Coagulation failure in pregnancy


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  • Hemostasis is a balancing act between clot formation and fibrinolysis or clot dissolution.
  • -In injuries, the exposure of collagen in the basement membrane stimulates platelets adhesion ---change in platelets shape ---- platelets reaction
    (TxA2,ADP, ATP, serotonin & active agents ) ----- vasoconstriction & further platelet aggregation ------- platelet plug.
    -Fibrin formation is the end product of enzymatic reaction , conducted by both extrinsic & intrinsic pathways.
  • Thrombin converts fibrinogen to fibrin monomer by initially cleaving fibrinopeptides A and B. After a loosely cross-linked fibrin clot is formed, FXIIIa is able to cross-link fibrin, leading to clot stabilization.
  • The process of fibrinolysis enables cross-linked clots to be degraded. The fibrinolytic process involves the zymogen plasminogen, which is converted to plasmin by tPA or uPA. PAI-1 and 2-antiplasmin are the physiologic inhibitors of plasminogen activator and plasmin, respectively.
  • this hypercoagulable state with local activation of clotting system is associated with increased risk of not only VTE but also DIC
  • The fibrinolytic system is responsible for disposing of fibrin after fulfilling its haemostatic function
    Plasma proteases are responsible for controlling the speed and extent of coagulation & fibrinolysis
  • Quantitative-Thrombotic thrombocytopenic purpura,Hemolytic uremic syndrome,
    Qualitative-Glanzmann's thrombasthenia,Bernard-Soulier syndrome(abnormal glycoprotein Ib-IX-V complex),Storage pool disorders,Paroxysmal nocturnal hemoglobinuria ,Gray platelet syndrome deficient alpha granules.,Delta storage pool deficiency: deficient dense granules.
    Disorders predisposing to thrombosis
    Antiphospholipid syndrome
    Lupus anticoagulant
    Anticardiolipin antibody ,Heparin-induced thrombocytopenia,Factor V Leiden and Activated Protein C Resistance ,Prothrombin mutation ,Protein C deficiency ,Protein S deficiency ,Antithrombin deficiency ,Abnormally raised levels of Factor VIII and Factor XI
  • The next inherited bleeding disorder which 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.
  • Patients with hemophilia A or B, because of prior treatment with factor VIII or IX, may develop antibodies directed against factor VIII or IX and may lead to life-threatening hemorrhage. more commonly develop such antibodies. In contrast, acquisition of these antibodies in nonhemophiliacs is rare. This phenomenon has also been identified rarely in women during the puerperium (Santoro and Prejano, 2009). In these cases, the prominent clinical feature is severe, protracted, repetitive hemorrhage from the reproductive tract starting a week or so after an apparently uncomplicated delivery (Reece and associates, 1988). The activated partial thromboplastin time is markedly prolonged. Treatment has included multiple transfusions of whole blood and plasma; huge doses of cryoprecipitate; large volumes of an admixture of activated coagulation factors, including porcine factor VIII; immunosuppressive therapy; and attempts at various surgical procedures, especially curettage and hysterectomy. Another treatment involves bypassing factor VIII or IX by the use of activated forms of factors VII, IX, and X. A recombinant activated factor VII
  • Prothrombin, under the right conditions, is converted to thrombin, which activates fibrin and begins the process of coagulation
  • -Often the patients are asymptomatic and pregnancy does not always exacerbate the disease.
    -If platelet count is more than 50x 10/L no treatment is necessary.
  • Out of pre- eclampsia’s various manifestations, a specific entity is HELLP syndrome.
  • Periportal or focal parenchymal necrosis in which hyaline deposits of fibrin like material lead to Obstruction of hepatic blood flow
    Hemolysis is due to a microangiopathic haemolytic anaemia (MAHA).
    Platelets are activated, and adhere to damaged vascular endothelial cells, resulting in increased platelet turnover with shorter lifespan.
    Decreased Platelet count in the HELLP syndrome is due to their increased consumption.
  • Thrombocytopenia occurs first followed by raised liver enzymes and last is hemolysis
    If DIC is not present – PT , aPPT, S. Fibrinogen will be normal
    If fibrinogen < 300 mg/dl along with other lab abnormality – DIC is suspected
    Positive D-dimer test is more sensitive indicator of sub clinical coagulopathy and may be positive before other coagulation studies are abnormal.
  • In general, there are three major options for the management of women with severe preeclampsia and HELLP syndrome
    These include:
    . In this situation, Steroid treatment is often used,
    Platelet transfusion – is required eithr before or after delivery, in presence of bleeding from puncture site, wound and intra peritoneal bleeding.
