Hemostasis and blood calcium regulation

for dental students

1. By, Avaneethram 1 st Yr. PG Dept. of P ediatric dentistry Hemostasis and Blood calcium regulation

2. Contents Introduction Events Pathway I ntrinsic Extrinsic Hemostasis Mechanical Chemical Thermal Calcium regulation Functions Chemical features Hypocalcemia Hypercalcemia Management Conclusion

3. Introduction Hemostasis is the process of forming clots in the walls of damaged blood vessels and preventing blood loss while maintaining blood in the fluid state within the vascular system .

4. Events Vascular constriction Formation of platelet plug Formation of blood clot Growth of fibrous tissue into the clot .

5. Vascular constriction The contraction results from:- Local myogenic spasms Local autacoid factors Nervous reflexes Platelets release T hromboxane-A2 which is responsible for vasoconstriction of smaller vessels . The more severely a vessel is traumatized, the greater the degree of vascular spasm. Mechanism Vasoconstriction is as a result of increased Ca ion conc. in smooth muscles. Hormonal components : Circulating epinephrine & activation of sympathetic nervous system. Interact with cell surface adrenergic receptors Increased intercellular Ca from sarcoplasmic reticulum

6. Factors : Exogenous – temperature (cold) Endogenous- Autonomic nervous system, hormones and mechanisms inherent to vasculature (myogenic response ) Medications: antihistamines, amphetamines, cocaine

7. Formation of platelet plug MECHANISM OF PLATELET PLUG • Platelet adhesion • Platelet activation • Platelet aggregation • Formation of temporary hemostatic plug

8. Platelets are enucleate cells 1-4 micro meters in size Normal blood concentration of platelets is 1.5L-3L/micro liters Formed in bone marrow from megakaryocytes T-1/2 is 8-12 days Eliminated from the circulation by tissue macrophages . Platelet cytoplasm contains active factors such as Actin and myosin molecules Thrombosthenin is another contractile protein which can cause platelets to contract. PLATELETS

9. PLATELET ADHESION AND AGGREGATION The activated sticky platelets stick to each other form Platelet aggregation. • TXA2 powerful vasoconstrictor & mobilization Ca from dense tubular system –activates myosin -actin cause release reaction –Platelet aggregation • This involves a series of self sustaining events • Leads to formation of platelet plug

10. MECHANISM OF PLATELET PLUG Platelet repair of vascular openings is based on several important functions of the platelet itself

11. BLOOD COAGULATION IN RUPTURED VESSEL Third mechanism for hemostasis is formation of blood clot. Clot begins to develop- severe trauma-15 to 20 sec minor trauma-1 to 2 min MECHANISM OF BLOOD COAGULATION

12. GENERAL MECHANISM In response to rupture of the vessel or damage to the blood itself-formation of prothrombin activator. Prothrombin activator catalyzes conversion of prothrombin to thrombin Thrombin catalyzes fibrinogen into fibrin fibers.   Then Fibrin Stabilizing Factor is released from platelets entrapped in the clot. Same thrombin that causes fibrin formation activates the Fibrin Stabilizing Factor, before FSF can have effect on fibrin fibers. Activated FSF forms strong covalent bond b/w monomer of the fibrin and multiple cross linkage b/w adjacent fibrin fibers.

13. BLOOD CLOT The clot is a meshwork Fibrin fibers also adhere to damaged surfaces of blood vessels . CLOT RETRACTION-SERUM Contraction causes expression of fluid from clot-serum Platelet contractile proteins contributes greatly to the clot retraction by activating Platelet Thrombosthenin They also helps compress fibrin mesh work into smaller mass. As the clot contracts, the edges are further pulled together, contributing ultimate state of Hemostasis.

