (VTE) .

Historical Perspective

• The etiological agent is 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.
• 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

• To view the classification of COVID-19, click here.

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 which exposes the vWF associated with a massive release of vWF, eventually activating the coagulation cascade.
  • 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.
• Hypercoagulable 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

• Coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus called SARS-CoV-2 and is the cause of thrombocytopenia in COVID-19 infection.

• To view causes of COVID-19, click here.

Differentiating COVID-19 associated coagulopathy from other Diseases

• 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.

• Coagulopathy in COVID-19 must also be differentiated from other diseases that cause DIC resulting in DVT and pulmonary embolism like:
  • Antithrombin III deficiency
  • Factor V Leiden mutation
  • Protein C deficiency
  • Protein S deficiency
  • Prothrombin gene mutation
  • Antiphospholipid antibody syndrome

For further information about the differential diagnosis, click here.

Diseases	Clinical manifestations						Para-clinical findings				Gold standard	Additional findings
	Symptoms			Physical examination
							Lab Findings		Imaging
	Symptoms of DVT	Symptoms of Pulmonary Embolism	Symptoms of Myocardial Infarction	Tenderness in extremities	Edema in extremities	Warmth in extremities	PT	aPTT	Doppler ultrasound	Chest CT scan
Antithrombin III deficiency	+	+	-	+	+	+	Normal	Normal Reduces the Increase in PTT after administration of heparin	Evidence of deep vein thrombosis (DVT) Should be used for diagnosis and follow up	Occlusion of brachiocephalic vein Large thrombus in superior vena cava	Decreased plasma antithrombin (AT III) activity	Nephrotic syndrome Decreased inhibition of factor II and Xa Antithrombin is a natural anticoagulant that is lost in the urine
Factor V Leiden mutation	+	+	+	+	+	+	N/A	↑	Recommended to do weekly Proximal DVT is more commonly observed as compared to distal DVT	Pulmonary embolism	N/A	Inactivates factor Va and factor VIIIa
Protein C deficiency	+	+	-	+	+	+	Normal	Normal / ↑	Hypercoagulation Recurrent venous thromboembolism	Venous thromboembolism Pulmonary embolism	Protein C functional assay ELISA assay: may produce false positive result in cross reaction with rheumatoid factor	Factor VIII elevation in acute phase Functional assay should not be performed if patient is on warfarin Purpura fulminans (skin necrosis) could be a form of presentation Risk of thrombotic skin necrosis following warfarin administration
Protein S deficiency	+	+	-	+	+	+	Normal	Normal / ↑	Hypercoagulation Recurrent venous thromboembolism	Pulmonary embolism Thrombosis of superior mesenteric vein	Protein S free antigen assay	When performing the gold standard test, beware of interference from samples positive for Factor V mutation, protein C deficiency and oral anticoagulants (rivaroxaban) Risk of thrombotic skin necrosis following warfarin administration Suspected in patients with a strong family history of VTE Post phlebitic syndrome Fetal loss
Prothrombin gene mutation	+	+	-	+	+	+	↑	N/A	Proximal DVT is more commonly observed as compared to distal DVT	Pulmonary embolism	Detection of mutation using restriction enzyme and PCR DNA testing for prothrombin G20210A mutation	Mutation causes increased production of prothrombin Increased blood levels of prothrombin lead to venous clots in the circulatory system Hormonal oral contraceptive pills can increase the risk of VTE
Disseminated intravascular coagulation (DIC)	+	+	+/-	+	+	+	↑	↑	Portal vein thrombosis is observed in patients with coexistent hepatitis B	Pulmonary embolism	N/A	Elevated fibrin degradation products (D-dimers) Decreased fibrinogen Decreased factor V and VIII Shistocytes (helmet cells) on peripheral blood smear Portal vein thrombosis
Antiphospholipid antibody syndrome	+	+	+/-	+	+	+	N/A	↑	Increased impedance of flow in uterine arteries at 12-20 weeks of gestation	Pulmonary embolism	Antiphospholipid antibody Anticardiolipin antibody Lupus anticoagulant Anti-β2GPI antibody	Both, arterial and venous thrombosis can occur History of spontaneous abortions False positive VDRL Stroke and transient ischemic attack (TIA) are most common forms of presentation of arterial thrombosis

Epidemiology and Demographics

Incidence

• 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 incidence of 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 incidence of venous thromboembolism (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 venous thromboembolism (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.

