Bleeding Disorders

Question 1

List the broad categories of mechanisms causing thrombocytopenia.

Answer 1

1) decreased production: bone marrow failure
2) increased consumption: immune, DIC, microangiopathy (TPP, HUS), multifactorial (sepsis, HIV)
3) Sequestration in spleen/portal circulation

Question 2

What occurs in immune thrombocytopenia purpura?

Answer 2

antibodies coat platelets with rapid destruction by macrophages in the spleen and liver

(child form is self limited following a viral infection, adult form is chronic)

Question 3

How do you treat ITP?

Answer 3

in adults: immunosuppressive therapies including corticosteroids, IVIG, splenectomy, ritixumab and some promise with thrombopoiesis

Question 4

What is the action of the drugs romiplostim and eltrombopag.

Answer 4

both are thrombopoietic drugs with the structure:

romiplostim: peptibody Ig heavy chain fused to peptide analog of thrombopoietin
eltrobopag: small molecule agonist of TPO receptor

both can cause marrow fibrosis

Question 5

What drugs are known to cause thrombocytopenia?

Answer 5

quinine, quinine, sulfa drugs and rifampin form immune complex mechanisms (similar to drug induced immune hemolysis) via “induced fit”

Question 6

When are platelet transfusions most useful?

Answer 6

used in treating severe thrombocytopenia, commonly used in cardiac surgery, and liver transplantation
limited by short survival in patients that are alloimmunized (may require HLA-matched platelets)

Question 7

What different conditions may lead to platelet dysfunction.

Answer 7

inherited disorders
drugs
uremia
monoclonal gammopathy (MM and Waldenstroms)
myelodysplasia and myeloproliferative disorders

Question 8

How is vWF disease transmitted and what are the consequences of inheriting the disease?

Answer 8

autosomal dominant with variable penetrance

due to deficiency of vWF there is mild or moderate bleeding tendency in most cases

Question 9

What laboratory findings would confirm suspected vWF disease?

Answer 9

defective platelet adherence on PFA-100
subnormal levels of vWF
aPTT may be prolonged if factor VIII is also low enough

Question 10

Most inherited factor deficiencies show _____ inheritance with exception for VIII, IX which are ____ - _____.

Answer 10

recessive

sex-linked

Question 11

Deficiency in factor VIII or IX lead to what diseases?

Answer 11

hemophilia A and B respectively, severity of disease is proportional to factor level
(“flip tip” inversion commonly leads to interruption of factor VIII)

Question 12

What is the characteristic presentation of a patient with hemophilia?

Answer 12

joint and muscle bleeding, treat by replacing the missing factor; deficiency in factor VIII or IX affects the propagation phase and so bleeding is most likely in situations where tissue factor exposure is relatively low

long aPTT and normal INR, aPTT corrects with mixing study

Question 13

Why does joint bleeding cause long term damage?

Answer 13

hemosiderin deposition leads to synovial inflammation and hypertrophy
bleeding leads to inhibition of proteoglycan synthesis and altered cartilage metabolism, and ultimately cartilage destruction and bone erosion

Question 14

List 4 ways in which you can acquire clotting factor deficiciency.

Answer 14

autoimmune destruction of a single factor (usually VIII)
vitamin K deficiency (II, VII, IX, X protein C and S
liver diesease
DIC

Question 15

What puts you at risk for vitamin K deficiency?

Answer 15

being a newborn with immature colonic bacteria
antibiotics wiping out colonic bacteria
poor absorption due to biliary obstruction
drugs that inhibit vitamin K (warfarin and related compounds)

Question 16

What lab tests could confirm vitamin K deficiency?

Answer 16

long PT and aPTT

low blood levels of vitamin K

Question 17

What is the most sensitive test for heparin?

Answer 17

thrombin time, aPTT can also and PT/INR at high levels

Question 18

Describe the pathogenesis of DIC.

Answer 18

uncontrolled disorganized activation of clotting and fibrinolytic systems with rapid formation and lysis of intravascular fibrin

is usually due to exposure of blood to excessive tissue factor and leads to the consumption of clotting and fibrinolytic enzymes and inhibitors, platelets

Question 19

What laboratory signs would accompany DIC? (comment on platelets, PT/aPTT, d-dimer and fibrinogen)

Answer 19

thrombocytopenia
long PT/INR +/- PTT
VERY elevated D-dimer
low fibrinogen

note: treatment centers on control of underlying disease

Question 20

Name 3 contributing factors that are important in the pathology of purpura fulminans.

Answer 20

tissue hypoperfusion (shock)
endothelial injury
intravascular fibrin formation 

usually causing tissue necrosis, multiple organ failure and most often seen in severe sepsis (mainly cytokine mediated)

Question 21

What is the cause and result of thrombotic thrombocytopenia purpura?

Answer 21

autoimmune destruction of enzymes (ADAMTS13) causes large vWF multimers that cause widespread formation of platelet aggregates in small vessels

the result is microangiopathic hemolytic anemia, thrombocytopenia, and multiple organ dysfunction (is fatal without plasma exchange, usually given with immunosuppression)

Question 22

What is typical of a peripheral smear of someone with TPP? What other lab tests may confirm the diagnosis?

Answer 22

schistocytes with very few platelets
thrombocytopenia, anemia
high LDH, low haptoglobin
often hemoglo binemia, hemoglobinuria
evidence of renal dysfunction
very low (<5%) ADAMTS-13

Question 23

Describe the injury that is present in HUS?

Answer 23

microangiopathic syndrome, mainly the kidneys are affected, usually associated with toxin producing E. coli (toxin injures endothelium)

**note atypical HUS is due to inherited defects in complement regulation