Clotting Disorders James Czarnecki, D.O.

Classification

Afibrinogenemia / Dysfibrinogenemia

Classification Disorders of nonplatelet hemostasis can be divided into 2 groups based on whether they increase or decrease coagulation: Coagulation-promoting conditions Coagulation-impeding conditions

Coagulation-promoting hemostasis Procoagulant afibrinogenemia / dysfibrinogenemia Protein C deficiency Protein S deficiency Antithrombin III deficiency Factor V Leiden deficiency Activated protein C resistance Disseminated intravascular coagulation

Coagulation-impeding Conditions Anticoagulant afrinogenemia/dysfibrinogenemia Factor V deficiency Factor VII deficiency Factor X – X III deficiency Hemophilia A Hemophilia B Hypoprothrombinemias

Pathophysiology

Pathophysiology Fibrinogen disorders may have both congenital and acquired etiologies. Congenital afibrinogenemia is defined as a deficiency or absence of fibrinogen (coagulation factor I) in the blood. Dysfibrinogenemias are classified as qualitative alterations in the conversion of fibrinogen to fibrin that are caused by structural defects.

Pathophysiology Approximately 300 abnormal fibrinogens have been reported, and about 83 structural defects have been identified. The most common structural defect involves the fibrinopeptides and their cleavage sites. The second most common involves the gamma-chain polymerization region.

Pathophysiology True prevalence of congenital fibrinogen disorders is unknown. No variation by race, age, or sex is known. Mortality is related to the severity of bleeding and/or to thrombotic complications at presentation.

Presentation

Presentation While most patients with dysfibrinogenemia are asymptomatic, some can present with: Bleeding diathesis Thrombophilia Both bleeding and thromboembolism Dysfibrinogenemias present particular problems for the obstetrician because women affected by these disorders are at risk of first-trimester bleeding, spontaneous abortion, and/or postpartum thrombosis.

Presentation (continued) Diagnosis of abrinogenemia / dysfibrinogenemia should be considered in a patient who has bleeding or thrombosis unexplained by other common disorders. A high level of clinical suspicion should be maintained in patients with other inherited disorders of hemostasis, such as protein C or S deficiency.

Presentation (continued) Laboratory diagnosis of dysfibrinogenemia is difficult Screen test results (PT, aPTT) may be WNL

Presentation (continued) Fibrinogen levels are decreased in: DIC Primary and secondary fibrinolysis Liver Disease Fibrinogen levels are increased in: Pregnancy Oral contraceptive use

Treatment Depends on clinical setting Plasma fibrinogen can be replacd by the infusion of fresh frozen plasma and cryoprecipatate. Prophylactic blood product or fibrinogen therapy has no role.

Protein C, Protein S, Antithrombin III, and Factor V Leiden Deficiencies

Background - General All are essential components of the coagulation process. All are synthesized by the liver and have a half-life in the range of 4-6 hours.

Antithrombin III Activated antithrombin III is a major inhibitor of thrombin and factor Xa, with smaller effects on factors IX, XI, and XII. Binds to the endothelial cell surface in the presence of injury. Forms a subendothelial cell matrix that neutralizes thrombin by complexing with it. Serves as a cofactor for exogenous heparin.

Protein C & S Are Vitamin K-dependent factors that participate in the thrombomodulin-protein C system. Thrombomodulin and thrombin form a complex on the endothelial cell plasma membrane in response to injury, with activated protein S serving as a cofactor.

Protein C & S This complex in turn attracts and binds protein C in the presence of calcium ion to produce activated protein C (aPC). aPC then inactivates factors Va and VIIIa, thus halting the coagulation cascade. Also neutralizes plasminogen-activator inhibitor-I, thereby facilitating fibrinolysis.

Antithrombin III / Protein C & S Deficiencies may lead to thrombophilia. Clinical thrombophilia is defined as an early thomboembolic episode (occurring before age 50) spontaneous thrombosis, recurrent thrombosis, unusual site of thrombosis, family history of thrombotic episodes, or coumarin-induced skin necrosis complications

Antithrombin III / Protein C & S Such patients may have an isolated or combined inherited deficiency in the proteins involved in coagulation. Diagnosis is confirmed by the identification of an isolated or combined inherited coagulant deficiency.

Antithrombin III / Protein C & S Affected patients with inherited thrombophilia are at risk of developing thromboembolic disease ranging from mild, superficial venous thrombosis to lethal pulmonary embolism.

Antithrombin III / Protein C & S The most frequent venous problem was DVT with or without pulmonary embolism: 90% in antithrombin III deficiency 88% in protein C deficiency 100% in protein S deficiency

Antithrombin III / Protein C &S The frequency of these defects in the population place: Antithrombin III deficiency at 0.5-9.4% Protein C deficiency at 1.4-8.6% Protein S deficiency at 1.4-7.5%

Factor V Leiden Factor V has both procoagulant and anticoagulant properties Activated factor V stimulates the formation of thrombin, whereas anticoagulant factor V acts as a cofactor for aPC in the degradation of factor VIII and factor VIIIa, thereby reducing thrombin formation

Factor V Leiden High procoagulant factor V levels may enhance prothrombinase activity and increase the risk of thrombosis. Low anticoagulant factor V levels can reduce aPC cofactor activity in the inactivation of factor VIII, which in turn might also promote thrombosis.

Factor V Leiden Factor V deficiencies can be classified as: Homozygous and heterozygous “true” factor V deficiency Combined factor V and factor VIII deficiencies Type I (association type) Type II (common defect)

Factor V Leiden Classification of the thrombotic factor V defects included: Homozygous and heterozygous factor V Leiden Combined heterozygous factor V Leiden and hertozygous true factor V deficiency

Factor V Leiden Factor V Leiden mutation (R506Q) is the most common cause of aPCR, which itself is defined as a hemostatic disorder characterized by a poor anticoagulant response to aPC. In this state, the activated form of factor V (factor Va) is more slowly degraded by aPC.

Factor V Leiden Most frequent clinical manifestations of aPCR or factor V Leiden deficiency are SVT or DVT and/or pulmonary embolism and thrombosis at an unusual site. Risk of thrombosis associated with pregnancy was high in the postpartum period, especially in homozygous women.

Factor V Leiden Mild prolongation of PT and aPTT may provide the first evidence of aPCR. Possibility should be immediately confirmed by specific factor V activity and antigen assays. Laboratory screening for aPCR is performed by functional tests measuring the effect of aPC on aPTT in plasma containing a heparin neutralizer.

Antithrombin III / Protein C & S / Factor V Leiden Treatment of these deficiencies requires a high index of clinical suspicion and laboratory investigation to confirm the diagnosis. Lifelong anticoagulation with oral warfarin is recommended in patients with proven thrombophilia.

Disseminated Intravascular Coagulation

DIC - Definition Defined as a syndrome characterized by an alteration in the elements involved in blood coagulation due to their use / destruction in widespread blood clotting within the vessels.

DIC - Background May be caused by a wide variety of disorders: Hemorrhage, trauma, sepsis, toxic shock syndrome. Endotoxin release, abruptio placentae, and amniotic fluid embolism. Sepsis is the most common cause of DIC.

DIC - Background Etiology and progression of DIC are multifactorial and are characterized by defects in the protein C system and in the antithrombin and tissue-factor inhibitor pathways. Release of tissue factor from endothelial cells or other circulating cells is the most common initiating event.

DIC - Background If natural inhibitors are abundant, and if the causative agent or disease is corrected, DIC may be halted in a compensated state. Persistence of the triggering agent leads to a consumption coagulopathy, with loss of fibrinogen and platelets and the potential for diffuse bleeding. Failure of the fibrinolytic system elicits deposition of microvascular fibrin and multisystem organ failure.

DIC - Epidemiology In a study of by Okajima et al examined the incidence, clinical presentation, and underlying disorders associated with DIC in a series of 1882 subjects, of which 204 were diagnosed as having DIC (overall incidence of 10.8%).

DIC - Epidemiology Malignancies led the list of underlying disorders with 33.8% of subjects having solid tumors, and 12.7% having hematologic malignancies.

DIC - Epidemology Rest of the patients had aortic aneurysm (10.8%), infections (6.4%), unspecified postoperative complications (4.4%), liver disease (2.9%), obstetric disorders (2.5%), and various miscellaneous diseases (26.5%) completed this diverse list.