14. VISCIOUS CIRCLE OF CLOT FORMATION Most important cause of this is the proteolytic action of thrombin For instance, thrombin has a direct proteolytic effect on prothrombin itself, hence more of thrombin forms Critical amount of thrombin causes more blood clotting and hence further more production of thrombin and hence called a vicious circle of clotting . INITIATION OF COAGUALTION FORMATION OF PROTHROMBIN ACTIVATOR These mechanisms are set into play by:- Trauma to the vascular wall and the adjacent tissues Contact of the blood with damaged endothelial cells Prothrombin activator is generally considered to be formed in these ways- a) Extrinsic pathway for initiating blood clotting b ) Intrinsic pathway for initiating blood clotting

15. CLOTTING FACTORS

16. Extrinsic and Intrinsic pathway for clot

17. Methods of Hemostasis Mechanical Thermal Chemical

18. Mechanical hemostasis Direct pressure Suture and ligation Gauze pack Ice packs

19. Chemical methods Pharmacological agents Sterile haemocoagulase solution Epinephrine Vitamin k Protamine Desmopressin Lysine analogs Etamsylate Topical hemostatic agent Passive Active

20. Epinephrine Causes direct vasoconstriction Can be applied topically and can be injected with LA Prolong analgesic effect Reduces bleeding during surgery Topical - The drug is applied with the help of gauze pack in concentration of 1:1000 over a oozing It is also injected along with local anesthetics in concentration of 1:80,000 and 1:2,00,000. Vitamin K • Plays important role in coagulation process • Helps in production of fibrinogen and prothrombin in liver • Route- orally and IV(slow) • IM and subcutaneous is not recommended because erratic absorption • Dose- Males: 120 mcg/day PO • Females: 90 mcg/day PO • 5-10 mg IV (dilute in 50 mL IV fluid and infuse over 20 min

21. Protamine • Reverse heparin anticoagulation activity • Adverse effect- anaphylaxis, acute pulmonary vasoconstriction, right ventricular failure • Contraindication -diabetic -pt undergone vasectomy -drug allergy -previous protamine exposure • Dose -1.0 -to- 1.5 mg protamine sulfate IV for every 100 IU of active heparin Desmopressin • Synthetic vasopressin analogues • Stimulates the release of von willibrand factor and factor Viii from the endothelial cells . • Enhances primary hemostasis • Slow iv infusion • Dose- 0.3 µg/kg diluted in 50ml saline and infused i.v over 30 min. • Reduces perioperative bleeding

22. Lysine Analogues • Inhibits the activation of plasminogen • Reduces the conversion of plasminogen into plasmin Epsilon aminocaproic acid- 1-15gm(loading dose) • F ollowed by maintenance dose of 1-2gm hourly • Total dose of 10-30gm • Oral- 500mg , • Inj – 5g/20 ml Tranexamic acid- loading dose 2-7gm • Followed by 20-250 mg hourly • Total dose of 3-10gm • Oral dose; 500 mg 6-8 hrly • Children; 1.25g/5 ml of syrup • Inj- 0.5-1g slow i.v infusion TID Ethamsylate • Reduces capillary bleeding • Increase the ability of platelets to stick together • Dose; 250-500 mg 8 hourly • Contraindication- hypersensitivity and blood porphyria.

23. Topical Hemostatic Agents • Passive - collagen based product - oxidized regenerated cellulose - gelatin • Active - thrombin product - pooled human plasma thrombin - recombinant thrombin

24. Collagen base products • Derived from bovine tendon or bovine dermal collagen • Further divides into – microfibrillar collagen hemostat eg . Avitene, ultrafoam, Instat. Absorbable collagen haemstat sponge eg . Helistat Oxidized regenerated cellulose • Eg. Surgicel, surgicel NU KIT • Absorbable white knitted fabric sheet with high or low density. • It should be use dry. Gelatins • Eg. Gel foam , gel foam plus, surgiform • Absorbable porcine gelatin hemostatic agent • Sponge or powder • Frequently used with saline with thrombin or epinephrine

25. Active Pooled human thrombin • Frozen liquid in vial form • Applied via saturated kneaded absorbable gelatin sponge • Eg. Evithrom Recombinant thrombin • Lyophilized powder in vial form • Used with sterile saline • Should be used within 24hr after reconstitution • Applied with pump or spray or via saturated kneaded absorbable gelatin sponge • Eg recothrom

26. Flowable hemostat agent • Combination of active and passive. • Blocking the blood flow as well as converting fibrinogen into fibrin at the site of bleeding • Combination of buvine gelatin ( Powder in vial form • Spray kit or gelatin sponge • Eg. Thrombin JMI ) and pooled human thrombin • Absorbable porcine gelatin + either of the 3 thrombin types.

