Purpura and Disorders of Microvascular Occlusion

Purpura represents visible hemorrhage into the skin or mucous membranes; in contrast to erythema due to vasodilation, it is nonblanching upon application of external pressure.

Purpura can be primary , where hemorrhage is an integral part of lesion formation, or secondary , where there is hemorrhage into established lesions due to factors such as venous hypertension, gravity, or thrombocytopenia.

As purpuric lesions fade, their color evolves from red-purple or blue to brown or yellow-green.

Primary purpura has a broad differential diagnosis, and it is helpful to categorize purpuric lesions based on their size and morphology.

• –

  Petechiae : ≤3 mm and macular ( Table 18.1 ; Fig. 18.1 A )

  Table 18.1

  Causes of petechiae and ecchymosis with minor trauma.

  DIC, disseminated intravascular coagulation; ITP, idiopathic thrombocytopenia purpura; TTP, thrombotic thrombocytopenic purpura.

  Courtesy, Warren W. Piette, MD.

  Petechiae (≤3 mm in diameter)

  Significant thrombocytopenia (e.g. <20,000/mm 3 ) Etiologies include ITP, TTP, DIC, drugs, and bone marrow infiltration/failure Platelet dysfunction Hereditary or acquired (e.g. due to aspirin or NSAIDs) Etiologies unrelated to platelets Increased intravenous pressure, e.g. due to the Valsalva maneuver (coughing, childbirth) or use of a blood pressure cuff (Rumpel–Leede sign) Trauma (often linear configuration) Scurvy (perifollicular distribution) Inflammatory conditions, especially in dependent sites (e.g. pigmented purpuric dermatoses, hypergammaglobulinemic purpura of Waldenström)

  Ecchymosis with minor trauma (lesions usually >1 cm in diameter)

  Defective coagulation Etiologies include anticoagulant use, hepatic insufficiency, and vitamin K deficiency Poor dermal support of blood vessels Etiologies include actinic purpura ( Fig. 18.1 B), corticosteroid use, scurvy, primary systemic amyloidosis, and Ehlers–Danlos syndrome Thrombocytopenia or platelet dysfunction (see above)

  

• –

  Ecchymoses : usually >1 cm and macular with round/oval to slightly irregular borders, and typically have an element of trauma in their pathogenesis (see Table 18.1 ; Fig. 18.1 B); a greater volume of hemorrhage leads to a hematoma , which is palpable

• –

  Retiform purpura : reticulated, branching or stellate morphology, which reflects occlusion of the vessels that produce the livedo reticularis pattern (see Ch. 87 ; Tables 18.2 and 18.3 ; Figs 18.1C and 18.2–18.9 )

  Table 18.2

  Causes of retiform purpura.

  PIGA , phosphatidylinositol glycan anchor class A; vWF, von Willebrand factor.

  Courtesy, Warren W. Piette, MD.

