الرحيم الرحمن الله الرحيم بسم الرحمن الله بسمCoagulation & Coagulation &

Fibrinolytic System Fibrinolytic System Disorders in Disorders in Obstetric & Obstetric & GynecologyGynecology

Normal haemostasis & the Normal haemostasis & the vascular treevascular tree

The normal function of coagulationThe normal function of coagulation & & fibrinolytic system is to maintain an intactfibrinolytic system is to maintain an intact but patent vascular treebut patent vascular tree..

Three main component plays a part in Three main component plays a part in normal haemostasisnormal haemostasis::

11..Vascular constrictionVascular constriction.. 22..Platelet plugPlatelet plug. .

33..Fibrin generationFibrin generation

--The fibrinolytic system is The fibrinolytic system is complementary to these activities & complementary to these activities & is responsible for the removal of is responsible for the removal of fibrin & the restoration of vascular fibrin & the restoration of vascular patencypatency..

Normal HaemostasisNormal Haemostasis--Vascular endothelium releases a potent Vascular endothelium releases a potent

antiplatelet agent called antiplatelet agent called prostacyclin (PGI2)prostacyclin (PGI2) which limits the size of any micro thrombi which limits the size of any micro thrombi formed , so it prevents overt thrombus formed , so it prevents overt thrombus formationformation..

--On the other hand the platelets release On the other hand the platelets release thromboxane A2 (TxA2) which performs a thromboxane A2 (TxA2) which performs a powerful platelet aggregationpowerful platelet aggregation. .

--If there is any imbalance between PGI2 & If there is any imbalance between PGI2 & TxA2 , the result can be a predisposition of TxA2 , the result can be a predisposition of either bleeding or thrombosiseither bleeding or thrombosis..

--In injuries, the exposure of collagen in the In injuries, the exposure of collagen in the basement membrane stimulates platelets basement membrane stimulates platelets adhesion change in platelets shape adhesion change in platelets shape platelets reaction platelets reaction

((TxA2,ADP, ATP, serotonin & active agentsTxA2,ADP, ATP, serotonin & active agents ) ) vasoconstriction & further platelet aggregation vasoconstriction & further platelet aggregation

platelet plug platelet plug . .

--Fibrin formation is the end product of Fibrin formation is the end product of enzymatic reaction , conducted by both enzymatic reaction , conducted by both extrinsic & intrinsic pathwaysextrinsic & intrinsic pathways . .

--In the extrinsic pathway the blood comes into In the extrinsic pathway the blood comes into contact with tissues & this will lead to fibrin contact with tissues & this will lead to fibrin formation by a serial reaction within a few formation by a serial reaction within a few secondsseconds..

Intinsic pathway Extrinsic Intinsic pathway Extrinsic pathwaypathway

• XIXI

•XIIa IXXIIa IX

• XIa VIIa VIIXIa VIIa VII

Thrombin CaThrombin Ca

•VIII VIIIa + IXaVIII VIIIa + IXa

X Xa +VaX Xa +Va

phospholipid Thrombinphospholipid Thrombin

( ( prothrombin converting principleprothrombin converting principle ) ) Va VVa V

II Prothrombin II a ThrombinII Prothrombin II a Thrombin

Fibrinogen FibrinFibrinogen Fibrin

Failure of normal fibrin Failure of normal fibrin formationformation

11..Insufficient fibrinogenInsufficient fibrinogen

22..Deficiencies in one or more of Deficiencies in one or more of clotting factorsclotting factors

33..Failure of normal fibrin stabilizationFailure of normal fibrin stabilization..

44..FDPs (fibrin degradation products)FDPs (fibrin degradation products)..

Coagulation InhibitorsCoagulation Inhibitors::

In addition to the clotting factors In addition to the clotting factors there are many substances that there are many substances that inhibits coagulationinhibits coagulation::

--Anti- thrombin III (AT III)Anti- thrombin III (AT III)

--Alpha 2 globulin inhibits Thrombin & Alpha 2 globulin inhibits Thrombin & factors Xa, XIIa ,XIa and IXafactors Xa, XIIa ,XIa and IXa..

--Protein C (endothelial cell )Protein C (endothelial cell ). .

--Protein S (endothelial cell & platelets )Protein S (endothelial cell & platelets ) ..

The fibrinolytic systemThe fibrinolytic systemPlasminogenPlasminogen

Plasminogen activators Plasminogen activators Anti-Anti-activatorsactivators

((in tissue & vessel wallin tissue & vessel wall ) )

PlasminPlasmin

Anti- plasminAnti- plasmin alph2 macroglobulinalph2 macroglobulin

alph1 antitrypsinalph1 antitrypsin

Fibrin FDPFibrin FDP

Coagulation & fibrinolytic system Coagulation & fibrinolytic system during pregnancyduring pregnancy

--Placental separation during the 3Placental separation during the 3rdrd stage of stage of labour represents a major haemostatic labour represents a major haemostatic challenge to the motherchallenge to the mother..

