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Porphyrias, Coagulation + PLT disorders, Lymphomas/Leukemias, Myeloproliferative Disorders

Terms in this set (89)

Porphyrias
Hereditary or acquired
defective heme synthesis
lead to accumulation of heme precursors.
ALA Dehdyratase
and
Ferrochelatase
inhibited in
lead poisoning
from delta ALA to PBG

and from protoporphyrin to Heme (adds the Iron)

microcytic anemia with basophilic stipling. GI and kidney disease.
headache, memory loss, demyelination
constipation, mental deteioration.
Porphobilinogen deaminase inhibited
acute intermittent porphyria
from PBG to Hydroxymethylbilane.
So Porphobilinogen, delta ALA, and corpophobilinogen accumulate in urine.

Often asymptomatic until stress.

PS:
Painful abdomen
Port wine colored urine
Polyneuropathy
Psychological disturbances
Precipitated by drugs=alcohol and starvation

treat with glucose and heme, which inhibit ALA Synthase, counteracting positive acitvtion by alcohol, barbituates, antiepileptics , smoking, calorie restriction, progesterone in puberty, phenobarbitol, griseofulvin, phenytoin.
port wine urine but no photosensitivity
acute intermittent porphyria

gets darker with light and air.
induced by low calorie diet
acute intermittent porphyria
induced by acitvtion by alcohol, barbituates, antiepileptics , smoking, calorie restriction, progesterone in puberty, phenobarbitol, griseofulvin, phenytoin.
acute intermittent porphyria
Uroporphyrinogen decarboxylase inhibited
uroporphyrinogen III to coproporphyrinogen III
uroporphyrin accumulates (TEA urine)

BLISTERING PHOTOSENSITIVITY
most common porphyria.
hand photosensitive bumps
early defects in heme synthesis
abd pain
neuropsych
port wine urine
later defects in heme synthesis
photosensitivity
due to porphyrinogens(PBG) that react with O2 when excited by UV.
tea urine
cell death due to peroxidation of membrane lipids
iron poisoning
and other sideroblastic causes: isoniazid poisoning, myelodysplatic syndrome, chloramphenicol, linezolid, alcohol, copper deficiency
deep tissue bleeding
coagulation disorders
mucocutaneous bleeding
nose bleeds
petechiae
gum bleeding
platelet disorders
hemophilias increase which?
aPTT only. INTRINSIC PATHWAY ONLY
VII-XLR
IX-XLR
XI -the autosomal recessive one

HEMARTHROSES-vitamin K deficiency can present this way too??? check
AFTER DENTISt-BLEEDS
EASY BRUISING

treat: desmopressin and factor that is missing.
vitamin K deficiency
PT and PTT increased
because VII is vitamin K dependent too.
II, VII, IX, X, protein C, protien S
Gp Ib defect
Bernard Soulier syndrome

platelet plug formation is defective
ADHESION defect between vWF and platelet
no aglutination on ristocetin cofactor assay
LARGE LARGE PLATELETS!!!!

normal platlet count, perhaps low
HIGH bleeding time
Gp IIb/IIIa defect
Glanzmann thrombasthenia

platelet formation is defective
AGGREGATION defect between platelets

normal platelet count = it is a QUALITATIVE PLT defect
HIGH bleeding time

high uremia from renal failure also increases bleeding time only, not PT or aPTT or low platelet count.
anti GpIIb/IIIa antibodies
immune thrombocytopenia
a problem with splenic macrophage consumption of platelet antibody complex.
often due to viral illness.
kids resolve fine. adults often have issues.
BRUISING.

LOW PLATELET COUNT because destroyed by spleen due to opsinization
and of course high bleeding time

HUGE many megakaryocytes on bone marrow biopsy!!!

treatment is IV Ig, steroids.

no coagulation cascade activation, normal PT
ADMSTS 13 deficiency
Thrombotic thrombocytopenic purpura

ADAMSTS 13 is aka vWF metalloprotease, which normally degrades vWF from a huge multimer into its smaller pieces.

Deficiency means that large vWF multimers increase platelet aedhesion and aggregation and thrombosis, causeing schistocytes
and high LDH
with hemolytic anemia

PENTAD:
neurologic symptoms
renal symptoms
fever
thrombocytopenia

treat with plasmapharesis and steroids.