  Disorder	Major features
  Microvascular platelet plugs
  Heparin-induced thrombocytopenia (HIT)	∼1–5% of patients receiving heparin ∗ (IV or SC) develop an Ab that binds to heparin–platelet factor 4 complexes and leads to ↓ platelets ± thrombosis, typically with onset on day 5–10 of therapy ∗ Retiform purpura can be distant from or at sites of heparin injection ( Fig. 18.2 )
  Thrombocytosis due to myeloproliferative disorders	Occurs in essential thrombocythemia > polycythemia vera; may be associated with secondary erythromelalgia (see Ch. 87 )
  Paroxysmal nocturnal hemoglobinuria	Acquired somatic PIGA mutation leads to complement-mediated injury of blood cells, resulting in hemolysis, thrombosis (especially venous), and cytopenias Other skin findings can include petechiae, hemorrhagic bullae, and leg ulcers Rx: eculizumab to inhibit terminal complement cascade (↑ meningococcemia risk)
  Thrombotic thrombocytopenic purpura (TTP) ± hemolytic uremic syndrome (HUS)	May be primary (Ab against or genetic defect in ADAMTS13 protease → reduced cleavage of vWF) or secondary (often with HUS, e.g. due to hemorrhagic colitis or drugs) Petechiae > retiform purpura; also fever, thrombocytopenia, microangiopathic hemolytic anemia, renal dysfunction, and CNS involvement
  Cold-related agglutination
  Cryoglobulinemia type I > cryofibrinogenemia †	Retiform purpura that favors acral sites ( Fig. 18.3 ); see Table 18.3
  Altered coagulation
  Antiphospholipid syndrome	See text and Table 18.4 ( Figs 18.4 and 18.5 )
  Protein C or S deficiency/dysfunction	Warfarin necrosis (protein C – short half-life, so function decreases faster than for procoagulant factors Fig. 18.6 ): 2–5 days after starting warfarin without heparin, especially if large loading dose; favors sites of abundant fat in women (see Fig. 17.5 ) Sepsis-associated purpura fulminans (protein C; see Fig. 18.1 C) Post-infectious purpura fulminans (Ab blocks protein S): ∼2 weeks after streptococcal infection or varicella Neonatal purpura fulminans (homozygous/compound heterozygous protein C > S defect; Fig. 18.7 )
  “Vascular coagulopathy”
  Livedoid vasculopathy	Often associated with thrombophilia ( Table 18.5 ); see text ( Fig. 18.8 )
  Degos disease (malignant atrophic papulosis)	Vaso-occlusive disorder of skin, GI tract, and CNS; favors young adults Small erythematous papules on trunk and extremities evolve over 2–4 weeks to porcelain white scars with rim of telangiectasias; similar lesions can be seen in antiphospholipid syndrome
  Sneddon syndrome – often in setting of antiphospholipid syndrome or adenosine deaminase 2 deficiency (± associated polyarteritis nodosa)	Triad of widespread livedo reticularis/racemosa (“broken” livedo), labile hypertension, and cerebrovascular disease; favors young women
  Embolization and/or crystal deposition
  Cholesterol emboli (“warfarin blue toe syndrome”)	Atherosclerosis (especially in older men) leads to emboli, often triggered by: (1) Arterial/coronary catheterization or thrombolytic therapy (hours–days later) (2) Prolonged anticoagulation (after 1–2 months of treatment) Retiform purpura of distal leg(s) + more extensive livedo reticularis ( Fig. 18.9 ) Fever, myalgias, multisystem involvement (e.g. renal, GI, CNS); often peripheral eosinophilia
  Other sources of emboli and/or crystal deposition	Infective endocarditis (acute > subacute ∗∗ ), marantic endocarditis, atrial myxomas, hypereosinophilic syndrome (with intracardiac thrombus ‡ ), systemic oxalosis (e.g. in primary hyperoxaluria), crystalglobulin vasculopathy (associated with monoclonal gammopathy)
  Reticulocyte/red blood cell occlusion (e.g. in sickle cell disease or severe malaria)
  Organisms within vessels (usually in immunocompromised patients)
  Ecthyma gangrenosum	See Ch. 61
  Vessel-invasive fungi	e.g. Aspergillus , Mucor (see Ch. 64 )
  Disseminated strongyloidiasis	“Thumbprint” purpura in periumbilical region
  Lucio phenomenon	Reactional state in lepromatous leprosy, primarily in Mexico and Central America (see Ch. 62 )
  Other causes
  Vasculitis (usually involving small and medium-sized vessels)	e.g. ANCA-associated vasculitides, polyarteritis nodosa (see Ch. 19 ); early lesions often exhibit prominent erythema and induration
  Calciphylaxis	See Ch. 42
  Necrotic spider bite reaction	See Ch. 72
  Intravascular lymphoma	Most often B cell ( Fig. 18.10 ); see Table 97.3

  ∗ Less common with low-molecular-weight heparin (≤1%) than unfractionated heparin; a transient decrease in the platelet count can also occur within the first 2 days of heparin therapy due to its direct effects on platelet activation.

  † May be an incidental finding in hospitalized patients; cold agglutinins rarely lead to acrocyanosis or purpura.

  ∗∗ Skin lesions on the hands and feet associated with subacute endocarditis are more likely to be tender red-purple papules due to immune complex deposition (“Osler nodes”),than purpuric macules representing septic emboli (“Janeway lesions”; more common in acute endocarditis).

  ‡ Cutaneous microthrombi and superficial thrombophlebitis have also been described.

  Table 18.3

  Classification of cryoglobulins.

  HCV, hepatitis C virus.

  Type	Composition	Associations	Pathophysiology	Clinical manifestations
  I	Monoclonal IgM or IgG >> IgA	Plasma cell dyscrasias, lymphoproliferative disorders	Vascular occlusion	Retiform purpura (often acral; Fig. 18.3 ), gangrene, acrocyanosis, Raynaud phenomenon
  II ∗∗	Monoclonal IgM ∗ (>IgG ∗ ) against polyclonal IgG	HCV, HIV, autoimmune connective tissue diseases, lymphoproliferative disorders	Vasculitis	Palpable purpura, arthralgias, peripheral neuropathy, glomerulonephritis
  III ∗∗	Polyclonal IgM ∗ against polyclonal IgG

  ∗ Typically have rheumatoid factor activity (i.e. are directed against the Fc portion of IgG).

  ∗∗ Referred to as “mixed” cryoglobulins.

  
  
  
  
  
  
  
  
  

• –

  Classic “palpable purpura” : round red-purple papules that are occasionally targetoid, with a component of blanching erythema in early lesions; represents the most common presentation of cutaneous small vessel vasculitis (see Ch. 19 ; Fig. 18.1 D)

A biopsy specimen can be helpful in determining the etiology of a purpuric eruption, e.g. whether there is vascular occlusion with minimal inflammation or vasculitis (inflammation and fibrinoid necrosis of vessel walls). Because secondary changes of vasculitis may be seen when an older lesion of microvascular occlusion is sampled, and likewise a late lesion of vasculitis may have minimal residual inflammation, it is preferable to choose a well-developed but relatively early lesion (e.g. 24–48 hours old).