    PCV and FFP – required if coagulopathy is present
  • The acquired disorders that lead to bleeding. These include
    DIC, vitamin K deficiency, liver disease, uremia and after massive transfusion
  • Coagulation failure in pregnancy

    2. 2.  Obstetrics is "bloody business." Although medical advances have dramatically reduced the dangers of childbirth, death from haemorrhage still remains a leading cause of maternal mortality  Hemorrhage is the single most important cause of maternal death worldwide. Obstetrical hemorrhage accounts for almost half of all postpartum deaths in developing countries
    3. 3. Learning objectives  Refresh about the normal coagulation cascade mechanisms and its triggers  To understand the alterations in coagulations & Fibrinolysis associated with pregnancy  Broad line classification of coagulation failure in pregnancy
    4. 4.  To get brief knowledge on some important causes of deranged coagulation in pregnancy  Understanding the pathogenesis of DIC syndrome, diagnosis, complications & management outlines
    5. 5. Haemostasis balancing act
    6. 6. Normal Haemostasis -Vascular endothelium releases a potent antiplatelet agent called prostacyclin (PGI2) which limits the size of any micro thrombi formed , so it prevents overt thrombus formation. -On the other hand the platelets release thromboxane A2 (TxA2) which performs a powerful platelet aggregation . -If there is any imbalance between PGI2 & TxA2 , the result can be a predisposition of either bleeding or thrombosis.
    7. 7. Normal Artery Endothelium Smooth Muscle Adventitia
    8. 8. Vascular Injury Damage
    9. 9. Hemostasis
    10. 10. Overview of blood coagulation Vessel Injury Platelet Activation Tissue Factor Coagulation Cascade Platelet Aggregation Platelet Plug Thrombin Clot Vasocon- striction
    11. 11. HAEMOSTASIS Primary + Secondary + Tertiary  Primary Hemostasis Platelet Plug Formation:dependent on normal platelet number & function  Secondary Hemostasis Activation of Clotting Cascade  Deposition & Stabilization of Fibrin  Tertiary Hemostasis Dissolution of Fibrin Clot:dependent on Plasminogen Activation
    12. 12. Normal haemostasis & the vascular tree The normal function of coagulation & fibrinolytic system is to maintain an intact but patent vascular tree. Three main components play a part in normal haemostasis: 1.Vascular constriction 2.Platelet plug 3.Fibrin generation
    13. 13. • The fibrinolytic system is complementary to these activities & is responsible for the removal of fibrin & the restoration of vascular patency.
    15. 15. Three pathways of blood coagulation are Extrinsic pathway Intrinsic pathway Common pathway
    16. 16. Coagulation Inhibitors In addition to the clotting factors there are many substances that inhibit coagulation: -Anti- thrombin III (AT III) -Alpha 2 globulin inhibits Thrombin & factors Xa, XIIa ,XIa and IXa. -Protein C (endothelial cell ) -Protein S (endothelial cell & platelets )
    17. 17. Coagulation & fibrinolytic system during pregnancy -Placental separation during the 3rd stage of labour represents a major haemostatic challenge to the mother. -Physiological adaptations occur during pregnancy to help the mother meet this haemostatic challenge . -Together the change in coagulation & fibrinolysis in pregnancy represents a hypercoagulable state .
    18. 18. Coagulation system during pregnancy -Plasma fibrinogen concentrations rise during pregnancy by about 50% , this means that double the amount of fibrinogen is available to pregnant woman at delivery . -Concentration of other clotting factors also rise , especially Prothrombin & factors V ,VII , VIII . IX , X , & XII. -Notable exception are factors XI & XIII ,whose concentrations fall during pregnancy. -Despite the increased potential to form thrombin in pregnancy , there is no compensatory rise in anti-thrombin III. -Platelet count shows little , if any , change.
    19. 19. . -Plasma plasminogen levels rise in tandem with the rise of fibrinogen. -Anti plasmins also rise so that the capacity to generate plasmin may be reduced in pregnancy . Fibrinolytic system during pregnancy
    20. 20. Coagulation & fibrinolysis during puerperium -Following delivery , major changes occur in the coagulation & fibrinolytic system. -Rise in plasminogen activator activity which return to non pregnant range within 30 min of delivery . -Fibrinogen level & platelets count rise during early puerperium. -Anti- thrombin activity increase. -Following the initial phase o f increased clotting factors in the puerperium ,the coagulation & fibrinolytic system gradually revert to normal within 6 weeks after delivery.
