Pathology of Hemorrhage

this is when the platelet count is less than 150,000

we see a normal PT and PTT

present with: mucosal membrane bleeding and microhemorrhages (petechiae, epistaxis, heavy menses, oral bleeding)

Thrombocytopenia

platelet deficiency caused by autoantibody-mediated destruction of platelets

this is a diagnosis of exclusion

these antibodies lead to an increase in platelet destruction

can be improved by a splenectomy

you see: bleeding into skin and mucosal surfaces, easy bruising, petechiae, nose bleeds, etc.

Chronic Immune Thrombocytopenic Purpura

labs: low platelet count, large platelets in perihperal blood, PT and PTT normal

Chronic Immune Thrombocytopenic Purpura

caused by autoantibodies (IgG) against platelets

commonly a disease of childhood

triggered by a viral illness

self-limiting

sudden onset with petechiae or bruising over the body

diagnosis of exclusion

Acute Immune Thrombocytopenic Purpura

Two conditions: excessive activation of platelets which deposit as thrombi in small blood vessels

can cause mucroangiopathic hemolytic anemia (becuase the RBCs have to squeeze past the clots and can get fucked up) and widespread organ dysfunction

the platelet consumption (meaning that all the platelets are going to these clots and are not available for use) leads to thrombocytopenia

Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS)

What are the differences in the clinical presentation of thrombotic thrombocytopenia purpura and hemolytic uremic syndrome?

TTP: pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, transient neuro defects, and renal failure

HUS: also has microangiopathic hemolytic anemia and thrombocytopenia but usually no neuro defects, prominent acute renal failure; frequent occurence in children

pathophysiology: inhibition or deficiency of the enzyme ADAMTS13

this leads to large vWF multimers accumulating and promoting platelet activation, adhesion, and aggregation (there is too much double-sided tape because the enzyme is being blocked so all the platelets are clotting)

Thrombotic Thrombocytopenic Purpura (TTP)

labs: low platelets, normal PT and PTT, low Hb, schistocytes “helmet cells” on smear

increased LDH and elevated creatine

Thrombotic Thrombocytopenic Purpura (TTP) and hemolytic uremic syndrome

strongly associated with infectious gastroenteritis caused by E coli strain O157:H7 enterohemorrhagic: prodices a shiga-like toxin that cuases endothelial injury provoking platelet activation and aggregation

typical Hemolytic uremic syindrome

associated with defects in the alternative complement pathway inhibitor deficiencies

complement factot H, membrane cofactor protein (CD46) or Factor I

atypical hemolytic uremic syndrome

IgG antibodies against the complex of heparin bound to platelet factor 4

binding of antibody to these complexes activates platelets and promotes thrombosis, even though thrombocytopenia present (paradoxical)

heparin-induced thrombocytopenia (HIT)

a deficiency of platelet membrane glycoprotein complex IB (GpIb)

leads to a decrease in adhesion of platelets

defect in platelet plug formation because there is no GpIb for the vWF to stick to for the platelets to adhere to the “double-sided tape” on the collagen

Bernard-Soulier syndrome

Do we see agglutination with ristocetin in Bernard-Soulier syndrome?

no aggregation because there is no GpIb for the vWF to bind to

defective platelet aggregation due to a decrease in GpIIb/IIIa expression

decreased platelet to platelet aggregation and defective plug formation

Plt count is usually normal and bleeding is often severe

Glanzmann thrombasthenia

Do we see agglutination with ristocetin in Glanzmann thrombasthenia?

yes because there is still GpIb for the vWF to bind eventhough there is no GpIIb/IIIa for aggregation

Explain the mixing study and coagulation disorders

coagulation disorders are caused by one of two things: deficiency in clotting factors or acquired factor inhibitors

if you add plasma to the patient’s plasma and it fixes the coagulation then it indicates that it was a deficiency in clotting factors (supplemented by the normal plasma)

if you add plasma to the patient’s plasma and it does not fix the coagulation then it indicates that it is due to factor inhibitors because even if you add more clotting factors from the normal plasma, the inhibitors will still inhibit coagulation

deficiency in factor VIII

can see hemarthroses (bleeding into the joints)

Hemophilia A

What do we expect the PT and PTT levels to be with hemophilia A? Why?

normal PT (extrinsic pathway is good)

prolonged PTT (intrinsic pathway not normal)

this is because its factor VIII being messed upwhich is part of the intrinsic pathway affecting PTT but not PT

What do we expect the PT and PTT levels to be with hemophilia B? Why?

normal PT (extrinsic pathway is good)

prolonged PTT (intrinsic pathway not normal)

this is because its factor IX being messed upwhich is part of the intrinsic pathway affecting PTT but not PT

What do we expect the PT and PTT levels to be with hemophilia C? Why?

normal PT (extrinsic pathway is good)

prolonged PTT (intrinsic pathway not normal)

this is because its factor XI being messed upwhich is part of the intrinsic pathway affecting PTT but not PT

factor IX deficiency

Hemophilia B

deficiency of factor XI (autosomal recessive, not X-linked)

Hemophilia C

What type of defect is Type I, II, and III of Von Willebrand disease?

I and III: are quantitative defects (I more mild and III being more severe little to no vWF)

II: qualitative defect affecting the structure or function of vWF

With Von Willebrand disease, do we see platelet aggregation with ristocetin?

no because there is no vWF/ not enough to bind to

When do we see excessive activation of coagulation and formation of thrombi in the microvasculature

not a primary disease, but aquired: usually obstetric complications, malignant neoplasms, sepsis, and major trauma

disseminated intravascular coagulation (DIC)

triggers:

• release of tissue factor or other procoagulants into circulation and

• widespread injury of endothelial cells

causative agents:

• procoagulants (Acute ptomyelocytic leukemia)

• endothelial injury

• TNF (mediator of endothelial injury)

• widespread endothelial injury (lupus, temp extremes, meningococci or rickettsiae infections

disseminated intravascular coagulation (DIC)

in infection by N. meningitidis, you have meningococcemia and fibrin thrombi wihtin microcirculation of the adrenal cortex leading to massive adrenal hemorrhages

Waterhouse-Friderichsen syndrome

contrast acute DIC versus chronic

acute: obstetric and trauma; bleeding dominant

chronic: cancer; usually more thrombosis

Labs: low platelet count, prolonged PT and PTT

schistocytes on smear

increased D-dimers

disseminated intravascular coagulation (DIC)

What are 3 major cuases of vitamin K deficiency?

• infant: lack of GI flora that produce vit K (we give them a shot at birth)

• antibiotic therapy: can disrupt vit K producing bacteria

• malabsorption disorders

affects factors 2, 7, 9, and 10

normal platelet count and bleeding time

prolonged PT and PTT (both intrinsic and extrinsic pathways affected)

Vitamin K deficiency