Fellowship of infertility Thrombophilia Dr .zhila Abedi Asl Fellowship of infertility Bahman hospital IVF center

Overview of Hemostasis Hemostasis is the process of blood clot formation at the site of vessel injury. When a blood vessel wall is disrupted, the hemostatic response must be quick, localized, and carefully regulated. Abnormal bleeding or thrombosis (ie, nonphysiologic blood clotting not required for hemostatic regulation) may occur when specific elements of these processes are missing or dysfunctiona.

PHASES OF THE HEMOSTATIC PROCESS Endothelial injury and formation of the platelet plug. Propagation of the clotting process by the coagulation cascade. Termination of clotting by antithrombotic control mechanisms. Removal of the clot by fibrinolysis. 

SUMMARY OF HEMOSTASIS When the pathways of clot formation and clot lysis are appropriately linked, a clot is laid down initially to stop bleeding, followed later by clot lysis and tissue remodeling . Abnormal bleeding can result from diminished clot generation or enhanced clot lysis, while excessive clot formation or reduced clot lysis can lead to excessive thrombosis. The following phases coordinate this overall process. •Platelets are activated at the site of vascular injury to form a platelet plug that provides the initial hemostatic response, including exposure of procoagulant phospholipids on the platelet surface and the assembly of components of the clotting cascade. •Generation or exposure of tissue factor at the wound site, its interaction with factor VIIa and the subsequent generation of activated factor X, are the primary physiologic events in initiating clotting, while components of the intrinsic pathway (ie, factors VIII, IX, XI) are responsible for amplification of this process. •The termination phase of coagulation involves antithrombin, tissue factor pathway inhibitor and the protein C pathway . This phase is critical in mediating the extent of clot formation, as demonstrated by the thrombotic disorders present in individuals with abnormalities in this pathway. •To restore vessel patency, the clot must be organized and removed. Plasminogen binds fibrin and tissue plasminogen activator (tPA) leading to active, proteolytic plasmin, which cleaves fibrin, fibrinogen, and a variety of plasma proteins and clotting factors. The plasminogen/plasminogen-activator system is complex, paralleling the coagulation cascade 

Maternal adaptation to pregnancy Pregnancy is a prothrombotic state due to changes in several procoagulant and anticoagulant factors . Most pregnant women do not require coagulation testing, but if testing is performed, the prothrombin time and activated partial thromboplastin time are typically normal or slightly decreased (shortened). Certain tests of coagulation such as the D- dimer lack sensitivity and specificity during pregnancy. Pregnancy-related hematologic changes generally return to baseline by six to eight weeks after delivery. Failure to do so indicates the need for additional evaluation.

Maternal adaptation to pregnancy PLATELETS    Platelet counts decline as pregnancy progresses, but they remain in the normal nonpregnant range (approximately 150,000 to 450,000/microL) . In the vast majority of uncomplicated pregnancies, the platelet count remains >100,000/microL and returns to the prepregnancy baseline level by several weeks postpartum. The most common cause is a normal physiologic response referred to as gestational thrombocytopenia (GT; also called incidental thrombocytopenia of pregnancy). GT is a diagnosis of exclusion; there are no specific laboratory tests. GT may recur in subsequent pregnancies. We generally do not evaluate women with a mild decrease in platelet count during pregnancy as long as they are asymptomatic and their platelet count is >100,000/microL. Moderate to severe thrombocytopenia (platelet count <100,000/microL) is rare in pregnancy, but when it occurs, it may be a medical emergency. Possible causes include immune thrombocytopenia, severe preeclampsia, sepsis with disseminated intravascular coagulation; hemolysis, elevated liver function tests, and low platelets syndrome; thrombotic thrombocytopenic purpura; antiphospholipid syndrome; and drug-induced thrombocytopenia.; early involvement of the consulting hematologist is advised.