--Physiological adaptations occur during Physiological adaptations occur during pregnancy to help the mother meet this pregnancy to help the mother meet this haemostatic challengehaemostatic challenge. .

--Together the change in coagulation & Together the change in coagulation & fibrinolysis in pregnancy represents a fibrinolysis in pregnancy represents a hypercoagulable statehypercoagulable state. .

Coagulation system during pregnancy

--Plasma fibrinogen concentrations rise during Plasma fibrinogen concentrations rise during pregnancy by about 50% , this means that double pregnancy by about 50% , this means that double the amount of fibrinogen is available to pregnant the amount of fibrinogen is available to pregnant woman at deliverywoman at delivery. .

--Concentration of other clotting factors also rise , Concentration of other clotting factors also rise , especially Prothrombin &factors V ,VII , VIII . IX , X , especially Prothrombin &factors V ,VII , VIII . IX , X , & XII& XII..

--Notable exception are Notable exception are factors XI & XIII ,whose factors XI & XIII ,whose concentrations fall during pregnancyconcentrations fall during pregnancy. .

--Despite the increased potential to form thrombin in Despite the increased potential to form thrombin in pregnancy , there is no compensatory rise in anti pregnancy , there is no compensatory rise in anti thrombin IIIthrombin III..

--Platelet count shows little , if any , changePlatelet count shows little , if any , change..

..

..-Plasma plasminogen levels rise in

tandem with the rise of fibrinogen.

-By contrast ,the euglobulin lysis time ,which measures plasminogen activator activity , is markedly prolonged.

-Anti plasmins also rise so that the capacity to generate plasmin may be reduced in pregnancy ..

Fibrinolytic system during pregnancy

Coagulation &fibrinolysis during puerperium

--Following delivery , major changes occur in the Following delivery , major changes occur in the coagulation & fibrinolytic systemcoagulation & fibrinolytic system. .

--Rise in plasminogen activator activity which Rise in plasminogen activator activity which return to non pregnant range within 30 min of return to non pregnant range within 30 min of deliverydelivery. .

--Fibrinogen level & platelets count rise during Fibrinogen level & platelets count rise during early puerperiumearly puerperium..

--Anti- thrombin activity increaseAnti- thrombin activity increase. .

--Following the initial phase o f increased clotting Following the initial phase o f increased clotting factors in the puerperium ,the coagulation & factors in the puerperium ,the coagulation & fibrinolytic system gradually revert to normal fibrinolytic system gradually revert to normal within 6 weeks after deliverywithin 6 weeks after delivery..

] ]Disorders of hemostasisDisorders of the platelet and vessel wall

Immune thrombocytopenic purpura( ITP )Thrombotic thrombocytopenic purpura( TTP )Hemolytic-uremic syndrome( HUS )

Glanzmann's thrombastheniaBernard-Soulier syndrome(abnormal glycoprotein Ib-IX-V complex)Storage pool disordersParoxysmal nocturnal hemoglobinuria Gray platelet syndrome deficient alpha granules .

Delta storage pool deficiency: deficient dense granules .Disorders of coagulation and thrombosis

-Disseminated intravascular coagulation -Factor deficiencies

Hemophilia A (Factor VIII deficiency) Hemophilia B (Factor IX deficiency, "Christmas disease") Hemophilia C (Factor XI deficiency, mild bleeding tendency)

Von Willebrand disease( the most common bleeding disorder )Factor inhibitors Platelet Dysfunction

Disorders predisposing to thrombosisDisorders predisposing to thrombosisHeparin-induced thrombocytopenia and thrombo and thrombo

("white clot syndrome("white clot syndromeAntiphospholipidAntiphospholipid syndrome

Lupus anticoagulantLupus anticoagulant Anticardiolipin antibodyAnticardiolipin antibody

Factor Factor V Leiden and Activated Protein C and Activated Protein C ResistanceResistance Prothrombin mutation Protein C deficiency Protein S deficiency

Antithrombin deficiencydeficiency Abnormally raised levels of Factor VIII and Abnormally raised levels of Factor VIII and Factor XIFactor XI

Bleeding disorders:

Bleeding disorders is either inherited Bleeding disorders is either inherited or acquiredor acquired::Inherited bleeding disordersInherited bleeding disorders::

11..VONVON Willebrand's disease (VWD)Willebrand's disease (VWD).. von willebrand factor is a plasma protein that has von willebrand factor is a plasma protein that has

two main functionstwo main functions::- - Stabilization of factor VIIIStabilization of factor VIII

- - Adherence of platelet to injured vessel wallsAdherence of platelet to injured vessel walls

--Generally, this is inherited as an autosomal dominant Generally, this is inherited as an autosomal dominant condition, although there are recessive variantscondition, although there are recessive variants . .

