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Transcript of Haemostasis
a process which causes bleeding to stop, meaning to keep blood within a damaged blood vessel .
(the opposite of hemostasis is haemorrage) History of Artificial
Hemostasis: The origin of Hemostasis dates back as far as ancient Greece; first referenced to being used in the battle of troy . It started with the realization that excessive bleeding inevitably equaled death. Vegetable and mineral styptics were used on large wounds by the Greeks and Romans until the takeover of Egypt around 332BC by Greece. At this time many more advances in the general medical field were developed based off the study of Egyptian mummification practice, which led to greater knowledge of the hemostatic process. Mechanism of haemostasis : - Blood
coagulation Vascular Spasm Platelet plug formation Vascular spasm :-
Damaged blood vessels constrict . Vascular spasm is the blood vessels first response to injury. The damaged vessels will constrict (vasoconstrict) which reduces the amount of blood flow through the area and limits the amount of blood loss
Contraction of the vessel results :-
1) Pain .
2) Local myogenic spasm
3) Release of local factors from traumatized tissue & platelet .
This response lasts for many minutes or even hours …….. As more chemicals are released more platelets stick and release their chemicals; creating a platelet plug and continuing the process in a positive feedback inhibition .
It lasts from 2-5 minutes .
There is a member of a class of pharmaceutical that decrease platelet aggregation and inhibit thrombus formation. They are effective in the arterial circulation, where anticoagulants have little effect. ( anti platelets ) Blood coagulation :- Clots form upon the conversion of fibrinogen
to fibrin, and its addition to the platelet plug
Coagulation or blood clotting uses fibrin threads that act as a glue for the sticky platelets . Von willebrand disease :- is associated with a defect in the ability of the body to create the platelet plug and the fibrin mesh that ultimately stops the bleeding. New research is concluding that the von Willebrand disease is much more common in adolescence. This disease negatively hinders the natural process of Hemostasis causing excessive bleeding to be a concern in patients with this disease. There are complex treatments that can be done including a combination of therapies, estrogen –progesterone preparations, desmopressin , and Von Willebrand factor concentrates. Platelet plug formation :- Platelets adhere to damaged endothelium to form platelet plug . they stick together (aggregation) to form a plug that temporarily seals the break in the vessel wall.
As platelets adhere to the collagen fibers of a wound they become spiked and much stickier. They then release chemical messengers such as:
Adenosine diphosphate ( ADP ) and thromboxane A .
These chemicals are released to cause more platelets to stick to the area 7-haemophilia by: Mohammed Ahmed 840 What is haemophilia? Haemophilia is a group of hereditary genetic disorders that impair the body's ability to control blood clotting or coagulation, which is used to stop bleeding when a blood vessel is broken. Haemophilia A (clotting factor VIII deficiency) is the most common form of the disorder, present in about 1 in 5,000–10,000 male births.Haemophilia B (factor IX deficiency) occurs in around 1 in about 20,000–34,000 male births.
Haemophilia lowers blood plasma clotting factor levels of the coagulation factors needed for a normal clotting process. Thus when a blood vessel is injured, a temporary scab does form, but the missing coagulation factors prevent fibrin formation, which is necessary to maintain the blood clot. A haemophiliac does not bleed more intensely than a person without it, but can bleed for a much longer time. In severe haemophiliacs even a minor injury can result in blood loss lasting days or weeks, or even never healing completely. In areas such as the brain or inside joints, this can be fatal or permanently debilitating Types of haemophilia The most abundant types of haemophilia are : A & B
Sufferers of haemophilia A are lacking in clotting factor VIII and represent 90% of all those affected by haemophilia. Haemophilia B sufferers are lacking in clotting factor IX. Both lead to inhibition of the intrinsic coagulation pathway . There are three levels of severity; mild, moderate or severe.
70% of haemophilia A sufferers have severe haemophilia and they will have less than 1% of the right amount of clotting factors. A sufferer of moderate haemophilia will have 1% - 5% of clotting factors and again there may be few obvious signs when young. Mild haemophilia represents having 5% to 40% of the usual amount of clotting factors.
It may take years for symptoms to appear, for example after an accident, surgery or major dentistry. Haemophilia from a genetic attitude: Haemophilia is an inherited X-linked recessive condition. The gene that causes haemophilia is carried by women and is passed on through the female line in the family. Males have the condition, and the gene that causes it is carried by women.
The genes responsible for clotting factors VIII and IX are found on the X chromosome. If the mother carries the haemophilia gene and the father does not have haemophilia: A male child will have a 50:50 chance of having haemophilia. A female child will have a 50:50 chance that she will carry the haemophilia gene.
