Bleeding Disorders

Front 1

How do platelets bind to von Willebrand factor?

Back 1

Platelets bind to von Willebrand factor (vWF) incorporated into the subendothelial matrix through their expression of glycoprotein Ib. Also, to a lesser extent, binding to collagen via glycoprotein Ia/IIa.

Front 2

Which rare bleeding disorders are not picked up on normal screening (PT, PTT)?

Back 2

vWF, FXIII, PAI-1, and alpha2AP

Front 3

Pt presents with history of deep tissue bleeding. PT and PTT are both prolonged and this does not correct with a mixing study. What condition would account for multiple inhibitors?

Back 3

Most likely lupus anticoagulant.

Front 4

What is the disease related to glycoprotein Ib defects?

Back 4

Defects in glycoprotein Ib result in Bernard-Soulier syndrome. A gain of function mutation in glycoprotein Ib results in excess binding of vWF, particularly of the high molecular weight multimers, resulting in platelet type vWD

Front 5

What disease is characterized by defective inter-platelet bridging during clot formation?

Back 5

After granule secretion, platelets aggregate via bridges formed by fibrinogen bound to platelet glycoprotein IIb/IIIa. The absence of, or a defect in, platelet glycoprotein IIb/IIIa results in Glanzmann thrombasthenia, a severe platelet function defect.

Front 6

Which dietary/herbal supplements affect platelet function?

Back 6

The herbal supplements
garlic, ginger, omega-3 fatty acids, vitamin E, and gingko
biloba are among the most commonly consumed supplements
known to affect platelet function.

Front 7

What are the causes of abnormal platelet function assay (PFA), with (Col/Epi >183 seconds, Col/ADP >122 seconds)?

Back 7

• Anemia (hematocrit <0.28)
• Thrombocytopenia (platelet count < 100 x 109/L)
• A significant platelet function defect other than aspirin

Front 8

What is the cause of Col/Epi closure time prolonged (>183 sec onds), Col/ADP result is normal (<122 seconds) on PFA?

Back 8

aspirin-induced platelet dysfunction is
most likely

Front 9

What are the problems with the PFA?

Back 9

PFA is limited by insufficient sensitivity, such that it rarely obviates the need for further testing, and its inability to distinguish between the 2 most common bleeding disorders, which are platelet function defects and vWD

Front 10

How does the platelet aggregation assay differentiate between the two most common types of platelet function disorders?

Back 10

If results demonstrate absent aggregation to all agonists except ristocetin, the pattern is diagnostic of Glanzmann thrombasthenia, whereas the opposite pattern is consistent with Bernard-Soulier syndrome.

Front 11

Name 4 medications that have activity in platelet function disorder-related bleeding?

Back 11

Desmopressin
Estrogen
rFVIIIa
antifibrinolytic agents (e.g. aminocaproic acid, Amicar)

Front 12

What are the relative and absolute contraindications to antifibrinolytic agents?

Back 12

Relative - hx of thrombosis or atherosclerosis.
Absolute - hematuria (bc obstructive uropathy secondary to clots could develop)

Front 13

What medication is useful in uremia-induced platelet dysfunction?

Back 13

Estrogens.

Front 14

What is the most common platelet function defect?

Back 14

The ADP secretion defect is the most common platelet
function defect and typically causes mild to moderate
mucocutaneous bleeding symptoms that are managed with
desmopressin, antifibrinolytic agents, and hormonal therapy
for menorrhagia.

Front 15

Describe the 3 types of vWD.

Back 15

Type 1 is a partial quantiative defect.
Type 2 is a qualitative defect.
Type 3 is a complete quantitative defect.

Front 16

Describe the 4 types of Type 2 vWD.

Back 16

Type 2A is defective multimerization, which is necessary for normal platelet adhesion.
Type 2B is a gain of function that leads too much binding to HMW multimers, which removes platelets from the circulating pool.
Type 2M is inability to bind to platelets.
Type 2N is defect in ability to bind and protect FVIII.