- -It is the most common inherited bleeding disorderIt is the most common inherited bleeding disorder . .

--In women, menorrhagia and delayed post partum In women, menorrhagia and delayed post partum hemorrhage are common presentationshemorrhage are common presentations

--Levels of von Willebrand factor can be Levels of von Willebrand factor can be normal in pregnancy because of the normal in pregnancy because of the increased production in the liverincreased production in the liver , ,

--but they return to pre-pregnancy but they return to pre-pregnancy values by three days post partum andvalues by three days post partum and

--that is why it is actually delayed post that is why it is actually delayed post partum hemorrhage that is more of partum hemorrhage that is more of an issuean issue . .

--Other clinical manifestations include Other clinical manifestations include bleeding, epistaxis, gingival bleedingbleeding, epistaxis, gingival bleeding

The next inherited bleeding disorder The next inherited bleeding disorder which are uncommon in females arewhich are uncommon in females are::

--hemophilia A: which is due to factor VIII deficiency and it is an X-linked recessive and females are usually carrier for the disease, rarely the female may be affected.

-Hemophilia B is also known as Christmas disease; it is factor IX deficiency. Again, it is an X-linked recessive and it is much less common than hemophilia A .

-Factor XI deficiency..

--Hypo pro-thrombinemiaHypo pro-thrombinemia

--This disorder is a deficiency in Prothrombin, or Factor II, a glycoprotein formed and stored in the liver .

-Prothrombin, under the right conditions, is converted to thrombin, which activates fibrin and begins the process of coagulation .

-Some patients may show no symptoms, and others will suffer severe hemorrhage .

-Patients may experience easy bruising, profuse nose bleeds, postpartum hemorrhage, excessively prolonged or heavy menstrual bleeding, and post-surgical hemorrhage .

-Hypo pro-thrombinemia may also be acquired rather than inherited, and usually results from a Vitamin K deficiency caused by liver diseases, newborn hemorrhagic disease, or a number of other factors..

ThrombocytopeniaThrombocytopenia

Thrombocytopenia is a reduction in platelet number below 150 000/microlCauses:

1 -incidental thrombocytopenia of pregnancy2 -increased consumption

3 -autoimmune thrombocytopenia (ITP).4 -SLE/APS

5-Activated clotting mechanism - Pre-eclampsia

- HELP syndrome - DIC

6-Thrombotic thrombocytopenic purpura7-Decreased platelet production (marrow suppression)

- sepsis- HIV

8 -Malignant marrow infiltration

Idiopathic Thrombocytopenic PurpuraIdiopathic Thrombocytopenic Purpura.. --Idiopathic thrombocytopenic purpura (ITP) is a common Idiopathic thrombocytopenic purpura (ITP) is a common

autoimmune disorder in which patients form antiplatelet autoimmune disorder in which patients form antiplatelet autoantibodies against platelet-specific antigensautoantibodies against platelet-specific antigens..

--Often the patients are asymptomatic and pregnancy does not Often the patients are asymptomatic and pregnancy does not always exacerbate the diseasealways exacerbate the disease . .

--If platelet count is more than 50x 10/L no treatment is If platelet count is more than 50x 10/L no treatment is necessarynecessary..

--Major bleeding is rarely seen unless the platelet count isMajor bleeding is rarely seen unless the platelet count is <<10x10/L10x10/L

--Maternal antibodies may cross the placenta and affect the fetus Maternal antibodies may cross the placenta and affect the fetus , causing neonatal thrombocytopenia, causing neonatal thrombocytopenia..

--four to ten percent of neonates are at risk of having sever four to ten percent of neonates are at risk of having sever thrombocytopenia at birth or during the 1thrombocytopenia at birth or during the 1stst week of life week of life..

--Traumatic vaginal delivery must be avoidedTraumatic vaginal delivery must be avoided..

-Platelet count and pediatric assessment is indicated and the infant’s platelet count followed carefully over the next week..

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Management of ITPManagement of ITP--Maternal indications for treatment of

thrombocytopenia should not differ from those for non pregnant individuals .