: If the father is affected by haemophilia and the mother is not a carrier
A female child will be a carrier (she is known as an obligate carrier).
male child will not be affected by the haemophilia gene and cannot pass haemophilia onto his future children. Signs and Symptoms Bleeding into muscles and joints, especially the knees, elbows, and ankles
Prolonged bleeding after a cut, tooth removal, surgery, or an accident.
Serious internal bleeding into vital organs, most commonly after a serious trauma Bleeding in the joints is the most common problem.
The symptoms of a joint bleed are as follows:
Tightness in the joint with no real pain.
Tightness and pain before any bleeding
Swollen and hot to touch, hard to move
All movement lost, severe pain
Bleeding slows after several days when the joint is full of blood
There can be disabling arthritis if this is not treated.
Bleeding in the brain can lead to very serious complications after only a single bump. Signs and symptoms include:
Changes in behaviour
Convulsions or seizures Treatment : The main treatment for Haemophilia A and B is factor concentrate therapy. This is either given as a prophylaxis therapy (‘preventative’) or ‘on-demand therapy’, (stopping bleeding when it occurs). There is no way of permanently increasing or replacing the clotting factors.
For those affected by severe and moderate haemophilia A, clotting factor is given regularly to try to prevent bleeds, pain and joint damage. Those affected by haemophilia B, treatment is usually given twice a week. Children often use factor concentrate more quickly, therefore need more regular injections. However, injection with purified clotting factors is very expensive The amount of replacement therapy required depends on the type of Haemophilia, age, the site and severity of bleeding, weight and whether or not the person has developed the antibody that neutralises or knocks out the activity of the clotting factors. These antibodies (inhibitors) develop in 20% of individuals affected with haemophilia A but just 1% of individuals affected with haemophilia B.
somedrugs must be avoided. For example, aspirin (and drugs containing aspirin) cannot be used, nor salicylates, ibuprofen and other nonsteroidal anti-inflammatory drugs, eg naproxen History of haemophilia: The first medical professional to describe a disease was Abulcasis. In the tenth century he described families whose males died of bleeding after only minor traumas The term "haemophilia" is derived from the term "haemorrhaphilia" which was used in a description of the condition written by Friedrich Hopff in 1828, while he was a student at the University of Zurich. In 1937, Patek and Taylor, two doctors from Harvard, discovered anti-haemophilic globulin Haemophilia has featured prominently in European royalty and thus is sometimes known as "the royal disease". Queen Victoria passed the mutation for Haemophilia Bto her son Leopold and, through some of her daughters, to various royals across the continent, including the royal families of Spain, Germany, and Russia. By: Mohammed El-Sakhawy 1-Introduction : by: Mohammed Mohsen 6- Haemostatic disorders Hemostasis disorders Blood clotting one of the nature's most fantastic creations but it sometimes goes wrong.
There are two major disorders of hemostasis:-
1-Bleeding disorders arise from abnormalities that prevent normal clot formation .
2-Thromboembolic disorders result from conditions that cause undesirable clot formation. 1-Bleeding disorders There are 2 major disorders :-
1-Inherited disorders e.g. vonwillebrand disorders and hemophilia.
2-Acquired disorders e.g.
, vascular disorders and
disseminated intravascular disorders. 1-Inherited disorders the most common hereditary bleeding disorder is von willebrand , found in up to 1% of the general population.
Von Willebrand disease is caused by a deficiency of von Willebrand factor(help the platelets to clump together) .
Symptoms :- abnormal menstrual bleeding,gums bleeding and skin rash
( increase vWF) 2- Acquired disorders:- Thrombocytopenia Low number of platelets in blood .
Decreased production , increased destruction and increased splenic sequestration( capturing )
1-Idiopathic thrombocytopenia purpra.
2-Thrombotic thrombocytopenia purpra. 2- Thromboembolic disorders blood clots form in blood vessels. They may travel through the bloodstream and block an artery.
Increase platelet function results in platelet adhesion, formation of platelet clot and disruption of blood flow
If a blood clot is detected, heparin (an anticoagulant) is started without delay. Then warfarin is helpful in moderate risk . Disseminated intravascular coagulation DIC leads to the formation of small blood clots inside the blood vessels throughout the body. As the small clots consume coagulation proteins and platelets.
Conditions associated with (DiC):-
Severe transfusion reactions, Rheumatologic illness,
hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, Vascular
abnormalities, Severe hepatic failure,
heat stroke/hyperthermia. 5- Regulatory mechanisms of hemostasis by: Mohammed Abdel Dayem The contents: 1 . Introduction to the regulation .
