- Basics of Purpura Fulminans
- Common causes
- Clinical findings
- Diagnostic tests
- Questions & discussion
- PDF of this chapter (or create customized PDF)
- Purpura fulminans is an extremely thrombotic subtype of disseminated intravascular coagulation, marked by microvascular thrombosis causing skin necrosis (most typically involving the extremities and digits).
- In adults, purpura fulminans is most commonly caused by severe infection. However, the primary risk to life and limb is often the purpura fulminans (rather than necessarily the underlying infection itself). It's not uncommon for patients to lose digits or limbs to the disease.
- Purpura fulminans is diagnosed clinically on the basis of patchy skin necrosis within an appropriate clinical context.
types of purpura fulminans
- Three types:
- (1) Congenital form (manifests shortly after birth, due to congenital deficiency of Protein C, Protein S, or Antithrombin-III)
- (2) Idiopathic or post-infectious form (extremely rare, due to auto-antibodies which deplete Protein S activity)
- (3) Acute Infectious form (most common form in adults, complication of severe disseminated intravascular coagulation)
- The remainder of this chapter discusses the acute infectious form.
acquired protein C deficiency
- Purpura fulminans can be caused by either congenital or acquired Protein C deficiency. In the context of septic shock, Protein C deficiency is acquired.
- Causes of Protein C deficiency include the following:(16635072)
- Consumption of protein C due to overwhelming thrombin generation. (30396911)
- Reduced hepatic synthesis due to liver dysfunction.
- Degradation of protein C by elastase released by white blood cells.
- Depletion of Protein C leads to an imbalance in the coagulation systems, with inadequate safeguards to prevent excessive coagulation.
consequences of protein C deficiency
- Normally, Protein C is activated by thrombin (IIa), an interaction which is facilitated by thrombomodulin (panel A above). Thrombin is generally pro-coagulant, but by activating Protein C, thrombin is participating in negative feedback inhibition of the coagulation system.
- Activated Protein C has several effects to dampen coagulation:
- Inactivation of factors Va and VIIIa (inhibiting enzymatic coagulation).
- Inhibition of Plasminogen-Activator Inhibitor 1 (PAI-1) – which overall will tend to favor fibrinolysis.
- Cleavage of protease-activated receptor-1 (PAR-1), which sends anti-inflammatory and anti-apoptotic signals to the endothelial cell (thereby protecting it).
- Deficiency of Protein C may lead to excess fibrin generation, as well as inadequate fibrinolysis. The result can be widespread fibrin deposition within the microvasculature, causing ischemic tissue damage.
- Bacterial infections
- Neisseria meningitides (~20% of patients develop purpura fulminans)
- Haemophilus influenza
- Streptococcus pneumoniae (especially status post splenectomy)
- Streptococcus pyogenes
- Capnocytophagia canimorsus
- Staphylococcus aureus
- Gram-negatives (Klebsiella pneumoniae, Eschericha coli, Pseudomonas aeruginosa, Proteus mirabilis)
- (Less common: Enterococcus faecalis, Leptospirosis, Rickettsia rickettsii, Vibrio parahaemolyticus)
- Varicella zoster virus
- West Nile Virus
- Protozoa: Plasmodium falciparum
- Fungal infections
- Cryptococcus neoformans
- Aspergillus spp.
- Fusarium spp.
1) initial skin findings
- Non-blanching, red patchy lesions on the skin with thin, lacy, irregular borders.
- Skin appears mottled.
- Typically lesions are most prominent in extremities.
- Initially, skin may be painful and indurated.
- These findings seem to represent the initial manifestation of microthrombi in small dermal vessels (29157918)
2) progression to skin necrosis within 24-48 hours
- Central necrosis occurs leading to black necrotic lesions (with full-thickness necrosis of the skin). With necrosis, skin may become insensate.
- Necrosis may begin in the extremities and subsequently extend proximally.
- Hemorrhage into necrotic skin may lead to bullae formation.
- Eventually, hard eschars may form.
involvement of other organs
- Skin findings are most obvious, but thrombosis of small-medium vessels elsewhere in the body may cause failure of other organs. As such, purpura fulminans may be conceptualized as an occlusive, small-vessel vasculopathy.
- Adrenal hemorrhage (Waterhouse-Friderichsen syndrome)
- This begins with infarction of small vessels within the adrenal glands, which subsequently leads to hemorrhagic transformation, with bleeding into the adrenal glands.
- This may lead to adrenal insufficiency which precipitates adrenal crisis.
- Renal failure due to glomerular thrombosis.
- Prolonged coagulation times
- This may be low, normal, or high. Infection tends to increase fibrinogen, whereas DIC may consume fibrinogen. Consequently, only a minority of patients have low fibrinogen levels.(32015972) Contrary to popular belief, a normal fibrinogen level excludes neither DIC nor purpura fulminans.