    21. 21. Coagulation changes in pregnancy  Bleeding during labour is dealt with effectively by - increased production of coagulation factors during pregnancy - increased blood volume - myometrial contraction
    22. 22. Classification of coagulation disorders in pregnancy
    23. 23. Congenital coagulopathies  Von-willebrand disease  Haemophilia A and B  Antithrombin deficiency Acquired coagulopathies-  PIH  Placental abruption  Retained dead fetus  Amniotic fluid embolus  Liver diseases  Anticoagulants: Aspirin and heparin
    24. 24. Platelet Abnormalities 1.QUANTITATIVE (not enough platelets) -Gestational thrombocytopenia -Idiopathic/Immunological thrombcytopenic purpura -HELLP syndrome -DIC 2.QUALITATIVE DISORDERS (poor platelet function) 3. Disorders predisposing to thrombosis Antiphospholipid syndrome
    25. 25. Screening tests for hemostasis TEST ASSESSMENT TESTS OF PRIMARY HEMOSTASIS Bleeding time Platelet and vascular phases PFA-100 system Platelet function Platelet count Quantitation of platelets Blood smear 1.Quantitative and morphological abnormalities of platelets 2.Detection of underlying haematological disorder TESTS OF SECONDARY HEMOSTASIS Clotting time Crude test of coagulation phase Prothrombin time Extrinsic and common pathways Activated partial thromboplastin time Intrinsic and common pathways
    27. 27. PLATELET COUNT NORMAL 150,000 - 400,000 CELLS/MM3 < 100,000 Thrombocytopenia 50,000 - 100,000 Mild Thrombocytopenia < 50,000 Severe Thrombocytopenia
    28. 28. INR INR: International normalized ratio - Established by the WHO and the International Committee on Thrombosis and Haemostasis for reporting the results of prothrombin tests -All PT results are standardized by this calculation: INR = ( Patient PT / Control PT) ISI ISI= International sensitivity index - Given by the manufacturer for each particular thromboplastin reagent and instrument combination
    29. 29. ACTIVATED PARTIAL THROMBOPLASTIN TIME Measures Effectiveness of the Intrinsic pathway & common pathway NORMAL VALUENORMAL VALUE 25-40 SECS25-40 SECS
    30. 30. APTT prolongs.. 1.Intrinsic pathway factor deficiencies (FXII, XI,VIII, IX, HMWK, prekallikrein ) - Inherited or acquired - Consumption (DIC) - PIVKA factors in cumarin therapy 2. Specific inhibitors against FXII, XI, VIII, IX, HMWK, prekallikrein 3. Lupus anticoagulant 4. Non-fractionated heparin therapy
    31. 31. THROMBIN TIME Time for Thrombin To Convert Fibrinogen Fibrin A Measure of Fibrinolytic Pathway NORMAL VALUENORMAL VALUE 9-13 SECS9-13 SECS
    32. 32. TT Prolongs.. 1.Hypofibrinogenaemia 2. Dysfibrinogenaemia 3.Non fractionated heparin 4.Fibrinogen/ fibrin degradation products 5. Chronic liver disease
    33. 33. SPECIFIC TESTS Tests for specific Platelet Functions 1. Platelet aggregation test 2. Flow cytometry 3. Test for platelet secretion 4. Clot retraction test 5. Platelet pro-coagulant activity Test for Coagulation Phase 1. Quantitative estimation of Fibrinogen 2. Coagulation factor assays 3. F XIII Qualitative assay Latex agglutination test for Fibrinolysis
    34. 34. Von Willebrand Disease
    35. 35. Von Willebrand Disease  Symptomatic patients usually present with evidence of a platelet defect  Considered in women with bleeding suggestive of a chronic disorder of coagulation.  During normal pregnancy, maternal levels of both factor VIII as well as vWF antigen increase substantively .  Because of this, pregnant women with vWD often develop normal levels of factor VIII coagulant activity as well as vWF antigen, Although the bleeding time still may be prolonged.
    36. 36.  If factor VIII activity is very low or if there is bleeding, treatment is recommended. Desmopressin by infusion may transiently increase factor VIII and vWF factor levels.  Pregnancy outcomes in women with von Willebrand disease are generally good, but postpartum hemorrhage is encountered in up to 50 percent of cases
    38. 38.  Patients with hemophilia A or B, because of prior treatment with factor VIII or IX, may develop antibodies directed against factor VIII or IX and may lead to life- threatening hemorrhage.  Rarely in puerperium, women resent as severe, protracted, repetitive hemorrhage from the reproductive tract starting a week or so after an apparently uncomplicated delivery  The activated partial thromboplastin time is markedly prolonged.  Treatment has included multiple transfusions of whole blood and plasma and clotting factors.
