【Covid-19】Drug for thrombosis in COVID-19: Western medicine & a TCM Prescription

This blog brief introduces some drugs and a TCM prescription that can be used in thrombosis treatment. 

Contents:

0. Preface / Revision

1. Thrombin Activation Inhibitor

2. Platelet Activation Inhibitor

3. TCM Prescription

4. References

0. Preface / Revision

As mentioned in 【Covid-19】Causes & mechanisms that promote thromboinflammation in COVID-19, there are 5 ways leads to thromboinflammation in Covid-19 patients, which are:

    a. Excessive ANG II

    b. Elevated Levels of Tissue Factor (TF)

    c. PAR Signaling

    d. Formation of Neutrophil Extracellular Traps (NETs)

    e. Purinergic signaling

 (There are other factors, but I only focus on these 5 ways.)

The main idea to treat thrombosis is to anticoagulant. Therefore, based on these mechanisms, treatment can be focused on thrombin and platelet activation inhibitors. The subdivision can be divided into:

Thrombin Activation Inhibitor including:

• Thrombin inhibitors
• Factor Xa inhibitors
• Recombinant protein C and inhibition of thrombin formation
• Inhibition of factor Xa, tissue factor

Platelet Activation Inhibitor including:

• PAR 1 Inhibitor
• P2Y12 Inhibitor
• GPIIa/IIIb (Integrin α2bβ3) Inhibitor

1. Thrombin Activation Inhibitor 

1a. Direct Thrombin inhibitors

Oral agent: Dabigatran (Pradaxa)

Parenteral agent: Argatroban, Bivalirudin (Angiomax), Desirudin (Iprivask) and Lepirudin (Refludan).

    * Parenteral agent is any non-oral means of administration. Generally, it refers to injection.

All of them can reversibly bind to the active site on the thrombin molecule, which eventually leads to the inactivation of fibrin (factor I) and directly prevents blood clots.

Direct Thrombin inhibitors mechanism

Risk / Disadvantages?

Dabigatran (Pradaxa):

• Pill big and hard to swallow. 
• can’t crush the pill as it will damage the drug
• Hard to reserve
• Must stay in original container or blister pack with a special desiccant (干燥剂) 
• to absorb all the moisture to avoid the drug from degrade or break down
• Only four months validity
• Side effects include:
• Dyspepsia
• an uncomfortable feeling in the upper middle part of your stomach area
• Dysmobility
• muscles of the digestive system become impaired
• Gastroesophageal reflux: acid reflux
• Bleeding

Argatroban

Side effect includes:

• Bleeding
• Chest pain
• Genitourinary tract: Urinary tract infection and abnormal kidney function
• Genitourinary tract includes kidneys, bladder, fallopian tubes, and penis.
• Hemorrhage
• GI side effect: Diarrhea, vomiting, infection and abdominal pain

Bivalirudin (Angiomax)

Side effect includes:

• Bleeding
• Hypotension 低血压
• Pain 
• Headache
• Nausea

Desirudin (Iprivask)

Side effect includes:

• Bleeding
• Deep vein thrombosis
• Nausea 

1b. Direct Factor Xa inhibitors

Oral agents: Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa) and Betrixaban (Bevyxxa). 

These inhibitors prevent the activation of factor X.

Direct Factor Xa inhibitors mechanism

Risk / Disadvantages?

Rivaroxaban (Xarelto):

• Back pain
• bleeding gums
• bloody stools

Apixaban (Eliquis):

• Blood in the eyes
• blood in the urine
• Confusion

Edoxaban (Savaysa):

• Bloody nose
• heavy non-menstrual vaginal bleeding
• pale skin

Betrixaban (Bevyxxa):

• Bloody nose
• heavy non-menstrual vaginal bleeding
• unusual tiredness or weakness

1c. Restoration of protein C activation and inhibition of thrombin formation

Parenteral agent: Drotrecogin alfa (activated)

As we concern, Factors Va and VIIIa are accelerators to coagulation, while protein C and S are the brake on coagulation.

Drotrecogin alfa activated human protein C. Therefore, protein C and protein S suppress coagulation thus they block the thrombin formation.

Protein C pathway show in blue colour

Risk / Disadvantages?

Drotrecogin alfa (activated):

• Blood in urine 
• Couching out blood 

1d. Inhibition of factor Xa, tissue factor

Parenteral agent: Tifacogin (recombinant TFPI)

Tifacogin, a recombinant TFPI expressed in Saccharomyces cerevisae, inhibits factor VIIa in a factor Xa-dependent fashion.

Factor VIIa and tissue factor are the prerequisites to activate factor Xa, which enter the intrinsic pathway.

Inhibition of factor Xa, tissue factor

Risk / Disadvantages?