(cf. HUS: e. coli, complement H, CD46, F1 excessive alternative complement, high WBCs like 50-60k, high retics, PT is still normal, and fibrin degradation products are high)

no coagulation involvement, normal aPTT and PT (cf. DIC)
HUS
no coagulation involvement, normal aPTT and PT
hemolytic anemia
renal failure
previous diarrhea
microangiopathic thrombosis
high LDH
G6PD deficiency
TTP
renal failure
fever
neurologic manifestations
TTP
low LDH
low haptoglobin
low Hb
high direct and total bilirubin
G6PD deficiency
any hemolytic disease
Autosomal Dominant platelet disorder
vWF disease
normal platelet count
but high bleeding time
-vWF disease
-can have high PTT due to VIII deficiency, as vWF protects and carries factor VIII.
-defective platelet to vWF adhesion
-mild but most common inherited bleeding disorder
low agglutinaton on ristocetin cofactor assay
vWF disease diagnosis. vWF levels are low, so addition of normal plasma will correct agglutination.

also GpIb deficiency (Bernard Soulier syndrome). But vWF levels are normal, so addition of normal plasma will not correct agglutination
NORMAL agglutination on ristocetin cofactor assay
Glanzman Thrombo. (IIIa/IIb defect). Because vWF and gpIb are all normal.

TxA2 defect beacuse of ASA administration.
treated with desmopressin
vWF disease
releases vWF stored in endothelium. and VIII
NO increased PTT following heparin administration
Antithrombin deficiency
Sepsis
Trauma
Obstetric complications (TF release mediated from damage, or amniotic fluid thromboplastin)
acute Pancreatitis
Malignancy
Nephrotic syndrome
Transfusions

STOP Making New Thrombi
DIC
widespread activation of clotting cascade leads to deficiency of clotting factors and thus BLEEDING from everywhere.

Schistocytes
high D Dimers
DIC
from cleaving fibrinogen
low fibrinogen
DIC
resistance to clot busting
upon administration of activated protein C.
Factor V Leiden-normal aPTT at baseline
mutated factor V resistant to degradation by activated protein C.
MOST COMMON cause of inherited hypercoagulability in whites.
hypercoagulable states that respond with clot canceling upon administration of activated protein C
Lupus-prolonged aPTT at baseline
folate or B12 deficiency with high homocysteine.
infection
cancer
no effect on PT, PTT, thrombin time
antithrombin deficiency
diminishes increased PTT normally following heparin administration.
increased risk of subcutaneous tissue necrosis after warfarin
protein C or S deficiency.
C and S degrade faster than clotting factors.
normally inactivate Va and VIIIa
protein C and S
high prothrombin
prothrombin gene mutation in 3' UTR.
venous clots.
first blood parameter to prolong in liver cirrhosis
PT
because factor VII has shortest half life
vWF made by
endothelium
not liver
2,3 BPG defect
His (+) to Ser (less + binding pocket of Hemoglobin)

2,3 BPG is NEGATIVE, so this defect limits 2,3 BPG binding and thus causes a leftward shift, with hemoglobin holding onto oxygen more.

Also consider hemoglobin mutations (chesapeake and Kempsey) that have higher affinities for oxygen due to other mutations.

Any high oxygen affinity hemoglobinopathy puts patient at risk of EPO ramp up and thus polycythemia
RBCs and 2,3 BPG
-RBCs always use glycolysis. [And HMP shunt. NO TCA. Anaerobic pyruvate to lactic acid (LDH) always. ]
-They can avoid Phosphoglycerate Kinase (makes ATP by turning 1,3 BPG into 3 phosphoglycerate)
-And instead shunt to a pathway that makes 2,3 BPG (involves a mutase and a phosphatase back to 3 phosphoglycerate). This path makes zero ATP, but increases 2,3 BPG in order to decrease Hb affinity for oxygen, favoring release of oxygen at tissues.
COX2 inhibitors selective
Normally, COX2 is thought of as the one that is only active in inflammation (not invovled in GI mucosa or PLATELET AGGREGATION,...
But COX2 specific inhibitors can cause increased thrombotic events due to decreased production of PGI2 (a vasodilator and anticoagulation prostaglandin made in endothelium by COX2 only)

Also both COX1 and COX2 are prsent in renal, thus inhibitors of both can increase hypertension and fluid retention.
Wiscott Aldrich Syndrome
eczema rash
recurrent infections
low platelet count (thrombocytopenia)
cryoprecipitate
contains
fibrinogen
factor VIII
factor XIII
vWF
fibronectin

used for coagulation deficiencies of fibrinogen of VIII.
frequent transfusions
secondary hemochromatosis risk
citrate
calcium chelator / present in blood transfusions.
will show parasthesias and spasms hypocalcemia
hyperkalemia
possible effect of frequent transfusions. RBCs may lyse in old blood units.
FFP
for
DIC
cirrhosis
immediate warfarin reversal

to increase coagulation factor levels
high neutrophil Alk phos
leukemoid reaction
-left shift (many band cells)

