Heme Onc [BLEEDING]

Introduction
Understanding bleeding can be complex. You probably
memorized the entire clotting cascade and PT/PTT valves for
every disease for Step 1. Let’s go over the essentials of hemostasis (1) (2) (3) (4)
instead of all the complexities. Primary hemostasis begins with endothelial injury,
releasing von Willebrand factor (1), sticking to platelets via
Primary Hemostasis is a function of platelets that starts with Glyc-Ib, adhesion (2). This activates the platelets and allow
for aggregation through fibrinogen and Glyc-IIb/IIIa. The
endothelial injury. From the endothelium, von Willebrand
end result is a fibrinogen mesh plug of platelets, ripe to be
factor (vWF) is released like sticky Velcro tentacles, snatching activated to fibrin in secondary hemostasis (shown below).
onto platelets via Glyc-Ib via a process called adhesion.
Adhesion activates platelets (release of granules and XII VII
rearrangement of protein surface). This allows fibrinogen to link VII
platelets via glycoprotein IIb/IIIa through a process called IX
aggregation. The end product is a platelet plug that stops the X Plasminogen
bleeding initially, with a fibrinogen mesh ready to start the heavy Prothrombin Thrombin tPA
duty clotting. Plasmin
Fibrinogen Fibrin Fibrin Split
Secondary Hemostasis ends with fibrinogen mesh turning into Products
fibrin. Along the way multiple clotting factors need to be
activated. Factor 7 is by its lonesome in the extrinsic pathway Superficial, Mucosal Patient with Bleeding Deep Bleeding
(measured by PT). Factors 8-12 (except 10) are in the intrinsic
Epistaxis Hemarthrosis
pathway (measured by PTT). The two pathways converge with Hematoma
Gingival Bleed
the activation of Factor 10, which together with Factor 5, turns Prolonged Bleeding
Menorrhagia
prothrombin to thrombin. Thrombin activates the fibrinogen
mesh on those platelets to activate clotting. The whole deal ends 1o Hemostasis 2o Hemostasis
by the activation of tPA, which dissolves the clot into split (Platelets) (Factor)
products. You’ll see how easy all the diseases are to understand
if you can just follow the pictures. Platelet Count Factor VII, VIII
PT/PTT/INR
Differential Decreased Normal
People like to jump to coagulation studies with bleeding. For the ↓ Platelets Platelet Fxn
most part that’s ok. Have a bleed? Get a CBC and Coags. But if
vWD
interested in determining the best test for the patient in front of Factor Acquired
Glanzmann’s
you, ask if they have platelet bleeding (superficial bleeding Smear Bernard-Soulier Deficiency Disease
secondary to platelet dysfunction) or factor bleeding (deep H+P Uremia
bleeding secondary to hemostasis dysfunction). Then, if it’s a BM Bx Drugs vWD Vit K Def
problem with platelets use platelet count and platelet function Hemophilia A Liver Dz
(only if count is normal as a ↓count or ↓function) to get near a Sequestration Hemophilia B DIC
diagnosis. If it’s factor bleeding use PT, PTT, INR, + Factor
Levels to narrow the differential. From there each disease has its ↓ Production ↑Destruction
own detail, confirmatory test, and treatment.
Aplastic Anemia ITP, TTP, DIC
We’re going to discuss only highlighted diseases in the coming
section - those commonly tested on Step. Check the “intern
section” for more on bleeding; it’s separated into an entire lecture Test Measuring What? Diagnosis / Diseases
for platelet bleeding and another dedicated to factor bleeding. PT Extrinsic Pathway Warfarin, Vit K, Factor 7
PTT Intrinsic Pathway Heparin, Lupus Anticoagulant
Bleeding Time Formation of Plug Platelet Disorder
(Platelet Fxn) Thrombocytopenia
Factor Levels Direct Measure Factor Deficiency
Mixing Study Difference Factor Deficiency
Between Inhibitors
vWF Direct Measure vWD
D-Dimer Indirect Measure of DIC
Fibrinogen fibrinolysis
Fibrin Split

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 Heme Onc [BLEEDING]

Von Willebrand…But What About?
1. Von Willebrand Disease Glanzmann’s Deficiency of GlycIIb/IIIa
A person with a platelet type bleeding and a normal platelet Thrombasthenia
count likely has vWD. If there’s ↓vWF, platelets can’t adhere. Ø Bernard-Soulier Deficiency of Glyc-Ib
Adhesion = Ø Aggregation = Ø Plug. Start by testing for Uremia Seen in Renal Failure
dysfunction of platelets with a bleeding time (archaic) or the Drugs We give patients medications to limit clotting
newer platelet function test then get a vWF assay. Since vWF ASA, Clopidogrel, NSAIDs, Abciximab
stabilizes Factor VIII there might also be factor type bleeding.
Treat with desmopressin to ↑vWF. If severe, give
cryoprecipitate or Factor VIII acutely.