    39. 39. Hypo pro-thrombinemia -This disorder is a deficiency in Prothrombin, or Factor II, a glycoprotein formed and stored in the liver. -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.
    40. 40. Thrombocytopenia Thrombocytopenia is a reduction in platelet number below 150000/ul Causes: 1- Incidental thrombocytopenia of pregnancy 2- Increased consumption 3- Autoimmune thrombocytopenia (ITP) 4- SLE/APS 5-Activated clotting mechanism - Pre-eclampsia - HELP syndrome - DIC 6-Thrombotic thrombocytopenic purpura 7-Decreased platelet production (marrow suppression) -sepsis -HIV 8- Malignant marrow infiltration
    41. 41. IDIOPATHIC THROMBOCYTOPENIC PURPURA -Idiopathic thrombocytopenic purpura (ITP) is a common autoimmune disorder in which patients form antiplatelet autoantibodies against platelet-specific antigens Payne and colleagues (1997) studies of maternal ITP showed that 12 percent of newborns of ITP patients had severe thrombocytopenia
    42. 42. -Major bleeding is rarely seen unless the platelet count is <10x10/L -Maternal antibodies may cross the placenta and affect the fetus , causing neonatal thrombocytopenia. -four to ten percent of neonates are at risk of having sever thrombocytopenia at birth or during the 1st week of life.
    43. 43. FEATURES SUGGESTIVE OF THROMBOCYTOPENIA  Platelet count < 100,000/mm3  Increased numbers of megakaryocytes  Increased platelet volume
    44. 44. THROMBOCYTOPENIC COAGULOPATHIES TREATMENT Conservative management • Corticosteriods – if platelet count <20,000/mm3 before the onset of labor or < 50,000/mm3 at time of deliver • High dose IV immunoglobulin produces increase in platelet count • Significant hemorrhage – immediate postpartum period platelet transfusion • The theoretical risk of intracranial haemorrhage in the thrombocytopenic foetus has not been shown to be reduced by C/S therefore C/S should be performed for obstetric reasons
    45. 45. HELLP SYNDROME The acronym HELLP was coined by Weinstein in 1982 to describe a syndrome consisting of Hemolysis, Elevated liver enzymes and Low platelet count. DEFINITION- It is a syndrome that is characterized by hepatic endothelial disruption followed by platelet activation, aggregation and consumption, ultimately resulting in ischemia and hepatocyte death. The findings of this multisystem disease are attributed to- Abnormal vascular tone Vasospasm Coagulation defects
    46. 46.  1) Classical histological lesion in LIVER  2) Haemolysis  3) Thrombocytopenia  HELLP Syndrome - 0.2 to 0.6% of all pregnancies. In a multicenter study conducted on women with HELLP syndrome 40 percent had adverse outcomes such as subcapsular liver hematoma ,eclampsia,placental abruption, acute kidney injury, and pulmonary edema,stroke, coagulopathy, acute respiratory distress syndrome, and sepsis.
    47. 47. Laboratory findings Laboratory criteria for diagnosis — 1. Low platelets - < 100,000/µL 2. Elevated liver enzymes – AST > 70 IU/L - LDH > 600 IU/L 3. Haemolysis – Abnormal peripheral smear - Total bilirubin > 1.2mg%  Leukocytosis  Coagulation factors  S. uric acid – raised  Hypoglycemia-
    48. 48.  Peripheral smear shows- Spherocytosis Schizocytes Reticulocytosis Anisocytosis Triangular cells Helmet cells Burr cells Polychromasia HELLP syndrome - Schizocytes (vertical arrows), spherocytes, stomatocytes, and spheroacanthocyte (oblique arrow)
    49. 49. MANAGEMENT 1) Immediate delivery - at or more than 34 weeks gestation. 2) Delivery within 48 hours after evaluation and stabilization of the maternal clinical condition and Steroid treatment-27 to 34 weeks of gestation, 3) Expectant (conservative) management -before 27 weeks gestation Platelet transfusion PCV and FFP ROLE OF TRANSFUSION
    50. 50. DIC  An acquired syndrome characterized by systemic intravascular coagulation  Coagulation is always the initial event  DIC is the most common maternal complication with a reported frequency varying from 4-38% SYSTEMIC ACTIVATION OF COAGULATION Intravascul ar deposition of fibrin Depletion of platelets and coagulation factors Thrombosis of small and midsize vessels Bleeding Organ failure DEATHDEATH
    51. 51. Obstetric causes of DIC Falls into three categories  conditions associated with release of tissue thromboplastin that activates extrinsic pathway - placental abruption - dead foetus - molar pregnancy  Conditions associated with endothelial damage leading to activation of intrinsic & extrinsic pathways - pre-eclampsia & eclampsia  Conditions having non-specific or indirect action - amniotic fluid embolism - gram negative septicaemia - saline abortion
    52. 52. Clinical manifestations of DIC  Those of the underlying cause  Those due to Complications of DIC
    53. 53. Haemorrhagic manifestations Involving skin & mucus membranes  Ecchymosis  Petechiae  Bleeding from the gum  Haematuria  GIT bleeding  Venopunctur oozing  Intracranial or intracerebral haemorrhage
    54. 54. Thrombotic manifestations  Neurologic with multifocal lesions , delirium & coma  Dermatologic with focal ischemia & superficial gangrene  Renal with cortical necrosis and uraemia  GIT acute ulceration with bleeding  Vascular occlusion causing pulmonary infarction or peripheral vascular gangrene
    55. 55. Lab results  Markedly decreased platelet count  Markedly Increased fibrin degradation products FDP’s  Fragmented RBCs & microspherocytes in peripheral blood film  Low fibrinogen , factor II , V & VII  Prolonged PT, PTT & TT
    56. 56. Microscopic findings in DIC  Fragments  Schistocytes  Paucity of platelets
    57. 57. ๓ ธันวาคม ๒๕๕๑ T. TATU 65 Fragmented RBC
    58. 58. Treatment of DIC • Remove underlying cause • Replenish depleted factors • FFP Provides source of most factors • Cryoprecipitate provides fibrinogen • Platelet and blood support • Cautious use of heparin
    59. 59. Thrombophilia : Is defined as a predisposition to thrombosis, secondary to any persistent or identifiable hypercoagulable state. Although these disorders are collectively present in about 15 percent of population, they are responsible for more than 50 percent of all thromboembolic events during pregnancy DVT alone - more common antepartum whereas pulmonary embolism - more common in the first 6 weeks postpartum. It can be inherited or acquired: It should also be considered, in patients who have recurrent pregnancy loss, unexplained IUFD's and early severe IUGR.
    60. 60. Causes of thrombophilia Inherited 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. -The risk of thrombosis during pregnancy among antithrombin- deficient women without a personal or family history is 3 to 7 percent, and it is 11 to 40 percent with such a history . -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.
    61. 61. 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
    62. 62. ANTIPHOSPHOLIPID SYNDROME  The antibodies are directed against cardiolipin(s) or against phospholipid-binding proteins such as B2- glycoprotein  Women with moderate-to-high levels of these antibodies may have antiphospholipid syndrome, which is defined by a number of clinical features such as thromboembolism or recurrent early trimester unexplained fetal deaths.  It is found to be associated with 3.4% of early pregnancy loss
    63. 63.  It is postulated that they may interfere with the normal function of phospholipids or phospholipid- binding proteins involved in coagulation regulation, including prothrombin, protein C, annexin V, and tissue factor. Many of these antibodies are directed against b2-glycoprotein I, which may itself function as a natural anticoagulant
    64. 64. CONCLUSION  Blood coagulation is a major component of haemostasis. Increased Coagulation factors levels in pregnancy is meant to minimize blood loss at time of delivery  This haemostatic mechanism could fail risking patient’s life  Thrombocytopenic coagulation failure and DIC syndrome are the most commonly seen in obstetric practice  Congenital causes of coagulation failure are uncommon and usually already diagnosed prior to pregnancy
    65. 65.  DIC syndrome is always secondary to an underlying pathology  If diagnosis of DIC is missed or appropriate action is delayed it can cause serious maternal morbidity or even death  Platelet transfusion and coagulation factor replacement or fresh blood transfusion are the main stay of treatment besides other supportive therapy  Use of heparin is controversial . Haematologist opinion should be sought before it’s use.
    66. 66. References  Robbins and Cotran 8th edition  Dacie and Lewis Practical Hematology 10th edition  Williams Obstetrics 23rd edition  Uptodate, emedicine  Various Websites
    67. 67. Thank You
    68. 68. ITP  it is certainly not unusual for women who have been in clinical remission for several years to have recurrent thrombocytopenia during pregnancy. Although this may be from closer surveillance, hyperestrogenemia has also been suggested as a cause  Platelet-associated IgG antibodies cross the placenta and may cause thrombocytopenia in the fetus- neonate  Payne and colleagues (1997) studies of maternal ITP showed that 12 percent of newborns had severe thrombocytopenia