-Therapy is not initiated unless platelets are < 50 000/microL or potential hemorrhages are present

-Corticosteroid 1mg/kg per day of prednisolone are given initially, maintained for 2-3 weeks then tapered slowly

-Intravenous immunoglobulin can be given for corticosteroid failure in Rh –positive women.

-Splenectomy is the last resort for patients who fail to respond to corticosteroid or immunoglobulin treatment.

-Platelet transfusion are not recommended except in life threatening situation.

The acquired disorders that lead to bleeding. These include DIC, vitamin K deficiency, liver disease, uremia and after massive transfusion .

DIC( Disseminated intravascular coagulation )-The name of this disorder arises from the fact that

malfunction of clotting factors cause platelets to clot in small blood vessels throughout the body .

-This action leads to a lack of clotting factors and platelets at a site of injury that requires clotting .

-Patients with disseminated intravascular coagulation (DIC) will bleed abnormally even though there is no history of coagulation abnormality .

-Symptoms may include minute spots of hemorrhage on the skin, and purple patches .

-A patient may bleed from surgery or intravenous injection (IV) sites. Related symptoms include vomiting, seizures, coma, shortness of breath, shock, severe pain in the back, muscles, abdomen, or chest..

--DIC is not a hereditary disorder or a common oneDIC is not a hereditary disorder or a common one . .--It is most commonly caused byIt is most commonly caused by : :

11--complications during pregnancy or deliverycomplications during pregnancy or delivery::- - Abruptio placentaAbruptio placenta . .

- - amniotic fluid embolusamniotic fluid embolus . .- - severe preeclampsiasevere preeclampsia . .

- - retained dead fetusretained dead fetus..- - sepsissepsis..

- - second-trimester abortionsecond-trimester abortion..

22--overwhelming infectionsoverwhelming infections , ,33--acute leukemia, metastasis canceracute leukemia, metastasis cancer..

44--extensive burns and traumaextensive burns and trauma . .55--even snakebiteseven snakebites..

- - Thrombi in the microcirculation activates the fibrinolytic process Thrombi in the microcirculation activates the fibrinolytic process andand leads to the release of fibrin degradation products, which inhibitleads to the release of fibrin degradation products, which inhibit normal coagulation. The consumption of platelets and normal coagulation. The consumption of platelets and coagulationcoagulation factors, as well as the above described inhibition of normalfactors, as well as the above described inhibition of normal coagulation, leads to both hemorrhagic and thromboticcoagulation, leads to both hemorrhagic and thrombotic consequencesconsequences..

laboratory investigationslaboratory investigations::

--Fibrinogen or fibrin degradation products highor fibrin degradation products high . .--Serum fibrinogen - lowSerum fibrinogen - low

--Prothrombin time (PT) -prolongedProthrombin time (PT) -prolonged--Partial throboplastin time (PTT) - prolongedPartial throboplastin time (PTT) - prolonged

--Platelet count lowPlatelet count low

Treatment of disseminated intravascular Treatment of disseminated intravascular coagulopathycoagulopathy

--Urgent haematological consultationUrgent haematological consultation - - Monitoring in intensive care uniteMonitoring in intensive care unite

--Check platelet countCheck platelet count--Give cryoprecipitate &fresh frozen plasmaGive cryoprecipitate &fresh frozen plasma

--Transfuse with fresh blood if availableTransfuse with fresh blood if available - -Treatment of the underlying causeTreatment of the underlying cause..

ThrombophiliaThrombophilia: : Is defined as a predisposition to thrombosis, secondary to any persistent or identifiable hypercoaguable state.

It can be inherited or acquired:

--It should be considered in

-a young patient who experiences atraumatic thrombosis .

-patients who have a family history of thrombosis .

-cases of recurrent thrombosis, especially when someone is already anti-coagulated

-when thrombosis occurs at an unusual site .

-It should also be considered, for our purposes, in patients who have recurrent pregnancy loss,

unexplained IUFD's and early severe IUGR.

::Causes of thrombophiliaCauses of thrombophiliaInhereted causes

1.Anti thrombin III deficiency::

--Anti thrombin III is a naturally occurring anticoagulant.

-It inactivate thrombin and factors IXa, Xa, XIa and XIIa.

-This is an autosomal-dominant condition .

-The clinical manifestation is thrombosis .

- It may be an acquired deficiency in patients who have DIC, nephrotic syndrome, liver disease, pre-eclampsia, during oral contraceptive use and during heparin therapy .

2.Protein C deficiency-is also autosomal dominant

-This is the next thrombophilia .

3-Protein S deficiency is also autosomal dominant .

4-Factor V Leiden mutation.

5.Prothrombin gene mutation.

Acquired causes of thrombophilia most common is Antiphospholipid syndrome

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