June 2015: Post summaries and take home points

Mast cells in wound healing
• When a wound occurs, the complement system is activated to form a clot.
• Complement molecules activate mast cells and induce degranulation.
• Mast cells work to prevent excessive clotting.
• Mast cells break down the extracellular matrix to make room for new cells to close the wound.
• Mast cells drive generation of new blood vessels.
• Histamine and tryptase mediate formation of new muscles.
Angioedema: Part 1
• Hereditary angioedema (HAE) is a heritable blood disorder that causes episodes of protracted swelling that can be life threatening.
• Angioedema is when fluid leaves the bloodstream and gets trapped between the deep dermis and subcutaneous tissue.
• Swells can last up to five days.
• About 30% of HAE patients get a pink ring rash.
• HAE patients do not have hives or itching.
• Swelling can affect any part of the body.
• Swelling of the tongue and throat can cause suffocation.
• Abdominal swells are often misinterpreted as “acute abdomen” requiring surgery.
• 85% of patients have type I.
• 15% have type II.
• Type III cases are rare.
• All three are treated similarly.
• Bradykinin causes blood vessels to dilate, decreasing blood pressure and causing fluid to become trapped in tissues.
• C1 inhibitor (C1INH) regulates the C1 protein, which activates the complement system (for fighting infections), controls formation of blood clots and generation of bradykinin.
Angioedema: Part 2
• In HAE type I, C1 inhibitor (C1INH), C4 and C2 levels are low; C1q is normal.
• In HAE type II, C1INH is normal or a little increased, C4 and C2 are low, C1q is normal; C1INH functions poorly.
• In HAE type III, C1INH is normal and functional; C4 may be normal.
• HAE attacks can cause airway constriction leading to suffocation.
• More than half of HAE patients will experience this type of swelling at least once.
• Swells usually last 2-3 days and then resolve.
• Antihistamines and steroids do not resolve this type of swelling.
• HAE has many triggers in common with mast cell disease, including foods, estrogen level, psychological stress and physical triggers.
• Cinryze, Berinert and Ruconest are C1INH solutions for IV use.
• Kalbitor is a kallikrein inhibitor for SQ injection.
• Firazyr is a bradykinin receptor blocker for injection.
• Medications like danazol and tranexamic acid are seeing less use with several new meds available.
Angioedema: Part 3
• Acquired angioedema (AAE) patients have deficiency of C1 esterase inhibitor (C1INH) that is not due to genetic defect.
• AAE is ten times less common than HAE.
• AAE often presents with low CH50, C2, C4 and sometimes C1q, poorly functioning or low C1 esterase inhibitor (C1INH).
• AAE can occur secondary to many autoimmune and hematologic diseases.
• Type I AAE has poor function of C1INH.
• Type II AAE has autoantibodies to C1INH.
• Idiopathic angioedema is three episodes of angioedema in 6-12 months without a clear reason.
• Type III HAE patients sometimes have mutations in the Factor XII gene, but not all.
• Type III patients have four attacks a year on average.
• Estrogen levels are more likely to induce angioedema in Type III patients than in other types of angioedema.
• Bruising and clotting issues are sometimes seen in type III HAE patients.
Angioedema: Part 4
• Deficiencies of complement molecules C1q, C1r, C1s, C2, C4 are associated with lupus like autoimmune conditions.
• Without these molecules, dead cells and debris cannot be removed and cause local inflammation.
• In HAE types I and II, complement molecules C2 and C4 are low.
• Deficiency in C2 and C4 might predispose to autoimmune disease.
• One study found 13.2% HAE patients had autoantibodies to thyroid.
• 47.5-48% of HAE patients had at least one autoantibody when tested with a panel for several autoantibodies.
• On average, 10% of the healthy population has at least one autoantibody.
• 12% of HAE patients had autoimmune disease when tested with a panel for several autoimmune conditions.
• HAE patients often have a decreased sense of smell.
• HAE patients have increased B cell activation and autoreactive B cells, which contributes to autoimmunity.
Activating the complement system: Classical, alternative and lectin pathways
• The complement system is many proteins that can circulate in the bloodstream.
• Other proteins can cut off pieces of these proteins to activate the proteins.
• Once the proteins are activated, they help kill infecting organisms.
• The classical pathway is activated by C1 protein when microbes are present.
• The alternative pathway is activated by the C3 protein changing into C3b.
• The lectin pathway is activated by two proteins called MBL and ficolin binding to the surfaces of microbes.
• These pathways release C3a and C5a, which activate mast cells.
• C1 inhibitor (C1INH) inactivates C1r and C1s to stop the complement pathway.
Deconditioning, orthostatic intolerance, exercise and chronic illness – Part 6
• Exercise can treat deconditioning due to orthostatic intolerance.
• Exercise can also exacerbate symptoms in deconditioned patients.
• It is worse when coupled with hot weather or eating before exercise.
• A sustained hand grip will raise blood pressure for a short time.
• Performing the hand grip when changing position or after exercising or eating can help mitigate OI symptoms.
• Leg crossing while tensing muscles can also help regulate blood pressure before standing.
• Multiple studies have demonstrated that regular exercise can help manage POTS.
• Recumbent exercise is helpful when starting to work out as it is less likely to trigger OI symptoms.
• Some patients are able to recover significant capability and are able to engage in athletic activities.
• Exercise for chronic fatigue and fibromyalgia patients has also had success in improving deconditioning symptoms and quality of life.
Deconditioning, orthostatic intolerance, exercise and chronic illness – Part 7
• Volume expansion (use of IV hydration or volume expander like dextran) can improve symptoms in deconditioned patients.
• Volume expansion does not improve exercise capacity.
• IV saline with exercise gives the best results for symptom relief.
• Volume expansion can mitigate the effect of heat stress on the body.
• Volume expansion alone stabilized blood supply to the head.
• 86% of POTS patients in a study reported IV saline as the best treatment for brain fog.
• Mast cell degranulation can cause hypotension and vasodilation.
• Mast cell mediator release can cause fluid loss from blood resulting in edema.
• Volume loading in the form of IV fluids may decrease mast cell symptoms due to deconditioning, orthostatic intolerance and capillary leakage.