Coagulation and Hemostasis - Part 2 PDF

‫‪Coagulation and Hemostasis‬‬ ‫‪Part 2 – Secondary Hemostasis‬‬ ‫تفريغ مالك عبد الرازق‬ ‫حتاليل طبية‬ ‫الله...

‫‪Coagulation and Hemostasis‬‬ ‫‪Part 2 – Secondary Hemostasis‬‬ ‫تفريغ مالك عبد الرازق‬ ‫حتاليل طبية‬ ‫اللهم بارك لي ف وقتي ‪ ,‬وال حترمني جهدي ‪ ,‬وال ترد دعوتي ‪ ,‬وعافني ف بدني ‪ ,‬وأصلح لي شأني ‪ ,‬وأشرح لي صدري ‪,‬‬ ‫ويسر لي أمري ‪ ,‬وأحلل عقدة من لساني يفقه قولي ‪ ,‬وأشدد من أزري ‪ ,‬وبارك لي ف علمي‬  Primary Vs. Secondary Hemostasis - Primary hemostasis refers to the role of blood vessels and platelets in the initial formation of a platelet plug in 3:55- 55, 955656 ld Plug response to vascular injury. & Secondary hemostasis (coagulation) is the reinforcement of the unstable platelet plug with chemically stable fibrin, follows and includes a series of interdependent, enzyme- mediated reactions.injury(9.5, 25-, Plug (1884 filorins! Plug it The endpoint of these reactions is the generation of thrombin, the enzyme that transforms the soluble protein fibrinogen to insoluble fibrin to stabilize the platelet plug. The process of fibrin formation is well balanced and controlled, limiting fibrin formation to the site of vessels injury. This localization prevents widespread or systemic coagulation activation. Hemostatic process: & 11. Is 1. keeps the blood fluid during normal circumstances. 2. Forms clots when needed. 3. Dissolves clots 4. Maintenance of vascular integrity & (18 endpointI1 · E secondary , intrinsic, extrinsic is slo jigitis. Is secondary hemosli! J.; 11 11.3 Is di -- Thrombin 5.5 traget 11. intrin,ext sis" is strong plug & ? Plug PH & reinforcement fibrin or Ibbor fibrinogen-fibrins · 1 55gl8,55 Chemostatic process nmin s S Is ↑ -. - sosa, 1 (resultnegative] cls hemostatic procell is is regulation -ssE5.s tight. 19 -> :next slide mechanism [preenzyme] coagulation ↑... its 3 coagulation cascadell (zymogen]=[inactive Is form) & circulation (1.8. 1 is so cloting factor I" !?555enzymes s ubstrate mogenetia(enzyme as a ·(XIIa) I substrate & (XI) - 35 15s -6 qboiz - &...9555,s 12 129 11 119 4 99 co-factor 10 a 10 13 18 #4 # I Ia > coagulation cascade. - Coagulation Mechanism The reactions Sinvolved in the coagulation process occur as cascade, in which the circulating, - inactive coagulation factor precursors (called zymogens) are activated to their active enzyme forms. Loading… Each zymogen serves first as the substrate for the preceding enzyme in the cascade, and when activated, serves as an enzyme for the subsequent zymogen.  Coagulation Cascade Coagulation cascade has two initial pathways which lead to fibrin formation: The contact activation pathway (also known as the intrinsic pathway) which requires enzymes and protein cofactors that Blood 211s.-89 requirment111 are present in plasma. ve Tissue factor pathway (also known as the extrinsic pathway) which requires enzymes and protein cofactors present in plasma as well as an activator (tissue factor) not found in blood under normal conditions. Blood vessel (lessis -> all Both converge in a third path called the common pathway to generate fibrin clot.......F -> surface contact Loading… Factors IX, X, II, VII require calcium for activation- Need vitamin K to be synthesized. -Thrombin is important for the cleavage and activation of factors V,VIII, XIIl and Fibrinogen  ---des XIIq, Xn11d5s XII (1$ 68 collagen or activated PIt II ·Gil ↳ Casca)! s 10188s Xa $1 X (1J5 S i factor Io, (8a] so-sod.-8. 9 factor Ca"SI - 8. ly).__ di (Sa] 5-08 entrici 81s: ser [9a, 102, 2a, 7a) Ils sitamin. I.I · [2a] Thrombin (1-5;1 54($) $51,81 - ↳ ⑤ - cofactor 1950 factor 13, factors, factor a is ⑧ - Extrinsic * 1j:Thrombind injury ,Js. s -=0,55588 Cascade (1.5- , dis -> Common · so 3 a 1 - Ia,7a,109,9a,la,12a 69 enzyme fibrin 91s.