- This is perhaps the most sensitive lab abnormality in purpura fulminans.
- The D-dimer is generally very elevated (typically in the range of ~5,000-30,000 ng/mL).
- Platelet count
- Thrombocytopenia is seen in most patients (e.g. in the range of roughly ~25,000-150,000/uL).
- Reduced levels of Protein C
- Levels will be reduced (e.g. below <40% of normal).
- At most hospitals this is a send-out test which takes days to return. As such, it cannot contribute to acute patient management.
- Skin biopsy may be used to differentiate purpura fulminans from other conditions (e.g. vasculitis). In purpura fulminans, biopsy will show dermal vessel thrombosis without vasculitis.
- Skin biopsy is usually unnecessary. In situations where the diagnosis of purpura fulminans is extremely likely based on clinical context, avoid delaying therapy while waiting for a skin biopsy.
Diagnosis is often evident, based on the observation of characteristic skin changes within a consistent clinical context (septic shock) and a consistent laboratory pattern. However, in situations where the diagnosis isn't clear, the following differential diagnosis should be considered:(29157918)
- Catastrophic anti-phospholipid syndrome (CAPS)
- Heparin-induced thrombocytopenia
- Necrotizing fasciitis
- Warfarin-induced skin necrosis
- Vasculitis (e.g., Henoch-Schonlein purpura, Cryoglobulinemic vasculitis)
- Thrombotic thrombocytopenic purpura (TTP)
- Cocaine/levamisole toxicity
antibiotics & source control
- Antibiotics: Selection will depend on scenario. Consider the use of meningeal dosing, if meningitis is possible (e.g. ceftriaxone 2 grams IV Q12). More on the treatment of meningitis here.
- Vasopressors & inotropes:
- Avoid vasoconstrictors as much as possible. Vasoconstrictors aren't the cause of tissue necrosis in purpura fulminans, but excess vasoconstrictors may nonetheless aggravate matters.
- Utilize agents which increase cardiac output if possible (e.g. choosing epinephrine as a primary agent, rather than norepinephrine).
- Avoid vasopressin, since it may promote digital ischemia more than other agents.
heparin & heparin resistance
evidentiary basis for using heparin?
- Several studies have evaluated the use of heparin in septic shock. These studies have generally been negative. However, studies have included a broad variety of “septic” patients (most of whom did not have purpural fulminans).
- Given that purpura fulminans is a pro-coagulant form of DIC marked by clinical thrombus formation, guidelines and expert opinion recommend the use of therapeutic anticoagulation with heparin.
heparin administration: nuts and bolts
- Therapeutic anticoagulation with heparin is a bit complicated for the following reasons:
- PTT will usually be elevated at baseline (making these labs unreliable to determine heparin effect). Note that elevated PTT aren't necessarily a contraindication to heparin, as this may not correlate with true coagulation tendency within the context of DIC.
- Patients are often resistant to heparin due to deficiency of anti-thrombin III as well as the up-regulation of heparin binding proteins.
- Optimal heparin anticoagulation may therefore involve the following:
- Heparin effect should ideally be determined based on anti-Xa levels (rather than PTT).
- High infusion rates may be required to overcome heparin resistance.(29157918)
- Moderate thrombocytopenia is common, but not necessarily a contraindication to heparin infusion. One center reported using therapeutic heparin infusions in patients with platelet counts >30,000/uL, which may be reasonable.(16635072)
antithrombin-III supplementation ??
- Antithrombin-III concentrates may be considered, particularly in cases of refractory heparin resistance.(30396911)
- However, caution is required in patients with thrombocytopenia, due to a risk of bleeding (especially if high doses of heparin are combined with supplemental antithrombin- III). A safer and simpler approach to heparin resistance may be to use higher doses of heparin, if feasible (noting that there is no well-defined “maximal dose” of heparin).
More on heparin resistance here.
Protein C concentrates
Activated Protein C (XIGRIS)
- Activated Protein C was previously investigated as a treatment for septic shock. It was ultimately found to be ineffective, leading to its withdrawal from the market.
- It remains possible that Activated Protein C might have been effective among a subset of patients with septic shock, disseminated intravascular coagulation, and microvascular thrombosis. However, Activated Protein C seems to have a higher rate of hemorrhagic complications when compared to Protein C concentrate.(16635072) Regardless, Activated Protein C was withdrawn from the market and is currently unavailable.
Protein C concentrate (CEPROTIN)
- Recombinant Protein C is a rational therapy for purpura fulminans, given that deficient Protein C is a cornerstone of the pathophysiology of purpura fulminans.(27583208)
- Studies on Protein C in purpura fulminans have not been adequately powered to prove any effect on mortality or patient-centered outcomes such as amputation. However, small studies in patients with purpura fulminans have demonstrated that Protein C concentrates can improve hematologic endpoints, including:(16635072)
- Improved Protein C activity (thus, there doesn't appear to be a need to use activated Protein C).