DIC - Diagnosis The diagnosis of DIC is based on both clinical suspicion of DIC and a combination of laboratory test findings. Patients with the following known underlying causes should be carefully observed for indications of the development of DIC:

DIC - Diagnosis Malignancy Trauma Aortic aneurysm Cerebral injury Hepatic surgery Burn injury Hypothermia Massive transfusion Prolonged surgery

DIC - Treatment Treatment can be divided into these components: Treatment of the underlying disorder Supportive management of bleeding complications Treatment aimed at the coagulation process

DIC - Treatment Triggering underlying disease must be treated aggressively. This may require surgical drainage of an abscess or necrotic tissue, antibiotic therapy, control of temperature, volume replacement, etc. Early recognition and treatment of DIC is the key to success, so a high index of clinical suspicion must be maintained.

DIC - Treatment Continued DIC is characterized by a consumption coagulopathy of platelets. Ongoing bleeding or rapid hemorrhage may lead to anemia. Treatment should be aimed at correction of the patient’s clinical condition, not at a measured deficit. Red blood cell transfusions may increase the fibrin deposition in DIC, so they should be used with caution.

DIC - Treatment Heparin has been used as the mainstay of treatment of DIC for more than 30 years with little evidence of benefit. A trial of low molecular weight dalteparin compared to unfractionated heparin showed less bleeding and better organ system scores, but it demonstrated no survival benefit.

DIC - Treatment Generally, the earlier treatment is initiated, the better the patient’s prognosis.

Coagulation-impairing Deficiencies

Factor V Deficiency

Factor V Deficiency Both procoagulant and anticoagulant properties Activated factor V stimulates the formation of thrombin Anticoagulant factor V acts as a cofactor for aPC in the degradation of factor VIII/VIIIa, thereby reducing thrombin formation

Factor V Deficiency Severity of the condition varies from bruising to lethal hemorrhage. Acquired inhibitors of factor V are rare causes of clinical bleeding, with severity ranging from mild to life threatening.

Factor V Deficiency Optimal treatment of patients with factor V inhibitors is uncertain. Combinations of therapies (plasma exchange and chemotherapy) may be needed in patients with serious hemorrhage caused by factor V deficiency or inhibitors.

Factor V Deficiency Combined deficiency of coagulation factor V and factor VIII is an autosomal recessive disorder observed in a number of populations around the world. The disease appears to be most common in the Mediterranean basin.

Factor VII Deficiency

Factor VII Deficiency It is a vitamin K-dependent glycoprotein essential to the extrinsic pathway of coagulation. Deficiencies may be inherited as an autosomal recessive characteristic or acquired in association with vitamin K deficiency, sepsis, autoantibodies, and inhibitors.

Factor VII Deficiency The prevalence of congenital deficiency is low, with only 238 individuals with factor VII gene mutations described in the world literature. Predisposition to bleeding is variable, and to some extent depends on the amount of plasma factor VII activity.

Factor VII Deficiency In congenital factor VII deficiency, the clinical picture is related to the levels of factor VII coagulant activity. Individuals homozygous for the mutation who have complete absence of factor VII activity in plasma usually die shortly after birth because of severe hemorrhage.

Factor VII Deficiency Clinical symptoms and factor VII activity levels in plasma are rather poorly related. Patients may have prolonged PTs, but the final diagnosis is established by quantitative factor VII assays.

Factor VII Deficiency Treatment consists of factor replacement with fresh frozen plasma, prothrombin complex concentrates, or factor VII concentrates. Recombinant activated factor VII is a very useful alternative. Because of the short half-life of factor VIIa, repeated doses must be administered.

Factor X Deficiency

Factor X Deficiency Usually inherited as an autosomal recessive trait, though it can be acquired. Characterized by defective activity in both the intrinsic and extrinsic pathways, impaired thromboplastin time, and impaired prothrombin consumption.

Factor X Deficiency Factor X circulates as a serine protease that is activated at the point of convergence of the intrinsic and extrinsic coagulation pathways. Activated factor Xa is involved in macromolecular complex formation with its cofactor factor Va, a phospholipid surface, and calcium to convert prothrombin into thrombin.

Factor X Deficiency Factor X deficiency may be acquired in patients with light chain-related amyloidosis. Treatment of acquired factor X deficiency is difficult. In 2001, therapy resorted to daily therapeutic plasma exchange with concomitant administration of intravenous immunoglobulin and steroids.

Factor X Deficiency The therapy produced a rapid increase in factor X levels, which controlled bleeding, and was followed by gradual recovery of normal factor X levels and correction of coagulation times. Splenectomy eliminates the acquired factor X deficiency in amyloidosis, but control of operative bleeding may require recombinant factor VII.