-1.3;enzyme is & 'sfunction s) note Another classification is based on the physiological characteristics: 1. Contact group (need contact with a negatively charged surface to be activated) ----- (Factors XII, XI, PK, HK) -'s 4 561-55 - 2. Prothrombin group (need vitamin K for synthesiss  Nomenclature of Procoagulants Each factor was assigned Roman number I through XIII. The Roman number was assigned according to the order of discovery of the respective factor, not its place in the 9.512s:"9.55 reaction sequence. (115$ sequance 5 Is Each factor has one or more common names in addition to the Roman number. The letter (a) following the Roman number indicates the activated from of the factor. However, there are several exceptions to this terminology. The activated form of F-II (prothrombin) is preferentially known as thrombin rather than F-IIa. Fibrinogen (F-I) is activated to fibrin. Tissue factor (TF) was assigned F-III, and calcium was assigned F-IV. (4) F-VI is no longer included in the cascade because it was originally assigned to the activated F-V is : Blood Clotting Factors Factor Number Alternative Name I Fibrinogen (Fibrin Zymogen) II Prothrombin (Thrombin Zymogen) III Tissue Factor IV Ionic Calcium (Ca+2) V Labile Factor (Proaccelerin) VI Unassigned (previously activated factor V) VII Stable Factor (Proconvertin) VIII Antihemophilic Factor IX Christmas Factor X Stuart-Prower Factor XI Plasma Thromboplastin Antecedent (PTA) XII Hageman Factor Ill = Fibrin stabilizing factor  Functional Classification Of Clotting Factors They can be classified according to their functions as : - Cofactor - Substrate Enzyme - yme 1-8s Cofactors : notenzyme neither substrate, 8,5159,8., Is a substance (other than the substrate) whose presence is essential for the activity of an enzyme. 5 2 Factor V and factor VIII function as cofactors for the activated F-Xa and F-IXa respectively. Both have no enzymatic activity. Protein S is the cofactor for activated protein C (will be - discussed later). (fa) TF is the cofactor for F-VIIa. -  Functional Classification Of Clotting Factors 3ds Ma I substrate 9 X i!, 58- - - I substrate 5 Substrate: 1888- Fibrinogen is classified as a substrate because it is the 7 · 3ls substrate for the enzyme thrombin, as well as, it does not become an activated enzyme. fibrin 1655 fibrinogen · Ic fibrin ( enzyme s Enzyme : - 8 1169 The coagulation factors that have enzymatic activity are secreted as zymogens, (pro-enzyme or inactive precursors) that must be modified to become active. Activation can be either by a conformational change of the molecule or proteolytic cleavage of one or more specific peptide bonds.  Functional Classification Of Clotting Factors (12, 11, 10,9,7,2) Enzyme (Cont.): - 5 6 -515,3859 2117d = · is a I Serine proteases include thrombin, F-XIIa, F-XIa, F-Xa, F- IXa and F-VIIa. => 4 > active form. S. 12 11 J. 18 These factors have a functional serine in their active sites. They hydrolyze arginine or lysine-containing peptide- bonds in their substrates. The hydrolysis is highly specific - for the substrate. Il Bond I119S S & F-XIIIa is the only coagulation protein with ② transglutaminase activity (It catalyzes the formation of - 9 bonds between glutamine and lysine residues on fibrin, S forming stable cross-links therefore it is called fibrin stabilizing factor. XIII flyss5& - serine proteases: they are named so because they have an important serine in the active site that is essential in catalytic activity. -Active forms of factors II, VII, IX, X, XI, XII are the serine proteases aminegroup II 5. isopeptide 1 Bond & glutamine anylgroups, lysine I Transglutaminase It is an enzyme that catalyzes the formation of an isopeptide bond between a free amine group (e.g. lysine) and the acyl group (e.g. glutamine). In other words :“ catalyze the covalent cross-linking of substrate proteins to form insoluble protein complexes that are resistant to Loading… degradation.” ↳ ine group Complex Formation on Phospholipid Membrane Coagulation process takes place on the surface of platelets: Phospholipids in the platelet membrane and tiny packages (microparticles) that are released from activated platelets help to control how clots form. The phospholipid surface serves to localize the reaction to the site of injury and increase the rate of activation by several orders of magnitude. In addition, the reactions are generally protected from inhibitors in these cell surface–associated complexes. D Three procoagulant complexes, the extrinsic Xase [R (extrinsic tenase), intrinsic Xase (intrinsic tenase), and S prothrombinase complexes assemble on the phospholipid membrane.  · ↓ ↓ E si - A protected from inhibitors V ~ - Er - - E - localize the reaction to the site of injury E increase the rate of activation 3 -E s.Re E - - ↳ e = ↳ i E E Coagulation process takes place on the surface of platelets S ↳. 3 ↓ E - - S 9. M is - I - · ⑳.s E · ↑ D ⑤ · · ⑳ ⑬ E.. a E E E. ↓ · Y & B 3 - I 5 95: - E 9 Er g - & 3 Eig ⑳ - ↳ E 3. E See E -e - - ot S a - ↑ S ·39. · B ·. B - Fir I ↑ C Be : - W O B Ay. E e. zi.Be. ↳. E E 3 E..bei &Er ;9:3 - ↑ · i S B. -- E I - - i 8 E he I E Si E · · E B ⑧ & s - T W  Complex Formation on Phospholipid Membrane - * The extrinsic Xase (tenase) complex: TF ,when - - exposed to blood upon vessel injury, reacts with F- - (7) VIIa in the presence of Ca2+ to activate F-X. - The intrinsic Xase (tenase) complex: F-IXa and F-VIIIa bind the membrane phospholipid in the presence of Ca2+ to activate F-X. Prothrombinase complex: F-Xa with F-Va bind the negatively charged phospholipid in the presence of Ca2+ to form this complex. This complex converts prothrombin (which is also bound to the membrane) to thrombin. The rate of this complex in activating prothrombin is more than 200,000 times faster than its activation by F-Xa alone.  · Blood Jessies ( 2:35 extrinsic xase complex 1. lid. enzymes;,acity T. 1 release as. Pathway 11 is ","e"s - IT 7.7 T. ddess is a extrinsical seas Illa? T.F 1-8 extrinsic II is - as4. "ilr it1;5s b. (a* (l 395.3 Phospholipid surface S. - 4 1n& 10 factor 5.5.5- ·Blood vessel (1 1,55 intrinsic vase complex. 8, 11,9,12 Ios 5surface II activated PH194 - Is Alla, b, * factor' - qa 83go intrinsic vase complex (1- surface I & Prothrombinase complex $ $11,5 PL 2 (a & 5a B, S Cofactor (12 factor 109 9j5,5 Phospholipd surface 11 ↳ fibrin II 88].g. fibrin IIS - ebblics 21-s-Is- ·ja: I-? Plug (j jdl.s>28+1 15s 53.Spidss-dis - is95% sed! ·......................... endothelial-- cell resting,inactivatedas activated collagen fiber greation - in e fibrinogen Coagulation Cascade Complexes Complex Components Function -> F-VIIa , TF , Cleaves F-IX and Extrinsic tenase Phospholipid, and - - F-X Ca2+ - - F-IXa , F-VIIIa , I Intrinsic tenase Phospholipid, and Cleaves F-X - Ca2+ - F-Xa , F-Va , Cleaves Prothrombinase Phospholipid, and Pl prothrombin Ca2+ - -  E L =. Ente visit a 3E - ③.... -E - · Si - = I g the - I E 3 · - - - ↓ & 8 - 9 - E S E - s ty" E - : - = · - - = - E. H - - - ·By S n : - - E. in E the - = I - g. - A w fo E S = I · ↓ - E ↳ - - e. & E - See - 5 s. 2 5. eEs & E E I eE 5. ⑤ -- 3 = - - - -set↑ w I ↳ W - Intrinsic pathway has more steps (slower) but is more efficient. - Extrinsic tenase can activate factor IX (skipping the need of contact activation of this pathway) to amplify the signal.  Intrinsic Pathway The intrinsic pathway of blood coagulation is so named due to the presence of all the required reactants - of this pathway in the circulation, with no external protein source required (unlike the extrinsic pathway that requires exposure to extravascular tissue factor for triggering). Also known as: The Contact Factors Pathway -> negatively charge. ofsurface. The Surface Mediated Pathway The Surface Contact Pathway -The main difference between intrinsic and extrinsic pathways in blood The main difference between intrinsic and extrinsic clotting is that intrinsic pathways in blood pathway clottingis activated is thatbyintrinsic a trauma inside the vascular pathway is system activated whereas by pathway extrinsic a trauma inside by is activated theexternal vascular system trauma  whereas extrinsic pathway is activated by external 12 ! The Intrinsic Pathway F-XII , F-XI , and plasma prekallikrein (PK), and high molecular - - - - weight kininogen (HK) were grouped together as the contact system, because they require the contact with artificial, negatively charged surfaces for zymogen activation in vitro. The intrinsic pathway is activated by the formation of the primary complex on collagen by HK, PK and F-XII. - - - Prekallikrein is converted to kallikrein and F-XII is activated (F-XIIa ). F-XIIa will convert F-XI into F-XIa. F-XIa will activate F-IX which with its co-factor F-VIII will form the intrinsic Xase complex and activates F-X to F-Xa. 1. 