27. Part 2

28. Blood Calcium Regulation Regulation of blood calcium concentrations is important for generation of muscle contractions and nerve impulses. calcium levels - High :membrane permeability to Na and membranes become less responsive. - Low :membrane permeability to Na and result in convulsions or muscle spasms. Blood calcium levels regulated by Parathormone Calcitriol Calcitonin

29. Parathormone Increase ca level by mobilizing ca from bone. Bone ca is of two types Rapidly exchangeable ca – small quantity, maintain (exchangeable ca) plasma ca level Slowly exchangeable ca – large quantity, bone (stable ca) remodeling

30. Calcitriol Steroid hormone synthesized in kidney Active form of vit D Increase blood ca by increased absorption from small intestine

31. Calcitonin Hormone by parafollicular cells of thyroid gland Ca lowering hormone Reduces blood ca level by decreasing bone resorption

32. Other Hormones GROWTH HORMONES – increasing intestinal ca absorption increases urinary excretion of ca GLUCOCORTICOIDS – decreases ca level by inhibiting intestinal absorption increased renal excretion of ca

33. Hypocalcemia Decreased secretion of PTH CAUSES Parathyroidectomy Thyroidectomy Autoimmune disease HYPOCALCEMIA AND TETANY Causes neuromuscular hyper excitability results in hypocalcemic tetany. Tetany results when ca level drops below 6mg/dl (normal 9.4mg/dl) When ca level falls below 4 mg/dl it become fatal. Worst affected are the laryngeal and bronchial muscles which leads to respiratory arrest and death.

34. Hypocalcemic Tetany Hyperexcitability of nerves and skeletal muscles resulting in painful muscle spasm(involuntary contraction of muscles or group of muscles ) – feet and hand. Signs and symptoms Hyper-reflexia and convulsion Carpopedal spasm Laryngeal stridor Cardiovascular changes Others decreased cell membrane permeability dry skin with brittle nail hair loss seizures mental retardation in child and dementia in adults

35. Latent or sub clinical tetany Neuromuscular hyperexcitability develops before tetany General weakness and cramp in feet and hand SIGNS Trousseau’s sign Chvostek’s sign Erb sign

36. Hypercalcemia Hypersecretion of PTH 3 types of hyperparathyroidism Primary – due e to tumour on one or more glands Secondary – physiological hypertrophy of gland other pathological conditions like – chronic renal failure - Vit D deficiency - rickets Tertiary – hyperplasia of all gland due to chronic secondary hyperparathyroidism

37. Hypercalcemia Increased plasma ca level SIGNS D epression of nervous system Sluggishness of reflex activity Lack of apatite Constipation Depressive effect of hypercalcemia noted when blood Ca level is increased to 12mg/dl Severe with 15mg/dl Lethal on 17mg/dl Other effects Bone disease : osteitis fibrosa cystic development Parathyroid poisoning : above 15mg/dl both ca and p increases leading ca p crystals p because kidney cannot excrete Ca and p deposits on tubules in kidney, thyroid gland, alveoli, gastric mucosa, and walls of arteries. Ca deposits results in dysfunction of organs In kidney renal stones are formed

38. Management Hypocalcemia severe symptomatic IV 10% ca gluconate 10 ml over 10 minute C ontinuous IV infusion of ca gluconate @ 0.1mmol/kg over 24 hrs. Continuous cardiac monitoring for bradycardia Severe asymptomatic Oral ca supplements @0.2 mmol/kg(max 10mmols or 400mg ca) 4* per day

39. Treatment approach for mild hypercalcemia Patients with asymptomatic or mildly symptomatic hypercalcemia (calcium <12 mg/dL) do not require immediate treatment. However , they should be advised to avoid factors that can aggravate hypercalcemia, including thiazide diuretics, volume depletion, prolonged bed rest or inactivity, and a high calcium diet (>1000 mg/day). Adequate hydration (at least six to eight glasses of water per day) is recommended to minimize the risk of nephrolithiasis. Additional therapy depends mostly upon the cause of the hypercalcemia.