2 . Classification of the regulatory mechanisms : a) system 1 anti-thrombin III .
b) system 2 protein C . clotting should take place to stop bleeding, but too much clotting would obstruct vessels and interfere with normal circulation of blood
Clots do not usually form in intact vessels because the endothelium . When the blood vessel was cut or injured, there was a homeostatic response to maintain the internal environment constant by reducing the blood out flow. This was to keep the normal amount of blood from being lost so as not to disturb the normal blood pressure and therefore the tissue oxygenation.
Regulation takes place at the level of the third step of the homeostatic response [ blood coagulation ] as it concerns the cascade of reactions that activate certain mediators . Similarities between system I and II
The nearby endothelial cells lining the wall of the cut vessel must be intact.
Availability of certain activator substrates [Heparin for I and thrombomodulin for II].
Performing a feed-back inhibition of coagulation cascade.
The blood undergoes either of them to regulate blood clot formation [same target]. The blood – Heparin level is normally low.
Mast cells of both blood [basophiles] and connective tissue [lying deep to the endothelial lining layer = at the sub endothelial tissue] start to secrete Heparin molecules from their dense granules.
These secreted molecules are liberated into the blood stream to reside on the surface on the nearby intact endothelial cells. By itself, it has little or no anticoagulant properties.
when it combines with antithrombin III, the effectiveness of antithrombin III for removing thrombin increases by a hundred fold to a thousand fold, and thus it acts as a natural anticoagulant.
In the presence of excess heparin, removal of free thrombin from the circulating blood by antithrombin III is almost instantaneous. This system is faster in case of presence of Heparin. System 2 : protein c Protein c is a plasma protein synthetized in the liver, entering the circulation, running toill the site of the cut and acting as an anti-coagulant Thrombin-thrombomodulin complex causes production of more plasmin .
This high level of plasmin is due to inactivation of the inhibitor of the tp-A .
The plasmin is a proteolytic enzyme that causes destruction of thrombin and other clotting factors Clotting factors .Identified by Roman numerals in order of discovery
Letter "a" is used to denote activation of a factor Factor
Fibrin stabilizing factor Production of clotting factors All of the clotting factors are synthesised in the liver except :-
1- factor III in tissues
2-factor IV comes from diet
3- factor VIII comes from Megakaryocytes and endothelial cells Classification of clotting factors according to their proprieties 1- Contact group a- Not consumed during coagulation
b- Present in serum and plasma
e.x. :- Factors XI, XII 3- Vitamin K dependent group a-Vitamin K is needed for synthesis which takes place in the liver
b- Not consumed during coagulation
c- Present in serum & plasma
e.x. :-Prothrombin, factors VII, IX, & X Role of clotting factors in formation of the blood clot 2-Clotting factors by: Mohammed saeid 9-anti coagulant in vitro by: Mohammed Mostafa Blood always clot in a short time when it is out of the body so we wont be able to make experiments or tests on this blood. So we use anticoagulants to prevent coagulation.
We use siliconized containers which is able to prevent blood coagulation for more than 1 hour. Siliconized containers prevent contact activation of platelets and factor XII( The major factors of intrinsic pathway).
Major used anticoagulants invitro:
5-Flouride EDTA(ethylenediaminetetraacetate): Its polyaminocarboxylic acid which was described by Ferdinand Munz.
Today it is synthesized from
sodium cyanide, formaldehyde and ethylenediamine. This result of sodium EDTA which is reduced to give us EDTA. Its polyaminocarboxylic acid which was described by Ferdinand Munz.
Today it is synthesized from
sodium cyanide, formaldehyde and ethylenediamine. This result of sodium EDTA which is reduced to give us EDTA. Citrate: it is mild chelating agent used
Mainly in the form of sodium citrate.
It has the same mechanism of EDTA as it binds to calcium ions preventing blood coagulation.
Citrate is used for tests of blood platelets as it causes less enlargements in MPV than EDTA. Heparin: It is a highly sulphated glycosaminoglycan.
Heparin can be used invivo as well as invitro coagulant.
Heparin binds to antithrombin III making it active by causing it conformational change that increase the activity of Anti thrombin III(inhibit factor II and Xa). oxalate oxalate binds to calcium ions
Which result in formation of insoluble precipitate (sodium oxalate).
Sodium oxalate is responsible for most of kidney stones. fluoride: Flouride is a member of halides.
It binds to calcium ions so it prevents blood coagulation.