Front 17

Which medical conditions are associated with acquired von Willebrand syndrome?

Back 17

lympho- and myeloproliferative disorders, aortic stenosis, hypothyroidism, essential thrombocytosis

Front 18

What are the caveats in interpreting vWF tests?

Back 18

Both vWF
and FVIII are acute-phase reactants and will increase to
between 2 and 5 times above baseline due to a variety of conditions
or circumstances. Increased estrogen levels, as with the use of oral
contraceptive agents, during pregnancy, or at/around the
time of ovulation, may also increase vWF levels. The blood
type also affects vWF levels; type O is associated with the lowest
levels, and type AB is associated with the highest levels.

Front 19

How is the amount of vWF determined?

Back 19

vWF antigen assay.

Front 20

How is the function of vWF determined?

Back 20

Platelet binding function is assessed with the ristocetin cofactor assay.
FVIII binding function is measured separately.

Front 21

What is the first-line treatment for mild to moderate bleeding in type 1 vWD?

Back 21

Desmopressin. Usually the intranasal preparation is used.

Front 22

What limits the dosing frequency and duration of desmopressin for vWD?

Back 22

Tachyphylaxis (decremental response due to depletion of the storage pool). Desmopression should be given only once daily for no more than 2-3 consecutive days.

Front 23

What is the treatment for bleeding in Types 2 and #3 vWD?

Back 23

vWF replacement therapy via concentrate, such as Humate-P. Antifibrinolytics are useful adjuncts.

Front 24

Describe acquired hemophilia.

Back 24

Caused by autoantibodies, most commonly against FVIII. Has been associated with pregnancy, malignancy and aging. More likely to cause soft tissue, abdominal and retroperitoneal hemorrhage than hemarthrosis.

Front 25

What are the cutoffs for mild, moderate and severe hemophilia?

Back 25

Mild 5-40% factor activity.
Moderate 1-5%.
Severe <1%.

Front 26

What should be done in the case of strong clinical suspicion for hemophilia but a normal aPTT?

Back 26

mild FIX deficiency may be associated with a normal screening test. Send for FIX activity.

Front 27

How is the dosing for factor XI and factor VIII replacement different?

Back 27

FVIII is 1 IU/kg per desired 2% increase in factor level.
FIX is a 1% increase per 1 IU/kg if plasma derived, and 0.6-0.8% if recombinant.

Front 28

Other than factor replacement, what drugs are used in the treatment of hemophilia?

Back 28

Adjunctive use of desmopression, antifibrinolytic agents and hormones can be used in the same way they are used for platelet defect disorders.

Front 29

What is the cutoff between low-titer, low responding and high-titer, high responding patients with hemophilia?

Back 29

< 5 Bethesda units despite repeated factor exposure characterizes a low-titer, low responder.

Front 30

How are low-titer, low responding patients with hemophilia and inhibitors managed?

Back 30

Using higher doses of factor replacement. Transient inhibitors may disappear within weeks.

Front 31

How are hemophilia patients with high-titer, high responsding inhibitors mananaged?

Back 31

By using bypassing agents (rFVIIIa or APCC) or by using immune tolerance induction.

Front 32

How is ITI (immune tolerance induction) different between patients with inhibitors to FIX vs FVIII?

Back 32

Factor IX inhibitor development is far less common that factor VIII inhibitor development. Patients with FIX deficiency may develop anaphylactoid reactions to infused FIX concentrate prior to or at the time of inhibitor emergence. Patients with FIX defi ciency may develop anaphylactoid reactions to infused FIX concentrate prior to or at the time of inhibitor emergence. FIX-deficient patients with inhibitors undergoing ITI are at risk for developing nephrotic syndrome. The overall success rate of ITI in FIX deficiency is 35%, far lower than the 75% achieved in FVIII deficiency.

Front 33

What are the two bypassing agents used in hemophilia patients with high-titer inhibitors?

Back 33

Activated prothrombin complex concentrate (APCC; FEIBA) and rFVIIIa (NovoSeven).

