PHRM 542 Bleeding Disorders and Platelet Disorders

Define thrombocytopenia

Too few platelets

Describe the extrinsic coagulation pathway

Initiated by release of tissue thromboplastin from damaged tissue

Cascade to factor VII, V, and X

Describe the intrinsic coagulation pathway

Initiated by platelets releasing Hageman factor (factor XII)

Cascade to factor XI to IX or VIII to X

What is required for either coagulation pathway?

Calcium

What are the two major clotting cascade disorders?

von Willebrand disease

Hemophilia

Define von Willebrand disease

Genetic lack of functional von Willebrand factor (VWF), needed to bind factor VIII to form platelet plugs

What are the three types of von Willebrand disease?

Type 1 = less protein

Type 2 = dysfunctional protein

Type 3 = no protein

What are the two types of hemophilia?

Type A = deficiency in factor VIII

Type B = deficiency in factor IX

What is the MOA of desmopressin?

Modified ADH nonapeptide with increased selectivity for V2:V1

V2 is located on renal cells and non-tubule cells regulating coagulation = makes body release more VWF

What effects are common in overdose of desmopressin?

Hyponatremia and seizures

What is the route of administration of desmopressin?

Intranasal

Describe the metabolism of desmopressin

Reduction of the disulfide bond and peptide cleavage

What is the MOA of aminocaproic acid?

Inhibit plasminogen activation to prevent clot dissolution

Describe the kinetics of aminocaproic acid

Zero order kinetics

Describe the metabolism of aminocaproic acid

Minor metabolism into adipic acid

What is the MOA of tranexamic acid?

Inhibit plasminogen activation to prevent clot dissolution

10x more potent than aminocaproic acid

Describe the distribution of tranexamic acid

Passes through placental barrier in to breast milk

What is the MOA of von Willebrand factor?

Recombinant VWF (rVWF) that promotes hemostasis by helping platelets adhere to collagen and protects factor VIII from proteolysis

What are notable ADEs of rVWF?

Hypersensitivity reaction and antibody production

Can increase thrombotic events and embolisms

Describe the metabolism of rVWF

Protein breakdown

Efanesoctocog alpha

Altuviiio

What is the MOA of Altuviiio?

Anti-hemophilic factor, Fc-VWF-XTEN fusion protein

What are notable ADEs of Altuviiio?

Hypersensitivity reaction and antibody production

HA, arthralgia, back pain

Describe the metabolism of Altuviiio

Protein breakdown

What is the MOA of emicizumab?

Monoclonal, bispecific antibody that binds two entities at once

Binds activated factor IX and factor X to bring them together and mediate the function of factor VIII

What are notable AEs of emicizumab?

Can increase clotting = thromboses and embolisms

Injection site reaction, HA, arthralgia

What is the route of administration of emicizumab?

Sub-cutaneous

Concizumab mtci

Alhemo

What is the MOA of Alhemo?

Targets tissue factor pathway inhibitor (TFPI) = natural soluble anticoagulant

When blocked = more coagulation

How often is Alhemo administered?

SQ once daily

What are ADEs of Alhemo?

Infusion reactions, HA, nausea, diarrhea

Marsticimab

Hympavzi

What is the MOA of Hympavzi?

Targets tissue factor pathway inhibitor (TFPI) = natural soluble anticoagulant

When blocked = more coagulation

How often is Hympavzi administered?

SQ once weekly

What are ADEs of Hympavzi?

Infusion reactions, HA, itching

What is a curative gene therapy for hemophilia A?

Valoctocogene roxaparvovec (Roctavian)

What is the MOA of Roctavian?

AAV-FVIII goes to liver to make FVIII

Vector integrates into host genome and expression is controlled by liver-specific promotor

How often is Roctavian administered?

Infused once, works for up to 5 years

What are ADEs of Roctavian?

Infusion reactions, increased liver enzymes, HA, nausea, fatigue

Risk of thromboses and hepatic malignancy

What is a curative gene therapy for hemophilia B?

Etranacogene dezaparvovec-DRLB (Hemegenix)

What is the MOA of Hemegenix?

AAV-FIX goes to liver to make FIX

Vector integrates into host genome, expressed in liver

How often is Hemegenix administered?

Infused once

What are notable ADEs of Hemegenix?

ALT elevation, CK increase, HA, infusion reaction, malaise, flu-like symptoms

Risk of hepatic malignancy

Fitusiran

Qfitlia

What is the MOA of Qfitlia?

RNAi based therapy that inhibits production of antithrombin, resulting in more thrombin activity

How often is Qfitlia administered?

SQ q2 months

What are risks associated with Qfitlia?

Increased clots, increased liver enzymes, gall bladder disease