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Hemostatic disorders
Disorders of hemostasis
39
Physiology
Graduate
09/09/2012

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Term
Afibrinogenemia
Definition
Congenital deficiency of fibrinogen
OR acquired after hemodilution, blood loss and/or consumption, during DIC, or in sepsis.
Rx: infuse with FFP, cryoprecipitate, or fibrinogen concentrates
Normal: 1.5-3g/L
Term
Parahemophilia
Definition
Deficiency of Factor V
1:1million
Auto recessive
Term
Thrombophilia
Definition
Tendency to form clots
-pathologic thrombosis is primary cause of mortality in the US-
DVT, Pulm embolism, MI, stroke
Mutations in Factor V are most common hereditary cause
e.g. factor V leiden (R506Q), etc
Mutation makes it resistant to cleavage by activated protein C (APC resistance) --> remains active, increases rate of thrombin generation
Term
von Willebrand disease
Definition
deficiency of vWf (and Factor VIII)
-platelets can't adhere to endothelium
*Most common coagulation disorder*
-results in bleeding tendency of mucous membranes, most apparent in tissues having high blood flow shear in narrow vessels (nosebleeds, GI bleeding, menorrhagia)
-Most are hereditary
-Acquired: aortic valve stenosis, type IIA (Heyde's syndrome)
-Also leads to factor VIII deficiency
Term
thrombotic thrombocytopenic purpura
Definition
TTP

Acquired (Ab-induced ADAMTS13-deficiency)
Congenital (absence of ADAMTS13)

-breakdown of vWf multimers + microangiopathic hemolytic anemia with fibrin deposition, platelet deposition, in small vessels, capillary necrosis

-brain most affected (TTP bites brain, nips, kidney)

Clinically: 30-50y/o, F>M, abrupt onset, 15% assoc with other dz
fever, pallor/anemia, hemorrhage, neurologic/renal abnormalities

Dx pentad (40% pts)
- thrombocytopenia
- MAHA (microangiopathic hemolytic anemia) - schistocytes, anemia, reticulocytosis, high LDH
- neurologic sx
- fever
- renal impairment

Path: hyaline thrombi in terminal arterioles/capillaries (made of vWf and platelets). UL-vWf multimers b/c absent ADAMTS13

Labs: high LDH, low haptoglobin, (-)DAT, blood smear with schistocytes, microscopic proteinuria and hematuria
ADAMTS13 low, IgG anti-ADAMTS13, UL-vWf multimers

Rx: Plasmapheresis (plasma exchange) to replace ADAMTS13 and remove anti-ADAMTS13 Abs; rituximab, follow platelet ct, LDH, sx, recombinant ADAMTS13, Eculizumab (mAb to C5 complement)
Term
Gray platelet syndrome
Definition
Lack of alpha granules
-contain factors involved with coagulation, inflammation, wound repair

Ghost-like appearance
Autosomal inheritance

Clinically: prolonged bleeding time

Labs: platelet aggregation normal (esp with AA and ristocetin, but variable with epi, collagen, ADP, thrombin)
Primary and secondary waves both decreased.
Mild thrombocytopenia, mod enlarged platelets.

Rx: platelet txfusion
Term
Hermansky-Pudlak
Definition
Lack of delta granules
Presents with albinism (oculocutaneous)
Auto recessive
Puerto Rico
Term
Glanzmann's thrombasthenia
Definition
*Aggregation problem*

-Deficiency of GPIIb/IIIa
deficient in platelet aggregation, can't bind to fibrinogen
-auto recessive, very uncommon

-clinically:
easy/large bruising, epistaxis, gingival bleeding, menorrhagia, complications w/pregnancy, trauma, surgery

Lab findingS:
normal platelet count/morphology, PROLONGED bleeding time, ABNORMAL platelet aggregation ---- only normal aggregation with Ristocetin; all other aggregates require GPIIb/IIIa

Rx: platelet txfusions, hormone therapy for menorrhagia, iron replacement therapy
Term
Bernard-Soulier syndrome
Definition
*Problem with adhesion*

Deficient in GPIb (the vWf receptor on platelets)
- difficulty adhering platelets
-very uncommon (auto recessive)
-mild thrombocytopenia
-GIANT PLATELETS on smear (big suckers)
-Ristocetin aggregation absent (needs GP1b and vWf for aggregation)

-Clinical sx:
Bruising, epistaxis (nosebleeds), gingival bleeding, menorrhagia, complications w/trauma and surgery

