Bleeding Disorders Flashcards
List the broad categories of mechanisms causing thrombocytopenia.
1) decreased production: bone marrow failure
2) increased consumption: immune, DIC, microangiopathy (TPP, HUS), multifactorial (sepsis, HIV)
3) Sequestration in spleen/portal circulation
What occurs in immune thrombocytopenia purpura?
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)
How do you treat ITP?
in adults: immunosuppressive therapies including corticosteroids, IVIG, splenectomy, ritixumab and some promise with thrombopoiesis
What is the action of the drugs romiplostim and eltrombopag.
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
What drugs are known to cause thrombocytopenia?
quinine, quinine, sulfa drugs and rifampin form immune complex mechanisms (similar to drug induced immune hemolysis) via “induced fit”
When are platelet transfusions most useful?
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)
What different conditions may lead to platelet dysfunction.
inherited disorders
drugs
uremia
monoclonal gammopathy (MM and Waldenstroms)
myelodysplasia and myeloproliferative disorders
How is vWF disease transmitted and what are the consequences of inheriting the disease?
autosomal dominant with variable penetrance
due to deficiency of vWF there is mild or moderate bleeding tendency in most cases
What laboratory findings would confirm suspected vWF disease?
defective platelet adherence on PFA-100
subnormal levels of vWF
aPTT may be prolonged if factor VIII is also low enough
Most inherited factor deficiencies show _____ inheritance with exception for VIII, IX which are ____ - _____.
recessive
sex-linked
Deficiency in factor VIII or IX lead to what diseases?
hemophilia A and B respectively, severity of disease is proportional to factor level
(“flip tip” inversion commonly leads to interruption of factor VIII)
What is the characteristic presentation of a patient with hemophilia?
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
Why does joint bleeding cause long term damage?
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
List 4 ways in which you can acquire clotting factor deficiciency.
autoimmune destruction of a single factor (usually VIII)
vitamin K deficiency (II, VII, IX, X protein C and S
liver diesease
DIC
What puts you at risk for vitamin K deficiency?
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)
What lab tests could confirm vitamin K deficiency?
long PT and aPTT
low blood levels of vitamin K
What is the most sensitive test for heparin?
thrombin time, aPTT can also and PT/INR at high levels
Describe the pathogenesis of DIC.
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
What laboratory signs would accompany DIC? (comment on platelets, PT/aPTT, d-dimer and fibrinogen)
thrombocytopenia
long PT/INR +/- PTT
VERY elevated D-dimer
low fibrinogen
note: treatment centers on control of underlying disease
Name 3 contributing factors that are important in the pathology of purpura fulminans.
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)
What is the cause and result of thrombotic thrombocytopenia purpura?
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)
What is typical of a peripheral smear of someone with TPP? What other lab tests may confirm the diagnosis?
schistocytes with very few platelets thrombocytopenia, anemia high LDH, low haptoglobin often hemoglo binemia, hemoglobinuria evidence of renal dysfunction very low (<5%) ADAMTS-13
Describe the injury that is present in HUS?
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