40. Treatment approach for moderate hypercalcemia Asymptomatic or mildly symptomatic individuals with chronic moderate hypercalcemia (calcium between 12 and 14 mg/dL) may not require immediate therapy. It is important to note that an acute rise to these concentrations may cause marked changes in sensorium, which requires more aggressive therapy. In these patients, treatment with saline hydration and bisphosphonates, as described for severe hypercalcemia on next page.

41. Treatment approach for severe hypercalcemia Patients with calcium >14 mg/dL (3.5 mmol/L) require more aggressive therapy . Volume expansion with isotonic saline at an initial rate of 200 to 300 mL/hour that is then adjusted to maintain the urine output at 100 to 150 mL/hour. In the absence of renal failure or heart failure, loop diuretic therapy to directly increase calcium excretion is not recommended, because of potential complications. Administration of salmon calcitonin (4 IU/kg) and repeat measurement of serum calcium in several hours. It can be repeated every 6 to 12 hours (4 to 8 IU/kg). The concurrent administration of zoledronic acid (ZA; 4 mg intravenously [IV] over 15 minutes) or pamidronate (60 to 90 mg over two hours), preferably ZA because it is superior to pamidronate in reversing hypercalcemia related to malignancy .

42. The administration of calcitonin plus saline should result in substantial reduction in serum calcium concentrations within 12 to 48 hours. The bisphosphonate will be effective by the second to fourth day, thereby maintaining control of the hypercalcemia. Additional , more aggressive measures are necessary in the rare patient with very severe, symptomatic hypercalcemia. Hemodialysis should be considered, in addition to the above treatments, in patients who have serum calcium concentrations in the range of 18 to 20 mg/dL and neurologic symptoms but a stable circulation or in those with severe hypercalcemia complicated by renal failure

43. THERAPY DOSE ROUTE MONITOR/COMMENT Normal Saline 200-300 mL/h IV Cardiopulmonary function with examination, central venous pressure and chest radiograph Furosemide 20-80 mg every 2-4 h or 40 mg/h CI IV Serum and urine electrolytes. Replace K, Mg, and PO4 based on serum levels and urinary losses Salmon calcitonin, 4-8 IU/kg every 6-12 h IM/SC Allergic reaction. Give a skin test of 1 IU intradermally before treatment. Effective only during first 48-72 h. Zoledronic acid 4 mg IV over 15 min every 2-4 weeks PRN IV Drug of choice for malignancy-associated hypercalcemia. Caution with chronic kidney disease and myeloma. Cinacalcet 30-90 mg b.i.d.- q.i.d. PO Take with meals. Monitor parathyroid hormone, Ca, and PO4 at least 12 h after dose. Gallium nitrate 200 mg/m2/day CI over 4 h PRN for 5 days IV Avoid in renal failure. Monitor creatinine, PO4, and complete blood count Dialysis. Low or no calcium dialysate Hemodialysis/ peritoneal dialysis Hypercalcemic crisis or refractory hypercalcemia. Useful in renal failure

44. CALCITONIN Safe and relatively nontoxic, Although a relatively weak agent, it works rapidly, lowering the serum calcium concentration by a maximum of 1 to 2 mg/dL (0.3 to 0.5 mmol/L) beginning within four to six hours. It’s most useful with hydration The efficacy of calcitonin is limited to the first 48 hours, even with repeated doses, indicating the development of tachyphylaxis, perhaps due to receptor downregulation. BISPHOSPHONATES They are effective in treating hypercalcemia resulting from excessive bone resorption of any cause. They are more potent than calcitonin and saline for patients with moderate or severe hypercalcemia. Their maximum effect occurs in two to four days, so that they are usually given in conjunction with saline and/or calcitonin, which reduce calcium concentration more rapidly. Bisphosphonates have potential nephrotoxicity

45. Reference Essentials of medical physiology – k Sembulingom Textbook of medical physiology – Guyton and Hall Mark S Cooper, Neil J L Gittoes - BMJ . 2008 Jun 7; 336(7656): 1298–1302. doi : 10.1136/bmj.39582.589433.BE