Rx: platelet txfusions, estrogen therapy for menorrhagia
Term
Deficiency of factor II (thrombin), V, VII, or X
Definition
incompatible with life
Term
Hemophilia A
Definition
Deficiency of Factor VIII
Term
Hemophilia B
Definition
Deficiency of Factor IX (christmas factor)
AKA "Christmas DZ"
Term
Severe thrombocytopenia
Definition
Platelets <20,000
Spontaneous hemorrhage
Petechiae, ecchymoses
Term
Purpura fulminans
Definition
Inability to turn off clotting
e.g. - Deficiency of ptns C and S
Exogenous clotting in microvasculature
-Warfarin skin necrosis (vit K antagonist, drops anti-coagulants II, VII, IX, X, ptns C and S)
-seen in neonates with ptn C and S deficiencies
Term
Deficiencies of extrinsic factors (TF or VII)
Definition
NOT compatible with life
Term
Deficiencies of intrinsic factors (VIII, IX, XI, XII)
Definition
ARE compatible with life
Term
Deficiency of common pathway factors (X, V, prothrombin (II)
Definition
NOT compatible with life
Term
Factor XIII deficiency
Definition
Severe bleeding
-activated by thrombin and cross links fibrin monomers, α-2 antiplasmin into fibrin clots
Term
Factor V Leiden
Definition
Produce mutated Factor V (cofactor for Xa's activation of prothrombin, activated by thrombin, controlled protein C)
**Most common cause of inherited hypercoagulability**
-Mutated form can't be degraded by PtnC
Term
Factor XII deficiency
Definition
These pts never bleed
-can't activate intrinsic pathway
-IX-->IXa by TF/VIIa from extrinsic pathway, to there's no functional deficit
Term
Storage pool disease
Definition
Delta granule abnormality

Auto dominant
mild to moderate bleeding
ADP and serotonin can't be stored

Labs: normal platelet count/morphology, prolonged bleeding time, normal aggregation with ristoceetin and AA, abnormal with ADP, collagen, Epi, and thrombin

Rx: DDAVP (promotes release of vWf and factor VIII); platelet txfusions
Term
Acquired platelet fxn disorder - ASA, NSAIDs
Definition
COX inhib impair crating TxA2
Alcohol prolongs bleeding time even more
Term
Acquired platelet fxn disorder - Abx
Definition
PCN, beta lactams (ticiarcillin, piperacillin)
Term
Acquired platelet fxn disorder - cardiovascular drugs
Definition
Ca2+ channel blockers
Term
Acquired platelet fxn disorder - Uremia (renal insuff)
Definition
Platelets normal
Prolonged bleeding time
Increased guanidinosuccinic acid, phenols, NO (disrupt adhesion and aggregation)

Clinically: ecchymoses, GI bleeds, surgical bleeding

Rx: Dialysis (remove increased toxins), Cryoprecipitate (esp vWf:VIII), DDAVP, Estrogens
Term
Sequestration of platlets
Definition
results in splenomegaly
Term
Decreased production of platelets results from:
Definition
Drugs (myelosuppressive)
Alcohol - suppresses platelet prod at BM level
Deficiency of B12 or folate
Radiation
Aplastic anemia
Term
Accelerated destruction of platelets results from:
Definition
Infection
DIC
Massive txfusion (dilution)
TTP (thrombotic thrombocytopenic purpura)
HUS (hemolytic uremic syndrome)
ITP (idiopathic thrombocytopenic purpura)
May Hegglin anomaly
Wiskott-Aldrich syndrome
HIT (heparin induced thrombocytopenia)
Term
ITP (idiopathic thrombocytopenic purpura)
Definition
Immune-mediated (anti-platelet Abs)
-coated platelets destroyed in reticuloendothel system (spleen, liver, BM)
-platelet life is hours to days

Subtypes:
Acute-kids 2-3y/o, <6mos thrombocytopenia, often resolves itself, prodromal viral infection
Chronic: Adults, esp females, >6mos thrombocytopenia, requires Rx

Clinically: petechiae, ecchymoses, mucous membranes, menorrhagia, hematuria, melena (blood in stool), dental, surgical procedures