Tifacogin:

• had been tested in Phase 3 clinical trials for sepsis but has not been approached by FDA
• Side effects: Increase the risk of bleeding

2. Platelet Activation Inhibitor

2a. PAR 1 Inhibitor

Oral agent: Vorapaxar and Atopaxar 

PAR1 Inhibitors or antagonists bind to PAR1 receptors to prevent receptor activation. Without the receptor, platelet not activated, therefore stopping occlusive thrombus from occurring

Risk / Disadvantages?

risk Vorapaxar: Increase the risk of bleeding

2b. P2Y12 Inhibitor  

Oral agents: Clopidogrel, Prasuragel, Ticagrelor 

Parenteral agent: Cangrelor

Purinergic signaling via ADP is a key mechanism for platelet activation.

Related receptors are P2Y12 and P2Y1.

P2Y12 belong to Gi class of GPCR, which inhibits cAMP pathway, ultimately causes activation of Gp2b 3a complex, which is fibrinogen receptor.

Without activation of P2Y12, the follow-up process will not happen. Therefore, there is no coagulation occurs.

Risk / Disadvantages?

Clopidogrel: 

• Irreversible P2Y1 receptor binding (non-competitive inhibitor) 
• Causes bleeding 
• Causes rash or sensitivity reaction 
• Causes Thrombotic Thrombocytopenic Purpura (TTP) 

* TTP: disorder that causes blood clots (thrombi) to form in small blood vessels 

--Serious: if block vessels and restrict blood flow to organs such as the brain, kidneys, and heart.

Prasuragel: 

• Irreversible P2Y1 receptor binding
• More risk of bleeding 

Ticagrelor: 

• Shortness of breath 
• Allergy 
• Bleeding 
• Ventricular pause 

Cangrelor:

• Abdominal or stomach pain or swelling
• back pain
• black, tarry stools

2c. GPIIa/IIIb (Integrin α2bβ3) Inhibitor

Parenteral agent: Abciximab, Tirofiban, Eptifibatide,​

As we know, GPIIa/IIIb complex is a fibrinogen receptor. It binds the platelet together via fibrinogen to form a nice platelet plug. This leads to thrombosis. 

These GPIIa/IIIb inhibitor inhibit platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets.

Gp2b 3a complex bind the platelet together via fibrinogen

Risk / Disadvantages?

Abciximab:​

• Irreversible​
• Used with heparin and aspirin as adjunct to PCI for the prevention of cardiac ischemic complications
• Side effects: Bleeding, Thrombocytopenia​

*Thrombocytopenia​: blood platelet count is low.

(Platelet also known as thrombocytes.)

Tirofiban & Eptifibatide:​

• Allergy​ (Tirofiban)
• Bleeding ​
• Thrombocytopenia​
• Renal Insufficiency ( Eptifibatide)

3. TCM Prescription

From the TCM aspect, thrombosis is due to deficiency of Qi and blood stasis, which leads to obstruction of veins and collaterals. Hence, Bu Yang Huan Wu Decoction which is able to supplement qi and activate blood, can be used in thrombosis treatment.

However, it is important to note that TCM doctors should be giving treatment based on syndrome differentiation.

Astraglus Root (黄芪), Angelica Sinensis (当归), Red Peony Root (赤芍), Chuanxiong Rhizome (川芎), Peach Kernel (桃仁), Safflower (红花), Earthworm (地龙)

Herbs in Bu Yang Huan Wu Decoction 补阳还五汤:

Sovereign 君: Astraglus Root (黄芪)---------120g

• Sweet and warm properties: 
• Strengthening primordial qi
• Promoting qi and blood circulation
• Removing blood stasis and removing collaterals

Minister 臣: Angelica Sinensis (当归)----------6g

• Sweet and pungent properties:
• Activating blood flow and eliminating blood stasis
• Nourish blood

Assistant 佐:

a. Red Peony Root (赤芍)----------4.5g

• Activating blood flow
• Dissipating blood stasis and relieve pain

b. Chuanxiong Rhizome (川芎)----------3g

• Reducing platelet activity and inhibiting aggregation of platelets

c. Peach Kernel (桃仁)----------3g

• Reduce blood viscosity

d. Safflower (红花)----------3g

• Can dredges the meridians 

All of the assistant herbs help Angelica Sinensis (当归) activating blood flow and eliminating blood stasis

Assistant and Courier 佐使: Earthworm (地龙)--------3g

• Unblock collateral and introduce the power of other medicines in the veins.

*Sovereign, minister, assistant and courier are the ingredients in a formula or prescription that have

different roles.

• Sovereign medicinal 君药: 
• the ingredient that provides the principal curative action on the main pattern/syndrome or primary symptom
• Minister medicinal 臣药:
• the ingredient that helps strengthen the principal curative action
• Assistant medicinal 佐药:
• the ingredient that treats the combined pattern/ syndrome, relieves secondary symptoms or tempers the action of the sovereign ingredient when the latter is too potent
• Courier medicinal 使药:
• the ingredient that directs action to the affected meridian/channel or site

4. References

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