Time and temperature have an effect on blood clot formation as increasment of time leads to clot formation.
When we increase the teperature the clot is formed faster. References:
1-guyton (2006), unit VI, chapter 36, page 466 and 467.
2 - http://www.clinchem.org/content/50/1/256.full
3- Hematology, Volume 11, Numbers 5-6, October/December 2006, pp. 317-319(3)
6- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1541764/ Vitamin K Introduction:
Vitamin K is a fat-soluble vitamin
Two natural forms:
Phylloquinone (vitamin K1) is the major form found in plant foods
Menaquinone (vitamin K2) is synthesized by the intestinal bacteria
Vitamin K3 is a synthetic, watersoluble form
Daily recommendations: 70-140 microgram per day. Vitamin K Physiological Role Activate clotting factors and endogenous anticoagulants
Cofactor in carboxylation of (Glu) of 12 proteins forming γ-carboxy glutamic acid (Gla)
Activate vitK-dependent Gla-proteins
Vitamin K-Dependent Gla-Protein:
Matrix Gla-protein (MGP) is the strongest inhibitor of tissue calcification
Osteocalcin after its carboxylation is able to bind calcium forming the bone matrix Anticancer Properties of Vitamin K Vit k signals damaged cells that might multiply into a tumor to begin apoptosis.
Vitamin K also triggers a DNA-degrading protein that cancer cells normally suppress. Causes of Vit K Deficiency: A diet with high intakes of salicylates Antibiotics (destroy beneficial int. bact.) Anticoagulants like Warfarin block Vit k Abnormal fat absorption (shortage of bile) In adults In newborns The intestinal tract is sterile Breast milk contains only 20% of the RDA Impairment of liver functions Deficiency Symptoms of Vit K Easy bruising Epistaxis Bleeding gums Vitamin K deficiency results in impaired blood clotting and prolonged coagulation time.
Symptoms: Blood in urine/stools Heavy menstrual bleeding 8-Vit k by : Mohammed koraym General view of blood coagulation By : mohamed mahmoud ibraheem .
Seat no. : 835 In this topic we will talk about:
1 . General mechanism of blood coagulation .
2 . conversion of Prothrombin to thrombin .
3 . Conversion of fibrenogen to fibrin .
4 . Initiation of blood coagulation . Blood coagulation : General mechanism of
1 . Formation of prothrombin activator .
2 . Conversion of prothrombin to thrombin .
3 . Conversion of fibrinogen to fibrin . Conversion of prothrombin to thrombin 1 . Prothrombin an alpha2-globulin & normal level is 15 mg/dl
2 . It is synthesised by liver .
3 . The role of vit .k . Conversion Fibrenogen to fibrin . 1 . Normal level >>> 100:700 mg/dl .
2 . Synthesized in liver .
3 . Pathologically coagulation of interstitial fluid.
Action of Thrombin on Fibrinogen to Form Fibrin.
1 . Formation of fibrin threads .
2 . Polymerization of fibrin monomers .
3 . Fibrin stabilizing factor .
4 . Clot retraction serum .
5 . Fate of the tissue . Initiation of blood coagulation 1 . When does blood clot form ??
2 . Prothrombin activator in senthesized by:
a) extrinsic pathway .
b) intrisic pathway . Lysis of blood clot Introduction :
Blood coagulation is the formation of an insoluble threadlike protein called fibrin.
Fibrin blood clots are ultimately dissolved in order to restore vascular patency. The enzymes involved are part of the fibrinolytic system.
The central component in the fibrinolytic system is the glycoprotein plasminogen. Plasminogen after partial cleavage by a plasminogen activator is converted to its active and form, plasmin. Its primary target is fibrin , it also degrades factors V, VIII .
The generation of plasmin occurs preferentially on the fibrin surface, which offers binding sites for plasminogen and its principle activator in blood. Plasminogen :
Human plasminogen is a single-chain glycoprotein containing 791 amino acid residues and 2% carbohydrate.
The plasminogen molecule contains a total of six structural domains .
The N-terminal portion of the molecule consists of five domains with the capacity to bind to fibrin. Plasminogen activators :
Plasminogen activators can be divided into two groups: endogenous activators (t-PA and u-PA), present in blood and other body fluids, and exogenous activators (e.g. streptokinase).
Tissue-type plasminogen activator (t-PA) : It is produced as a single-chain molecule by the vascular endothelial cells and is secreted into the plasma continuously or by an acute release reaction following stimulation of certain endothelial cell receptors.