Maternal adaptation to pregnancy COAGULATION AND FIBRINOLYSIS   Normal pregnancy is a prothrombotic state . The shift in the balance between the hemostatic and fibrinolytic systems serves to prevent excessive hemorrhage during placental separation. Compared with nonpregnant women, pregnant women have a marked increase in some coagulation factors, reduced fibrinolysis, and increased platelet reactivity. As a consequence, there is increased risk for thromboembolic complications. While these changes increase the risk of thrombosis, they are not in and of themselves an indication for intervention.

The following changes Increased procoagulant factors: •Procoagulant factors fibrinogen, factors II, VII, VIII, X, XII, and XIII increase by 20 to 200 percent . •The prohemostatic von Willebrand factor (VWF) can increase substantially from baseline during pregnancy. Studies have reported that VWF increases by two- to fourfold during pregnancy, peaks within 24 hours postpartum, and returns to baseline by one month postpartum . Reduced anticoagulant factors •The anticoagulant protein S decreases physiologically in nearly all pregnant women, such that they appear protein S deficient based on reference ranges established for normal populations (measured as total protein S, free protein S, and protein S activity) . If a pregnant woman has a venous thromboembolism (VTE) during pregnancy and concern for an inherited thrombophilia, testing of protein S levels should be deferred until after delivery. However, most pregnant women with VTE do not require thrombophilia testing. •The anticoagulant antithrombin (AT) decreases by approximately 20 percent . Immediately after birth, AT levels fall to 30 percent below baseline level, with a nadir reached approximately 12 hours after delivery. AT levels return to baseline by 72 hours postpartum. The relatively large and rapid changes in the postpartum levels of AT have not been consistently documented, likely in part because both the reduction and resolution are swift . Reduced fibrinolysis •Activity of fibrinolytic inhibitors increases, including thrombin activatable fibrinolytic inhibitor, plasminogen activator inhibitor-1 (PAI-1), and PAI-2 . PAI-1 levels increase markedly derived from the placenta and decidua.

INHERITED THROMBOPHILIAS Inherited thrombophilia is a genetic tendency to venous thrombosis. The most common inherited thrombophilias are the factor V Leiden (FVL) mutation and the prothrombin gene mutation (PGM), which together account for 50 to 60 percent of cases of an inherited (primary) hypercoagulable state in Caucasian populations. Deficiencies in protein S, protein C, and antithrombin (AT) account for most of the remaining cases. FVL mutation Prothrombin G20210A mutation leading increased prothrombin level Protein S deficiency Protein C deficiency AT deficiency

KNOWN AND POSSIBLE COMPLICATIONS Risk of VTE Risk of pregnancy complications; Spontaneous abortion, fetal loss, and stillbirth Fetal growth restriction Preeclampsia  Abruption Fetal demise, growth restriction, preterm birth, perinatal stroke, and cerebral palsy have been reported, but these reports included only a few affected patients .

SELECTION OF PATIENTS FOR SCREENING History of VTE associated with a transient risk factor . History of idiopathic (unprovoked) VTE, recurrent VTE, or VTE in association with estrogen-progestin contraceptive use or pregnancy. No prior VTE but a first degree relative with a history of a high-risk thrombophilia.

Not screen the following women Women with a history of recurrent or nonrecurrent early fetal loss, abruption, fetal growth restriction, or preeclampsia.  There is a lack of evidence of a causal association between inherited thrombophilia and these conditions, and a lack of evidence that administration of anticoagulant drugs to such women is effective in improving pregnancy outcomes  Couples with IVF failure .  Inherited thrombophilia is not associated with failure to conceive or implantation failure. FVL heterozygosity is associated with a significantly shorter median time to conception (11 weeks) compared with non- carriers (23 weeks) (HR 1.94, 95% CI 1.03-3.65), suggesting improved implantation rates . Inherited thrombophilias have been associated with higher live birth rates following assisted reproductive technologies (ART), further evidence of thrombophilia-associated enhanced implantation

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