Front 34

Which bypassing agent should be used in FIX deficient hemophilia patients who have had an infusion reaction to FIX product?

Back 34

rFVIIIa, because APCC (FEIBA) is FIX based

Front 35

If a hemophilia patient, in whom the current goal is to decrease the inhibitor titer, bleeds, which bypassing agent should be used?

Back 35

rFVIIIa, as it does not stimulate the FVIII or FIX inhibitor titer.

Front 36

How is acquired hemophilia treated?

Back 36

With steroids, cyclophosphamide and Rituxan, stepwise in that order.

Front 37

What is the difference in inheritance pattern between Hemophilia A and B, vs. the more rare factor deficiencies?

Back 37

Hemophilia A and B are X-linked, whereas the other disorders are caused by somatic mutations and affect both sexes equally.

Front 38

Factor X deficiency has been associated with what systemic disease other than liver dysfunction?

Back 38

amyloidosis; due to adsorption of the clotting factor
onto the abnormal accumulated amyloid

Front 39

Factor V deficiency may develop by what drug exposure(s)?

Back 39

A deficiency of FV
may occur due to cross-reacting antibody development after
exposure to topical thrombin or use of antimicrobials such as
cephalosporins.

Front 40

Deficiency of which clotting factor has been associated with a specific factor antibody in the antiphopholipid antibody syndrome?

Back 40

Factor II

Front 41

Describe the disorder of combined FV and FVIII defieciency.

Back 41

Combined FV and FVIII deficiency results from mutations in the gene that codes for a protein (endoplasmic reticulum Golgi intermediate compartment [ERGIC]-53) required for assembly and secretion of these 2 similarly structured proteins.

Front 42

What is the mechanism of combined vitamin K dependent clotting factor deficiency?

Back 42

The combined vitamin
K coagulation factor deficiency is due to a number of
mutations in enzymes involved in the vitamin K pathway.

Front 43

What conditions are recognized as causes for acquired FXIII deficiency?

Back 43

Cardiopulmonary bypass and Inflammatory bowel disease.

Front 44

Which two clotting factor deficiencies are associated with catastrophic intracranial hemorrhage?

Back 44

FX, FXIII; FVII can also be associated with CNS bleeds, but less so.

Front 45

What is the difference between FFP and cryoprecipitate?

Back 45

Cryoprecipitate only contains significant levels of FVIII, VWF, fibronectin, FXIII and fibrinogen. Cryoprecipitate is not a source of all coagulation factors and therefore is not appropriate replacement therapy in patients with global coagulation factor deficiencies, for example, with liver disease. Cryoprecipitate use should be reserved for patients with documented isolated hypofibrinogenemia

Front 46

What are the two congenital conditions resulting in hyperfibrinolysis?

Back 46

PAI-1 deficiency and alpha2AP deficiency. Both are autosomal recessive.

Front 47

Name 5 conditions that can predispose to hyperfibrinolysis.

Back 47

1. liver disease
2. DIC
3. surgery, particularly cardiac
4. prostatic diseases
5. APL

Front 48

What are the two most widely used antifibrinolytic agents?

Back 48

EACA and TXA (tranexamic acid)

Front 49

What is ristocetin?

Back 49

Ristocetin is an antibiotic, obtained from Amycolatopsis lurida, previously used to treat staphylococcal infections. It is no longer used clinically because it caused thrombocytopenia and platelet agglutination. It is now used solely to assay those functions in vitro in the diagnosis of conditions such as von Willebrand disease (vWD) and Bernard-Soulier syndrome. Platelet agglutination caused by ristocetin can occur only in the presence of von Willebrand factor multimers, so if ristocetin is added to blood lacking the factor (or its receptor -- see below), it will not coagulate.
In an unknown fashion, the antibiotic ristocetin causes von Willebrand factor to bind the platelet receptor glycoprotein Ib (GpIb), so when ristocetin is added to normal blood, it causes agglutination