Drugs for Coagulation Disorders Flashcards
Factors XII –> XIIa is the start of which pathway? 1)
It is activated by exposure of 2);
Other necessary components for this pathway to initiate are 3)
1) INTRINSIC
2) Subendothelial collagen (SEC)
3) Prekallikrein (PK); High Molecular Weight Kininogen (HK)
Factor VII–> VIIa is the start of which pathway? 1)
it is activated by 2)
1) extrinsic
2) Tissue factor (TF) also called thromboplastin
Hemophilia A vs. B
(1) A is caused by a
deficiency of factor VIII.
(2) B is caused by a
deficiency of factor IX.
von Willebrand factor is the carrier molecule for 1) protecting it from degradation and removal
1) circulating factor VIII
A deficiency in 1) reduces the half-life of factor VIII and decrease plasma factor VIII levels.
1) von Willebrand Factor
Platelet membrane receptors include the 1) , binding to collagen (C);
2) binding von Willebrand factor (vWF);
3) binds fibrinogen and other macromolecules.
1) glycoprotein (GP) Ia receptor
2) GP Ib receptor
3) GP IIb/IIIa
Antiplatelet prostacyclin
(PGI2) is released from
the 1)
1) endothelium
Aggregating substances
released from the degranulating platelet include 1)
adenosine diphosphate (ADP), thromboxane A2 (TXA2), and serotonin (5-HT)
vWF promotes platelet adhesion by interacting with 1);
A deficiency of vWF reduces 2)
1) GP Ib receptor on PLATELETS
2) platelet adhesion
vWF plays a dual role in hemostasis affecting both platelet adhesion and coagulation; explain.
affects platelets adhesion–> Gp1b receptors on platelets;
affect coagulation–> vWF inc. half life of Factor VIII
Fibrinolysis:
Plasmin is generated by the proteolytic cleavage of 1) , a plasma protein that is synthesized in the 2)
1) plasminogen
2) liver
Fibrinolysis
The proteolytic cleavage of plasminogen is catalyzed by 1) , which is synthesized and secreted by the 2)
1) tissue plasminogen activator
(t-PA)
2) endothelium
What does the endothelium secrete?
What does endothelium store?
Secretes Tissue plasminogen activator;
vWF
PGI2 (antiplatelet);
Stores vWF-Factor VIII complex (this is where desmpressin acts)
Fibrinolysis:
Plasmin exerts its anticoagulant effect by proteolytically cleaving 1)
into 2)
1) fibrin
2) fibrin degradation products
Hemophilia
The bleeding manifestations include 1), 2) hemorrhages, and excessive bleeding after
surgery or trauma.
1) palpable ecchymoses, hemarthroses
(bleeding into joint spaces),
Hemophilia
severity of bleeding correlates with the degree of deficiency of factor 1)
1) VIII or IX
Hemophilia Disease severity:
Severe–> 1)
Moderate–> 2)
Mild–> 3)
1) Frequent spontaneous hemorrhages and
hemarthroses
2) Excessive bleeding following mild trauma
3) Few symptoms or excessive bleeding only
after significant trauma or surgery
Clinical manifestations are variable including asymptomatic, mucocutaneous
bleeding (e.g., epistaxis, gingival bleeding, menorrhagia), easy bruising, and
postoperative bleeding.
von Willebrand Disease
several types of von Willebrand Disease. Those that are
amenable to therapy include 1)
1) types 1, 2A, 2B, 2M, and 3
Systemic inflammation is associated with systemic activation of coagulation; 1) is the most severe form. There are many diverse triggers for 1).
Disseminated intravascular coagulation (DIC)
DIC leads to 1) in the microvasculature often with 2) as coagulation factors and platelets are consumed
1) fibrin clot formation
2) compensatory bleeding
Vitamin K is a 1) vitamin;
Vitamin K1 (2) is found in green leafy vegetables;
Vitamin K2 is produced by 3)
1) fat-soluble
2) phytonadione
3) bacteria in the large intestine
Vitamin K
a. Cofactor in the activation of 1)- without vitamin K
they remain inactive precursors
b. Also required for the active forms of 2)
1) factors II, VII, IX, and X
2) proteins C and S
Vitamin K deficiency
Causes bleeding as a result of marked deficiency of 1) referred to as 2).