2. -is inflamatory (Is5 Deficiencies in F-XII, MWHK, and Prekallikrein don’t cause - bleeding disorders (Indication for their minor role in coagulation ) -Autoactivation of FXII occurs by contact with negatively charged surfaces, which induce a conformational change that makes the protein more susceptible toautocatalysis. Many non-physiologic substances (glass, kaolin, celite, ellagic acid) have been associated with in vitro FXII autoactivation and are used as activators in the reagents for the APTT test. - 1 = I -The human contact system consists of plasma proteins, which - after contact to foreign surfaces - are bound to them, thereby activating the zymogens of the system into enzymes. This activation mechanism gave the system its name - contact system. It is considered as a procoagulant and proinflammatory response mechanism, as activation finally leads to the generation of fibrin and bradykinin. To date, no physiological processes have been described that are mediated by contact activation. However, contact system factors play a pathophysiological role in numerous diseases, such as cardiovascular diseases, arthritis, colitis, sepsis, and cancer.  (2) - - * - activate an => x- Xa -> 0 5 ss - exposure the Cascade 11 -Is - 65. 8.385 # -3 - Bound FXlla cleaves PK to kallikrein, which with HK as - -> a cofactor can then reciprocally proteolytically activate surface-bound FXII to FXIla. -The generation of FXlla - and kallikrein by reciprocal activation amplifies these - - - reactions. - - In addition to activating PK to kallikrein, FXlla has - other enzymatic functions in hemostasis. As the first 19 enzyme in the intrinsic pathway, FXIla converts FXI to its - active form, FXla, in a reaction that requires HK as a - - - - cofactor. -FXIla activates the fibrinolytic and complement - - - systems. I plasminogen-> Plasmin - primary complex - The intrinsic - pathway is activated by the formation of the primary complex on collagen by HK, - PK and F-XII. - -  a Factor IX activation > 9 [I In the intrinsic pathway, F-XIa activates F-IX in the - - presence of Ca2+ and does not require any other - cofactor. [ The extrinsic pathway complex& F-VIIa/TF also activates - F-IX.This extrinsic pathway for FIX activation - bypasses the contact activation system. - When activated, F-IXa forms a complex (intrinsic Xase) with cofactor F-VIIIa and Ca2+ on the surface of activated platelets to activate F-X. - a -> known as Christmas disease Deficiency in F-IX will result in Hemophilia B disease. - Factor IX activation  Factor VIII It is synthesized in the liver and circulates in plasma in association with VWF. is carrier offactor?-- adhesion (1 - ↑ Labile factor F-VIII/VWF complex stabilizes F-VIII and protects it from - inhibition or degradation. This association prolongs its circulating time from about 2 hours to 12 hours. In - - addition, this association protects F-VIII from inactivation by the activated protein C (will be discussed later). ~ It F-VIII circulates in an inactive form due to this association, upon its activation by thrombin, it dissociates from VWF to become the active form and serves as cofactor to F-IXa. 8 Deficiency in F-VIII will cause Hemophilia A disease.  * ↳ ↳ - Protein C with it’s cofactor protein S inactivate factors V,VIII. I (remember role of thrombomodulin in activation of proteins C). - VWF binds to FVIII, preventing FVIII from binding to ↑ ↓ phospholipids and activated platelets and protecting it against ↑ inactivation by activated protein C. It does not, however, prevent thrombin activation of FVIII but facilitates thrombin proteolytic cleavage. - a I ee IE 3 · 8 ~3 a E ↳ ↳ : 9 e be - 3 E. i - = - - B a & E P... Es 5. EB W E & = I I E S C 7 - - 8 a L E * = 3  The Extrinsic Pathway When vessel injury occurs, nonvascular cells (fibroblasts, vascular adventitial cells) with TF on their surface are exposed to the blood. TF binds F-VIIa in the presence of Ca2+ forming the F-VIIa/TF complex. Once formed, this complex initiates the extrinsic pathway of blood coagulation, converting F-X to F-Xa (extrinsic Xase complex). - The FVIIa/TF complex also can activate FIX of the intrinsic pathway, bypassing the need for contact activation of this pathway. FXa, thrombin, and FVIIa itself can feed back to activate more FVII to FVIIa  Tissue Factor factors Also known as Tissue thromboplastin or F-III. endothelium (t 2; It is a trans-membrane lipoprotein expressed on most non-- vascular cells. It is not normally expressed by cells that are in contact with flowing blood. Sometimes, ⑲ monocytes and ⑬ endothelial cells can be stimulated to produce TF by- endotoxin, immune complex or complement component C5. I 2. ei 2,1118;T.fs12ebest blogs TF It is the cellular receptor and cofactor for F-VII and F-VIIa. TF and the platelet phospholipid surface have similar - functions in coagulation; both attract calcium ions to facilitate the formation of procoagulant enzyme complexes at the injury site. 6 Prothrombinase (1_j  I Factor VII It is one of the vitamin K dependent factors produced by liver. * so fibrin F-VII circulates in two forms, the inactive zymogen F-VII - and the active enzyme F-VIIa (about 1% only). Free F-VIIa is a very weak enzyme in the absence of TF. => however, this small amount of F-VIIa can be used to initiate the coagulation cascade when injury exposes TF. - To Binding of TF to F-VIIa, promotes the activation of F-X. - - however, binding of TF to F-VII facilitates F-VIIa to - > - autocatalyze more F-VII to F-VIIa. Dis. It factor 55. - 7 T.f F.Ulla promotes activation ofEx + -> + x-3Xa T.f F-VII * F-VIIa -> - * 5; in - factor ISI =  The Common Pathway The intrinsic and extrinsic pathways converge on the common pathway as both pathways activate F-X. F-X is another vitamin K dependent factor. Upon its activation, - - the prothrombinase complex (F-Xa , F-Va , Phospholipid, and Ca2+) activates prothrombin to thrombin. Thrombin in turn cleaves fibrinogen into soluble fibrin. - - - Thrombin also activates F-XIII which together with - Ca2+crosslink the soluble fibrin and form stable crosslinked is - - insoluble fibrin clot. · -gi isfactor +factor, 5 p5$ $.5,;c00s, 5 & F-V (labile factor) can be activated by both thrombin and F-Xa. - - - F-Va is the cofactor to F-Xa. It binds a specific site on the activated platelet surface, providing a binding site for F-Xa. = => coagulation cascades: factor 15 is 8, factors, pilisbo!s-  factors 155 s * bis. Its factor fall Binding, sau surface ofPHt)) ite - 100 + 10 85 factor 9a, factor 10 $ 00  #(2) Release of thrombin Prothrombin is a vitamin K dependent factor that can bind to the negatively charged phospholipid of the activated- platelets. it is activated by the prothrombinase complex to thrombin,- which does not contain a binding site to the negatively charged phospholipid, therefore, thrombin will be released... Thrombin 4! Prothrombin (1  Role of Thrombin (as Procoagulant anticoagulant $ is s Thrombin I procoagulant) ~ Procagulant11 & gi5 to inhibition -> formation of Plasmin to avoid fibrin clot Thrombin can also inhibit fibrinolysis by activating TAFI - (thrombin activatable fibrinolysis inhibitor). -s & ⑮S agli; i.e. Plasmin bs is - PAI. Plasminogen I;S5--ngles 2 5 tPA activater  °@°@π* &..4681/51-Thrambin II FPA, 3.5. fpB. fibrin - fibrinogen (13.3651 The => most strong against & Thrombin II Ig ·o I note II de9 - Thrombin generation is critical for normal hemostasis; it has a number of diverse roles, both procoagulant and anticoagulant 1 2 - - Small amounts of thrombin are sufficient for fibrin formation and platelets activation but large amounts of thrombin is needed to activate TAFI so thrombin activates factor XI in order to activate intrinsic pathway thus amplifying thrombin production Thrombinl Jj(il = "lb. Other functions to Thrombin & Chemo-attractant for neutrophils (inflammatory function). Thrombin has a cellular proliferation function. It is a mitogen for fibroblasts. Also it stimulates platelets to release PDGF (platelets derived growth factor) which is a mitogen. Loading… wound healing process & i Also has anti-thrombotic functions : Excess amounts of thrombin activate protein C and initiates -> > fibrinolysis and wound repair. Pathway 58.