Urokinase-type plasminogen activator (u-PA) : is mainly produced in the kidneys as an inactive single-chain molecule . u-PA has its major function in tissue-related proteolysis. 2) Exogenous :
Streptokinase (SK) is an exogenous plasminogen activator , derived from streptococci bacteria.
It is not an enzyme and functions by forming a complex with human plasminogen . This complex can function as an activator of other plasminogen molecules. Fibrinolytic system inhibitors :
The plasminogen activator inhibitors are PAI-1,which is synthesized in endothelial cells, adipocytes, and the liver; PAI-2, which is synthesized in placenta, monocytes, and macrophages; and PAI-3, which is identical to the protein C inhibitor .
The physiologically important inhibitor of plasmin is the liver-synthesized antiplasmin. 5-Fibrinolytic therapy
Fibrinolytic therapy involves the use of special drugs that work to break up blood clots that are blocking a major artery. In the event of a heart attack, the use of finbrinolytic agents could save a life. The best outcome for a heart attack victim occurs if fibrinolytic therapy is administered within 12 hours or less after the onset of symptoms. The efficiency of the fibrinolytic drugs depend on the age of the clot.
It is important to remember that fibrinolytic therapy is not without risks. All of these drugs have a high risk for causing severe bleeding. Anticoagulants In Vivo Definition: It is a substance that prevents coagulation (clotting) of blood and can be used as a medication for thrombotic disorders.
There are two types of anticoagulants :
Parenteral : heparin , Low molecular weight heparin and fondaparinux
Oral : Coumarins as Warfarin Heparin: Heparin is a highly sulfated GAG and has very high negative charge.
Heparin is usually stored within the secretory granules of mast cells and released only into the blood vessels at sites of injury.
It’s action is immediate .It works by activating heparin co-factor (antithrombin III). Which inactivates several clotting factors e.g: XIIa , XIa , Xa , IIa and XIIIa.
Intravenous and Subcutaneous administration.
Intramuscular injection is contraindicated.
Heparin is not absorbed when given oraly. Low Molecular Weight Heparins : Consist of short chains of polysaccharide they are obtained by various methods of fractionation or depolymerisation of heparin.
Examples : Certoparin , Dalteparin ,Enoxaparin , Nadroparin.
Mechanism of action :
LMWH act mainly on factor Xa .
Antithrombin III is the major plasma inhibitor of coagulation proteases . LMWHs inhibit the coagulation process through binding to AT . This binding leads to a conformational change of AT which accelerates its inhibition of thrombin (factor IIa) and activated factor X (factor Xa). Once dissociated, the LMWH is free to bind to another antithrombin molecule and subsequently inhibit more thrombin. Difference between heparin and LMWH : LMWH causes less bleeding than heparin .
No need for monitoring of the PTT coagulation parameter as required for high dose heparin.
Smaller risk of osteoporosis in long-term use.
Smaller risk of HIT.
Only subcutaneous. Adverse Effects : Bleeding either local at site of injection or systemic.
HIT but less common than unfractioned heparin.
It is related chemically LMWH
It is given subcutaneously .
It's advantage is that the risk for thrombocytopenia is much lower. Oral Anticoagulants :(Coumadins) Mechanism Of Action Of Warfarin :
It interferes with the formation of prothrombin II and other clotting factors VII , IX and X. During the formation of these clotting factors in the liver , Vitamin K is converted into an inactive form called epoxide form , which is then reduced to active form by an enzyme called epoxide reductase . Since warfarin is structurally similar to vitamin k , therefore it acts as competitive inhibitor of this enzyme and thus decreases the active form of the vitamin that form the clotting factors. Control Of Therapy : Prothrombin time (PT) : adjust the dose so that PT is double the normal value .
International Normalized Ratio (INR) : Dose is adjusted so that INR is 2 .
Adverse Effects :
Hemorrhage : If the INR is out of range (due to accidental or deliberate overdose )and may cause hemoptysis (coughing up blood), bleeding from nose or gums, or blood in urine or stool.
Contraindicated in pregnancy, as it may cause bleeding in the fetus, spontaneous abortion , warfarin are also teratogens
Drug Interaction : This may affect the anticoagulation effect by increasing or decreasing it. Other Oral Anticoagulants are : Phenindione which functions as a vitamin k antagonist.
Atromentin which is an similar in biological activity to heparin , possesses antibacterial activity and smooth muscle stimulant .It also induces apoptosis in human leukemia cells. Control of therapy: The heparin dose is changed so that the PTT result is about 2 times the normal value .
Side Effects :
Heparin Induced thrombocytopenia (HIT)
Antidote to Heparin Overdose: