Coagulation and pharmaconutrition

Coagulation (blood clotting) is a process that prevents excessive bleeding when a blood vessel is injured. Usually, a blood clot dissolves once the injury has healed however sometimes a clot will form inside a blood vessel without any obvious injury and/or may not dissolve naturally.

Vitamin K is commonly associated with the coagulation process however there are other important nutrients including -

Calcium

Important in the activation of several coagulation factors, including -

• facilitating Factor IV binding to phospholipids,
• conversion of prothrombin to thrombin, Factor XIII to XIIIa, and Factor X to Xa,
• activating thromboplastin.

Magnesium

Reduces platelet aggregation and thereby increases time to clotting.

Low magnesium is prothrombotic and increases the risk of thrombosis by stimulating thromboxane synthesis – thromboxane is produced by platelets.

Factor IX requires both calcium and magnesium, as it has specific binding sites for each. The calcium-dependent activation of factor IX via the intrinsic pathway activator factor XIa is accelerated by magnesium.

Magnesium is essential for the activation of vitamin D, and also for its inactivation when levels are too high ie optimal magnesium status is required for optimal vitamin D status.

Magnesium is also essential for the activation of vitamin C.

Vitamin D

Vitamin D both directly and indirectly, affects the coagulation cascade by mechanisms such as -

• downregulating tissue factor (TF) which initiates coagulation activation,
• decreasing platelet aggregation, tumour necrosis factor effects, TNF-α-induced expression, thrombin generation, clot density, fibrinolysis and thrombosis,
• upregulating antithrombin (AT), thrombomodulin (TM), and tissue factor pathway inhibitor (TFPI) expression,
• suppressing NF-κB (Nuclear Factor-κ Beta) activation,
• modulating plasminogen activator inhibitor-1 (PAI-1) and thrombospondin-1 expression in smooth cells.

There is an inverse correlation between vitamin D status and -

• mean platelet volume (MPV),
• development of deep venous thromboembolism (DVT) and unprovoked venous thromboembolism (VTE).

There is a positive correlation between vitamin D status and TFPI level.

Vitamin C

Vitamin C has both pro- and anticoagulatory effects -

Procoagulation

Vitamin C works to lower the plasma levels of nitric oxide.

Anticoagulation

Vitamin C actions include -

• restoring normal platelet function by scavenging Reactive Oxygen Species (ROS) and disrupting the ROS-platelet-activation cycle;
• inhibiting thrombin-induced and P-selectin mediated platelet aggregation and platelet-endothelial adhesion and therefore preventing microthrombus formation;
• inhibiting the pH-dependent thrombin-induced release of plasminogen-activator-inhibitor-1 from platelets;
• inhibiting NF-κB - a transcription factor known to stimulate the production of cytokines, chemokines, leukocyte adhesion molecules.

Copper

Copper is important in the functions of Factors VI and VIII.

A deficiency in copper is associated with reactive thrombocytosis.

Further, either alone and in combination with manganese and/or mercury, copper has been found to adversely affect thrombus formation and consequently potentially increase the risk for thrombotic events in exposed individuals.

Manganese

Can bind to several coagulation cascade components, including laminin, collagen type IV, cellular and plasma fibronectin, plasminogen and fibrinogen.

Vitamin E

Is associated with having indirect anticoagulation properties such as -

• suppressing vitamin K activity – proposed mechanism of action is interference with Vitamin K precursors,
• inhibiting protein kinase C which is important in platelet aggregation,
• inhibiting platelet aggregation, and platelet-mediated thrombus formation,
• decreasing glutamate production – glutamate is required for Factor IX production.

Retinol

Vitamin A and its derivatives (retinoic acid and retinaldehyde) have significant antithrombotic properties through inhibition of thrombin and platelet aggregation.

Omega-3

Omega-3 PUFAs (polyunsaturated fatty acids) exhibit potent antithrombotic effects against -

• platelet activating factors,
• other prothrombotic pathways such as thrombin, collagen, and adenosine diphosphate.

NF-κB can be downregulated by omega-3 fatty acids.

Homocysteine

Homocysteine favours a pro-coagulant state and platelet adhesion.

The effects of homocysteine, directly and indirectly on the coagulation cascade include inducing activation of the coagulation cascade, triggering activation of NF-kB, correlation with interleukin 6 (IL-6), IL-1 receptor antagonist, and fibrinogen, disturbing endothelial function, and reducing thrombus permeability and solubility sensitivity.

Important nutrients in homocysteine formation include – riboflavin, pyridoxine, folic acid, cobalamin, and choline ie inadequate status of any of these results in homocysteine formation.

Clinical Questions

What actions will you initiate when you see someone prescribed medications that negatively impact the status of nutrients associated with the coagulation cascade, will you recommend regular monitoring of –

• coagulation status ie that it does not become dysfunctional?
• status of key nutrients involved in the coagulation cascade?
• prescribed medications that negatively impact nutrients important in the coagulation cascade?

Conclusions

Coagulation is a very intricate cascade that is at risk of disruption from external factors such as prescribed medications with disruption manifesting as either clotting or inability to clot – both consequences can cause significant harm.

Case study

The comments refer to the drug-nutrient, drug-food, and PharmacoNutrition effects only.

Data summary

Medical History with Nutritional Aspect

Biochemistry with Nutritional Aspect

Medications That May Adversely Affect Nutritional Status

Summary of medications, nutrients and transporters

Biochemistry 

Relevant available biochemistry within acceptable ranges.

Glycaemia 

Currently prescribed 2 medications that alter glycaemia, being frusemide and risperidone.

Pharmaconutrition

The side effects profile of Mrs AGJ's prescribed medicines include -

- 5 medications that include nausea.

- 4 medications that include constipation.

- 3 medications that include hyperglycaemia.

Lasix increases urinary excretion of calcium, magnesium, potassium, sodium and thiamine.

Regular monitoring sodium levels recommended whilst mirtazepine prescribed.

Dietary levels of caffeine intake in conjunction with paracetamol inhibit antinocieception.

Concurrent ingestion of paracetamol and iron resulted increased rate of iron absorption and decreased extent of drug absorption; the authors advise drug and iron interventions to be administered at different times from each other.

Bowel management 

- no regular intervention prescribed;

- oral PRN aperient prescribed;

- no Nurse Initiated interventions administered.

Staff comments

Staff advise Mrs AGJ typically consumes toast and drinks at breakfast, quarter main course and half dessert at midday, and unable to advise evening meal intake. A further comment is Mrs AGJ seems to enjoy fruit drinks and milky coffees (half milk + half water).

Observations

Mrs AGJ is a small, slender, pale, colourful lady who was participating in an activity which I interrupted. She told me she has lost her appetite because she is concerned about family matters (a daughters marriage breakup), she has a nasty taste in her mouth, and her wound is getting worse and could also be impacting on her appetite. Mrs AGJ did tell me she likes milk drinks, and usually enjoys her food.

Mrs AGJ is either remaining weight stable or continuing to lose weight.

Pharmaconutrition comments

Mrs AGJ’s diagnoses include chronic pain - nutritional factors that may be useful to consider in pain management include -

   - magnesium – proposed mechanism magnesium blocks the NMDA receptor channels in the spinal cord and thus limits the influx of calcium ie reduces the risk of excitotoxicity and consequent exacerbation of pain. Currently prescribed frusemide which increases magnesium excretion.

UTIs

Mrs AGJ’s diagnoses include UTI - nutritional factors that may be useful to include UTI management include -

   - zinc – recurrent UTIs deplete immune system and consequently zinc status therefore advisable to check zinc status and if low then short term (90-120 days) intervention recommended. Currently prescribed frusemide which increases zinc excretion.

What else would you include?

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The information in this article is provided to support Health Professionals. It is not an exhaustive protocol and Health Professionals are advised that adequate professional supervision is accessed to ensure that Duty of Care obligations with respect to safe administration of medicines is met for each consumer.