Factor XI Deficiency

Factor XI Deficiency The congenital deficiency of blood coagulation factor XI results in a systemic blood-clotting defect called hemophilia C or Rosenthal syndrome, which may resemble classic hemophilia. It is a key component of the intrinsic pathway of blood coagulation in vitro, but its exact role in vivo is uncertain.

Factor XI Deficiency Factor XI is activated by thrombin and may participate in clot formation once coagulation has been initiated by other mechanisms. Risk of bleeding depends on the severity of the deficiency in certain situations and on the location of the bleeding site in others.

Factor XI Deficiency Approximately 40-50% of all persons lacking factor XI are of Ashkenazi Jewish extraction. May be considered in patients evaluated for hemorrhage or unexplained, prolonged aPTT or through family or other genetic studies.

Factor XI Deficiency Individuals with factor XI deficiency need to be careful in planning for elective surgery and dental extractions. Successful treatments have included fresh frozen, fibrin glue, antifibrinolytic drugs, desmopressin, and factor XI concentrates.

Factor XII Deficiency

Factor XII Deficiency Defined as an absence or reduced level of blood coagulation factor XII (Hageman factor). Initiates the intrinsic coagulation cascade and is linked to the fibrinolytic, kallikrein-kinin, and complement systems. Promotes the conversion of factor XI to its activated form.

Factor XII Deficiency Typically occurs in the absence of a patient or family history of hemorrhagic disorders and is marked by prolonged clotting time. May be considered in patients with prolonged aPTT, normal PT, normal bleeding time, and no clinical history of bleeding. Confirmed by normalization of aPTT with plasma component therapy and by factor assay.

Factor XII Deficiency Has clinical significance when attempts are made to heparinize patients who have this condition. Routine coagulation tests used return abnormal findings in patients with factor XII deficiency and are useless for monitoring anticoagulation in these patients. Alternative monitoring systems, such as chromogenic heparin assay, citrated thrombin time, and recalcified thrombin time, must instead by used.

Factor XIII Deficiency

Factor XIII Deficiency Is a decrease or absence of factor XIII that prevents blood-clot formation and results in a clinical hemorrhagic diathesis. Factor XIII is an enzyme found in plasma, platelets, and monocytes.

Factor XIII Deficiency In plasma, factor XIII has 2 subunits: the a subunit, which is the active enzyme and the b subunit, which is a carrier protein. Activated factor XIII stimulates cross-linkage of fibrin as a means of stabilizing a clot.

Factor XIII Deficiency Congenital deficiency is a severe autosomal recessive bleeding disorder associated with a characteristic pattern of neonatal hemorrhage and lifelong bleeding diathesis. Untreated patients have a high mortality rate. Intracranial hemorrhage is a frequent complication.

Factor XIII Deficiency The disorder affects both sexes, and bleeding may occur during pregnancy. Acquired factor XIII deficiency has been described in: Henoch-Scholein purpura, various forms of colitis, erosive gastritis, and some forms of leukemia. Inhibitors to factor XIII are rare.

Factor XIII Deficiency Treatment requires lifelong prophylactic therapy with at least monthly infusions of factor XIII concentrate, even during pregnancy.

Competency Exam

Question One All of the following are causes of disseminated intravascular coagulation. Pick the one cause which is the most common: Hemorrhage Toxic shock syndrome Endotoxin release Sepsis Amniotic fluid embolism

Question One All of the following are causes of disseminated intravascular coagulation. Pick the one cause which is the most common: Hemorrhage Toxic shock syndrome Endotoxin release Sepsis Amniotic fluid embolism

Question Two True or False: The prevalence of antiprothrombin III and protein C and protein S in the general population is greater than 20%.

Question Two True or False: The prevalence of antiprothrombin III and protein C and protein S in the general population is greater than 20%.

Antithrombin III / Protein C &S The frequency of these defects in the population place: Antithrombin III deficiency at 0.5-9.4% Protein C deficiency at 1.4-8.6% Protein S deficiency at 1.4-7.5%

Question Three Which of the following deficiencies results in a systemic blood-clotting defect called Rosenthal syndrome: Factor V Factor VII Factor XI Factor XII Factor XIII

Question Three Which of the following deficiencies results in a systemic blood-clotting defect called Rosenthal syndrome: Factor V Factor VII Factor XI Factor XII Factor XIII

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