1) factors II, VII, IX,
and X
2) vitamin K deficiency bleeding (VKDB)
Occurs in newborns- the have limited 1) at birth since
transplacental passage is limited
1) vitamin K stores
refers to Vitamin K deficiency
Vitamin K deficiency–> patients with 1) or malabsorption
1) poor nutrition
Vitamin K absorption depends on 1) and 2) to create micelles;
thus, Diseases of the 3) can lead to malabsorption
1) bile acids
2) pancreatic enzymes
3) intestine or pancreas
1) may sterilize the large intestine and prevent vitamin K2 production
1) Broad spectrum antibiotics
Broad spectrum antibiotics may sterilize the large intestine and
prevent 1)
1) vitamin K2 production
Plasma-derived Factor VIII:
Derived from plasma of thousands of donors and can
therefore 1)
1) potentially transmit disease
Plasma-derived Factor VIII:
In an effort to make the product safer, donors are screened, plasma is tested for evidence of infection, and virus is reduced through 1) (e.g., dry heat, pasteurization, solvent detergent treatment)
1) purification and inactivation procedures
Prion disease remains a concern as well as yet unidentified
viruses that currently used methods would not inactivate
Plasma-derived Factor VIII:
Produced using recombinant DNA technology using cultured cells (Chinese hamster ovary cells or baby hamster kidney cells)
Recombinant factor VIII
advantage of Recombinant factor VIII over plasma derived;
Because it is not derived from blood donations, the risk of
transmitting infections is low
Recombinant factor VIII:
Produced using 1) using cultured cells (Chinese hamster ovary cells or baby hamster kidney cells) transfected with the human factor VIII gene.
1) recombinant DNA technology
Factor VIII dosage for minor bleeding vs sustain a desired level;
administered as a single dose for
minor bleeding, or every 12 hours or by continuous infusion to sustain a desired level of factor VIII
Primary prophylaxis (regular replacement therapy) with Factor VIII started at a young age in Hemophilia pts before onset of 1)
1) joint bleeding
A/E Factor VIII replacement:
Formation of 1), anti-factor VIII antibodies (usually 2) subclass), which inhibit factor VIII activity
1) inhibitors
2) IgG
Viral infection associated with use of plasma-derived products
Plasma derived Factor VIII
Thrombophlebitis at the infusion site
Factor VIII replacement
AE–>Bacterial contamination of the concentrate
Factor VIII replacement
AE–> Catheter-related infections (often a central venous line is
necessary)
Factor VIII replacement
Primary prophylaxis
a) Cost (very expensive
Factor VIII replacement
Desmopressin causes release of 1) from endogenous 2) storage site
1) factor VIII and vWF
2) endothelial
DDAVP (desmopressin):
Adequate for 1) in patients with mild hemophilia A. Treatment with DDAVP will not result in hemostasis
in patients with 2) or those who do not respond well.
1) minor bleeding episodes;
2) severe hemophilia A
DDAVP (desmopressin) admin
Intranasal spray or intravenous administration
(1) Facial flushing
(2) Has antidiuretic effects so can cause water retention and dilutional
hyponatremia
DDAVP (desmopressin)
Hemophilia B treatment
Same as for factor VIII replacement except the product is factor IX.