To view the epidemiology and demographics for COVID-19, click here.

Age

• There is insufficient information regarding age-specific prevalence or incidence of COVID-19-associated coagulopathy.

Gender

• There is insufficient information regarding gender-specific prevalence or incidence of COVID-19-associated coagulopathy.

Race

• There is insufficient information regarding race-specific prevalence or incidence of COVID-19-associated coagulopathy.

Risk Factors

Common hypothesized risk factors for coagulopathy in COVID-19 pneumonia based on studies include:

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

Other general risk factors for venous thromboembolism (VTE) are:

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

To view the risk factors of COVID-19, click here.

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

• Routine screening with imaging is not done as there is no evidence to indicate an improvement in clinical outcomes.
• 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.

To view screening for COVID-19, click here.

Natural History, Complications, and Prognosis

Natural History

• If left untreated, patients with coagulopathy may progress to develop VTE, arterial thrombosis, or microvascular thrombosis and ultimately succumb to death.

Complications

• Thrombotic complications :
  • Deep Vein Thrombosis
  • Pulmonary Embolism
  • Ischemic stroke
  • Myocardial infarction
  • Ischemic limbs
  • Systemic arterial events
  • Clotting of central venous catheters, dialysis catheters, and dialysis filters

Prognosis

Prognosis depends on numerous factors:

• Increased D-dimer levels- poor prognosis
• Increased fibrin degradation product (FDP) levels
• ICU admission

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

To view natural history, complications, and prognosis of COVID-19, click here.

Diagnosis

Diagnostic Study of Choice

• The diagnosis of coagulopathy in COVID-19 is based mainly on the laboratory findings showing a pro-coagulant profile.
• The pre-test probability of DVT and PE can be calculated using the Wells' criteria
• Computed tomography with pulmonary angiography (CTPA) is the diagnostic test of choice. Ventilation/Perfusion scan may also be done, but may not be of much yield in patients with COVID-19.
• To view the study of choice for diagnosis of COVID-19, click here.
  

History and Symptoms

The symptoms depend on the vessels and the organ systems involved.

Pulmonary Embolism: Many symptoms of PE overlap with the respiratory symptoms seen in COVID-19.

• Maybe asymptomatic
• Dyspnea
• Chest pain
• Cough
• Some other rare presentations include- hemoptysis, shock, hypotension, death.

A positive history of the following is suggestive of and contributory:

• Immobilization or prolonged hospitalization
• Recent surgery
• Trauma
• Obesity
• History of previous venous thromboembolism (VTE)
• Malignancy
• Stroke with hemiplegia or immobility
• Age >65 years

Deep Vein Thrombosis

• Swelling
• Edema
• Pain
• Warmth

Arterial thrombosis involving various systems show the following symptoms:

• Ischemic Stroke: Various focal neurological deficits depending on the large artery involved
• Myocardial infarction: Chest pain radiating to left arm and neck, sweating, dyspnea
• Acute ischemic limb: Pain, pallor, poikilothermia, pulselessness, paresthesia, paralysis

To view the history and symptoms of COVID-19, click here.

Physical Examination

Pulmonary Embolism

Physical examination of patients with Pulmonary Embolism is usually remarkable for:

• Tachycardia
• Tachypnea
• Diaphoresis

Deep Vein Thrombosis

Physical examination of patients with Deep Vein Thrombosis includes:

• Unilateral swelling/edema with a difference in diameters
• Warmth
• Tenderness
• Dilated veins
• Homan's sign may also be seen but is unreliable.

Arterial thrombosis:

• Ischemic Stroke: Focal neurological deficits depending on the vessel involved
• Myocardial Infarction: Uncomfortable appearing patient with diaphoresis
• Ischemic Limb: Pallor, poikilothermia, pulselessness, paresthesia, paralysis

To view the complete physical examination in COVID-19, click here.

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 which includes:
    • 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

To view the laboratory findings on COVID-19, click here.

Electrocardiogram

An ECG may be helpful in the diagnosis of pulmonary embolism or myocardial infarction caused due to hypercoagulability in COVID-19.

• Findings on an ECG suggestive of/diagnostic of pulmonary embolism include tachycardia and S1Q3T3 pattern.
• Findings on an ECG suggestive of/diagnostic of myocardial infarction include STE elevation in various leads.
• To view the electrocardiogram findings on COVID-19, click here.
  

X-ray

• There are no specific x-ray findings associated with PE.
• However, an x-ray may be helpful in ruling out other causes with similar symptoms like pneumonia, cardiogenic causes of dyspnea, and pneumothorax.
• To view the x-ray finidings on COVID-19, click here.
  

Echocardiography or Ultrasound

• Echocardiography may be helpful in the diagnosis of pulmonary embolism.
• Compressive Ultrasound may be helpful in the diagnosis of deep vein thrombosis
• To view the echocardiographic findings on COVID-19, click here.
  

CT scan

CTPA and Ventilation Perfusion(V/Q) Scan

• Prompt diagnosis of PE in COVID-19 patient is difficult in this regard that various symptoms of COVID-19 overlap with that of pulmonary embolism. American Society of Hematology provides the following guidelines regarding the diagnosis of pulmonary embolism:
  • Normal d-dimers level in a patient with low to moderate pretest probability is sufficient to rule out the diagnosis of PE. D-dimers level is usually elevated in COVID-19 patients. This is not applicable to a patient with a high pretest probability.
  • Inpatient with suspected PE with symptoms like hypotension, tachycardia, and sudden drop in oxygen saturation with a high pretest probability of PE, computed tomography with pulmonary angiography is used for the diagnosis. Contraindication to the use of CTPA warrants investigation with ventilation/perfusion scan.

Right-sided segmental and subsegmental pulmonary arterial filling defects (yellow arrows) in keeping with acute distal pulmonary emboli. Case courtesy of Dr Gianluca Martinelli, <a href="https://radiopaedia.org/">Radiopaedia.org</a>. From the case <a href="https://radiopaedia.org/cases/76817">rID: 76817</a>

To view the CT scan findings on COVID-19, click here.

MRI

• There are no MRI findings associated with coagulopathy of COVID-19 unless it is used to diagnose and evaluate an ischemic stroke caused by it.
• To view the MRI findings on COVID-19, click here.
  

Other Imaging Findings

There are no other imaging findings associated with coagulopathy of COVID-19.

Other Diagnostic Studies

• To view other diagnostic studies for COVID-19, click here.
  

Treatment

Medical Therapy

Prophylactic dose of anticoagulation

• Drug- Low-molecular-weight heparin (LMWH) is preferred over unfractionated heparin to reduce contact with the patient.
• Unfractionated heparin may be used in case of unavailability or severe renal impairment.

Indications:

• All inpatients in the absence of active bleeding
• To be held only if platelet counts fall below 25 x 109/L, or fibrinogen less than 0.5 g/L
• In case of a history of heparin-induced thrombocytopenia(HIT), fondaparinux is used.

Intermediate or therapeutic dose anticoagulation

• Preferred regimen: Enoxaparin 40 to 60 mg once daily

Indications:

• Critically ill patients or ICU patients
• According to a study, a better prognosis was seen in patients who met the SIC (Sepsis-induced coagulopathy) criteria or had marked elevated D-dimer levels and were put on anticoagulant therapy(mainly with low molecular weight heparin)

Therapeutic/ full-dose anticoagulation

• Preferred regimen: Enoxaparin 1 mg/kg every 12 hours

Indications:

• Suspected VTE/PE
• Confirmed VTE/PE
• Clotting in catheters, or extracorporeal circuits like ECMO and CRRT.

Post-discharge thromboprophylaxis

• Drug and dose- Regulatory-approved regimen
  • Preferred regimen (1): Betrixaban 160 mg on day 1, followed by 80 mg once daily for 35-42 days
  • Preferred regimen (2): Rivaroxaban 10 mg daily for 31-39 days

Indications:

• Patients with documented venous thromboembolism (VTE) require thromboprophylaxis for up to 90 days after discharge.
• Some patients who do not have VTE but require extended thromboprophylaxis include:
  • Acute medical illness, older age, immobilization, recent surgery, or trauma.
• Most of these criteria are met by patients with COVID-19, and they require thromboprophylaxis for up to 90 days after discharge.

Bleeding in COVID-19

• Transfusion and replacement; discontinuation or reversal of anticoagulation are the mainstay of treatment
• Transfuse platelets if the platelet count is less than 50 x 109/L
• Administer plasma if the INR is above 1.8
• Order fibrinogen concentrate or cryoprecipitate if the fibrinogen level is less than 1.5 g/L

• To view medical treatment for COVID-19, click here.

References

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