cf. CML with low LAP , also has high WBC count and left shift.
hodgkin lymphoma meaning
40% of lymphomas
localized, single group of nodes.
Prognosis better
Reed Sternburg Cells- secrete cytokines and recruit other immune cells.
Bimodal distribution.
Men more often except nodular sclerosing type
EBV association.
B signs-fever, night sweats, weight loss. Because of cytokines from Reed-Sternburg cells.
non hodgkin lymphoma meaning
multiple peripheral nodes.
60% of lymphomas
worse prognosis
HIV/autoimmune association
Majority are B cells
20-40 peak incidence
extranodal involvement is common.
fewer constitutional signs
HIV and RA show hyperplasia of
cortex of lymph nodes
Viral illness shows expansion of
paracortex of lymph node
T cells
draining cancer shows expansion of
medulla of lymph node
CD30 and CD15 positive
Reed Sternburg cells
2 owl eyes. 15X2=30
strong stromal or lymphocytic reaction against RS cells
better prognosis
lymphocyte mixed or depleted forms of hodgkin lymphoma
worse prognosis
nodular sclerosing form of hodgkin lymphoma
men and women equally
lymphocytic broad pink fibrous bands and nodules
RS cells sit in lacunar spaces. called lacunar cells.
nodular sclerosing form of hodgkin lymphoma
diffuse large B cell lymphoma
older adults
but 20% in children
most common type of non Hodgkin lymphoma in adults.
aggressive with poor differentiation
t(8;14)
Burkitt Lymphoma
high grade
C-myc overexpression
adolescents or young adults
endemic form=jaw lesion
sporadic form=pelvic or abdomen
starry sky appearance with macropahges interspersed between sheets of lymphocytes
t(14;18)
follicular lymphoma
indolent course.
can progress to DLBCL
Bcl-2 overexpression-anti apoptotic.
painless
waxing and waning lymphadenopathy******
nodular, small cells monoclonal kappa to gamma ratio very high.(20)
CLEAVED NUCLEI
t(11;14)
mantle cell lymphoma
low grade
cyclin D1 overexpression. progress through G1 to S cell cycle transition.
CDK1 phosphorylates regulators.
small homogenous cells painless lymphadenopathy.
HTLV
adult T cell lymphoma
mature CD4 T cells
IV drug abuse association
Japan, W. Africa, Caribbean
Lytic bone lesions
hypercalcemia
cerebriform nuclei
Sezary mycosis fungoides
mature CD4 T cells.
presents with skin patches (cutaneous T cell lymphoma)
atypical CD4 T cells with brainnucle8.
T cell leukemia = SEZARY syndrome- the progressed form.
Rouleaux RBC formation
Multiple Myeloma
overproduction of monoclonal IgG and IgA (lower antigenic diversity and increased infecions) (causes rouleaux accumulatio of RBCs)
overproduction of RANKL(leads to lytic lesions of bone=skull punched out lesions and back pain/ then hypercalcemia) Also remember IL-1 binds OB and stimulates OCs.
Light chain (amyloid AL in heart and kidneys-Bence Jones proteinuria)
monoclonal plasma cell overproliferation

MGUS= monoclonal expansion of plasma cells, but asymptomatic. no CRAB findings, and may develop into multiple myeloma.
Multiple myeloma and other lytic bone cancers are due to increased IL-1/TNF alpha. Remember the other name for IL-1 is osteoclast activating factor.
...
pseudo pelger huet
neutrophils with bilobed nuclei
typically after chemo
treat with HSC or support.
transfusion
DNA methylation inhibitors to increase DNA.

myelodysplastic syndrome = stem cell disorders involving ineffective hematopoeisis
defects in cell maturation of all nonlymphoid lineages.
Caused by denovo mutations or environmental exposures
-radiation, benzene, chemotherapy.
Risk of transformation to AML.
IgM spike
hyperviscosity syndrome with blurred vision, Raynaud, retinal hemorrhage or stroke, vsual or neural symptoms.
no hypercalcemia
no renal involvement
no anemia
no bone lytic lesions or back pain
Waldenstrom macroglobulinemia
anemia
infections
hemorrhage
leukemia
high WBC in bone marrow, leads to marrow failure and anemia, infections (low mature WBCs), low platelets (hemorrhages)
leukemia can infiltrate liver, spleen, lymph nodes, skin
t(12;21)
the better prognosis form of T-ALL

