Drugs for Coagulation Disorders Flashcards by LL Cool G

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)

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Factor VII–> VIIa is the start of which pathway? 1)

it is activated by 2)

1) extrinsic

2) Tissue factor (TF) also called thromboplastin

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Hemophilia A vs. B

(1) A is caused by a
deficiency of factor VIII.
(2) B is caused by a
deficiency of factor IX.

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von Willebrand factor is
the carrier molecule for
1)  
protecting it from
degradation and removal

1) circulating factor VIII

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A deficiency in 1) reduces the half-life of factor VIII and decrease plasma factor VIII levels.

1) von Willebrand Factor

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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

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Antiplatelet prostacyclin
(PGI2) is released from
the 1)

1) endothelium

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Aggregating substances

released from the degranulating platelet include 1)

adenosine diphosphate (ADP), 
thromboxane A2 (TXA2), 
and serotonin (5-HT)

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vWF promotes platelet adhesion by interacting with 1);

A deficiency of vWF reduces 2)

1) GP Ib receptor on PLATELETS

2) platelet adhesion

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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

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Fibrinolysis:

Plasmin is generated by the proteolytic cleavage of 1) , a plasma protein that is synthesized in the 2)

1) plasminogen

2) liver

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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

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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)

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Fibrinolysis:
Plasmin exerts its anticoagulant effect by proteolytically cleaving 1)
into 2)

1) fibrin

2) fibrin degradation products

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Hemophilia
The bleeding manifestations include 1), 2) hemorrhages, and excessive bleeding after
surgery or trauma.

1) palpable ecchymoses, hemarthroses

(bleeding into joint spaces),

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Hemophilia

severity of bleeding correlates with the degree of deficiency of factor 1)

1) VIII or IX

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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

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Clinical manifestations are variable including asymptomatic, mucocutaneous
bleeding (e.g., epistaxis, gingival bleeding, menorrhagia), easy bruising, and
postoperative bleeding.

von Willebrand Disease

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several types of von Willebrand Disease. Those that are

amenable to therapy include 1)

1) types 1, 2A, 2B, 2M, and 3

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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)

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DIC leads to 1) in the microvasculature often with 2) as coagulation factors and platelets are consumed

1) fibrin clot formation

2) compensatory bleeding

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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

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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

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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)

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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