Pocket Medicine: The Massachusetts General Hospital Handbook of Internal Medicine (66 page)

thrombosis (HIT): screen for DVT; unclear duration of subsequent anticoag (until plt count recovers, often ~2–3 mo if no clot);
25–50% thrombosis rate w/in 30 d

• Heparin use if h/o HIT: if PF4 Ab
(typically >100 d after dx) → re-exposure to UFH reasonable (eg, for surgery); HIT recurrence low
Hemolytic-uremic syndrome (HUS) & thrombotic thrombocytopenic purpura (TTP)

• Definition: vascular occlusive disorders w/ systemic (TTP) or intrarenal (HUS) plt aggreg.

→ thrombocytopenia & mechanical injury to RBCs (MAHA) (
NEJM
2002;347:589)

HUS triad
= thrombocytopenia + MAHA + renal failure

TTP pentad
(all 5 in only ~5%) = thrombocytopenia + MAHA (100%) ± Δ MS (65%) ± renal failure (50%) ± fever (25%)

• Pathophysiology: mechanism in most HUS cases is distinct from TTP (
NEJM
1998;339:1578)

HUS
: Shiga toxin binds & activates renal endothelial cells & plts → intrarenal thrombi

TTP
: ↓ ADAMTS13 protease activity
or
inhibitor→ persistence of large vWF multimers on endothelial surface → adhesion and aggregation of passing platelets → thrombosis

• Clinical manifestations and associations

HUS
: usually in children; prodrome of bloody diarrhea due to enterohemorrhagic
E. coli

TTP
: usually in adults;
idiopathic, drugs
(CsA, tacrolimus, gemcitabine, mitomycin-C, ticlopidine, clopidogrel, quinine), HIV, pregnancy, HSCT, autoimmune disease, familial

• Dx: unexplained
thrombocytopenia
(typically <20k) +
MAHA
→
sufficient for dx
schistocytes
(>2–3/hpf),
Coombs, normal PT/PTT & fibrinogen, ↓↓ ADAMTS13 ↑↑ LDH (tissue ischemia + hemolysis), ↑ indirect bili., ↓↓ haptoglobin, ↑ Cr (esp. in HUS)

Biopsy: arterioles filled with platelet hyaline thrombi

Ddx: DIC, vasculitis, malignant hypertension, preeclampsia/HELLP syndrome

• Treatment:
urgent plasma exchange
± glucocorticoids if suspected; FFP if delay to plasma exchange (
Blood
2010;116:4060); ? eculizumab in HUS (
NEJM
2011;364:2561);
plt transfusions contraindicated
→ ↑ microvascular thrombosis (
NEJM
2006;354:1927)
Disseminated intravascular coagulation (DIC):
see “Coagulopathies”

DISORDERS OF PLATELET FUNCTION

Tests of platelet function

• Bleeding time: global screen of platelet function;
not reliable and rarely used
• Platelet aggregation tests: measure aggregation in response to agonists (eg, ADP)
von Willebrand’s disease (vWD)
(
NEJM
2004;351:683 & 2012;367:1954)
• von Willebrand’s factor (vWF) function = platelet glue & plasma carrier of factor VIII • vWD most common inherited (usually auto dom) bleeding disorder;
85% (type 1) have partial quantitative defic of vWF,
15% (type 2) have qualitative defic in vWF

• Acquired vWD: a/w many disorders (malig, MPN w/ ↑ plt count; autoimmune; hypo-thyroidism; drugs) and caused by different mechanisms (anti-vWF Abs, ↑ clearance, ↓ synthesis); Heyde’s syndrome = vWF destruction by severe AS, a/w GI AVMs/bleed • Diagnosis: ↓
vWF:Ag
, ↓
vWF activity
(measured by ristocetin cofactor assay), ↓
factor VIII
, ± ↑ PTT, ± ↓ platelets; confirm with
vWF multimer analysis
• Clinical condition, factor VIII levels and ristocetin cofactor assay useful to guide Rx decision • Rx:
desmopressin
(dDAVP, IV/IN) → ↑ endothelial cell release of vWF; efficacy depends on type (avoid in Type 2), ∴ ✓ response before use w/ subseq. bleeding or procedures;

vWF replacement
: cryoprecipitate, factor VIII concentrates rich in vWF, recomb. vWF

Uremic bleeding

• Uremia → platelet dysfunction including ↓ aggregation, impaired adhesiveness • Treatment:
dDAVP
, cryoprecipitate, correct anemia (improves plt aggregation and

adhesion by increasing plt interactions with endothelium), consider holding anti-plt agents

COAGULOPATHIES

Further coagulation tests

• Mixing study: useful if ↑ PT or PTT; mix Pt’s plasma 1:1 w/ normal plasma and retest PT/PTT normalizes → factor
deficiency
; PT/PTT remains elevated → factor
inhibitor
• Coagulation factor levels: useful if mixing study suggests factor deficiency

DIC → all factors consumed; ∴ ↓ factors V and VIII liver disease → ↓ all factors
except
VIII; ∴↓ factor V, normal factor VIII vitamin K deficiency → ↓ factors II, VII, IX, X (and protein C, S); ∴ normal V and VIII

•
DIC screen
: fibrinogen (consumed), fibrin degradation products (FDPs,
due to intense fibrinolysis), D-dimer (more specific FDP test that detects degradation of X-linked fibrin)
Hemophilias
(
NEJM
2001;344:1773)
• X-linked recessive
factor VIII
(hemophilia A) or
factor IX
(hemophilia B)
deficiency
• Classification: mild (5–25% normal factor activity), moderate (1–5%) or severe (<1%) • Clinical manifestations: hematomas, hemarthroses, bruising, bleeding (mucosal, GI, GU) • Diagnosis: ↑ PTT (normalizes w/mixing study), normal PT & vWF, ↓ factor VIII or IX

• Treatment: purified/recomb. factor VIII or IX concentrate, desmopressin (mild disease), aminocaproic acid; recomb. factor VIIa if factor inhib., cryo (only has factor VIII)
Coagulation factor inhibitors

• Etiologies: hemophilia (treated with factor replacement); postpartum; lymphoproliferative disorders and other malignancies; autoimmune diseases; most commonly anti–factor VIII • Diagnosis: ↑ PTT (does
not
normalize w/mixing study); Bethesda assay quantitates titer • Treatment: high titer →
recomb. factor VIIa
, porcine factor concentrates, activated prothrombin complex; others → high-purity human factor, plasmapheresis, immunosupp. w/ steroids, cyclophosphamide and/or rituximab (
Curr Opin Hematol
2008;15:451)
Disseminated intravascular coagulation (DIC)
(
NEJM
1999;341:586)
• Etiologies: trauma, shock, infection, malignancy (esp. APL), obstetric complications • Pathogenesis:
massive
activation of coagulation that overwhelms control mechanisms
thrombosis
in microvasculature → ischemia + microangiopathic hemolytic anemia acute consumption of coagulation factors and platelets →
bleeding
chronic DIC → able to replete factors and platelets →
thrombosis
• Diagnosis: ↑ PT, ↑ PTT, ↓
fibrinogen
(may be
nl
b/c acute phase),
FDP
/
D-dimer
, ↓ plts,
schistos, ↑ LDH, ↓ hapto;
chronic
DIC:
FDP/D-dimer, variable plts, other labs nl • Treatment: treat underlying process; support with
FFP
,
cryoprecipitate
(goal fibrinogen