2. Thrombocytopenia Thrombocytopenia
This is a topic all on its own. Get the general idea of each potential TTP ↓ Platelets + Fever + ↓Plt+ Exchange Never give
cause and learn what to look for. If all cell lines are decreased AMS + RF + MAHA ↓RBC Transfusion platelets
then it’s an aplastic anemia (a production problem). If the spleen HIT On Heparin 5-7d Ø hx ↓Plt Stop Heparin Tirofiban
is really big it’s sequestration (a sequestration problem). The 3-4 d with h/o HIT only
other forms of thrombocytopenia all involve destruction of DIC Any systemic or severe dz, ↓Plt Tx Underlying Plts
platelets. Heparin-Induced Thrombocytopenia (HIT) occurs in s/p OB, s/p trauma oozing ↑PT Disease cryo
patients on Heparin (usually on day 5-7 of tx). To alleviate stop from every hole ↑PTT whole blood
the heparin and get HIT-Antibodies. If the patient has the ITP Female with ↓platelets but ↓Plt Plt<20 or bleeding IVIG
classic pentad (↓platelets, fever, altered mental status, renal nothing else Plt >20 Steroids
failure, Microangiopathic hemolytic anemia) then they have Refractory: Splenectomy
TTP. Do a plasma exchange and absolutely avoid platelet
transfusion. Finally, if she has a thrombocytopenia and all the
others have been ruled out assume she has ITP - an autoimmune
“hemolysis” of platelets. Fight with IVIg or Rhogam right now,
steroids chronically, and splenectomy if refractory.

3. Hemophilia
An X-linked recessive (boys only) disorder that affects Factor 8
(type A) or Factor 9 (type B). It’s a deep factor type bleeding in
children (hemarthrosis is classic). vWD should be ruled out.
Since Factor VIII doesn’t last very long transfuse only when the
patient’s actively bleeding.

4. Liver Disease + Vitamin K Deficiency

The liver needs vitamin K and Vitamin K needs a liver. Either
way, factors 2, 7, 9, and 10 (also protein C+S) are broken,
messing up both the intrinsic and extrinsic pathways and
producing a factor type bleeding. If the patient’s cirrhotic,
antibiotics killed intestinal K-producing bacteria, or
iatrogenically we blocked the effect with warfarin there could be
a bleed. The move should be to test for factor levels. Ultimately,
however, K will have to be given. If there’s no improvement after
K it’s liver disease. If it improves they were just lacking vitamin
K.

5. Disseminated Intravascular Coagulation (DIC)

Occurs in significant systemic disease (sepsis, shock,
malignancy) where clotting goes crazy; many clots form where
there should be none. This leaves Ø platelets and Ø clotting
factors for where the holes actually are. This person bleeds from
everywhere. There isn’t one single test, but together an ↑ PT ↑
PTT (factors), ↓ Fibrinogen (except in early disease), a D-
Dimer / Fibrin Split Products and the clinical history give a
strong argument. Treat by giving everything back (platelets,
cryoprecipitate, blood) and fix the underlying disease.

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 Heme Onc [BLEEDING]

Disease Patient PT PTT Bleeding Diagnosis Treatment

Time
vWD Platelet Bleeding Normal Count - - vWF Assay DDAVP
BS Glyc Ib Assay Factor VII
GT Glyc IIb/IIIa
Uremia + Renal Failure CMP / E-Lytes Dialysis
Drugs Clopidogrel, ASA, NSAIDS Med List Stop
Aplastic ↓ in all cell lines - - BM Bx Fix Cause Underlying
Platelet Anemia (hypocellular)
Dysfunction Splenic ↓platelet and a big spleen Splenomegaly ?
Sequestration U/S of Spleen
HIT ↓platelets + Heparin (day 5-7) - - HIT-Ab Stop Heparin, start Tirofiban
TTP Fever, RF, ↓plt, MAHA, AMS - - Clinical Plasma Exchange, NEVER plts
HUS Fever, RF, ↓plt, diarrhea - - Clinical Plasma Exchange, NEVER plts
ITP ↓platelets in a female, everything - - Diagnosis of Exclusion IVIG or Rhogam (acute)
else ruled out Steroids (Chronic) Splenectomy (refractory)
Hemophilia Boys with Hemarthrosis - - Factor Levels, Factors only with Bleeding
r/o vWD
Vit K Antibiotics for gut ↑ - Vit K levels or just give Vit K Vitamin K
Deficiency or ↓Leafy Greens
Factor Liver Dz Older, EtOH, cirrhosis, Hep B/C ↑ - Vit K, if Ø correction, diagnosis is Stop Drinking, Manage chronic disease,
Dysfunction Liver Dz Manage Complications
Warfarin Pt with Afib, DVT, PE or other ↑ - Patient Med List, INR Vit K, Blood is Needed
need for anticoagulation
DIC Sepsis, Trauma, Malignancy, ↑ - Fibrinogen ↓ Fix underlying disease
Bleeding from everywhere D-Dimer ↓ Cryo, FFP, Blood

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