1) and 2) bind competitively to plasminogen
blocking the binding of plasminogen to fibrin and subsequent conversion to plasmin
1) Aminocaproic acid and tranexamic acid
Clinical use: Inhibits clot lysis for treatment of oral bleeding because of the high concentration of fibrinolytic enzymes found in saliva
Antifibrinolytics–> Aminocaproic acid and tranexamic acid
Treatment of inhibitors in hemophilia for Patients with a LOW inhibitor titer:
(1) High doses of the ____ can control bleeding
(2) ____ may be useful
specific factor;
Antifibrinolytics
Treatment of inhibitors in hemophilia for Patient with a high inhibitor titer:
Treatment of bleeding episodes requires use of agents which 1)
1) bypass the factor to which the antibody is directed; usually against Factor VIII or XI;
Treatment of inhibitors in hemophilia for Patient with a high inhibitor titer:
1) contain vitamin K-dependent factors II, VII, IX, and X,
activated factor VII and IX;
1) Prothrombin complex concentrate (PCC) and activated PCC (aPCC)
PCC vs. aPCC
aPCC contains more of the
activated factors than PCC;
Adverse effects
a) Pulmonary emboli
b) DVT
c) MI
Prothrombin complex concentrate (PCC) and activated PCC
aPCC
Treatment of inhibitors in hemophilia for Patient with a high inhibitor titer:
Other option is 1)
1) Recombinant factor VIIa;
Recombinant factor VIIa
i) Only active at site of tissue injury where 1) is
present thus low risk of 2)
ii) Not plasma-derived so low risk of 3)
1) tissue factor
2) systemic thrombotic effects
3) viral transmission
Advantages of Recombinant Factor VIIa over PCC/aPCC to treat inhibitors in hemophilia patients with HIGH inhibitor titer
Recombinant factor VIIa
i) low risk of systemic thrombotic effects
ii) low risk of viral transmission;
Adverse effects of PCC/aPCC
a) Pulmonary emboli
b) DVT
c) MI
Treatment of inhibitors in hemophilia:
1), which involves regular infusion of high doses of the factor to which the antibody is directed, may eradicate the inhibitor
1) Immune tolerance therapy
Treatment of inhibitors in hemophilia:
1) are used as
adjuncts
1) Immunosuppressants (e.g., cyclophosphamide, prednisone)
Therapy is costly, time-consuming and often requires placement of a
central venous line
Treatment of inhibitors in hemophilia:
Pain management in Hemophilia:
Usually the cause of pain is 1) so controlling the 1) eases pain;
Chronic pain results from permanent joint changes thus use 2) or drugs for pain management that don’t affect platelet function such as 3)
1) bleeding
2) Intraarticular dexamethasone
3) Acetaminophen, opioid analgesics, and COX-2 inhibitor (celecoxib)
Local measures including pressure, ice, and topical thrombin can control
superficial bleeding
General treatment of von Willebrand Disease
Drug treatment of von Willebrand Disease:
Systemic therapy is used for bleeding that cannot be controlled in this manner and for prevention of bleeding during 1)
1) surgery.
Drug treatment of von Willebrand Disease:
The goal is to correct platelet adhesion and coagulation defects by stimulating the release of 1) or by administering products
containing 2).
1) endogenous vWF
2) vWF and factor VIII
Replacement therapy (plasma derived) in von Willebrand Disease indication:
used in types 2B, 2M, and 3 von Willebrand Disease;
also types 1 or 2A who are
unresponsive to desmopressin
in pts with types 1 or 2A who are
unresponsive to desmopressin; use:
replacement therpay
Plasma-derived vWF-containing products (two types)
A) 1) factor VIII concentrates contain sufficient functional vWF or
B) Plasma-derived vWF/FVIII complex (human)
1) Virus-inactivated
AE
a. Formation of inhibitors
b. Viral infection associated with use of plasma-derived products
c. Thrombophlebitis at the infusion site
Plasma-derived vWF-containing products
Effective for patients with adequate endogenous stores of vWF including most patients with type I disease and some with type 2A.
Desmopressin
If unrecognized and left untreated, DIC may lead to death as a result of 1)
1) hemorrhage or thrombosis
Most important step in therapy is to treat the underlying disease (e.g.,
antibiotics and vasoactive agents in treatment of sepsis and shock).
Drug treatment of DIC
Drug treatment of DIC:
Fresh frozen plasma replaces 1)(a bunch of things); used for bleeding problems
1) clotting factors, fibrinogen, protein S, protein C, and antithrombin
in DIC patients where thrombosis predominates, use:
Heparin
Vitamin K deficiency: use 1)
Phytonadione which is Vit K1;
Infants usually receive an intramuscular injection at birth
Phytonadione–> for Vit. K dependent bleeding prophylaxis