ALL in general:
Down sydnrome association.
T-ALL: children. boys more commonly, mediastinal mass.
Peripheral blood and bone marrow have HIGH LYMPHOBLASTS
TdT+ for marker of pre-T and pre-B cells
B -ALL has CD10+
most responsive to therapy
can spread to CNS and testes.
t(9;22) T-ALL is poor prognosis, more common in adults. (Philadelphia chromosome)
thymic mass in teenager
tDT positive
T cell ALL
mediastinal mass and SVC syndrome
T -ALL
CD20
CD5
small cell lymphoma or Chronic Lymphocytic Leukemia
OVER 60
most common adult leukemia
HB cell neoplasm
asymptomatic, slow progression
smudge cells
autoimmune hemolytic anemia-bad Igs from neoplasm cause RBC lysis
(low IgG because neoplastic B cells make no IgG)
CLL has more peripheral blood lymphocytosis than bone marrow involvement (SLL)
TRAP +
hairy cell leukemia
middle aged men****
mature B cell tumor in elderly
hair projections
causes marrow FIBROSIS and dry tap on aspiration. ****
splenomegaly of red pulp. MASSIVE!!!
flow cytometry diagnosis or TRAP+
not in lymph nodes
treat with cladribine or pentostatin or adenosine deaminase inhibitor 2CDA., purine degradation adenosine accumulates leading to death.
t(15;17)
Acute Promyelocytic Myelogenous leukemia. treated with ATRA.
PML-RARA fusion.

AML in general:
most common leukemia in adults
pancytopenia (cf. CML myeloproliferative)
65 year median onset
Auer rods (MPO+)
peroxidase + (MPO)
increast myeloblasts on peripheral smear
Down Syndrome association
associated with alkylating chemotherapy, radiation, myeloproliferative disorders.
DIC is common presentation****
t(9;22)
CML
48-84 year peak
philadlephia chromosome= BCR-ABL fusion protein leads to constitutive intracellular tyrosine kinase activity (JAK2 is this too)
high neutrophils
high metamyelocytes
high basophils
can transform into AML or ALL.
VERY LOW LAP due to low activity of MATURE granulocytes (cf. leukomoid reaction which looks identical except high LAP)
IMATINIB is BCR-ABL TK antibody
Dohle Bodies
RER-bound ribosomes
accumulate in leukomoid rea tion neutrophils.
infalmmation and infection
high LAP
S-100 positive
Langerhans Cell Hitiocytosis
a collective group of proliferatie disorders of dendritic cells.
children: lytic bone lesions
and skin rash
or as
recurrent otitis media with mass involving mastoid bone
cells are immature and do not effectively stimulate primary T cells via antigen presentation.
Cells are mesodermal origin

also express CD1a

tennis racket Birbeck granules are characteristic.
JAK2
involved in hematopoietic growth factor signaling
gain of function JAK2 mutation often found in chronic myeloproliferative disorders (except CML, which has BCR_ABL)

intracellular tyrosine kinase (STAT is the transcription factor)
intense itching after hot shower
polycythemia vera
high RBCs
high PLTs
itch is due to basophils
facial plethora
splenomegaly
"aquagenic pruritis"
rare but classic symptom (erythromelaggia-severe burning pain and red blue coloration due to episodic blood clots in extremities)swelling
hyperviscous blood
bud chiari syndrome is possible-liver hepatic vein clot
JAK2 mutation-makes hematopoietic cells more sensitive to EPO.
Can be secondary if due to high EPO. PvO2 is normal if main problem is JAK2 mutation, not EPO.

tx: phlebotomy
abnormal platelet overproduction
essential thrombocytosis
specific for overproduction of platelets only and they are abnormal platelets.
enlarged MEGAKARYOCYTES*********
High platelet count
JAK2 mutation again.
BLEEDING.
teardrop cells
myelofibrosis
proliferation of fibroblasts in response to proliferation of monoclonal cell lines.
dry tap
often massive splenomegaly
JAK2 mutation again
pancytopenia

also keep in mind osteosarcomas or osteofibrosis.?
high altitude produces
secondary appropriate absolute polycythemia
with high EPO due to LOW O2 saturation. results in LARGE RBCs(new ones)
low plasma volume from burns produces
relative polycythemia
epo and rbc mass and o2 sat are all normal
just lost some volume.
lung disease or congenital heart disease causesr
secondary appropriate absolute polycythemia
just like high altitude
with high EPO due to LOW O2 saturation. results in LARGE RBCs(new ones)

COPD
obesity hypoventilation syndrome
sleep apnea that cuases low oxygenation
renal cell carcinoma
hepatocellular carcinoma
hydronephrosis
produce
ectopic EPO
INappropriate secondary absolute polycythemia
normal O2 saturation, high EPO, high RBC mass, normal plasma volume.
low EPO polycythemia
polycythemia vera
INR high
means thin blood
warfarin is working
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