Evans syndrome - ITP w/Coombs+ autoimmune hemolytic anemia

Rx: Steroids (slow thinning of endothel cells, decreases size of fenestrations, blocks reticuloendothel cell consumption of sensitized platelets, reduces Ab production); splenectomy, IVIg (blocks reticuloendothelial system), Danazol, Rituximab, Cyclosporine A, Vincristine, Thrombopoeitin (Nplate, Pomacta)
Term
May Hegglin anomaly
Definition
Auto recessive
Mut in MYH-9
MACROthrombocytopenia
DOHLE bodies in neuts (blue discoloration)
Term
Wiskott-Aldrich syndrome
Definition
XLR inheritance
MICROthrombocytopenia
eczema
Immunodeficiency

Rx: irradiated platelet txfusion
BMT
Term
HIT (heparin-induced thrombocytopenia)
Definition
Abs to heparin-PF4 complex
-complex binds to Fc receptors --> intense platelet activation w/thrombocytopenia and hypercoagulable state

3-5% of pts exposed to standard porcine heparin
Occurs 5-14 days after exposure to heparin (first time) or within a few days (second time)

Complications:
Thrombosis (rarely, arterial thrombosis --> gangrene and amputatioin) (more common, venous thrombosis - DVT, PE, cerebral)

Labs: thrombocytopenia (<150,000) or decrease of 50% from baseline. ELISA is sensitive, not specific. GOLD STANDARD: SRA (serotonin release assay) - contained in delta granules, marker of platelet activation

Rx: stop heparin, give thrombin inhibitors (refludin, argatroban).
Hypercoagulable state can persist for 3 weeks, platelet count recovers in 3-5 days
Term
Thrombotic Microangiopathy (TMA)
Definition
Causes: infection, stem cell txplant, HELLP syndrome, antiphospholipid Ab syndrome, vasculitis, txplant Rx, DIC, TTP (acquired/congenital), HUS (shiga-toxin induced and atypical)

Char by:
MAHA (microangiopathic hemolytic anemia)
thrombocytopenia (platelets consumed as they form small clots in vessels)
microvasc thrombosis w/platelets/fibrin
organ dysfxn
Term
Familial TTP - Upshaw Schulman syndrome
Definition
See TTP
Congenital ADAMTS13 deficiency

Rx: prophylactic FFP infusions to restore ADAMTS13
Term
HUS (hemolytic uremic syndrome)
Definition
subtypes: shiga-toxin assoc, atypical HUS (genetic), secondary HUS

Triad: MAHA (microangiopathic hemolytic anemia), thrombocytopenia (mild), acute renal injury
Term
Shiga-toxin assoc HUS
Definition
E-coli O157:H7
Peak incidence in very young and very old

Course: acute onset diarrhea, hemorrhagic colitis, pallor, abd pain, vom, dark red/black urine

Pathogenesis: induced apoptosis in glomerular endothel cells --> chemokine/cytokine expression --> WBC inflammation --> endothel damage, microvasc thrombosis (from platelet and fibrin deposition); may bind complement inhib --> MAC activation

Organ damage results from decreased perfusion through glomerular endothel (from damage from fibrin deposits)

Labs: MAHA (DAT(-), hemolysis (high bilirubin, LDH, low haptoglobin), schistocytes); thrombocytopenia; renal failure (high BUN, creatine); stool culture - Stx gene detected by PCR

Rx: supportive, RBC txfusions for anemia, NO platelet txfusions, dialysis, eculizumab

Prognosis: 25% have neurologic involvement (stroke, seizure, coma), high mortality in older pts, decreased GFR, ESRD, HTN
Term
Atypical HUS
Definition
identical sx to shiga-toxin assoc HUS

Affects children and adults, 25-37% familial

Triad: MAHA, thrombocytopenia, acute renal injury

Clinically: sudden onset, low HgB, low platelets, renal insufficiency, uncontrolled activation of alternative complement pathway)

Dx: rule out shiga-toxin assoc HUS
Rule out TTP (ADAMTS13 deficiency

Rx: plasma therapoy, eculizumab
Term
Secondary HUS
Definition
causes: infections, cancer, chemo, pregnancy, systemic dz
Term
Vitamin K deficiency
Definition
Acquired disorder of hemostasis

Vit K absorbed in ileum, requires bile salts

Causes

Sources 1/3 from Diet = (green leafy veggies - darker is better; chewing tobacco) 2/3 from intestinal flora

Fxn: co-factor in gamma carboxylation of Glu residues in Factors II, VII, IX, and X; Ca2+ bridges these factors with PLs to work.
Also activates Ptn C and S
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