- Reduced D-dimer (implying successful braking of enzymatic coagulation).
- Increasing levels of fibrinogen and anti-thrombin III.
- Reduction of pathologically elevated plasminogen activator inhibitor type-I (PAI-1).(10632475)
- Post-marketing surveillance and case series suggest that Protein C replacement is safe.(20723255) In particular, this seems to lack the hemorrhage risk which was observed with activated Protein C (XIGRIS).
- Overall Protein C concentrate seems to be a rational therapy, albeit one which is not supported by Level-I RCT evidence.
- A reasonable dose might be a loading dose of ~100 units/kg, followed by ~50 units/kg q6hr.(31449632, 12794428)
- Further information on CEPROTIN may be found at the MedScape monograph here.
blood product replacement
Blood product replacement in patients with purpura fulminans is tricky. Overzealous replacement could theoretically aggravate thrombus formation. However, allowing coagulation levels to fall extremely low could also be dangerous (particularly in patients who are receiving heparin infusions). A reasonable approach could be as follows:(16635072)
- Maintain a fibrinogen level >~80 mg/dL (using either fibrinogen concentrates or cryoprecipitate).
- Maintain a platelet level >~30,000/uL among patients on therapeutic heparin infusion. For patients who aren't receiving heparin, a usual platelet transfusion threshold might be appropriate (e.g. targeting >~10,000/uL).
For patients with digital ischemia and threat of digital amputation, the following treatments may be attempted:
- Topical nitroglycerine for local vasodilation of hypoperfused extremities.
intravenous epoprostanol infusion ??
- Low-dose epoprostenol infusion has been described in case reports to improve distal perfusion and potentially reduce tissue loss (e.g. starting at a dose of 2 ng/kg/min).(21396502) Other case reports have used iloprost, a similar agent which isn't available intravenously in the United States.(30871501)
- Evidence supporting epoprostanol consists solely of a few case reports. This is indirectly buttressed by evidence regarding epoprostenol in digital ischemia due to refractory Raynaud's phenomenon.(27465880)
- In patients with threatened perfusion of their digits who are at risk of amputation, a clinical trial of epoprostenol might be considered under close supervision.
- Epoprostenol can cause hypotension, so this therapy would be contraindicated in patients with severe hemodynamic instability. Other side-effects are less serious (e.g. nasuea, vomiting, abdominal pain, diarrhea).
general conceptualization as a burn wound
- Extensive skin necrosis due to purpura fulminans may mimic burns.
- Some authors have suggested that patients with extensive involvement should be treated in burn centers, but in practice this is rarely done.(32513908)
extremity compartment syndrome
- (1) Aggressive fluid administration leads to tissue edema.
- (2) Skin necrosis prevents the skin from stretching (especially if circumferential skin is involved with purpura fulminans).
- Extremity compartment syndrome may be a major driver for the need to amputate limbs. Although purpura fulminans involves the dermis, it usually spares the underlying tissue.
- Early surgical decompression with fasciotomy may potentially decrease the need for amputation.(31524150)
- Compartment syndrome often is not obvious (and in many cases it may go entirely unrecognized). When in doubt, surgical consultants should be involved early.
Proper wound management and expeditious surgical evaluation can help reduce the mortality and minimize amputations. –Asif M et al. 2019, John Hopkins Burn Center
vitamin K supplementation
administration of vitamin K
- A key pathophysiological problem in purpura fulminans is deficiency of Protein C. Synthesis of this protein is dependent on Vitamin K.
- In patients with suspected or possible vitamin K deficiency, replacement of this vitamin should be considered. Some authors have suggested that deficiency of vitamin K could contribute to a tendency towards developing purpura fulminans.(15186640)
- Detection of Vitamin K deficiency may be challenging, because most patients will have an elevated INR due to disseminated intravascular coagulation.
avoidance of warfarin
- One of the first effects of warfarin is causing depletion of Protein C and Protein S. This may cause a transient hypercoagulable state (which is the pathophysiology underlying warfarin-induced skin necrosis).
- The primary pathophysiologic problem in purpura fulminans is a deficiency of Protein C. Therefore, initiation of warfarin in a patient with purpura fulminans would be illogical and potentially dangerous.
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questions & discussion
To keep this page small and fast, questions & discussion about this post can be found on another page here.
- Failure to involve surgical consultants early in patients who require fasciotomy for compartment syndrome.
- Failure to provide specific therapy for purpura fulminans (these patients will often respond poorly to usual sepsis care).
- Excessive use of blood product replacement (e.g. fresh frozen plasma, platelets) in patients who are not bleeding.
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