- Protein -> - 1,55! 9 s = 7 tPA Stimulates endothelial cells to release tissue plasminogen - activator (tPA). -> note hrumbomodulin - - Thrombin binds to TM, and activates protein C, - and stimulates endothelial cells to release tPA, ↳ ↓ prostacyclin, and endothelium-derived relaxing - ° factor (EDRF, also known as nitric oxide [NO]). - - 81s vasodilator is 185 The Common Pathway - (a2 PL +factor + 5  Fibrinogen only substrated 1 2. Found in plasma and platelets alpha granules. Fibrinogen is composed of 3 pairs of non-identical polypeptide chains. 29 disulfide bonds join the three pairs of chains. Due to folding of the ends of these chains on each other, a tri-nodular structure of fibrinogen is formed. The central nodule (the E domain) and the two outer nodules (the D domains). 655556/s I A - central Thrombin binds to the central E region of fibrinogen and cleaves specific arginine–glycine bonds, releasing four peptides from the fibrinogen molecule. - The resulting molecule is called a fibrin monomer. - The cleavage of FPA and FPB exposes binding sites in the central E nodule that interact with complementary sites on the Gamma chain of the D nodule of other fibrin monomers, creating a D–E contact. The polymerization sites on the D nodule are always available and interact with the complementary sites on the E nodule exposed after thrombin cleavage of FPA and FPB. The spontaneous polymerization continues by the addition of a third monomer forming a D–D contact as well as another D–E contact. &553:5888,0551 FA, fa (18584 · fibrin Is...dis other fibrinclot slide 44 I factor 13 a *  Factor XIII I The final reaction in fibrin formation is the stabilization of the fibrin polymer catalyzed by F-XIIIa by cross-linking between fibrin monomers. (+ 5. It?s Lysi sbs,s 1 8.69 & w - It also cross-links fibrinolytic inhibitors (PAI and TAFI) to the - - fibrin clot, therefore, they are localized at the fibrin clot 53 formation. for II. iso- crosslink healing & 681,*d5 Predigestive filorin clot FXIIIa is thus a calcium-dependent transglutaminase that catalyzes the formation of covalent peptide bonds within the fibrin polymer. These bonds are formed between the terminal D-regions of Gamma chains of two adjacent fibrin monomers. - FXIIIa also cross-links fibrinolytic inhibitors to the fibrin clot, including Alpha 2 antiplasmin, plasminogen activator inhibitor-2 (PAI-2), and TAFI. The localization of these fibrinolytic inhibitors to the fibrin clot results in the inhibition of plasmin formation and protects the clot from premature lysis. Finally, FXIIIa cross-links fibrin to extracellular matrix molecules, helping to anchor the fibrin clot to the vessel wall and promoting wound healing.  42 25,3 Formation of fibrin polymer: Thrombin cleaves the A and - B fibrinopeptides from the E nodule of fibrinogen to form fibrin monomer. - The cleavage permits the spontaneous growth of fibrin polymers at the E 00 nodule assembles with the D nodules of other fibrin monomers. different F-XIIIa in the presence of two i cross link 1. domain - Ca2+ is responsible for E (a+ 2 8- 128s catalyzing the formation of covalent bonds between D = nodules thus stabilizing the lattice formation.  ‫الهلم إين أستودكع ما رقأت وما حظفت وما عتملت‪ ،‬رفده يل نعد احيتج‬ ‫إيله إكن ىلع لك يشء قدري‬ ‫يلع رمحتك‪ ،‬وذّركين ما سنتي واطلق هب سلاين‪،‬‬ ‫يلع تفوح اعلارفني حبكمتك‪ ،‬وارشن ّ‬‫الهلم اتفح ّ‬ ‫ووقي هب زعيم حبولك ووقكت‪ ،‬فإّهن ال وحل وال وقة إال كب اي أرح ارلاّ محني‬ ‫رّب ارشح يل صدري‪ ،‬وّرسي يل أرمي‪ ،‬واحلل عقـدًة من سلاين‪ ،‬فيهقوا وقلـي‬