HEMA Chapter 40 (Reading Assignment)

Coagulation cascade

The hemostatic system is referred to as?

Thrombin

It converts fibrinogen to fibrin clot

Secondary Hemostasis

Initiated by Tissue Factor Pathway (TFP)

PT and APTT

Routine coagulation tests used to identify a hemostatic defect in a bleeding patient

Acquired Coagulopathy

Multiple coagulation defects rather than specific protein defects

Von Willebrand factor

This factor helps platelets adhere to the injured vessel wall, binding to exposed collagen at A3 domain and to the platelet receptor GP Ib/IX/v complex

Phosphatidylserine

Activated platelets offer the most important source of negatively charged phospholipids, which is?

Vitamin K

It is required for essential y-carboxylation reaction that takes place on glutamic acid residue of each protein located in their amino acid terminal regions

Protein S

It is a natural anticoagulant which is Vitamin-K dependent and acts as a cofactor for APC

• Factor II

• Factor VII

• Factor IX

• Factor X

Phospholipid-bound proenzymes are the following:

• Factor XI

• Factor XII

• Prekallikrein

Surface-bound proenzymes are the following:

Contact System

Surface-bound proenzymes are also called?

Prekallikrein and HMWK

Not associated with bleeding but have a role in arterial and venous thrombosis

Polyphosphate (PolyP)

• It is identified as an activator of the contact phase

• It is a potent activator of thrombin and coagulation FXI

• Accelerates FV activation and abolishes the inhibitory effect of TFPI

Tissue factor

47-kDa protein that is an essential cofactor for activated FVIIa

Factor VIII (Antihemophilic Factor)

• A 330-kDa protein that when activated to FVIIIa, serves as a cofactor for FIX in the activation of FX

• Absence of this factor will associate with the most severe bleeding disorder such as hemophilia

Factor V

A 330-kDA protein with homology to FVIII that when activated to FVa, serves as a cofactor for FXa in the activation of FII (Prothrombin) to thrombin

Fibrinogen

It is the principal adhesive molecule for platelet aggregation

Factor VIII and IX

Deficiencies in which factors are the most common bleeding disorders in patients who survive gestation and birth?

Plasminogen

It is converted to plasmin mainly by endogenous tissue plasminogen activator (tPA)

PAI-1

It is the major inhibitor of tPA and TcuPA

a2-Antiplasmin

It is the most potent and highly selective inhibitor of plasmin

TAFI

• It is a carboxypeptidase that removes lysine residues from fibrin, indirectly controlling plasmin activity by interfering with plasminogen and tPA binding to fibrin.

• It also regulates the fibrinolytic system

Plasmin

It is a potent protease that recognizes multiple substrates and degrades soluble fibrinogen

• Thrombin formation

• Clot formation

• Cross-linking by FXIIIa

• Plasmin-mediated fibrin degradation

D-D dimer presence confirms:

Antithrombin (AT)

It is the main serine protease inhibitor of the plasma serine protease inhibitor system.

Protein C

A 62-kDa vitamin K–dependent protein that functions as an inhibitor when activated.

Factor Va and Factor VIIIa

The complex formed by APC + EPCR needs to dissociate in order to allow binding of APC with protein S to inactivate?

Protein S

A 69-kDa protein which allows APC to bind to cell surfaces in such a manner as to orient itself to inactivate FVa and FVIIIa.

• EPCR

• PAR 1

• ApoER2

APC binds to three receptors on endothelial cells:

APC

It reduces thrombin formation, stimulates fibrinolysis, and initiates inflammation to reduce thrombosis risk.

Factor IIa and Factor Xa

Antithrombin (AT) exerts its anticoagulant effect primarily by inhibiting which factors?

• Heparin-binding site

• Reactive site (Arg329-Ser394)

The two functional sites of Antithrombin:

Antithrombin (AT)

The presence of __________ gives heparin its anticoagulant properties.

Heparin cofactor II

It is a serpin that specifically inhibits thrombin in the presence of dermatan sulfate.

Protein Z inhibitor

It is a serpin that specifically inhibits factor Xa in the presence of its cofactor, protein Z

C1 esterase inhibitor

It is the most potent inhibitor of FXIIa, kallikrein, and FXIa in plasma.

C1 esterase inhibitor

It serves to regulate the amount of free bradykinin in the intravascular compartment and reduce inflammatory events

Type I and II hereditary angioedema

The absence of C1 inhibitor is the causative factor for:

Hereditary angioedema

It is a disorder associated with excessive bradykinin delivered to tissues

TFPI

Kunitz-type serine protease inhibitor

TFPI

It is the most potent inhibitor of the FVIIa–tissue factor complex

amyloid β-protein precursor (AβPP)

This inhibitor is believed to be a cerebral anticoagulant

PGI2

It is a vasodilator and inhibits platelet aggregation

Cartilage oligomeric matrix protein (COMP)

• It inhibits thrombin and acts as a natural anticoagulant in mice.

• It determines a dose-dependent prolongation of thrombin time.

Regulation of TF expression

Major control mechanism for the initiation of hemostasis

Intrinsic pathway

Which pathway amplifies and propagates thrombin generation?

TF pathway

Which pathway is the initiator of coagulation?

9:1 ratio (blood:citrate)

Whole blood is collected in 3.2% sodium citrate (blue top) in a:

International normalized ratio (INR)

It was developed to harmonize PT results for monitoring vitamin K antagonist (VKA) therapy

APTT

This test generally assesses coagulation factors in the intrinsic pathway as well as the common pathway

APTT-FS

Which APTT reagent has the highest amount of PL?

APTT-LA

Which APTT reagent has the smallest amount of PL?

Bovine thrombin

In thrombin time, what type of thrombin is added to the patient’s plasma?

Fibrinogen assay

It is measured routinely in a bleeding patient and patients with cirrhosis.

Thrombin time (Clauss method)

The fibrinogen assay is based on?

Clot undergoing lysis in the circulation

Increased D-dimers suggest:

Disseminate intravascular coagulation (DIC)

Elevated D-dimer levels suggest:

DVT and Pulmonary embolism

Decreased D-dimer levels suggest:

Every 6 to 12 months

The APTT therapeutic range established for each new lot number of APTT reagents is:

Heparin resistance due to high FVIII

An anti-Xa assay should be used to monitor UFH in the case of:

Anti-Xa assay

Provides accurate measurement of both UFH and low molecular-weight heparin (LMWH) levels

One-stage clot-based assays

Most commonly used methods for coagulation factors

Nonparallel curve

The curve obtained in the presence of LA is known as a:

Normal APTT

Hemophilia A patients on Emicizumab have :

TEG and ROTEM

Two global hemostasis assays with similar principles for viscoelastic measurement of a clot in real time

Amount of thrombin generated

Clotting time in ROTEM or reaction time in TEG reflects:

FIBTEM

Test which contains cytochalasin B to block platelet function

Hemophilia A

Most common severe congenital bleeding disorder

VWF (2N)

Abnormality in which a missense mutation in VWF impairs its capacity to bind to and promote FVIII secretion into plasma

50%

Hemophilia A carriers are expected to have approximately ____ of normal factor activity

Prenatal diagnosis

Performed at a number of high-risk obstetric centers by chorionic villous sampling at 9 to 14 weeks’ gestation

Fetoscopic blood sampling

• Performed at 20 weeks’ gestation for coagulation factor analysis

• Higher risk; less precise

Fetal deoxyribonucleic acid

Detectable in maternal circulation within 10 days of conception

To prevent or reverse bleeding episodes, spontaneously occurring, traumatic, or surgically induced.

Primary principle of hemophilia treatment:

Recombinant FVIII and FIX concentrates

Treatment of choice for hemophilia A and B

A simple mixing test as described previously for the APTT can:

Imidazole buffered saline (IBS)

In the Classic Bethesda assay, patient’s plasma is serially diluted with

1 BU

Amount of inhibitor antibody in patient plasma that inhibits half the FVIII activity in the control plasma

Measures the inhibitor titer against factor VIII

What is the purpose of the Bethesda assay?

Emicizumab

Genetically engineered bispecific IgG antibody that functions as an “FVIII mimetic”

Fitusiran (Sanofi-Genzyme)

Therapy for hemophilia A and B which interferes with antithrombin synthesis in the liver and, thus, leads to increased thrombin generation in vivo

Concizumab (Novo Nordisk)

Third disruptive therapy for Hemophilia A & B in which monoclonal antibody blocks TFPI

Ashkenazi Jews

FXI deficiency is common in:

Afibrinogenemia

Bleeding disorder of variable severity

Hypofibrinogenemia

Decreased level of normal fibrinogen that has a similar but milder pattern of bleeding

Dysfibrinogenemia

Qualitative fibrinogen deficiency characterized by the production of dysfunctional fibrinogen

Reptilase

It clots fibrinogen by liberating only fibrinopeptide A

Cryoprecipitate

Serves as a good source of fibrinogen when replacement is needed

Factor II deficiency

Rarest inherited coagulation factor deficiency

• Mucosal tract bleeding

• Bleeding after invasive procedures

The most frequent symptoms of Factor V deficiency:

Platelet transfusion

Acquired factor V deficiency is treated with:

Homozygous FX deficiency

It is a severe bleeding disorder that presents in infancy

Factor VII deficiency

The most common rare hereditary coagulation factor deficiency

Factor XIII deficiency

• It can determine delayed bleeding usually 24 to 36 hours after surgery or trauma

• Spontaneous bleeding also occurs

• Clot dissolution in 5M urea

• Monochloroacetic acid

It is useful for the diagnosis of Factor XIII deficiency

Euglobulin lysis time (ELT)

Evaluates the global function of the fibrinolytic system

Microangiopathic hemolytic anemia (MHA) with schistocytes and helmet cells

PBS examination for acute and chronic DIC shows:

Plasma

In a patient w/ acute DIC with bleeding, what is used to correct coagulopathy?

Factor VIII and VWF

Hepatocytes synthesize all coagulation factors except: